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Ruberu TLM, Braun D, Parmigiani G, Biswas S. Adjusting for Ascertainment Bias in Meta-Analysis of Penetrance for Cancer Risk. Stat Med 2025; 44:e10323. [PMID: 39865362 PMCID: PMC11881752 DOI: 10.1002/sim.10323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 10/07/2024] [Accepted: 12/13/2024] [Indexed: 01/28/2025]
Abstract
Multi-gene panel testing allows efficient detection of pathogenic variants in cancer susceptibility genes including moderate-risk genes such as ATM and PALB2. A growing number of studies examine the risk of breast cancer (BC) conferred by pathogenic variants of these genes. A meta-analysis combining the reported risk estimates can provide an overall estimate of age-specific risk of developing BC, that is, penetrance for a gene. However, estimates reported by case-control studies often suffer from ascertainment bias. Currently, there is no method available to adjust for such bias in this setting. We consider a Bayesian random effect meta-analysis method that can synthesize different types of risk measures and extend it to incorporate studies with ascertainment bias. This is achieved by introducing a bias term in the model and assigning appropriate priors. We validate the method through a simulation study and apply it to estimate BC penetrance for carriers of pathogenic variants in the ATM and PALB2 genes. Our simulations show that the proposed method results in more accurate and precise penetrance estimates compared to when no adjustment is made for ascertainment bias or when such biased studies are discarded from the analysis. The overall estimated BC risk for individuals with pathogenic variants are (1) 5.77% (3.22%-9.67%) by age 50 and 26.13% (20.31%-32.94%) by age 80 for ATM; (2) 12.99% (6.48%-22.23%) by age 50, and 44.69% (34.40%-55.80%) by age 80 for PALB2. The proposed method allows meta-analyses to include studies with ascertainment bias, resulting in inclusion of more studies and thereby more accurate estimates.
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Affiliation(s)
| | - Danielle Braun
- Department of Biostatistics, Harvard T.H. Chan School of Public Health
- Department of Data Science, Dana Farber Cancer Institute
| | - Giovanni Parmigiani
- Department of Biostatistics, Harvard T.H. Chan School of Public Health
- Department of Data Science, Dana Farber Cancer Institute
| | - Swati Biswas
- Department of Mathematical Sciences, University of Texas at Dallas
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2
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Eikenboom EL, van Leeuwen L, Groenendijk F, Woolderink JM, Van Altena AM, Van Leerdam ME, Spaander MC, van Doorn HC, Wagner A. Outcomes of endometrial cancer prevention strategies in patients with Lynch syndrome: a nationwide cohort study in the Netherlands. EClinicalMedicine 2025; 79:103006. [PMID: 39816931 PMCID: PMC11733057 DOI: 10.1016/j.eclinm.2024.103006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 11/22/2024] [Accepted: 11/27/2024] [Indexed: 01/18/2025] Open
Abstract
Background Female Lynch syndrome carriers have an increased risk of developing endometrial cancer. Regardless, research on endometrial carcinoma tumorigenesis is scarce and no uniform, evidence-based gynaecological management guidelines exist. We therefore described gynaecological surveillance and surgery outcomes in a nation-wide Lynch syndrome cohort. Methods For this retrospective cohort study, female Lynch syndrome carriers, prospectively registered in the Dutch Lynch syndrome database (StOET), were included up to February 28th 2022. Carriers were linked to the Dutch national pathology (PALGA) database. The number of carriers with/without gynaecological surveillance, number of index carriers with endometrial carcinoma before Lynch syndrome diagnosis were assessed, as well as uptake of risk-reducing surgery and characteristics of endometrial carcinomas including the requisite for adjuvant therapy according to current guidelines. Overall survival after endometrial carcinoma diagnosis was analyzed using Kaplan Meier time to event analyses, cumulative incidence was calculated after adjusting for competing risks (death and prophylactic hysterectomy). Findings In total, 1046 registered female Lynch syndrome carriers were eligible for surveillance, of whom 313 (30.0%) did not have surveillance and 21.4% (n = 224 of 1046) opted for prophylactic hysterectomy. In carriers with surveillance, more cases of endometrial carcinoma and hyperplasia were found than in those without (37 endometrial carcinomas (7.3%) and 28 hyperplasias (5.5%) in 506 carriers with surveillance versus 14 (2.6%) and 4 (0.7%) in 540 carriers without surveillance, respectively); carriers with surveillance were generally younger than those without (median 56 years [IQR 48-65] versus median 65 years [IQR 49-75] at database assembly, respectively; p < 0.0001). Endometrial carcinomas were predominantly of endometrioid type and FIGO stage IA, regardless of surveillance. Adjuvant external beam radiotherapy was required in one patient in both groups. Overall survival after endometrial carcinoma diagnosis did not differ between carriers with or without surveillance or carriers with endometrial carcinoma before LS diagnosis (p = 0.51). For all endometrial carcinomas together, including index carriers, cumulative incidence was 22.7% at age 70. Interpretation In a nation-wide cohort of Lynch syndrome carriers, nearly one-third of eligible carriers did not undergo gynaecological surveillance. Endometrial carcinomas diagnosed during surveillance were slightly more often stage FIGO IA, but this did not seem to substantially decrease the requisite for adjuvant therapy or affect overall survival, questioning effectiveness of current gynaecological management. Prospective research should further assess this, as well as patient preferences. Funding None.
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Affiliation(s)
- Ellis L. Eikenboom
- Department of Clinical Genetics, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
- Department of Gastroenterology & Hepatology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Lotte van Leeuwen
- Department of Clinical Genetics, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Floris Groenendijk
- Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Jorien M. Woolderink
- Department of Obstetrics and Gynecology, Martini Hospital Groningen, Groningen, the Netherlands
| | - Anne M. Van Altena
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Monique E. Van Leerdam
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, the Netherlands
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute Amsterdam, the Netherlands
| | - Manon C.W. Spaander
- Department of Gastroenterology & Hepatology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Helena C. van Doorn
- Department of Gynecologic Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Anja Wagner
- Department of Clinical Genetics, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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3
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Бричева ЭБ, Нагаева ЕВ, Бровин ДН, Бондаренко ЕВ, Шеремета МС, Безлепкина ОБ, Олина ТС, Коваленко ТВ. [Thyroid cancer in a child with Cowden syndrome]. PROBLEMY ENDOKRINOLOGII 2024; 70:84-90. [PMID: 39509640 PMCID: PMC11610633 DOI: 10.14341/probl13445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 04/02/2024] [Indexed: 11/15/2024]
Abstract
Cowden disease (Cowden syndrome) refers to PTEN-associated hamartoma tumor syndromes. It arises due to a mutation in the phosphatase and tensin homolog gene, one of the main functions of which is cell cycle regulation. The presence of a mutation in the gene leads to uncontrolled cell growth, and patients have a lifelong increased risk of neoplasms of various degrees of malignancy. This article presents a clinical case of Cowden syndrome with an early debut at the age of 7 years. The combination of macrocephaly (SDS of head circumference >2) with various skin manifestations (facial trichilemmomas, acral keratosis, papillomatous papules) and the presence of benign and/or malignant neoplasms are pathognomonic for Cowden syndrome. Of the malignancies, breast and thyroid cancer, colorectal cancer, renal cell carcinoma, and endometrial cancer are the most common. Thyroid carcinoma has been shown to have an earlier age of manifestation and often occurs already in childhood. This determines the need to screen patients with a proven mutation in the PTEN gene for nodal neoplasms from an early age. If surgical treatment is necessary, thyroidectomy remains preferable due to the frequent recurrence of nodules, as well as the uncertain potential for malignancy due to the low study of thyroid nodules in patients with mutations in the PTEN gene.
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Affiliation(s)
- Э. Б. Бричева
- Национальный медицинский исследовательский центр эндокринологии
| | - Е. В. Нагаева
- Национальный медицинский исследовательский центр эндокринологии
| | - Д. Н. Бровин
- Национальный медицинский исследовательский центр эндокринологии
| | | | - М. С. Шеремета
- Национальный медицинский исследовательский центр эндокринологии
| | | | - Т. С. Олина
- Республиканская детская клиническая больница
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Giovino C, Subasri V, Telfer F, Malkin D. New Paradigms in the Clinical Management of Li-Fraumeni Syndrome. Cold Spring Harb Perspect Med 2024; 14:a041584. [PMID: 38692744 PMCID: PMC11529854 DOI: 10.1101/cshperspect.a041584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
Approximately 8.5%-16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant-a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li-Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning-based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention.
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Affiliation(s)
- Camilla Giovino
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Vallijah Subasri
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Frank Telfer
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - David Malkin
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Division of Hematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada
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5
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Katz SJ, Abrahamse P, Furgal A, Hodan R, Tocco RS, Ward KC, Hamilton AS, Wallner LP, Kurian AW. Genetic Counseling, Testing, and Family Communication Into Survivorship After Diagnosis of Breast Cancer. J Clin Oncol 2024; 42:3123-3129. [PMID: 39008790 PMCID: PMC11377164 DOI: 10.1200/jco.24.00122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 05/01/2024] [Accepted: 05/14/2024] [Indexed: 07/17/2024] Open
Abstract
PURPOSE To examine receipt of genetic testing and communication with relatives about results into survivorship after diagnosis of breast cancer. METHODS Women age 20-79 years diagnosed with early-stage breast cancer in 2014-2015 and reported to the Georgia and Los Angeles County SEER registries were surveyed approximately 7 months and 6 years after diagnosis (n = 1,412). We asked about genetic counseling, testing, and communication with relatives about results. We categorized women into indications for testing on the basis of clinical guidelines at the time of diagnosis and at the time of the follow-up survey (FUPs). RESULTS A total of 47.4% had indications for genetic testing at any time: 28.0% at baseline and an additional 19.4% at the time of the FUPs (only); 71.9% (95% CI, 67.4 to 76.4) of those with a baseline indication reported genetic testing versus 53.3% (95% CI, 47.3 to 59.2) with an indication at FUPs only and 35.0% (95% CI, 31.6 to 38.4) with no indication (P < .001). There were no significant racial or ethnic differences in receipt of testing, controlling for age and clinical indications (P = .239); results for genetic counseling were similar. Only 3.4% of survivors had direct-to-consumer genetic testing (DTCt) for cancer. Testers who reported a pathogenic variant (n = 62) were much more likely to have talked to most or all their first-degree adult relatives about genetic testing than those with a variant of unknown significance (n = 49) or a negative finding (n = 419): 62.7% versus 38.8% and 38.0%, respectively (P < .001). CONCLUSION Many women with indications for genetic counseling and testing into survivorship do not receive it. But those tested reach out to family members on the basis of the clinical relevance of their results. Very few patients obtained DTCt, which suggests that these tests do not substitute for clinical testing in breast cancer survivors.
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Affiliation(s)
- Steven J Katz
- Department of Medicine, University of Michigan, Ann Arbor, MI
- Department of Health Management and Policy, School of Public Health, University of Michigan, Ann Arbor, MI
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Paul Abrahamse
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI
| | - Allison Furgal
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI
| | - Rachel Hodan
- Cancer Genetics, Stanford Health Care, Stanford, CA
| | - Rachel S Tocco
- Department of Medicine, University of Michigan, Ann Arbor, MI
| | - Kevin C Ward
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GE
| | - Ann S Hamilton
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Lauren P Wallner
- Department of Medicine, University of Michigan, Ann Arbor, MI
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI
| | - Allison W Kurian
- Department of Medicine, Stanford University, Stanford, CA
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA
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Veney DJ, Wei LY, Toland AE, Presley CJ, Hampel HL, Padamsee TJ, Lee CN, Irvin WJ, Bishop MJ, Kim JJ, Hovick SR, Senter LA, Stover DG. A video intervention to improve patient understanding of tumor genomic testing in patients with cancer. Cancer Med 2024; 13:e70095. [PMID: 39258462 PMCID: PMC11387988 DOI: 10.1002/cam4.70095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 06/14/2024] [Accepted: 07/29/2024] [Indexed: 09/12/2024] Open
Abstract
INTRODUCTION Tumor genomic testing (TGT) is standard-of-care for most patients with advanced/metastatic cancer. Despite established guidelines, patient education prior to TGT is frequently omitted. The purpose of this study was to evaluate the impact of a concise 4 min video for patient education prior to TGT. METHODS Based on a quality improvement cycle, an animated video was created to be applicable to any cancer type, incorporating culturally diverse images, available in English and Spanish. Patients undergoing standard-of-care TGT were enrolled at a tertiary academic institution and completed survey instruments prior to video viewing (T1) and immediately post-viewing (T2). Instruments included: (1) 10-question objective genomic knowledge; (2) 10-question video message-specific knowledge; (3) 11-question Trust in Provider; (4) attitudes regarding TGT. RESULTS A total of 150 participants were enrolled. For the primary objective, there was a significant increase in video message-specific knowledge (median 10 point increase; p < 0.0001) with no significant change in genomic knowledge/understanding (p = 0.89) or trust in physician/provider (p = 0.59). Results for five questions significantly improved, including the likelihood of TGT impact on treatment decision, incidental germline findings, and cost of testing. Improvement in video message-specific knowledge was consistent across demographic groups, including age, income, and education. CONCLUSIONS A concise, 3-4 min, broadly applicable video incorporating culturally diverse images administered prior to TGT significantly improved video message-specific knowledge across all demographic groups. This resource is publicly available at http://www.tumor-testing.com, with a goal to efficiently educate and empower patients regarding TGT while addressing guidelines within the flow of clinical practice.
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Affiliation(s)
- Deloris J. Veney
- Division of Medical OncologyOhio State University Comprehensive Cancer CenterColumbusOhioUSA
| | - Lai Y. Wei
- Department of Biomedical InformaticsOhio State UniversityColumbusOhioUSA
| | - Amanda E. Toland
- Division of Human Genetics, Department of Internal MedicineThe Ohio State University Comprehensive Cancer CenterColumbusOhioUSA
- Department of Cancer Biology and GeneticsThe Ohio State UniversityColumbusOhioUSA
| | - Carolyn J. Presley
- Division of Medical OncologyOhio State University Comprehensive Cancer CenterColumbusOhioUSA
| | - Heather L. Hampel
- Division of Clinical Cancer Genomics, Department of Medical Oncology and Therapeutics ResearchCity of Hope National Medical CenterDuarteCaliforniaUSA
| | - Tasleem J. Padamsee
- Division of Health Services Management and PolicyCollege of Public Health, The Ohio State UniversityColumbusOhioUSA
| | - Clara N. Lee
- Division of Health Services Management and PolicyCollege of Public Health, The Ohio State UniversityColumbusOhioUSA
- Present address:
Division of Plastic and Reconstructive SurgeryUniversity of North CarolinaChapel HillNorth CarolinaUSA
| | | | | | - James J. Kim
- Bon Secours‐Mercy Health St. ElizabethYoungstownOhioUSA
| | | | - Leigha A. Senter
- Division of Human Genetics, Department of Internal MedicineThe Ohio State University Comprehensive Cancer CenterColumbusOhioUSA
| | - Daniel G. Stover
- Division of Medical OncologyOhio State University Comprehensive Cancer CenterColumbusOhioUSA
- Department of Biomedical InformaticsOhio State UniversityColumbusOhioUSA
- Pelotonia Institute for Immuno‐Oncology, Ohio State University Comprehensive CancerColumbusOhioUSA
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7
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Huang X, Chen C, Lin Y, Wang C, Zhou X, Xu Y, Sun Q, Zhou Y. Pedigree analysis exploring the inconsistency between diverse phenotypes and testing criteria for germline TP53 mutations in Chinese women with breast cancer. Breast Cancer Res Treat 2024; 206:653-666. [PMID: 38878125 PMCID: PMC11208215 DOI: 10.1007/s10549-024-07341-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/10/2024] [Indexed: 06/27/2024]
Abstract
PURPOSE In the present study, we addressed the inconsistency between the testing criteria and diverse phenotypes for germline TP53 mutation in patients with breast cancer in the Chinese population. METHOD We proposed a new added item (synchronous or metachronous bilateral breast cancer) as one of the testing criteria (aimed at high-penetrance breast cancer susceptibility genes) and applied it for determining TP53 germline mutation status in 420 female patients with breast cancer using multigene panel-based next-generation sequencing, Sanger sequencing, and mass spectrometry. RESULTS We found that 1.4% of patients carried a pathogenic or likely pathogenic germline TP53 mutation. Compared with BRCA mutation carriers (8.0%) and non-carriers (7.1%), TP53 mutation carriers (33.3%) developed breast cancer earlier. The majority of TP53 mutation carriers (66.7%) developed breast cancer after age 30 and had bilateral breast cancer (33.3%). Pedigree investigation of four TP53 carriers and a patient with a TP53 variant of unknown significance revealed that neither of their parents harbored the same mutations as the probands, indicating that the mutations might occur de novo. CONCLUSION Our study revealed distinguishing features of TP53 carriers among Chinese women with breast cancer, which is inconsistent with the currently used testing criteria; therefore, the newly proposed testing criteria may be more appropriate.
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Affiliation(s)
- Xin Huang
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Chang Chen
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Yan Lin
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Changjun Wang
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Xingtong Zhou
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Ying Xu
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Qiang Sun
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Yidong Zhou
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China.
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Hodan R, Picus M, Stanclift C, Ormond KE, Pichardo JM, Kurian AW, Ricker C, Idos GE. Family communication of cancer genetic test results in an ethnically diverse population: a qualitative exploration of more than 200 patients. J Community Genet 2024; 15:363-374. [PMID: 38814439 PMCID: PMC11410745 DOI: 10.1007/s12687-024-00712-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 05/18/2024] [Indexed: 05/31/2024] Open
Abstract
Previous research on family communication of cancer genetic test results has primarily focused on non-Hispanic White patients with high-risk pathogenic variants (PV). There are limited data on patient communication of moderate-risk PVs, variants of uncertain significance (VUS), and negative results. This qualitative study examined communication of positive, negative, and VUS hereditary cancer multi-gene panel (MGP) results in an ethnically and socioeconomically diverse population. As part of a multicenter, prospective cohort study of 2000 patients who underwent MGP testing at three hospitals in California, USA, free-text written survey responses to the question: "Feel free to share any thoughts or experiences with discussing genetic test results with others" were collected from participant questionnaires administered at 3 and 12-months post results disclosure. Content and thematic analyses were performed using a theory-driven analysis, Theory of Planned Behavior (TPB), on 256 responses from 214 respondents. Respondents with high perceived utility of sharing genetic test results often reported positive attitudes towards sharing test results and direct encouragement for genetic testing of others. Respondents with high self-efficacy in the sharing process were likely to report high perceived utility of sharing, whereas patients with low self-efficacy more often had VUS results and were more likely to report uncertainty about sharing. Consistent with TPB, our findings suggest that clinician reinforcement of the utility of genetic testing may increase intent for patients to communicate genetic information. Our findings suggest that clinicians should focus on strategies to improve patient understanding of VUS results.
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Affiliation(s)
- Rachel Hodan
- Cancer Genetics and Genomics, Stanford Health Care, Stanford, CA, USA.
- Department of Pediatrics (Genetics), Stanford University School of Medicine, Stanford, CA, USA.
| | - Miles Picus
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Caroline Stanclift
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Kelly E Ormond
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, CA, USA
- Health Ethics and Policy Lab, Department of Health Sciences and Technology, (DHEST), ETH-Zurich, Zurich, Switzerland
| | | | - Allison W Kurian
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA
- Department of Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Charité Ricker
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
- Los Angeles General Medical Center, Los Angeles, CA, USA
| | - Gregory E Idos
- Division of Gastroenterology, City of Hope, Duarte, CA, USA
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9
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Klatte DCF, Starr JS, Clift KE, Hardway HD, van Hooft JE, van Leerdam ME, Potjer TP, Presutti RJ, Riegert-Johnson DL, Wallace MB, Bi Y. Utilization and Outcomes of Multigene Panel Testing in Patients With Pancreatic Ductal Adenocarcinoma. JCO Oncol Pract 2024; 20:1081-1090. [PMID: 38621197 DOI: 10.1200/op.23.00447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 12/28/2023] [Accepted: 03/07/2024] [Indexed: 04/17/2024] Open
Abstract
PURPOSE Guidelines recommend germline genetic testing (GT) for patients with pancreatic ductal adenocarcinoma (PDAC). This study aims to evaluate the utilization and outcomes of multigene panel GT in patients with PDAC. METHODS This retrospective, multisite study included patients with PDAC diagnosed between May 2018 and August 2020 at Mayo Clinic Arizona, Florida, and Minnesota. Discussion, uptake, and outcomes of GT were compared before (May 1, 2018-May 1, 2019) and after (August 1, 2019-August 1, 2020) the guideline update, accounting for a transition period. RESULTS The study identified 533 patients with PDAC, with 321 (60.2%) preguideline and 212 (39.8%) postguideline. Patient characteristics did not differ between the preguideline and postguideline periods. GT was discussed in 34.3% (110 of 321) of preguideline and 39.6% (84 of 212) of postguideline patients (odds ratio [OR], 1.26 [95% CI, 0.88 to 1.80]) and subsequently performed in 80.9% (89 of 110) of preguideline and 75.0% (63 of 84) of postguideline patients (OR, 1.10 [95% CI, 0.75 to 1.61]). Of 152 tested patients, 26 (17.1%) had a pathogenic variant (PV), of whom 17 (11.2%; 17 of 152) were PDAC-associated. Over the entire study period, GT was more likely in younger patients (65 v 70 years; P < .001), those seen by a medical oncologist (82.9% v 69.0%; P < .001), and those surviving more than 12 months from diagnosis (70.4% v 43.4%; P < .001). Demographics and personal/family cancer history were comparable between patients with and without a PDAC PV. CONCLUSION GT remains underutilized despite National Comprehensive Cancer Network guideline recommendations. Given the poor prognosis of PDAC and potential implications of GT, efforts to increase utilization are needed to provide surveillance and support to both patients with PDAC and at-risk family members.
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Affiliation(s)
- Derk C F Klatte
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Jason S Starr
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL
| | - Kristin E Clift
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL
| | - Heather D Hardway
- Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL
| | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Monique E van Leerdam
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Thomas P Potjer
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - R John Presutti
- Department of Family Medicine, Mayo Clinic, Jacksonville, FL
| | | | - Michael B Wallace
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL
- Department of Gastroenterology, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
| | - Yan Bi
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL
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10
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Tinterri C, Gentile D, Caruso F, Cortesi L, De Laurentiis M, Fortunato L, Santini D, Turchetti D, Ferrari A, Zambelli A, Senonetwork Italia Breast Centre Responders. BRCA Testing for Patients Treated in Italy: A National Survey of Breast Centers Associated with Senonetwork. Curr Oncol 2024; 31:3815-3825. [PMID: 39057154 PMCID: PMC11276301 DOI: 10.3390/curroncol31070282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 06/25/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Breast units (BUs) provide breast cancer (BC) care, including prevention, treatment, and genetic assessment. Genetic research has highlighted BRCA1/2 mutations as key hereditary BC risk factors. BRCA testing is crucial for personalized treatment and prevention strategies. However, the integration of BRCA testing in Italian BUs faces multiple challenges. This study, by Senonetwork Italia, aimed to evaluate genetic testing practices and identify obstacles within Italian BUs. METHODS Senonetwork Italia conducted a 16-question web-based survey involving 153 BUs. The survey assessed aspects of BRCA testing, including timing, urgency, counseling, patient selection, and multi-gene panels. RESULTS Of the 153 BUs, 109 (71.2%) responded. Testing before surgery was performed by 70.6% of centers, with urgent cases acknowledged by 87.2%. Most centers (56.0%) arranged urgent pre-test counseling within a week. BRCA mutation status influenced treatment decisions in 99.1% of cases. Multi-gene panels were used by 33.0% of centers for all genetic counseling cases, while 56.0% followed standard referral criteria. The main challenges included cost, reimbursement, and reporting timelines. CONCLUSIONS This survey highlights significant variations in BRCA testing practices across Italian BUs and identifies key logistical and financial challenges. There is a need for standardized practices of genetic testing to ensure personalized and effective BC management in Italy.
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Affiliation(s)
- Corrado Tinterri
- Breast Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy;
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Milan, Italy;
| | - Damiano Gentile
- Breast Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy;
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Milan, Italy;
| | - Francesco Caruso
- HICC Humanitas Istituto Clinico Catanese, 95045 Misterbianco, Italy;
| | - Laura Cortesi
- Azienda Ospedaliera-Universitaria di Modena, Università degli Studi di Modena e Reggio Emilia, 41121 Modena, Italy;
| | - Michelino De Laurentiis
- Dipartimento di Oncologia Senologica, Istituto Nazionale Tumori “Fondazione PASCALE”, 80131 Napoli, Italy;
| | - Lucio Fortunato
- Breast Centre, Azienda Ospedaliera San Giovanni-Addolorata, 00184 Rome, Italy;
| | - Donatella Santini
- IRCCS Azienda Ospedaliero, Universitaria di Bologna Policlinico di Sant’Orsola, 40138 Bologna, Italy;
| | - Daniela Turchetti
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy;
- Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Alberta Ferrari
- Fondazione IRCCS Policlinico San Matteo di Pavia, 27100 Pavia, Italy;
| | - Alberto Zambelli
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Milan, Italy;
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy
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11
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Magaton IM, Arecco L, Mariamidze E, Jankovic K, Stana M, Buzzatti G, Trevisan L, Scavone G, Ottonello S, Fregatti P, Massarotti C, von Wolff M, Lambertini M. Fertility and Pregnancy-Related Issues in Young BRCA Carriers With Breast Cancer. Breast Cancer (Auckl) 2024; 18:11782234241261429. [PMID: 38882447 PMCID: PMC11179469 DOI: 10.1177/11782234241261429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 05/06/2024] [Indexed: 06/18/2024] Open
Abstract
Approximately 10% to 15% of breast cancer cases in young women are diagnosed in patients harbouring germline (g) pathogenic or likely pathogenic variants (PVs) in the BReast CAncer 1 (BRCA1) or BReast CAncer 2 (BRCA2) genes. Preclinical and clinical studies showed a potential negative effect of germline BRCA1/2 (gBRCA1/2) PVs on ovarian reserve and reproductive potential, even before starting anticancer therapies. The aim of this article is to summarize the current literature on the fertility potential of young gBRCA1/2 PVs carriers with breast cancer and the risk of gonadotoxicity associated with anticancer treatments. Moreover, we describe the available evidence on the efficacy of fertility preservation techniques in young gBRCA1/2 PVs carriers and the safety data on having a pregnancy after breast cancer treatment.
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Affiliation(s)
- Isotta Martha Magaton
- Division of Gynaecological Endocrinology and Reproductive Medicine, University Women's Hospital, Inselspital, Bern, Switzerland
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Luca Arecco
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, Genoa, Italy
| | - Elene Mariamidze
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Medical Oncology & Hematology, Todua Clinic, Tbilisi, Georgien
| | - Kristina Jankovic
- Department of Medical Oncology, University Clinic Center Nis, Nis, Serbia
| | - Mihaela Stana
- Department of Medical Oncology, Elysee Hospital, Alba Iulia, Romania
| | - Giulia Buzzatti
- Department of Medical Oncology, Unit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Lucia Trevisan
- Department of Medical Oncology, Unit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Graziana Scavone
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Silvia Ottonello
- Departent of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Piero Fregatti
- Department of Surgery, U.O.C. Clinica di Chirurgia Senologica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Surgical Sciences and Integrated Diagnostic (DISC), School of Medicine, University of Genoa, Genoa, Italy
| | - Claudia Massarotti
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI Department), University of Genoa, Genoa, Italy
- Academic Unit of Obstetrics and Gynecology, Maternal-Child Department, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Michael von Wolff
- Division of Gynaecological Endocrinology and Reproductive Medicine, University Women's Hospital, Inselspital, Bern, Switzerland
| | - Matteo Lambertini
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, Genoa, Italy
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12
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Makhetha M, Walters S, Aldous C. The review of genetic screening services and common BRCA1/2 variants among South African breast cancer patients. J Genet Couns 2024; 33:481-492. [PMID: 37528630 DOI: 10.1002/jgc4.1755] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 07/10/2023] [Accepted: 07/14/2023] [Indexed: 08/03/2023]
Abstract
The South African genetic screening services for breast cancer comprise targeted and comprehensive tests that screen for the presence of genetic alterations. Clinically, these variants determine the risk of disease development as well as treatment approaches best suited for carriers. The current targeted tests screen for seven pathogenic sequence variants, which are mainly common among Whites, a population that constitutes 9.1% of South Africa. However, these tests are offered to all patients despite consistent negative results observed among Blacks, Indians, and Mixed ancestry (known as Coloreds in South Africa). Consequently, Blacks, White, and Colored patients who potentially carry other variants receive unbefitting treatment, resulting in poor clinical response, recurrence, and high mortality. This review aimed to identify the presence and incidence of pathogenic variants in BRCA1/2 previously reported in all South African populations. We selected literature using a scoping review approach, from which we included eight articles and two reports. Overall, we identified 59 BRCA1 and 60 BRCA2 pathogenic sequence variants from a cohort of 5709 patients and unknown patients from 90 families. The most reported variant was BRCA2 c.7943delG, which was common in White and Colored patients. None of the seven common variants was reported in either Blacks or Indians, which demonstrates the urgency to tailor genetic tests which are optimal for all South African patients and present a range of variants which could serve as diagnostic targets for Black, Indian, and Colored patients.
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Affiliation(s)
- Mpoi Makhetha
- Department of Clinical Medicine, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | | | - Colleen Aldous
- Department of Clinical Medicine, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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13
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Shao B, Di L. Metastatic breast cancer with double heterozygosity for the BRCA1 and BRCA2 genes responding to olaparib: A case report. Oncol Lett 2024; 27:253. [PMID: 38646498 PMCID: PMC11027096 DOI: 10.3892/ol.2024.14387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 02/07/2023] [Indexed: 04/23/2024] Open
Abstract
Olaparib was the first poly ADP-ribose polymerase inhibitor approved for patients with cancer with mutations in either BRCA1 or BRCA2 in China. To the best of our knowledge, however, no study has described the efficacy of olaparib for patients with breast cancer with double mutations in BRCA1 and BRCA2. The present case report describes a patient with breast cancer with deleterious germline mutations in both BRCA1 and BRCA2. The 56-year-old patient with multiple metastatic breast cancer underwent breast cancer resection with 12 years interval between removal of the left and right breast. Germline mutations in both BRCA1 (S405X) and BRCA2 (W2990X) were identified by NGS. She received two cycles of chemotherapy with a combination of albumin-bound paclitaxel and capecitabine; the response was progressive disease. Subsequently, the patient was treated with a gradual dosage of decreasing olaparib (600 to 300 mg BID) for 6 months until grade 3 anemia could not be alleviated by giving erythropoietin and iron, and CT imaging showed a partial response (35% reduction). The patient then switched to exemestane therapy due to the continuous grade 3 anemia. In conclusion, the present study reported a female patient with double heterozygosity of BRCA1 and BRCA2 who benefited from olaparib monotherapy. Thus, olaparib may be a suitable treatment for such patients.
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Affiliation(s)
- Bin Shao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Lijun Di
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
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14
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Arumugam M, Tovar EA, Essenburg CJ, Dischinger PS, Beddows I, Wolfrum E, Madaj ZB, Turner L, Feenstra K, Gallik KL, Cohen L, Nichols M, Sheridan RTC, Esquibel CR, Mouneimne G, Graveel CR, Steensma MR. Nf1 deficiency modulates the stromal environment in the pretumorigenic rat mammary gland. Front Cell Dev Biol 2024; 12:1375441. [PMID: 38799507 PMCID: PMC11116614 DOI: 10.3389/fcell.2024.1375441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/17/2024] [Indexed: 05/29/2024] Open
Abstract
Background Neurofibromin, coded by the NF1 tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1)-a tumor predisposition syndrome caused by a germline NF1 mutation-have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which NF1 mutations lead to breast cancer tumorigenesis is not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer. Approach To accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer. Results We identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-deficient mature adipocytes in the rat mammary gland have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with in vitro differentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance. Conclusion Collectively, this study uncovered the previously undescribed role of Nf1 in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary glands will create a foundation for developing early detection strategies of breast cancer among NF1 patients.
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Affiliation(s)
- Menusha Arumugam
- Department of Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Elizabeth A. Tovar
- Department of Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Curt J. Essenburg
- Department of Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Patrick S. Dischinger
- Department of Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Ian Beddows
- Biostatistics ad Bioinformatics Core, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Emily Wolfrum
- Biostatistics ad Bioinformatics Core, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Zach B. Madaj
- Biostatistics ad Bioinformatics Core, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Lisa Turner
- Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Kristin Feenstra
- Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Kristin L. Gallik
- Optical Imaging Core, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Lorna Cohen
- Optical Imaging Core, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Madison Nichols
- Flow Cytometry Core, Van Andel Research Institute, Grand Rapids, MI, United States
| | | | - Corinne R. Esquibel
- Optical Imaging Core, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Ghassan Mouneimne
- University of Arizona Cancer Center, Tucson, AZ, United States
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States
| | - Carrie R. Graveel
- Department of Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Matthew R. Steensma
- Department of Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
- Helen DeVos Children’s Hospital, Spectrum Health System, Grand Rapids, MI, United States
- Michigan State University College of Human Medicine, Grand Rapids, MI, United States
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15
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Bensenane R, Beddok A, Lesueur F, Fourquet A, Warcoin M, Le Mentec M, Cavaciuti E, Le Gal D, Eon-Marchais S, Andrieu N, Stoppa-Lyonnet D, Kirova Y. Safety of the Breast Cancer Adjuvant Radiotherapy in Ataxia-Telangiectasia Mutated Variant Carriers. Cancers (Basel) 2024; 16:1417. [PMID: 38611095 PMCID: PMC11010818 DOI: 10.3390/cancers16071417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
The Ataxia-Telangiectasia Mutated (ATM) gene is implicated in DNA double-strand break repair. Controversies in clinical radiosensitivity remain known for monoallelic carriers of the ATM pathogenic variant (PV). An evaluation of the single-nucleotide polymorphism (SNP) rs1801516 (G-A) showed different results regarding late subcutaneous fibrosis after breast radiation therapy (RT). The main objective of this study was to evaluate acute and late toxicities in carriers of a rare ATM PV or predicted PV and in carriers of minor allele A of rs1801516 facing breast RT. Fifty women with localized breast cancer treated with adjuvant RT between 2000 and 2014 at Institut Curie were selected. Acute and late toxicities in carriers of a rare PV or predicted PV (n= 9), in noncarriers (n = 41) and in carriers of SNP rs1801516 (G-A) (n = 8), were examined. The median age at diagnosis was 53 years old and 82% of patients had an invasive ductal carcinoma and 84% were at clinical stage I-IIB. With a median follow-up of 13 years, no significant difference between carriers and noncarriers was found for acute toxicities (p > 0.05). The same results were observed for late toxicities without an effect from the rs1801516 genotype on toxicities. No significant difference in acute or late toxicities was observed between rare ATM variant carriers and noncarriers after breast RT for localized breast cancer.
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Affiliation(s)
- Rayan Bensenane
- Department of Radiation Oncology, Institut Curie, 75248 Paris, France; (R.B.); (A.F.)
| | - Arnaud Beddok
- Department of Radiation Oncology, Institut Godinot, 51454 Reims, France;
- CRESTIC EA 3804, University Reims Champagne-Ardenne, 51454 Reims, France
| | - Fabienne Lesueur
- Inserm U900, Institut Curie, PSL Research University, Mines ParisTech, 75248 Paris, France; (F.L.); (E.C.); (D.L.G.); (S.E.-M.); (N.A.)
| | - Alain Fourquet
- Department of Radiation Oncology, Institut Curie, 75248 Paris, France; (R.B.); (A.F.)
| | - Mathilde Warcoin
- Department of Genetics, Institut Curie, 75248 Paris, France; (M.W.); (M.L.M.); (D.S.-L.)
- Inserm U830, Institut Curie, Paris-Cité University, 75248 Paris, France
- Paris Sciences & Lettres Research University, 75248 Paris, France
| | - Marine Le Mentec
- Department of Genetics, Institut Curie, 75248 Paris, France; (M.W.); (M.L.M.); (D.S.-L.)
- Inserm U830, Institut Curie, Paris-Cité University, 75248 Paris, France
- Paris Sciences & Lettres Research University, 75248 Paris, France
| | - Eve Cavaciuti
- Inserm U900, Institut Curie, PSL Research University, Mines ParisTech, 75248 Paris, France; (F.L.); (E.C.); (D.L.G.); (S.E.-M.); (N.A.)
| | - Dorothée Le Gal
- Inserm U900, Institut Curie, PSL Research University, Mines ParisTech, 75248 Paris, France; (F.L.); (E.C.); (D.L.G.); (S.E.-M.); (N.A.)
| | - Séverine Eon-Marchais
- Inserm U900, Institut Curie, PSL Research University, Mines ParisTech, 75248 Paris, France; (F.L.); (E.C.); (D.L.G.); (S.E.-M.); (N.A.)
| | - Nadine Andrieu
- Inserm U900, Institut Curie, PSL Research University, Mines ParisTech, 75248 Paris, France; (F.L.); (E.C.); (D.L.G.); (S.E.-M.); (N.A.)
| | - Dominique Stoppa-Lyonnet
- Department of Genetics, Institut Curie, 75248 Paris, France; (M.W.); (M.L.M.); (D.S.-L.)
- Inserm U830, Institut Curie, Paris-Cité University, 75248 Paris, France
| | - Youlia Kirova
- Department of Radiation Oncology, Institut Curie, 75248 Paris, France; (R.B.); (A.F.)
- University Versailles, 02100 St. Quentin, France
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16
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Ruberu TLM, Braun D, Parmigiani G, Biswas S. Bayesian meta-analysis of penetrance for cancer risk. Biometrics 2024; 80:ujae038. [PMID: 38819308 PMCID: PMC11140851 DOI: 10.1093/biomtc/ujae038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 07/12/2023] [Accepted: 05/01/2024] [Indexed: 06/01/2024]
Abstract
Multi-gene panel testing allows many cancer susceptibility genes to be tested quickly at a lower cost making such testing accessible to a broader population. Thus, more patients carrying pathogenic germline mutations in various cancer-susceptibility genes are being identified. This creates a great opportunity, as well as an urgent need, to counsel these patients about appropriate risk-reducing management strategies. Counseling hinges on accurate estimates of age-specific risks of developing various cancers associated with mutations in a specific gene, ie, penetrance estimation. We propose a meta-analysis approach based on a Bayesian hierarchical random-effects model to obtain penetrance estimates by integrating studies reporting different types of risk measures (eg, penetrance, relative risk, odds ratio) while accounting for the associated uncertainties. After estimating posterior distributions of the parameters via a Markov chain Monte Carlo algorithm, we estimate penetrance and credible intervals. We investigate the proposed method and compare with an existing approach via simulations based on studies reporting risks for two moderate-risk breast cancer susceptibility genes, ATM and PALB2. Our proposed method is far superior in terms of coverage probability of credible intervals and mean square error of estimates. Finally, we apply our method to estimate the penetrance of breast cancer among carriers of pathogenic mutations in the ATM gene.
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Affiliation(s)
| | - Danielle Braun
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
- Department of Data Science, Dana Farber Cancer Institute, Boston, MA 02215, United States
| | - Giovanni Parmigiani
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
- Department of Data Science, Dana Farber Cancer Institute, Boston, MA 02215, United States
| | - Swati Biswas
- Department of Mathematical Sciences, University of Texas at Dallas, Richardson, TX 75080, United States
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17
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Kast K, Rhiem K, Larsen M, Wappenschmidt B, Schmutzler R. Phenotype analysis of families with TP53 germline variants at the Center for Familial Breast and Ovarian Cancer, Cologne. Cancer Med 2024; 13:e6920. [PMID: 38230850 PMCID: PMC10905677 DOI: 10.1002/cam4.6920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 12/07/2023] [Accepted: 12/31/2023] [Indexed: 01/18/2024] Open
Abstract
PURPOSE Tumor protein p53 (TP53) pathogenic variant (PV) carriers are identified during genetic testing for hereditary causes of cancer. PVs in TP53 are associated with the Li-Fraumeni syndrome (LFS), and thus, surveillance and preventive measures are important for TP53 PV carriers. However, the penetrance of TP53 PVs can be low if the Chompret criteria are not fulfilled. In this study, we compared the phenotypic characteristics of families that did and did not fulfill the LFS criteria according to Chompret. METHODS The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) database was used to identify index patients with a likely pathogenic/pathogenic TP53 variant and their family members. The study investigated the type of variant, pedigree, age of onset, number of primary tumors, and histological type of BC. RESULTS TP53 PV were present in the index cases of 35 families, 57% (20/35) of which fulfilled the Chompret criteria. The median age of onset at first BC diagnosis was lower in families that fulfilled the Chompret criteria compared to those who did not. Four of all diseased individuals were minors (4%; 4/105) when malignancy was first diagnosed. Sarcomas and brain tumors occurred in 10% (10/105) and in 7% (7/105) of all diseased persons, respectively. BC was the most frequently occurring first tumor (60%; 62/105) and additional malignancy (45%; 20/44) in this cohort. Subsequent malignancies developed in 31% (20/65) of the individuals who fulfilled the Chompret criteria compared with 15% (6/40) of those who did not. CONCLUSION The tumor spectrum and age of onset found in this study showed that tumors other than BC had low disease penetrance in TP53 PV carriers identified using the GC-HBOC criteria for genetic testing.
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Affiliation(s)
- K. Kast
- Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical FacultyUniversity Hospital CologneCologneGermany
| | - K. Rhiem
- Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical FacultyUniversity Hospital CologneCologneGermany
| | - M. Larsen
- Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical FacultyUniversity Hospital CologneCologneGermany
| | - B. Wappenschmidt
- Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical FacultyUniversity Hospital CologneCologneGermany
| | - R. Schmutzler
- Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical FacultyUniversity Hospital CologneCologneGermany
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18
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Nowlen CJ, Daniels M, Uzunparmak B, Ileana Dumbrava EE, Yuan Y, Patel KP, Rayes N, Harkenrider J, Wathoo C, Veazie J, Luna KA, Wang W, Horombe C, Javle M, Ahnert JR, Yap TA, Arun B, Lu KH, Meric-Bernstam F. Limited Independent Follow-Up with Germline Testing of Variants Detected in BRCA1 and BRCA2 by Tumor-Only Sequencing. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2024; 7:7-17. [PMID: 38327755 PMCID: PMC10846638 DOI: 10.36401/jipo-23-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 08/28/2023] [Accepted: 10/10/2023] [Indexed: 02/09/2024]
Abstract
Introduction Genomic profiling is performed in patients with advanced or metastatic cancer, in order to direct cancer treatment, often sequencing tumor-only, without a matched germline comparator. However, because many of the genes analyzed on tumor profiling overlap with those known to be associated with hereditary cancer predisposition syndromes (HCPS), tumor-only profiling can unknowingly uncover germline pathogenic (P) and likely pathogenic variants (LPV). In this study, we evaluated the number of patients with P/LPVs identified in BRCA1 and BRCA2 (BRCA1/2) via tumor-only profiling, then determined the germline testing outcomes for those patients. Methods A retrospective chart review was performed to identify patients with BRCA1/2 variants on tumor-only genomic profiling, and whether they had germline testing. Results This study found that of 2923 patients with 36 tumor types who underwent tumor-only testing, 554 had a variant in BRCA1/2 (19.0%); 119 of the 554 patients (21.5%) had a P/LP BRCA1/2 variant, representing 4.1% of the overall population who underwent genomic profiling. Seventy-three (61.3%) of 119 patients with BRCA1/2 P/LPV on tumor-only testing did not undergo germline testing, 34 (28.6%) had already had germline testing before tumor-only testing, and 12 (10.1%) underwent germline testing after tumor-only testing. Twenty-eight germline BRCA1/2 P/LPVs were detected, 24 in those who had prior germline testing, and 4 among the 12 patients who had germline testing after tumor-only testing. Conclusion Tumor-only testing is likely to identify P/LPVs in BRCA1/2. Efforts to improve follow-up germline testing is needed to improve identification of germline BRCA1/2 alterations.
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Affiliation(s)
- Carol J. Nowlen
- The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Molly Daniels
- Department of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Burak Uzunparmak
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ecaterina E. Ileana Dumbrava
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ying Yuan
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Keyur P. Patel
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nadine Rayes
- Department of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jacqueline Harkenrider
- Department of Obstetrics, Gynecology, and Reproductive Sciences, The University of Texas Health Science Center at Houston John P. and Katherine G. McGovern Medical School, Houston, TX, USA
| | - Chetna Wathoo
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jennifer Veazie
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Krystle A. Luna
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wanlin Wang
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chacha Horombe
- Department of Enterprise Development & Integration, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jordi Rodon Ahnert
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Timothy A. Yap
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Banu Arun
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Karen H. Lu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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19
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Koster R, Schipper LJ, Giesbertz NAA, van Beek D, Mendeville M, Samsom KG, Rosenberg EH, Hogervorst FBL, Roepman P, Boelens MC, Bosch LJW, van den Berg JG, Meijer GA, Voest EE, Cuppen E, Ruijs MWG, van Wezel T, van der Kolk L, Monkhorst K. Impact of genetic counseling strategy on diagnostic yield and workload for genome-sequencing-based tumor diagnostics. Genet Med 2024; 26:101032. [PMID: 38006283 DOI: 10.1016/j.gim.2023.101032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 11/17/2023] [Accepted: 11/19/2023] [Indexed: 11/26/2023] Open
Abstract
PURPOSE Genome sequencing (GS) enables comprehensive molecular analysis of tumors and identification of hereditary cancer predisposition. According to guidelines, directly determining pathogenic germline variants (PGVs) requires pretest genetic counseling, which is cost-ineffective. Referral for genetic counseling based on tumor variants alone could miss relevant PGVs and/or result in unnecessary referrals. METHODS We validated GS for detection of germline variants and simulated 3 strategies using paired tumor-normal GS data of 937 metastatic patients. In strategy-1, genetic counseling before tumor testing allowed direct PGV analysis. In strategy-2 and -3, germline testing and referral for post-test genetic counseling is based on tumor variants using Dutch (strategy-2) or Europen Society for Medical Oncology (ESMO) Precision Medicine Working Group (strategy-3) guidelines. RESULTS In strategy-1, PGVs would be detected in 50 patients (number-needed-to counsel; NTC = 18.7). In strategy-2, 86 patients would have been referred for genetic counseling and 43 would have PGVs (NTC = 2). In strategy-3, 94 patients would have been referred for genetic counseling and 32 would have PGVs (NTC = 2.9). Hence, 43 and 62 patients, respectively, were unnecessarily referred based on a somatic variant. CONCLUSION Both post-tumor test counseling strategies (2 and 3) had significantly lower NTC, and strategy-2 had the highest PGV yield. Combining pre-tumor test mainstreaming and post-tumor test counseling may maximize the clinically relevant PGV yield and minimize unnecessary referrals.
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Affiliation(s)
- Roelof Koster
- The Netherlands Cancer Institute, Amsterdam, The Netherlands.
| | - Luuk J Schipper
- The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | | | | | - Kris G Samsom
- The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | | | - Paul Roepman
- Hartwig Medical Foundation, Amsterdam, The Netherlands
| | | | - Linda J W Bosch
- The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | - Gerrit A Meijer
- The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Emile E Voest
- The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Edwin Cuppen
- Hartwig Medical Foundation, Amsterdam, The Netherlands
| | | | - Tom van Wezel
- The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | - Kim Monkhorst
- The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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20
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Penvose KN, Reed SD, Sepulveda JMG, Mastylak A, Scott A, Hayes T, Shank J, Havrilesky LJ. Development and testing of patient-centered education about hormone replacement therapy for women at high genetic risk of breast and ovarian cancer. Gynecol Oncol 2024; 181:91-98. [PMID: 38150837 DOI: 10.1016/j.ygyno.2023.11.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/17/2023] [Accepted: 11/22/2023] [Indexed: 12/29/2023]
Abstract
OBJECTIVE In this study, we aimed to develop education to assist BRCA mutation carriers in making informed decisions about HRT in the context of risk-reducing surgery, while simultaneously clarifying their treatment-specific values and reducing decisional conflict. METHODS We enrolled premenopausal BRCA mutation carriers ages 19-49 without prior cancer or risk-reducing salpingo-oophorectomy to structured interviews in which they reviewed education about the risks and benefits of HRT. Materials included literature-derived data demonstrating associations between HRT and commonly considered health outcomes (breast cancer, vasomotor symptoms, sexual functioning, cardiovascular disease, osteoporosis, and blood clots). Participants completed the 16-item Decisional Conflict Scale (DCS) before and after education, communicated their preferences by rating and ranking the six outcomes, and provided feedback to inform iterative revisions of the educational content. RESULTS 25 participants completed interviews. DCS scores decreased significantly from 54.6 to 22.8 following education (p < 0.001); sub-scores for uncertainty (71.7 to 37.3), informed (71.7 to 15.3), values clarity (53.7 to 17.0), effective decision (44.2 to 25.5), and support (35.0 to 17.7) also decreased significantly. Participants ranked cardiovascular disease as the most important outcome to consider, followed by breast cancer, osteoporosis, blood clots, decline in sexual function, and hot flashes. Participants with prior mastectomy (N = 10) ranked breast cancer as the most important outcome 25% of the time, compared to 80% in participants without mastectomy (N = 15). CONCLUSION Following education, BRCA mutation carriers had significantly less decisional conflict regarding the choice to use HRT. This pilot study was successful in generating a prototype educational aid for further testing.
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Affiliation(s)
- Katherine N Penvose
- Duke University School of Medicine, Duke University Health System, Durham, NC, USA
| | - Shelby D Reed
- Preference Evaluation Research Group, Duke Clinical Research Institute, Duke University, Durham, NC, USA
| | | | - Alicja Mastylak
- Preference Evaluation Research Group, Duke Clinical Research Institute, Duke University, Durham, NC, USA
| | - Amelia Scott
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Durham, NC, USA
| | - Taylor Hayes
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Durham, NC, USA
| | | | - Laura J Havrilesky
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Durham, NC, USA.
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21
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Fortuno C, Feng BJ, Carroll C, Innella G, Kohlmann W, Lázaro C, Brunet J, Feliubadaló L, Iglesias S, Menéndez M, Teulé A, Ballinger ML, Thomas DM, Campbell A, Field M, Harris M, Kirk J, Pachter N, Poplawski N, Susman R, Tucker K, Wallis M, Williams R, Cops E, Goldgar D, kConFab Investigators, James PA, Spurdle AB. Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum. JCO Precis Oncol 2024; 8:e2300453. [PMID: 38412388 PMCID: PMC10914239 DOI: 10.1200/po.23.00453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/23/2023] [Accepted: 12/21/2023] [Indexed: 02/29/2024] Open
Abstract
PURPOSE Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies. MATERIALS AND METHODS We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals. RESULTS Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years. CONCLUSION The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.
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Affiliation(s)
- Cristina Fortuno
- Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Bing-Jian Feng
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Courtney Carroll
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Giovanni Innella
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Wendy Kohlmann
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Conxi Lázaro
- Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Hereditary Cancer Program, ONCOBELL, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Hereditary Cancer Program, ONCOBELL, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
- Precision Oncology in Girona, IDIBGI, Girona, Spain
| | - Lidia Feliubadaló
- Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Hereditary Cancer Program, ONCOBELL, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
| | - Silvia Iglesias
- Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Mireia Menéndez
- Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Alex Teulé
- Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Hereditary Cancer Program, ONCOBELL, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Mandy L. Ballinger
- St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales, Australia
- Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - David M. Thomas
- Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- Centre for Molecular Oncology, Faculty of Medicine, University of New South Wales, New South Wales, Australia
| | - Ainsley Campbell
- Department of Clinical Genetics, Austin Health, Melbourne, Victoria, Australia
| | - Mike Field
- Familial Cancer Service, Royal North Shore Hospital, St Leonards, New South Wales, Australia
| | - Marion Harris
- Monash Health Familial Cancer Service, Melbourne, Victoria, Australia
| | - Judy Kirk
- Familial Cancer Service, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia
| | - Nicholas Pachter
- Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia
| | - Nicola Poplawski
- Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Rachel Susman
- Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Kathy Tucker
- Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, New South Wales, Australia
- Prince of Wales Clinical School, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
| | - Mathew Wallis
- Tasmanian Clinical Genetics Service, Tasmanian Health Service, Royal Hobart Hospital, Hobart, Tasmania, Australia
- School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - Rachel Williams
- Prince of Wales Clinical School, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
- Prince of Wales Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia
| | - Elisa Cops
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - David Goldgar
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - kConFab Investigators
- kConFab, Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - Paul A. James
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - Amanda B. Spurdle
- Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
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22
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Boujemaa M, Nouira F, Jandoubi N, Mejri N, Bouaziz H, Charfeddine C, Ben Nasr S, Labidi S, El Benna H, Berrazega Y, Rachdi H, Daoud N, Benna F, Haddaoui A, Abdelhak S, Samir Boubaker M, Boussen H, Hamdi Y. Uncovering the clinical relevance of unclassified variants in DNA repair genes: a focus on BRCA negative Tunisian cancer families. Front Genet 2024; 15:1327894. [PMID: 38313678 PMCID: PMC10834681 DOI: 10.3389/fgene.2024.1327894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/02/2024] [Indexed: 02/06/2024] Open
Abstract
Introduction: Recent advances in sequencing technologies have significantly increased our capability to acquire large amounts of genetic data. However, the clinical relevance of the generated data continues to be challenging particularly with the identification of Variants of Uncertain Significance (VUSs) whose pathogenicity remains unclear. In the current report, we aim to evaluate the clinical relevance and the pathogenicity of VUSs in DNA repair genes among Tunisian breast cancer families. Methods: A total of 67 unsolved breast cancer cases have been investigated. The pathogenicity of VUSs identified within 26 DNA repair genes was assessed using different in silico prediction tools including SIFT, PolyPhen2, Align-GVGD and VarSEAK. Effects on the 3D structure were evaluated using the stability predictor DynaMut and molecular dynamics simulation with NAMD. Family segregation analysis was also performed. Results: Among a total of 37 VUSs identified, 11 variants are likely deleterious affecting ATM, BLM, CHEK2, ERCC3, FANCC, FANCG, MSH2, PMS2 and RAD50 genes. The BLM variant, c.3254dupT, is novel and seems to be associated with increased risk of breast, endometrial and colon cancer. Moreover, c.6115G>A in ATM and c.592+3A>T in CHEK2 were of keen interest identified in families with multiple breast cancer cases and their familial cosegregation with disease has been also confirmed. In addition, functional in silico analyses revealed that the ATM variant may lead to protein immobilization and rigidification thus decreasing its activity. We have also shown that FANCC and FANCG variants may lead to protein destabilization and alteration of the structure compactness which may affect FANCC and FANCG protein activity. Conclusion: Our findings revealed that VUSs in DNA repair genes might be associated with increased cancer risk and highlight the need for variant reclassification for better disease management. This will help to improve the genetic diagnosis and therapeutic strategies of cancer patients not only in Tunisia but also in neighboring countries.
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Affiliation(s)
- Maroua Boujemaa
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Fatma Nouira
- Laboratory of Bioactive Substances, Center of Biotechnology of Borj Cedria, University of Tunis El Manar, Hamam, Tunisia
| | - Nouha Jandoubi
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Nesrine Mejri
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
- Medical Oncology Department, Abderrahman Mami Hospital, Faculty of Medicine Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Hanen Bouaziz
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
- Surgical Oncology Department, Salah Azaiez Institute of Cancer, Tunis, Tunisia
| | - Cherine Charfeddine
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
- High Institute of Biotechnology of Sidi Thabet, Biotechpole of Sidi Thabet, University of Manouba, Ariana, Tunisia
| | - Sonia Ben Nasr
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
- Department of Medical Oncology, Military Hospital of Tunis, Tunis, Tunisia
| | - Soumaya Labidi
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
- Medical Oncology Department, Abderrahman Mami Hospital, Faculty of Medicine Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Houda El Benna
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
- Medical Oncology Department, Abderrahman Mami Hospital, Faculty of Medicine Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Yosra Berrazega
- Medical Oncology Department, Abderrahman Mami Hospital, Faculty of Medicine Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Haifa Rachdi
- Medical Oncology Department, Abderrahman Mami Hospital, Faculty of Medicine Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Nouha Daoud
- Medical Oncology Department, Abderrahman Mami Hospital, Faculty of Medicine Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Farouk Benna
- Radiation Oncology Department, Salah Azaiez Institute, Tunis, Tunisia
| | | | - Sonia Abdelhak
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Mohamed Samir Boubaker
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
- Laboratory of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis, Tunisia
| | - Hamouda Boussen
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
- Medical Oncology Department, Abderrahman Mami Hospital, Faculty of Medicine Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Yosr Hamdi
- Laboratory of Biomedical Genomics and Oncogenetics, LR20IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia
- Laboratory of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis, Tunisia
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23
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Wilczyński J, Paradowska E, Wilczyński M. High-Grade Serous Ovarian Cancer-A Risk Factor Puzzle and Screening Fugitive. Biomedicines 2024; 12:229. [PMID: 38275400 PMCID: PMC10813374 DOI: 10.3390/biomedicines12010229] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 01/14/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024] Open
Abstract
High-grade serous ovarian cancer (HGSOC) is the most lethal tumor of the female genital tract. Despite extensive studies and the identification of some precursor lesions like serous tubal intraepithelial cancer (STIC) or the deviated mutational status of the patients (BRCA germinal mutation), the pathophysiology of HGSOC and the existence of particular risk factors is still a puzzle. Moreover, a lack of screening programs results in delayed diagnosis, which is accompanied by a secondary chemo-resistance of the tumor and usually results in a high recurrence rate after the primary therapy. Therefore, there is an urgent need to identify the substantial risk factors for both predisposed and low-risk populations of women, as well as to create an economically and clinically justified screening program. This paper reviews the classic and novel risk factors for HGSOC and methods of diagnosis and prediction, including serum biomarkers, the liquid biopsy of circulating tumor cells or circulating tumor DNA, epigenetic markers, exosomes, and genomic and proteomic biomarkers. The novel future complex approach to ovarian cancer diagnosis should be devised based on these findings, and the general outcome of such an approach is proposed and discussed in the paper.
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Affiliation(s)
- Jacek Wilczyński
- Department of Gynecological Surgery and Gynecological Oncology, Medical University of Lodz, 4 Kosciuszki Str., 90-419 Lodz, Poland
| | - Edyta Paradowska
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland;
| | - Miłosz Wilczyński
- Department of Surgical, Endoscopic and Gynecological Oncology, Polish Mother’s Health Center—Research Institute, 281/289 Rzgowska Str., 93-338 Lodz, Poland;
- Department of Surgical and Endoscopic Gynecology, Medical University of Lodz, 4 Kosciuszki Str., 90-419 Lodz, Poland
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24
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Kim HY, Park J, Moon SJ, Jeong S, Hong JH, Lee JK, Cho GJ, Cho HW. Short-term Impact of Hormone Replacement Therapy on Risk of Breast Cancer in BRCA Mutation Carriers: A Nationwide Study in South Korea. Cancer Res Treat 2024; 56:143-148. [PMID: 37591780 PMCID: PMC10789953 DOI: 10.4143/crt.2023.653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/30/2023] [Indexed: 08/19/2023] Open
Abstract
PURPOSE BRCA1/2 mutations are well-known risk factors for breast and ovarian cancers in women. Risk-reducing salpingo-oophorectomy (RRSO) is the standard treatment for preventing ovarian cancer with BRCA mutations. Postmenopausal syndrome (symptoms after RRSO can be alleviated by hormone replacement therapy (HRT); however, the use of HRT in carriers of BRCA mutations has been controversial because of the concern that HRT increases the risk of breast cancer. This study aimed to evaluate the effects of HRT in BRCA mutation carriers who underwent RRSO. MATERIALS AND METHODS A total of 151 carriers, who underwent RRSO between 2013 and 2020 after the diagnosis of BRCA1 or BRCA2 mutations were selected and followed up for a median of 3.03 years. Patients were divided into two groups: those who received HRT after RRSO (n=33) and those who did not (n=118). We compared the incidence of breast cancer over time between these two groups. RESULTS There was no significant difference in the incidence of breast cancer between women who received HRT and those who did not (p=0.229). Multivariate logistic regression analysis, adjusted for age and parity revealed no significant difference in the risk of breast cancer between these two groups (hazard ratio, 0.312; 95% confidence interval, 0.039 to 2.480; p=0.278). CONCLUSION In this study, we found no relationship between post-RRSO HRT and breast cancer in the population with BRCA mutations. Therefore, healthcare providers may consider the alleviation of symptoms of postmenopausal syndrome through HRT in patients who underwent RRSO.
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Affiliation(s)
- Hye Yeon Kim
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jisoo Park
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Seok Joo Moon
- Smart Healthcare Center, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Sohyeon Jeong
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jin Hwa Hong
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jae Kwan Lee
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Geum Joon Cho
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
- Smart Healthcare Center, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Hyun-Woong Cho
- Department of Obstetrics and Gynecology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
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25
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Veney D, Wei L, Toland AE, Presley CJ, Hampel H, Padamsee TJ, Lee CN, Irvin WJ, Bishop M, Kim J, Hovick SR, Senter L, Stover DG. A Video Intervention to Improve Patient Understanding of Tumor Genomic Testing in Patients with Cancer. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.12.05.23299443. [PMID: 38106014 PMCID: PMC10723483 DOI: 10.1101/2023.12.05.23299443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Background Tumor genomic testing (TGT) has become standard-of-care for most patients with advanced/metastatic cancer. Despite established guidelines, patient education prior to TGT is variable or frequently omitted. The purpose of this study was to evaluate the impact of a concise (3-4 minute) video for patient education prior to TGT. Methods Based on a quality improvement cycle, an animated video was created to be applicable to any cancer type, incorporating culturally diverse images, available in English and Spanish. Patients undergoing standard-of care TGT were enrolled at a tertiary academic institution and completed validated survey instruments immediately prior to video viewing (T1) and immediately post-viewing (T2). Instruments included: 1) 10-question objective genomic knowledge/understanding; 2) 10-question video message-specific knowledge/recall; 3) 11-question Trust in Physician/Provider; 4) attitudes regarding TGT. The primary objective was change in outcomes from before to after the video was assessed with Wilcoxon signed rank test. Results From April 2022 to May 2023, a total of 150 participants were enrolled (MBC n=53, LC n=38, OC n=59). For the primary endpoint, there was a significant increase in video message-specific knowledge (median 10 point increase; p<0.0001) with no significant change in genomic knowledge/understanding (p=0.89) or Trust in Physician/Provider (p=0.59). Results for five questions significantly improved, including the likelihood of TGT impact on treatment decision, incidental germline findings, and cost of testing. Improvement in video message-specific knowledge was consistent across demographic groups, including age, income, and education. Individuals with less educational attainment had had greater improvement from before to after video viewing. Conclusions A concise, 3-4 minute, broadly applicable video incorporating culturally diverse images administered prior to TGT significantly improved video message-specific knowledge across all demographic groups. This resource is publicly available at http://www.tumor-testing.com, with a goal to efficiently educate and empower patients regarding TGT while addressing guidelines within the flow of clinical practice. Clinical Trial Registration ClinicalTrials.gov NCT05215769.
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Affiliation(s)
- Deloris Veney
- Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210 USA
| | - Lai Wei
- Department of Biomedical Informatics, Ohio State University, Columbus, OH, 43210 USA
| | - Amanda E. Toland
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210 USA
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210 USA
| | - Carolyn J. Presley
- Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210 USA
| | - Heather Hampel
- Division of Clinical Cancer Genomics, Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010
| | - Tasleem J. Padamsee
- Division of Health Services Management and Policy, College of Public Health, The Ohio State University, Columbus, OH, 43210, USA
| | - Clara N. Lee
- Division of Health Services Management and Policy, College of Public Health, The Ohio State University, Columbus, OH, 43210, USA
| | - William J. Irvin
- Bon Secours Cancer Institute at St. Francis, Richmond, Virginia, USA
| | | | - James Kim
- Bon Secours-Mercy Health St. Elizabeth, Youngstown, Ohio, USA
| | - Shelly R. Hovick
- School of Communication, Ohio State University, Columbus, OH, 43210 USA
| | - Leigha Senter
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210 USA
| | - Daniel G. Stover
- Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210 USA
- Department of Biomedical Informatics, Ohio State University, Columbus, OH, 43210 USA
- Pelotonia Institute for Immuno-Oncology, Ohio State University Comprehensive Cancer, Columbus, OH, 43210 USA
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26
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Joshi S, Murali-Nanavati S, Shylasree TS, Hawaldar R, Tripathi S, Sahay A, Noronha J, Jain U, Thomas A, Kowtal P, Vanmali V, Nair NS, Parmar V, Badwe RA, Sarin R. Synchronous and Metachronous Breast and Ovarian Cancers: Experience from a Single Tertiary Care Cancer Centre in India. Indian J Surg Oncol 2023; 14:809-821. [PMID: 38187845 PMCID: PMC10767083 DOI: 10.1007/s13193-023-01749-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 04/12/2023] [Indexed: 01/09/2024] Open
Abstract
Women with either breast cancer (BC) or ovarian cancer (OC) have a 1.5-2 times higher risk of developing the other. Discerning discrete primaries versus metastases from either can be challenging. Clinico-pathological and outcome details of patients diagnosed with both BC and OC from December 1994 to August 2018 were retrospectively evaluated at a single tertiary cancer centre. We report the pattern of presentation and recurrences with case-based illustrations. Out of 139 patients, presentation was BC-first in 66.2%, OC-first in 24.5% and synchronous cancers (SC) in 9.3% of women. The median age at diagnosis in BC-first, OC-first and SC was 42 years, 48 years and 49 years, respectively. The most common histological subtype was invasive breast carcinoma-no special type (74.8%) in BC and serous cystadenocarcinoma (81.3%) in OC. BC presented at an early stage in 67.6% while OC presented at an advanced stage in 48.2% of patients. Germline mutation results were available in 82% with 61.4% of the cohort exhibiting a mutation- BRCA1 mutation being the most common. The median time to development of second cancer was 77.4 months and 39.4 months in BC-first and OC-first, respectively. At a median follow-up of 9.47 years, disease-free survival was 32.6%, 32.4% and 30.8% in BC-first, OC-first and SC, respectively (p < 0.001). In hereditary breast and ovarian cancer, BC-first patients have a better prognosis while synchronous malignancies have worse oncological outcomes. Deaths are mainly due to OC progression. Appropriate surveillance and prophylactic intervention in young patients with breast cancer may improve overall outcomes.
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Affiliation(s)
- Shalaka Joshi
- Department of Surgical Oncology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
| | - Sridevi Murali-Nanavati
- Department of Surgical Oncology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
- Department of Breast Surgical Oncology, Nanavati Max Super Speciality Hospital, Mumbai, India 400056
| | - T. S. Shylasree
- Department of Surgical Oncology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
| | - Rohini Hawaldar
- Clinical Research Secretariat, Tata Memorial Centre, Dr E Borges Road, Parel, Mumbai India 40012
| | - Sagar Tripathi
- Department of Pathology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
| | - Ayushi Sahay
- Department of Pathology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
| | - Jarin Noronha
- Department of Surgical Oncology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
| | - Urvashi Jain
- Department of Surgical Oncology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
- Guy’s and St Thomas’ NHS Foundation Trust, London, UK
| | - Anand Thomas
- Department of Surgical Oncology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
| | - Pradnya Kowtal
- Clinical Cancer Genetics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), and Homi Bhabha National Institute, Navi Mumbai, India
| | - Vaibhav Vanmali
- Clinical Research Secretariat, Tata Memorial Centre, Dr E Borges Road, Parel, Mumbai India 40012
| | - Nita S. Nair
- Department of Surgical Oncology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
| | - Vani Parmar
- Breast Surgery, Department of Surgical Oncology, Tata Memorial Centre and Homi Bhabha National Institute, Parel, Mumbai India
| | - Rajendra A. Badwe
- Department of Surgical Oncology, Tata Memorial Centre and Homi Bhabha National Institute, Dr E Borges Road, Parel, Mumbai India 40012
| | - Rajiv Sarin
- Clinical Cancer Genetics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), and Homi Bhabha National Institute, Navi Mumbai, India
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27
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Guyonnet E, Kim SJ, Xia YY, Giannakeas V, Lubinski J, Randall Armel S, Eisen A, Bordeleau L, Eng C, Olopade OI, Tung N, Foulkes WD, Couch FJ, Aeilts AM, Narod SA, Kotsopoulos J. Physical Activity During Adolescence and Early-adulthood and Ovarian Cancer Among Women with a BRCA1 or BRCA2 Mutation. CANCER RESEARCH COMMUNICATIONS 2023; 3:2420-2429. [PMID: 38019076 PMCID: PMC10683556 DOI: 10.1158/2767-9764.crc-23-0223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/15/2023] [Accepted: 11/14/2023] [Indexed: 11/30/2023]
Abstract
In the general population, physical activity has been associated with a lower risk of several cancers; however, the evidence for ovarian cancer is not clear. It is suggested that early-life physical activity may differentially impact risk. Whether this is true among women at high risk due to a pathogenic variant (mutation) in the BRCA1 or BRCA2 genes has not been evaluated. Thus, we performed a matched case-control study to evaluate the association between adolescent and early-adulthood physical activity and ovarian cancer. BRCA mutation carriers who completed a research questionnaire on various exposures and incident disease and with data available on physical activity were eligible for inclusion. Self-reported activity at ages 12-13, 14-17, 18-22, 23-29, and 30-34 was used to calculate the average metabolic equivalent of task (MET)-hours/week for moderate, vigorous, and total physical activity during adolescence (ages 12-17) and early-adulthood (ages 18-34). Conditional logistic regression was used to estimate the OR and 95% confidence intervals (CI) of invasive ovarian cancer associated with physical activity. This study included 215 matched pairs (mean age = 57.3). There was no association between total physical activity during adolescence (ORhigh vs. low = 0.91; 95% CI: 0.61-1.36; Ptrend = 0.85), early-adulthood (ORhigh vs. low = 0.78; 95% CI: 0.51-1.20; Ptrend = 0.38) and overall (ORhigh vs. low = 0.81; 95% CI: 0.54-1.23; Ptrend = 0.56) and ovarian cancer. Findings were similar for moderate (Ptrend ≥ 0.25) and vigorous (Ptrend ≥ 0.57) activity. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, physical activity should continue to be encouraged to promote overall health. SIGNIFICANCE In this matched case-control study, we observed no association between physical activity during adolescence or early-adulthood and subsequent risk of ovarian cancer. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, being active remains important to promote overall health and well-being.
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Affiliation(s)
- Emma Guyonnet
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Shana J. Kim
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Yue Yin Xia
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Vasily Giannakeas
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- ICES, Toronto, Ontario, Canada
| | - Jan Lubinski
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Susan Randall Armel
- Bhalwani Familial Cancer Clinic, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- Department of Medical Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Andrea Eisen
- Toronto-Sunnybrook Regional Cancer Center, Toronto, Canada
| | - Louise Bordeleau
- Department of Oncology, Juravinski Cancer Centre, Hamilton, Canada
| | - Charis Eng
- Genomic Medicine Institute, Center for Personalised Genetic Healthcare, Cleveland Clinic, Cleveland, Ohio
| | | | - Nadine Tung
- Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - William D. Foulkes
- Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montréal, Quebec, Canada
| | - Fergus J. Couch
- Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Amber M. Aeilts
- Division of Human Genetics, Ohio State University Medical Center, Comprehensive Cancer Center, Columbus, Ohio
| | - Steven A. Narod
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Joanne Kotsopoulos
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
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28
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Bu R, Siraj AK, Al-Rasheed M, Iqbal K, Azam S, Qadri Z, Haqawi W, Tulbah A, Al-Dayel F, Almalik O, Al-Kuraya KS. Identification and characterization of ATM founder mutation in BRCA-negative breast cancer patients of Arab ethnicity. Sci Rep 2023; 13:20924. [PMID: 38017116 PMCID: PMC10684510 DOI: 10.1038/s41598-023-48231-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/23/2023] [Indexed: 11/30/2023] Open
Abstract
Breast cancer (BC) is the most prevalent malignancy among women worldwide with germline pathogenic variants/likely pathogenic variants (PVs/LPVs) in BRCA1/2 accounting for a large portion of hereditary cases. Recently, heterozygous PVs/LPVs in the ATM serine/threonine kinase or Ataxia-telangiectasia mutated gene (ATM) has been identified as a moderate susceptibility factor for BC in diverse ethnicities. However, the prevalence of ATM PVs/LPVs in BC susceptibility in Arab populations remains largely unexplored. This study investigated the prevalence of ATM PVs/LPVs among BC patients from Saudi Arabia, employing capture-sequencing technology for ATM PVs/LPVs screening in a cohort of 715 unselected BC patients without BRCA1/2 PVs/LPVs. In addition, founder mutation analysis was conducted using the PHASE program. In our entire cohort, four unique PVs/LPVs in the ATM gene were identified in six cases (0.8%). Notably, one recurrent LPV, c.6115G > A:p.Glu2039Lys was identified in three cases, for which haplotype analysis confirmed as a novel putative founder mutation traced back to 13 generations on average. This founder mutation accounted for half of all identified mutant cases and 0.4% of total screened cases. This study further reveals a significant correlation between the presence of ATM mutation and family history of BC (p = 0.0127). These findings underscore an approximate 0.8% prevalence of ATM germline PVs/LPVs in Arab BC patients without BRCA1/2 PVs/LPVs and suggest a founder effect of specific recurrent ATM mutation. These insights can help in the design of a genetic testing strategy tailored to the local population in Saudi Arabia, thereby, enabling more accurate clinical management and risk prediction.
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Affiliation(s)
- Rong Bu
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Abdul K Siraj
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Maha Al-Rasheed
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Kaleem Iqbal
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Saud Azam
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Zeeshan Qadri
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Wael Haqawi
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Asma Tulbah
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Fouad Al-Dayel
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Osama Almalik
- Department of Surgery, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia
| | - Khawla S Al-Kuraya
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Saudi Arabia.
- Research Centre at KFNCCC, Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, MBC#98-16, P.O. Box 3354, 11211, Riyadh, Saudi Arabia.
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29
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Martorana D, Barili V, Uliana V, Ambrosini E, Riva M, De Sensi E, Luppi E, Messina C, Caleffi E, Pisani F, Percesepe A. Reassessment of the NF1 variants of unknown significance found during the 20-year activity of a genetics diagnostic laboratory. Eur J Med Genet 2023; 66:104847. [PMID: 37751797 DOI: 10.1016/j.ejmg.2023.104847] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 07/05/2023] [Accepted: 09/17/2023] [Indexed: 09/28/2023]
Abstract
The finding of variants of uncertain significance (VUS) in the activity of a diagnostic genetic laboratory is a common issue, which is however provisional and needs to be periodically re-evaluated, due to the continuous advancements in our knowledge of the genetic diseases. Neurofibromatosis type 1, caused by the occurrence of heterozygous pathogenic NF1 variants, is a good model for studying the evolution of VUS, due to the widespread use of genetic testing for the disease, the constant enrichment of the international databases with NF1 variants and the full adult penetrance of the disease, which makes genotyping the parents a crucial step in the diagnostic workflow. The present study retrospectively reviewed and reinterpreted the genetic test results of NF1 in a diagnostic genetic laboratory in the period from January 1, 2000 to December 31, 2020. All the VUS were reinterpreted using the 2015 consensus standards and guidelines for the interpretation. Out of 589 NF1 genetic tests which were performed in the period, a total of 85 VUS were found and reinterpreted in 72 cases (84.7%): 21 (29.2%) were reclassified as benign/likely benign, whereas 51 (70.8%) were recoded as pathogenic/likely pathogenic with a significant trend distribution (Chi square test for trend p = 0.005). Synonymous VUS have mainly been reclassified as class 1 and 2 (7/8, 87.5%), whereas missense variants have been attributed to class 4 and 5 in 38 out of the 58 cases (65.5%). These findings underline an improvement in the classification of variants over time, suggesting that a reinterpretation of the genetic tests should be routinely performed to support the physicians in the clinical diagnosis of genetic diseases.
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Affiliation(s)
- Davide Martorana
- Medical Genetics, University Hospital of Parma, 43126, Parma, Italy; CoreLAB Research Center, University Hospital of Parma, 43126, Italy
| | - Valeria Barili
- Medical Genetics, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Vera Uliana
- Medical Genetics, University Hospital of Parma, 43126, Parma, Italy
| | - Enrico Ambrosini
- Medical Genetics, University Hospital of Parma, 43126, Parma, Italy
| | - Matteo Riva
- Medical Genetics, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Erika De Sensi
- Medical Genetics, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Elena Luppi
- Medical Genetics, University of Bologna, Italy
| | - Corinne Messina
- Medical Genetics, University Hospital of Parma, 43126, Parma, Italy
| | - Edoardo Caleffi
- Plastic Surgery, University Hospital of Parma, 43126, Parma, Italy
| | - Francesco Pisani
- Children's Neuropsychological Services, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Antonio Percesepe
- Medical Genetics, University Hospital of Parma, 43126, Parma, Italy; Medical Genetics, Department of Medicine and Surgery, University of Parma, Parma, Italy.
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30
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Sellers TA, Peres LC, Hathaway CA, Tworoger SS. Prevention of Epithelial Ovarian Cancer. Cold Spring Harb Perspect Med 2023; 13:a038216. [PMID: 37137500 PMCID: PMC10411689 DOI: 10.1101/cshperspect.a038216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Given the challenges with achieving effective and durable treatment for epithelial ovarian cancer, primary prevention is highly desirable. Fortunately, decades of research have provided evidence for several strategies that can be deployed to optimize risk reduction. These include surgery, chemoprevention, and lifestyle factor modifications. These broad categories vary in terms of the magnitude of risk reduction possible, the possible short-term and long-term side effects, the degree of difficulty, and acceptability. Thus, the concept of a risk-based model to personalize preventive interventions is advocated to guide discussion between care providers and women at risk. For women with inherited major gene mutations that greatly increase risk of ovarian cancer, surgical approaches have favorable risk to benefit ratios. Chemoprevention and lifestyle factor modifications portend a lower degree of risk reduction but confer lower risk of undesirable side effects. Since complete prevention is not currently possible, better methods for early detection remain a high priority.
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Affiliation(s)
- Thomas A Sellers
- Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, USA
| | - Lauren C Peres
- Department of Cancer Epidemiology, Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Cassandra A Hathaway
- Department of Cancer Epidemiology, Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
| | - Shelley S Tworoger
- Department of Cancer Epidemiology, Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA
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31
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DiSilvestro JB, Haddad J, Robison K, Beffa L, Laprise J, Scalia-Wilbur J, Raker C, Clark M, Lokich E, Hofstatter E, Dalela D, Brown A, Bradford L, Toland M, Stuckey A. Barriers to hormone therapy following prophylactic bilateral salpingo-oophorectomy in BRCA1/2 mutation carriers. Menopause 2023; 30:732-737. [PMID: 37192837 DOI: 10.1097/gme.0000000000002201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
OBJECTIVE This study aimed to identify barriers to hormone therapy (HT) use among women with BRCA1/2 mutations after prophylactic bilateral salpingo-oophorectomy (BSO). METHODS A cross-sectional, electronic survey was conducted of BRCA1/2 mutation carriers at Women and Infants Hospital, Yale Medical Center, Hartford Healthcare, and Maine Medical Center. This study was a subanalysis of a subset of female BRCA1/2 mutation carriers who had undergone a prophylactic BSO. Data were analyzed using the Fisher's exact test or t test. RESULTS We performed a subanalysis of 60 BRCA mutation carriers who underwent a prophylactic BSO. Only 24 women (40%) reported ever using HT. HT use was higher in women who underwent their prophylactic BSO at age younger than 45 years (51% vs. 25%, P = 0.06). Among all women who had a prophylactic BSO, the majority (73%) reported that a provider talked to them about using HT. Two thirds reported having seen contradictory information in the media about long-term consequences of HT. Seventy percent listed their provider as the primary influence in their decision to start HT. The most common reasons for not starting HT included it not being recommended by their physician (46%) and that it was not necessary (37%). CONCLUSIONS BRCA mutation carriers frequently undergo prophylactic BSO at young ages, and less than half report using HT. This study highlights barriers to HT use, such as patient fears and physician discouragement, and identifies potential areas to improve educational efforts.
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Affiliation(s)
- Jessica B DiSilvestro
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
| | - Jessica Haddad
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
| | - Katina Robison
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
| | - Lindsey Beffa
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
| | - Jessica Laprise
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
| | - Jennifer Scalia-Wilbur
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
| | - Christina Raker
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
| | - Melissa Clark
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
| | - Elizabeth Lokich
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
| | - Erin Hofstatter
- Cancer Genetics and Prevention Program, Yale Cancer Center, Yale School of Medicine, New Haven, CT
| | - Disha Dalela
- Cancer Genetics and Prevention Program, Yale Cancer Center, Yale School of Medicine, New Haven, CT
| | - Amy Brown
- Department of Medical Oncology, Hartford Healthcare Cancer Institute, Hartford, CT
| | - Leslie Bradford
- Division of Gynecologic Oncology, Maine Medical Partners, Scarborough, ME
| | - Maris Toland
- Division of Gynecologic Oncology, Maine Medical Partners, Scarborough, ME
| | - Ashley Stuckey
- From the Department of Obstetrics-Gynecology, Program in Women's Oncology, Brown University/Women and Infants Hospital, Providence, RI
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32
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Imterat M, Harter P, Rhiem K, Heitz F, Schneider S, Concin N, Moubarak M, Welz J, Vrentas V, Traut A, Hahnen E, Schmutzler R, du Bois A, Ataseven B. Incidence and Prognostic Impact of Deleterious Germline Mutations in Primary Advanced Ovarian Carcinoma Patients. Cancers (Basel) 2023; 15:2534. [PMID: 37174000 PMCID: PMC10177155 DOI: 10.3390/cancers15092534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Data on deleterious variants in genes other than BRCA1/2 remain limited. A retrospective cohort study was performed, including primary OC cases with TruRisk® germline gene panel testing between 2011 and 2020. Patients with testing after relapse were excluded. The cohort was divided into three groups: (A) no mutations, (B) deleterious BRCA1/2 mutations, and (C) deleterious mutations in other genes. A total of 702 patients met the inclusion criteria. Of these 17.4% (n = 122) showed BRCA1/2 mutations and a further 6.0% (n = 42) in other genes. Three-year overall survival (OS) of the entire cohort was significantly longer in patients with germline mutations (85%/82.8% for cohort B/C vs. 70.2% for cohort A, p < 0.001) and 3-year progression-free survival (PFS) only for cohort B (58.1% vs. 36.9%/41.6% in cohort A/C, p = 0.002). In multivariate analysis for the subgroup of advanced-stages of high-grade serous OC, both cohorts B/C were found to be independent factors for significantly better outcome, cohort C for OS (HR 0.46; 95% CI 0.25-0.84), and cohort B for both OS and PFS (HR 0.40; 95% CI 0.27-0.61 and HR 0.49; 95% CI 0.37-0.66, respectively). Germline mutations were detected in a quarter of OC patients, and a quarter of those in genes other than BRCA1/2. Germline mutations demonstrate in our cohort a prognostic factor and predict better prognosis for OC patients.
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Affiliation(s)
- Majdi Imterat
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
- Department of Gynaecologic Oncology, Hadassah Medical Centers, Faculty of Medicine, Hebrew University of Jerusalem, Kalman Ya’Akov Man St., Jerusalem 91905, Israel
| | - Philipp Harter
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
| | - Kerstin Rhiem
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, 50931 Cologne, Germany; (K.R.); (E.H.); (R.S.)
| | - Florian Heitz
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
- Department for Gynecology with the Center for Oncologic Surgery Charité Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Stephanie Schneider
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
| | - Nicole Concin
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
| | - Malak Moubarak
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
| | - Julia Welz
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
| | - Vasileios Vrentas
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
| | - Alexander Traut
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
| | - Eric Hahnen
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, 50931 Cologne, Germany; (K.R.); (E.H.); (R.S.)
| | - Rita Schmutzler
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, 50931 Cologne, Germany; (K.R.); (E.H.); (R.S.)
| | - Andreas du Bois
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
| | - Beyhan Ataseven
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen Mitte (KEM), 45136 Essen, Germany; (P.H.); (F.H.); (S.S.); (N.C.); (M.M.); (J.W.); (V.V.); (A.T.); (A.d.B.); (B.A.)
- Academic Department of Gynecology, Gynecologic Oncology and Obstetrics, Klinikum Lippe, Medical School, University Medical Center East Westphalia-Lippe, Bielefeld University, 33615 Bielefeld, Germany
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He D, Li H, Li Y, Xu Z, Wang C, Tang Y, Wu F, Zhen X, Wang S. Tumor-targeting semiconducting polymer nanoparticles: efficient adjuvant photothermal therapy using ultra-low laser power inhibits recurrences after breast-conserving surgery. NANOSCALE 2023; 15:6252-6262. [PMID: 36908261 DOI: 10.1039/d2nr06692k] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
The need for adjuvant therapy to inhibit local recurrence after breast-conserving surgery with minimal side effects is great. Adjuvant photothermal therapy (aPTT) has the potential to replace radiotherapy and eliminates its inherent damage to healthy tissues. Herein, we functionalized semiconducting polymer nanoparticles (SPNs) with cRGD-peptide and silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) (NIR775) to target breast cancer and perform aPTT under an ultra-low laser power (0.2 W cm-2) after breast-conserving surgery (BCS). The synthesized RGD-SPNNIR775 showed an excellent photothermal conversion efficiency and biocompatibility and was demonstrated to accumulate in tumors specifically. The BCS could be performed with confidence under the guidance of preoperative and postoperative fluorescence imaging. Notably, the aPTT completely inhibited the local recurrence after the BCS without compromising the cosmetic effect of the BCS. These results indicate the prospect of RGD-SPNNIR775 as a theranostic nanoplatform for efficient aPTT using an ultra-low laser power to control recurrence after BCS.
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Affiliation(s)
- Doudou He
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Haoze Li
- MOE Key Laboratory of High Performance Polymer Materials and Technology and Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China.
| | - Yang Li
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Ziqing Xu
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Chuanbin Wang
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Yuxia Tang
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Feiyun Wu
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Xu Zhen
- MOE Key Laboratory of High Performance Polymer Materials and Technology and Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China.
| | - Shouju Wang
- Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Acevedo F, Walbaum B, Camus M, Manzor M, Muñiz S, Medina L, Petric M, Reyes P, Domínguez F, Puschel K, Merino T, Bravo ML, Pinto MP, Ibáñez C, Hughes K, Sánchez C. Access disparities and underutilization of germline genetic testing in Chilean breast cancer patients. Breast Cancer Res Treat 2023; 199:363-370. [PMID: 36988750 DOI: 10.1007/s10549-023-06909-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/04/2023] [Indexed: 03/30/2023]
Abstract
PURPOSE Latin American reports on genetic cancer risk assessments are scarce. In Chile, current breast cancer (BC) guidelines do not define strategies for germline genetic testing. Our study sought to quantify the disparities in access to genetic testing in Chilean BC patients, according to international standards and their clinical characteristics to explore improvement strategies. METHODS Retrospective analysis of invasive BC databases including patients treated in a Public Hospital (PH) and in an Academic Private Center (AC) in Santiago, Chile between 2012 and 2021. RESULTS Of 5438 BC patients, 3955 had enough data for National Comprehensive Cancer Network (NCCN) categorization. From these, 1911 (48.3%) fulfilled NCCN criteria for germline testing, of whom, 300 were tested for germline mutations and 268 with multigene panels. A total of 65 pathogenic variants were found in this subset. As expected, BRCA1/2 mutations were the most frequent (17.7%). Access to genetic testing was higher in AC versus PH (19.6% vs. 10.3%, p = 0.0001). Other variables associated with germline genetic testing were BC diagnosis after 2018, being 45 years old or younger at diagnosis, BC family history (FH), FH of ovarian cancer, non-metastatic disease, and triple-negative subtype. CONCLUSION In our cohort, 15% of BC patients who met NCCN criteria for germline testing were effectively tested. This percentage was even lower at the PH. Current recommendations encourage universal genetic testing for BC patients; however, our findings suggest that Chile is far from reaching such a goal and national guidelines in this regard are urgently needed. To our knowledge, this is the first study of its kind in Chile and Latin America.
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Affiliation(s)
- Francisco Acevedo
- Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 8330077, Santiago, Chile
- Fundación Chile Sin Cáncer, Santiago, Chile
| | - Benjamín Walbaum
- Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 8330077, Santiago, Chile
- Fundación Chile Sin Cáncer, Santiago, Chile
| | - Mauricio Camus
- Departamento de Cirugía Oncológica, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Manuel Manzor
- Cirugía Oncológica, Hospital Dr. Sótero del Río, Santiago, Chile
| | - Sabrina Muñiz
- Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 8330077, Santiago, Chile
| | - Lidia Medina
- Centro de Cáncer, Red de Salud UC Christus, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Militza Petric
- Cirugía Oncológica, Hospital Gustavo Fricke, Valparaíso, Chile
| | - Paula Reyes
- Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 8330077, Santiago, Chile
| | - Francisco Domínguez
- Departamento de Cirugía Oncológica, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Klaus Puschel
- Departamento de Medicina Familiar, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Tomas Merino
- Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 8330077, Santiago, Chile
| | - M Loreto Bravo
- Support Team for Oncological Research and Medicine (STORM), Providencia, Santiago, Chile
| | - Mauricio P Pinto
- Support Team for Oncological Research and Medicine (STORM), Providencia, Santiago, Chile
| | - Carolina Ibáñez
- Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 8330077, Santiago, Chile
| | - Kevin Hughes
- Division of Oncologic & Endocrine Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - César Sánchez
- Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, 8330077, Santiago, Chile.
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Oh M, McBride A, Bhattacharjee S, Slack M, Jeter J, Abraham I. Economic value of knowing BRCA status: BRCA testing for prostate cancer prevention and optimal treatment. Expert Rev Pharmacoecon Outcomes Res 2023; 23:297-307. [PMID: 36649640 DOI: 10.1080/14737167.2023.2169137] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND We aimed to estimate the incremental lifetime effects, costs, and net-monetary-benefit (NMB) of knowing BRCA information by testing of patients with low-risk localized prostate cancer (PCa) in the US and guiding subsequent screening and treatment, and the cumulative savings or losses of yearly cohort testing over 16 years. We compared two strategies: (1)'with BRCA information' and (2)'without BRCA information.' We also estimated the expected value of perfect information. METHODS The incremental NMB (INMB) quantified the monetized benefit per person of knowing BRCA status. The net-monetized-value of knowing BRCA information was estimated by multiplying the INMB with the eligible population. RESULTS The INMBs of knowing BRCA information were $43,357 (payer) and $43,487 (society). in payer and societal perspectives, respectively. Escalated to the eligible patients in 2020, knowing BRCA status resulted in net monetized lifetime value of $1.7 billion (payer and society) for the 2020 cohort; and yielded accumulated net-monetized-value of $28.0 billion (payer) and $28.1 billion (society) over 16 yearly cohorts of eligible PCa patients. CONCLUSIONS The economic value of knowing BRCA status for all low-risk localized PCa patients in the US provides short-term and long-term evidence for BRCA testing to screen early and optimize treatment.
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Affiliation(s)
- Mok Oh
- College of Pharmacy, University of Arizona, Tucson, AZ, USA
| | - Ali McBride
- Cancer Center - North Campus, The University of Arizona, Tucson, AZ, USA
| | | | - Marion Slack
- College of Pharmacy, University of Arizona, Tucson, AZ, USA.,Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, Tucson, AZ, USA
| | - Joanne Jeter
- Health Huntsman Cancer Institute, University of Utah
| | - Ivo Abraham
- Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, Tucson, AZ, USA
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Manley K, Ryan N, Jenner A, Newton C, Hillard T. Counselling of path_ BRCA carriers who are considering risk-reducing oophorectomy. Post Reprod Health 2023; 29:42-52. [PMID: 36757900 DOI: 10.1177/20533691231156640] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
path_BRCA 1/2 increases a woman's lifetime risk of breast and ovarian cancer. Interventions can be offered which manage cancer risk; annual breast screening from age 30, chemoprevention and, once a woman's family is complete, risk-reducing surgery. The latter is the most effective method of reducing cancer in path_BRCA carriers; salpingo-oophorectomy reduces breast and ovarian cancer, respectively, by up to 50% and 95%. Factors affecting a woman's decision to undergo risk-reducing surgery are complex; dominant factors include risks of surgery, effect on cancer outcomes and menopausal sequelae. Specific information relating to hormone replacement and non-hormonal alternatives are an important consideration for women but, are often overlooked. Informative counselling is required to enable satisfaction with the chosen intervention whilst improving survival outcomes. This review paper outlines the current data pertaining to these decision-making factors and provides a proforma to enable effective counselling.
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Affiliation(s)
- Kristyn Manley
- Department of Gynaecology, 1984University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
- The Academic Women's Health Unit, Translational Women's Health Sciences, 152004University of Bristol, Bristol, UK
| | - Neil Ryan
- The Academic Women's Health Unit, Translational Women's Health Sciences, 152004University of Bristol, Bristol, UK
- Department of Gynaecology Oncology, Royal Infirmary of Edinburgh, Edinburgh
| | - Abigail Jenner
- Department of Gynaecology, 1984University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
- Department of Oncology, 1556Royal United Hospitals Bath, Bath, UK
| | - Claire Newton
- Department of Gynaecology, 1984University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
- The Academic Women's Health Unit, Translational Women's Health Sciences, 152004University of Bristol, Bristol, UK
| | - Timothy Hillard
- Department of Gynaecology, 6655University Hospitals Dorset, Poole, UK
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Rivera Rivera JN, Conley CC, Castro-Figueroa EM, Moreno L, Dutil J, García JD, Ricker C, Quinn GP, Soliman H, Vadaparampil ST. Behavioral beliefs about genetic counseling among high-risk Latina breast cancer survivors in Florida and Puerto Rico. Cancer Med 2023; 12:4701-4706. [PMID: 35941731 PMCID: PMC9972095 DOI: 10.1002/cam4.5111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/13/2022] [Accepted: 07/19/2022] [Indexed: 11/12/2022] Open
Abstract
Compared with non-Hispanic White women, Latina women are less likely to receive genetic counseling (GC) and testing (GT) following BC diagnosis. This study used secondary data analysis to explore beliefs about GC among Latina BC survivors in and outside the US mainland. GC/GT-naïve, high-risk, Spanish-preferring Latina BC survivors (n = 52) in FL and PR completed the Behavioral Beliefs about GC scale. Participants reported high positive beliefs about GC (M = 4.19, SD = 0.92); the majority agreed that GC was beneficial to understand cancer risk (90%) and promote discussion (87%) in their family. Participants reported low-to-moderate scores for barriers (Ms = 1.53-3.40; SDs = 0.59-0.90). The most frequently endorsed barriers were desire for additional GC information (M = 3.44; SD = 0.90), and GC logistic concerns (M = 2.71; SD = 0.80). No statistically significant differences for barriers and benefits scales were identified by place of residence (all ps ≥ 0.12). These findings highlight the importance of delivering culturally sensitive GC information to high-risk Latina BC survivors.
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Affiliation(s)
| | - Claire C Conley
- Georgetown University, Washington, District of Columbia, USA
| | | | | | - Julie Dutil
- Ponce Health Sciences University, Ponce, Puerto Rico, USA
| | | | - Charité Ricker
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
| | - Gwendolyn P Quinn
- Grossman School of Medicine, Department of OB-GYN New York, New York University, New York, New York, USA
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Long-Term Non-Cancer Risks in People with BRCA Mutations following Risk-Reducing Bilateral Salpingo-Oophorectomy and the Role of Hormone Replacement Therapy: A Review. Cancers (Basel) 2023; 15:cancers15030711. [PMID: 36765666 PMCID: PMC9913268 DOI: 10.3390/cancers15030711] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/19/2023] [Accepted: 01/21/2023] [Indexed: 01/26/2023] Open
Abstract
Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is the gold standard preventative option for BRCA mutation carriers at high risk for ovarian and breast cancer. However, when performed at the recommended ages of 35-45 years, RRBSO induces immediate premature surgical menopause, along with the accompanying adverse psychosocial, cardiovascular, bone, and cognitive health consequences. While these health consequences have been thoroughly studied in the general population, little is known about the long-term health outcomes in the BRCA population. Hormone replacement therapy (HRT) until the average age of natural menopause can help mitigate these health risks, yet the initiation of HRT is a complex decision among BRCA carriers due to concern of increasing the already high risk of breast cancer in these people. This review summarizes the current research on long-term non-cancer risks in BRCA carriers following RRBSO-induced premature surgical menopause, and highlights the existing evidence in support of HRT use in this population.
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Lan T, Li Y, Wang Y, Wang ZC, Mu CY, Tao AB, Gong JL, Zhou Y, Xu H, Li SB, Gu B, Ma P, Luo L. Increased endogenous PKG I activity attenuates EGF-induced proliferation and migration of epithelial ovarian cancer via the MAPK/ERK pathway. Cell Death Dis 2023; 14:39. [PMID: 36653376 PMCID: PMC9849337 DOI: 10.1038/s41419-023-05580-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 01/06/2023] [Accepted: 01/10/2023] [Indexed: 01/20/2023]
Abstract
The type I cGMP-dependent protein kinase (PKG I) is recognized as a tumor suppressor, but its role in EGFR regulated epithelial ovarian cancer (EOC) progression remains unclear. We evaluated the in vivo and in vitro effects of activated PKG I in EGF-induced EOC cell proliferation, migration, and invasion. The expressions of EGFR and PKG I were elevated, but the activated PKG I was decreased in EOC tissues of patients and cells lines. The addition of 8-Br-cGMP, a specific PKG I activator, attenuated the EGF-induced EOC cell proliferation, migration, and invasion in vitro. Similarly, activated PKG I also attenuated EOC progression in vivo using an EOC xenograft nude mouse model. The activated PKG I interacted with EGFR, causing increased threonine (693) phosphorylation and decreased tyrosine (1068) phosphorylation of EGFR, which resulted in disrupted EGFR-SOS1-Grb2 combination. Subsequently, the cytoplasmic phosphorylation of downstream proteins (c-Raf, MEK1/2, and ERK1/2) were declined, impeding the phosphorylated ERK1/2's nucleus translocation, and this reduction of phosphorylated tyrosine (1068) EGFR and ERK1/2 were also abolished by Rp-8-Br-cGMPS. Our results suggest that the activation of PKG I attenuates EGF-induced EOC progression, and the 8-Br-cGMP-PKG I-EGFR/MEK/ERK axis might be a potential target for EOC therapy.
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Affiliation(s)
- Ting Lan
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
| | - Ying Li
- Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
| | - Yue Wang
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
| | - Zhong-Cheng Wang
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
| | - Chun-Yan Mu
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
| | - Ai-Bin Tao
- Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jian-Li Gong
- Perlmutter Cancer Center and Department of Surgery, NYU Langone Health, New York, NY, USA
| | - Yuan Zhou
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
| | - Hao Xu
- Department of Gynecology Huangshi Love & Health Hospital affiliated to Hubei Polytechnic University, Hubei City, Wuhan Province, China
| | - Shi-Bao Li
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
- Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
| | - Bing Gu
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
- Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
| | - Ping Ma
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
- Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
| | - Lan Luo
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
- School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
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Impact of the 2018 ACR Supplemental Screening Recommendations on MRI Eligibility in Breast Cancer Survivors. J Am Coll Radiol 2023; 20:71-78. [PMID: 36516954 DOI: 10.1016/j.jacr.2022.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 11/03/2022] [Accepted: 11/16/2022] [Indexed: 12/14/2022]
Abstract
PURPOSE The 2018 ACR recommendations for breast cancer screening in women at higher than average risk include new recommendations for supplemental breast MRI for patients with personal histories of breast cancer (PHBCs) who carry hereditary cancer gene mutations, have dense breast tissue, or were diagnosed before 50 years of age. In comparison, prior guidelines recommended supplemental MRI only for women with PHBCs who carried hereditary cancer gene mutations. The aim of this study was to quantify the increase in the number of patients with breast cancer for whom supplemental breast MRI would now be recommended. METHODS Data were extracted from the electronic health records of patients presenting for screening or diagnostic mammography at an urban academic medical center between July 20, 2020, and July 19, 2021. Data extracted included patient-reported PHBC, age at time of breast cancer diagnosis, and hereditary cancer gene mutation carrier status. Descriptive statistics are reported, evaluating the rate of eligibility for supplemental breast MRI in a retrospective population given the new ACR guidelines. RESULTS Of the 2,950 patients with self-reported PHBCs who presented for breast cancer screening in the year between July 2020 and July 2021, 1,805 (61%) met the criteria for supplemental breast MRI according to the 2018 guidelines compared with only 3.6% using pre-2018 guidelines. CONCLUSIONS Measuring the impact of the 2018 ACR supplemental MRI recommendations using real-world data at a single urban academic medical center demonstrated a 15-fold increase in potential eligibility for supplemental breast MRI in patients with PHBCs.
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Senter L, Veney D, Surplus T, Haynam M, Adams EJ, Hampel H, Toland AE, Presley CJ, Padamsee TJ, Lee CN, Hovick SR, Stover DG. Patient Understanding of Tumor Genomic Testing: A Quality Improvement Effort. JCO Oncol Pract 2023; 19:e8-e14. [PMID: 36130146 PMCID: PMC10166357 DOI: 10.1200/op.22.00316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/29/2022] [Accepted: 08/16/2022] [Indexed: 01/14/2023] Open
Abstract
PURPOSE Tumor genomic testing (TGT) has become increasingly adopted as part of standard cancer care for many cancers. Despite national guidelines around patient education before TGT, available evidence suggests that most patients' understanding of genomics remains limited, particularly lower-income and minority patients, and most patients are not informed regarding potential incidental germline findings. METHODS To investigate and address limitations in patient understanding of TGT results, a Plan-Do-Study-Act (PDSA) approach is being used to assess needs, identify opportunities for improvement, and implement approaches to optimize patient education. We reviewed published guidelines related to pre-TGT provider-patient education and to identify key points (Plan). A provider quality improvement survey was completed (Do), which highlighted inconsistency in pre-TGT discussion practice across providers and minimal discussion with patients regarding the possibility of incidental germline findings. RESULTS Patient focus groups and interviews (N = 12 patients) were completed with coding of each transcript (Study), which revealed themes including trouble differentiating TGT from other forms of testing, yet understanding that results could tailor therapy. The integration of data across this initial PDSA cycle identified consistent themes and opportunities, which were incorporated into a patient-directed, concise animated video for pre-TGT education (Act), which will form the foundation of a subsequent PDSA cycle. The video addresses how TGT may/may not inform treatment, the process for TGT using existing tissue or liquid biopsy, insurance coverage, and the potential need for germline genetics follow-up because of incidental findings. CONCLUSION This PDSA cycle reveals key gaps and opportunities for improvement in patient education before TGT.
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Affiliation(s)
- Leigha Senter
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Deloris Veney
- Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Taylor Surplus
- School of Communication, Ohio State University, Columbus, OH
| | - Marcy Haynam
- Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Elizabeth J. Adams
- Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
- Division of Clinical Cancer Genomics, Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA
| | - Amanda E. Toland
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH
| | - Carolyn J. Presley
- Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Tasleem J. Padamsee
- Division of Health Services Management and Policy, College of Public Health, The Ohio State University, Columbus, OH
| | - Clara N. Lee
- Recruitment, Intervention and Survey Shared Resource, Ohio State University Comprehensive Cancer Center, Columbus, OH
| | | | - Daniel G. Stover
- Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH
- Department of Biomedical Informatics, Ohio State University, Columbus, OH
- Pelotonia Institute for Immuno-Oncology, Ohio State University Comprehensive Cancer, Columbus, OH
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Nassar A, Zekri ARN, Kamel MM, Elberry MH, Lotfy MM, Seadawy MG, Hassan ZK, Soliman HK, Lymona AM, Youssef ASED. Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study. Genes (Basel) 2022; 14:106. [PMID: 36672847 PMCID: PMC9858960 DOI: 10.3390/genes14010106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/23/2022] [Accepted: 12/08/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Precision oncology has been increasingly used in clinical practice and rapidly evolving in the oncology field. Thus, this study was performed to assess the frequency of germline mutations in early and late onset familial breast cancer (BC) Egyptian patients using multi-gene panel sequencing to better understand the contribution of the inherited germline mutations in BC predisposition. Moreover, to determine the actionable deleterious mutations associated with familial BC that might be used as biomarker for early cancer detection. METHODS Whole blood samples were collected from 101 Egyptian patients selected for BC family history, in addition to 50 age-matched healthy controls. A QIAseq targeted DNA panel (human BC panel) was used to assess the frequency of germline mutations. RESULTS A total of 58 patients (57.4%) out of 101 were found to have 27 deleterious germline mutations in 11 cancer susceptibility genes. Of them, 32 (31.6%) patients carried more than one pathogenic mutation and each one carried at least one pathogenic mutation. The major genes harboring the pathogenic mutations were: ATM, BRCA2, BRCA1, VHL, MSH6, APC, CHEK2, MSH2, MEN1, PALB2, and MUTYH. Thirty-one patients (30.6%) had BRCA2 mutations and twenty (19.8%) had BRCA1 mutations. Our results showed that exon 10 and exon 11 harbored 3 and 5 mutations, respectively, in BRCA1 and BRCA2 genes. Our analysis also revealed that the VHL gene significantly co-occurred with each of the BRCA2 gene (p = 0.003, event ratio 11/21), the MSH2 gene (p = 0.01, 4/10), the CHEK2 gene (p = 0.02, 4/11), and the MSH6 gene (p = 0.04, 4/12). In addition, the APC gene significantly co-occurred with the MSH2 gene (p = 0.01, 3/7). Furthermore, there was a significant mutually exclusive event between the APC gene and the ATM gene (p = 0.04, 1/36). Interestingly, we identified population specific germline mutations in genes showing potentials for targeted therapy to meet the need for incorporating precision oncology into clinical practice. For example, the mutations identified in the ATM, APC, and MSH2 genes. CONCLUSIONS Multi-gene panel sequencing was used to detect the deleterious mutations associated with familial BC, which in turns mitigate the essential need for implementing next generation sequencing technologies in precision oncology to identify cancer predisposing genes. Moreover, identifying DNA repair gene mutations, with focus on non-BRCA genes, might serve as candidates for targeted therapy and will be increasingly used in precision oncology.
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Affiliation(s)
- Auhood Nassar
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Abdel-Rahman N. Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Mahmoud M. Kamel
- Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
- Baheya Centre for Early Detection and Treatment of Breast Cancer, Giza 3546211, Egypt
| | - Mostafa H. Elberry
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Mai M. Lotfy
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Mohamed G. Seadawy
- Biological Prevention Department, Chemical Warfare, 4.5 km Suez-Cairo Rd, Almaza, Cairo 11351, Egypt
| | - Zeinab K. Hassan
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Hany K. Soliman
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Ahmed M. Lymona
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Amira Salah El-Din Youssef
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
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Cost-Effectiveness of Risk-Reducing Surgery for Breast and Ovarian Cancer Prevention: A Systematic Review. Cancers (Basel) 2022; 14:cancers14246117. [PMID: 36551605 PMCID: PMC9776851 DOI: 10.3390/cancers14246117] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/04/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
Policymakers require robust cost-effectiveness evidence of risk-reducing-surgery (RRS) for decision making on resource allocation for breast cancer (BC)/ovarian cancer (OC)/endometrial cancer (EC) prevention. We aimed to summarise published data on the cost-effectiveness of risk-reducing mastectomy (RRM)/risk-reducing salpingo-oophorectomy (RRSO)/risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) for BC/OC prevention in intermediate/high-risk populations; hysterectomy and bilateral salpingo-oophorectomy (BSO) in Lynch syndrome women; and opportunistic bilateral salpingectomy (OBS) for OC prevention in baseline-risk populations. Major databases were searched until December 2021 following a prospective protocol (PROSPERO-CRD42022338008). Data were qualitatively synthesised following a PICO framework. Twenty two studies were included, with a reporting quality varying from 53.6% to 82.1% of the items scored in the CHEERS checklist. The incremental cost-effectiveness ratio/incremental cost-utility ratio and cost thresholds were inflated and converted to US$2020, using the original currency consumer price index (CPI) and purchasing power parities (PPP), for comparison. Eight studies concluded that RRM and/or RRSO were cost-effective compared to surveillance/no surgery for BRCA1/2, while RRESDO was cost-effective compared to RRSO in one study. Three studies found that hysterectomy with BSO was cost-effective compared to surveillance in Lynch syndrome women. Two studies showed that RRSO was also cost-effective at ≥4%/≥5% lifetime OC risk for pre-/post-menopausal women, respectively. Seven studies demonstrated the cost-effectiveness of OBS at hysterectomy (n = 4), laparoscopic sterilisation (n = 4) or caesarean section (n = 2). This systematic review confirms that RRS is cost-effective, while the results are context-specific, given the diversity in the target populations, health systems and model assumptions, and sensitive to the disutility, age and uptake rates associated with RRS. Additionally, RRESDO/OBS were sensitive to the uncertainty concerning the effect sizes in terms of the OC-risk reduction and long-term health impact. Our findings are relevant for policymakers/service providers and the design of future research studies.
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Le Compte CG, Lu SE, Ani J, McDougall J, Walters ST, Toppmeyer D, Boyce TW, Stroup A, Paddock L, Grumet S, Lin Y, Heidt E, Kinney AY. Understanding cancer genetic risk assessment motivations in a remote tailored risk communication and navigation intervention randomized controlled trial. Health Psychol Behav Med 2022; 10:1190-1215. [PMID: 36518606 PMCID: PMC9744218 DOI: 10.1080/21642850.2022.2150623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/13/2022] [Indexed: 12/14/2022] Open
Abstract
Background National guidelines recommend cancer genetic risk assessment (CGRA) (i.e. genetic counseling prior to genetic testing) for women at increased risk for hereditary breast and ovarian cancer (HBOC). Less than one-half of eligible women obtain CGRA, leaving thousands of women and their family members without access to potentially life-saving cancer prevention interventions. Purpose The Genetic Risk Assessment for Cancer Education and Empowerment Project (GRACE) addressed this translational gap, testing the efficacy of a tailored counseling and navigation (TCN) intervention vs. a targeted print brochure vs. usual care on CGRA intentions. Selected behavioral variables were theorized to mediate CGRA intentions. Methods Breast and ovarian cancer survivors meeting criteria for guideline-based CGRA were recruited from three state cancer registries (N = 654), completed a baseline survey, and were randomized. TCN and targeted print arms received the brochure; TCN also participated in a tailored, telephone-based decision coaching and navigation session grounded in the Extended Parallel Process Model and Ottawa Decision Support Framework. Participants completed a one-month assessment. Logistic regression was used to compare the rate of CGRA intentions. CGRA intentions and theorized mediator scores (continuous level variables) were calculated using mixed model analysis. Results CGRA intentions increased for TCN (53.2%) vs. targeted print (26.7%) (OR = 3.129; 95% CI: 2.028, 4.827, p < .0001) and TCN vs. usual care (23.1%) (OR = 3.778, CI: 2.422, 5.894, p < .0001). Perceived risk (p = 0.023) and self-efficacy (p = 0.035) mediated CGRA intentions in TCN. Conclusions Improvements in CGRA intentions and theorized mediators support the use of a tailored communication intervention among women at increased HBOC risk. (Clinicaltrials.gov: NCT03326713.)Trial registration: ClinicalTrials.gov identifier: NCT03326713.
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Affiliation(s)
- Circe Gray Le Compte
- Biobehavioral Cancer Health Equity Research Lab, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Shou-En Lu
- Rutgers Environmental Epidemiology and Statistics, Rutgers University School of Public Health, Rutgers, The State University of New Jersey University, New Brunswick, NJ, USA
| | - Julianne Ani
- Biobehavioral Cancer Health Equity Research Lab, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Jean McDougall
- Department of Internal Medicine, Division of Epidemiology, Biostatistics, and Preventive Medicine, University of New Mexico, Albuquerque, NM, USA
| | - Scott T. Walters
- Department of Health Behavior and Health Systems, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Deborah Toppmeyer
- Stacy Goldstein Breast Cancer Center, LIFE Center, Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Tawny W. Boyce
- Biostatistics Shared Resource, UNM Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA
| | - Antoinette Stroup
- New Jersey State Cancer Registry, Stroup Research Center, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Lisa Paddock
- Cancer Surveillance Research Program, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Sherry Grumet
- LIFE Center, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Yong Lin
- Department of Biostatistics and Epidemiology, School of Public Health, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey University, New Brunswick, NJ, USA
| | - Emily Heidt
- Biobehavioral Cancer Health Equity Research Lab, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Anita Y. Kinney
- Department of Biostatistics and Epidemiology, School of Public Health, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey University, New Brunswick, NJ, USA
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Baranwal A, Hahn CN, Shah MV, Hiwase DK. Role of Germline Predisposition to Therapy-Related Myeloid Neoplasms. Curr Hematol Malig Rep 2022; 17:254-265. [PMID: 35986863 DOI: 10.1007/s11899-022-00676-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2022] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Therapy-related myeloid neoplasms (t-MNs) are aggressive leukemias that develop following exposure to DNA-damaging agents. A subset of patients developing t-MN may have an inherited susceptibility to develop myeloid neoplasia. Herein, we review studies reporting t-MN and their association with a germline or inherited predisposition. RECENT FINDINGS Emerging evidence suggests that development of t-MN is the result of complex interactions including generation of somatic variants in hematopoietic stem cells and/or clonal selection pressure exerted by the DNA-damaging agents, and immune evasion on top of any inherited genetic susceptibility. Conventionally, alkylating agents, topoisomerase inhibitors, and radiation have been associated with t-MN. Recently, newer modalities including poly (ADP-ribose) polymerase inhibitors (PARPi) and peptide receptor radionucleotide therapy (PRRT) are associated with t-MN. At the same time, the role of pathogenic germline variants (PGVs) in genes such as BRCA1/2, BARD1, or TP53 on the risk of t-MN is being explored. Moreover, studies have shown that while cytotoxic therapy increases the risk of developing myeloid neoplasia, it may be exposing the vulnerability of an underlying germline predisposition. t-MN remains a disease with poor prognosis. Studies are needed to better define an individual's inherited neoplastic susceptibility which will help predict the risk of myeloid neoplasia in the future. Understanding the genes driving the inherited neoplastic susceptibility will lead to better patient- and cancer-specific management including choice of therapeutic regimen to prevent, or at least delay, development of myeloid neoplasia after treatment of a prior malignancy.
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Affiliation(s)
- Anmol Baranwal
- Division of Hematology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55906, USA
| | - Christopher N Hahn
- Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia
- Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Mithun Vinod Shah
- Division of Hematology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55906, USA.
| | - Devendra K Hiwase
- Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
- Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia.
- South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
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Yuan L, Lu Z, Sun G, Cao D. Identification and verification of a 4-gene signature predicting the overall survival of cervical cancer. Medicine (Baltimore) 2022; 101:e31299. [PMID: 36281082 PMCID: PMC9592452 DOI: 10.1097/md.0000000000031299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Cervical cancer (CC) is one of the most common gynecological malignancies, ranking fourth in both incidence and mortality in women worldwide. Early screening and treatment are of great significance in reducing the incidence and mortality of CC. Due to the complex molecular mechanisms of tumor progression, the predictive power of traditional clinical information is limited. In this study, an effective molecular model is established to assess prognosis of patients with CC and guide clinical treatment so as to improve their survival rate. Three high quality datasets (GSE138080, GSE52904, GSE67522) of expression profiling were obtained from gene expression omnibus (GEO) database. Another mRNA expression and clinicopathological data of CC were obtained from The Cancer Genome Atlas (TCGA) dataset. The bioinformatic analyses such as univariate analysis, multivariate Cox proportional-hazards model (Cox) analysis and lasso regression analysis were conducted to select survival-related differentially expressed genes (DEGs) and further establish a prognostic gene signature. Moreover, the performance of prognostic gene signature was evaluated based on Kaplan-Meier curve and receiver operating characteristic (ROC) curve. Gene set enrichment analysis (GSEA) and tumor immunity analysis were carried out to elucidate the molecular mechanisms and immune relevance. A 4-gene signature comprising procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), spondin1 (SPON1), secreted phosphoprotein 1 (SPP1), ribonuclease H2 subunit A (RNASEH2A) was established to predict overall survival (OS) of CC. The ROC curve indicated good performance of the 4-gene signature in predicting OS of CC based on the TCGA dataset. The 4-gene signature classified the patients into high-risk and low-risk groups with distinct OS rates of CC. Univariate analysis and multivariate Cox regression analysis revealed that the 4-gene signature was an independent factor affecting the prognosis of patients with CC. Our study developed a 4-gene signature capable of predicting the OS of CC. The findings may be beneficial to individualized clinical treatment and timely follow-up for patients with CC.
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Affiliation(s)
- Lu Yuan
- From the Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No. 745, Wuhan, China
| | - Zijun Lu
- From the Department of Gynecology and Obstetrics, Wuhan University of Science and Technology, No. 2, Wuhan, China
| | - Guoqiang Sun
- From the Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No. 745, Wuhan, China
- * Correspondence: Dongmei Cao, Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No. 745, Wuluo Road, Hongshan District, Wuhan 430070, China (e-mail: ), and Guoqiang Sun, Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No. 745, Wuluo Road, Hongshan District, Wuhan 430070, China (e-mail: )
| | - Dongmei Cao
- From the Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No. 745, Wuhan, China
- * Correspondence: Dongmei Cao, Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No. 745, Wuluo Road, Hongshan District, Wuhan 430070, China (e-mail: ), and Guoqiang Sun, Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No. 745, Wuluo Road, Hongshan District, Wuhan 430070, China (e-mail: )
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Conley CC, Rivera Rivera JN, Castro-Figueroa EM, Moreno L, Dutil J, García JD, Ricker C, Quinn GP, Soliman H, Vadaparampil ST. Provider discussion of genetic counseling among high-risk Spanish-preferring Latina breast cancer survivors. Transl Behav Med 2022; 12:900-908. [PMID: 36205471 PMCID: PMC9540969 DOI: 10.1093/tbm/ibac031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Among high-risk breast cancer (BC) survivors, genetic counseling (GC) and genetic testing (GT) may inform cascade testing and risk management. Compared to non-Hispanic White BC survivors, Spanish-preferring Latina BC survivors are less likely to report discussing GC with a healthcare provider. However, few studies have examined Latinas' experiences with GC/GT, particularly outside of the mainland USA. This study aimed to compare frequency of provider discussion of GC between Spanish-preferring Latina BC survivors living in Florida (FL) and Puerto Rico (PR). We conducted secondary data analysis of baseline assessments from a randomized pilot of an educational intervention for Spanish-preferring Latina BC survivors. Participants (N = 52) were GC/GT-naive, but met clinical criteria for GC/GT referral. Participants self-reported sociodemographic, clinical, and cultural variables, including previous provider discussion of GC. Descriptive statistics characterized frequency of GC discussion. Logistic regression examined the relationships between sociodemographic, clinical, and cultural characteristics and GC discussion. Only 31% of participants reported previous GC discussion. More participants from PR reported having GC discussions (43% vs. 21% in the mainland USA). In multivariable analyses, greater likelihood of GC discussion was associated with PR (vs. mainland USA) residence (odds ratio [OR] = 6.00, p = .03), older age at baseline (OR = 1.19, p = .04), and younger age at BC diagnosis (OR = 0.80, p = .03). Few high-risk Spanish-preferring Latina BC survivors in the mainland USA and PR had discussed GC with their providers. These results highlight a gap in the implementation of evidence-based genetics guidelines. Provider-directed interventions may be needed to increase uptake of GC/GT among Latina BC survivors.
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Affiliation(s)
- Claire C Conley
- Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA
| | | | | | | | - Julie Dutil
- Ponce Health Sciences University, Ponce 00716, Puerto Rico
| | | | - Charité Ricker
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Gwendolyn P Quinn
- Grossman School of Medicine, New York University, New York, NY 10016, USA
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Whitworth PW, Beitsch PD, Patel R, Rosen B, Compagnoni G, Baron PL, Simmons R, Brown EA, Gold L, Holmes D, Smith LA, Kinney M, Grady I, Clark P, Barbosa K, Lyons S, Riley L, Coomer C, Curcio L, Ruiz A, Khan S, MacDonald H, Hughes K, Hardwick MK, Heald B, Munro SB, Nielsen SM, Esplin ED. Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer. JAMA Netw Open 2022; 5:e2232787. [PMID: 36136330 PMCID: PMC9500554 DOI: 10.1001/jamanetworkopen.2022.32787] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
IMPORTANCE National Comprehensive Cancer Network guidelines currently recommend germline testing for high-risk genes in selected patients with breast cancer. The clinical utility of recommending testing all patients with breast cancer with multigene panels is currently under consideration. OBJECTIVE To examine the implications of universal testing of patients with breast cancer with respect to clinical decision-making. DESIGN, SETTING, AND PARTICIPANTS Patients from a previously reported cohort were assessed as in-criteria or out-of-criteria according to the 2017 guidelines and underwent testing with a multigene germline panel between 2017 to 2018. Patients were women and men aged 18 to 90 years, with a new and/or previous diagnosis of breast cancer who had not undergone either single or multigene testing. Clinicians from 20 community and academic sites documented patient clinical information and changes to clinical recommendations made according to test findings. Association between prevalence of pathogenic or likely pathogenic germline variants and previously unreported clinical features, including scores generated by the BRCAPRO statistical model, was determined. Data were analyzed from April 2020 to May 2022. EXPOSURE New and/or previous diagnosis of breast cancer. MAIN OUTCOMES AND MEASURES Disease management recommendations that were changed as a result of genetic testing results are reported. RESULTS Clinicians were asked to assess changes to clinical management as a result of germline genetic testing for 952 patients. Informative clinician-reported recommendations were provided for 939 (467 in-criteria and 472 out-of-criteria) of the patients with breast cancer (936 [99.7%] female; 702 [74.8%] White; mean [SD] age at initial diagnosis, 57.6 [11.5] years). One or more changes were reported for 31 of 37 (83.8%) in-criteria patients and 23 of 34 (67.6%) out-of-criteria patients with a pathogenic or likely pathogenic variant. Recommendations were changed as a result of testing results for 14 of 22 (63.6%) out-of-criteria patients who had a variant in a breast cancer predisposition gene. Clinicians considered testing beneficial for two-thirds of patients with pathogenic or likely pathogenic variants and for one-third of patients with either negative results or variants of uncertain significance. There was no difference in variant rate between patients meeting the BRCAPRO threshold (≥10%) and those who did not (P = .86, Fisher exact test). No changes to clinical recommendations were made for most patients with negative results (345 of 349 patients [98.9%]) or variants of uncertain significance (492 of 509 patients [96.7%]). CONCLUSIONS AND RELEVANCE In this cohort study, germline genetic testing was used by clinicians to direct treatment for most out-of-criteria patients with breast cancer with pathogenic or likely pathogenic germline variants, including those with moderate-risk variants. Universal germline testing informs clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer.
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Affiliation(s)
- Pat W. Whitworth
- Nashville Breast Center, Nashville, Tennesee
- TME Breast Care Network, Dallas, Texas
| | - Peter D. Beitsch
- TME Breast Care Network, Dallas, Texas
- Invitae, San Francisco, California
| | - Rakesh Patel
- TME Breast Care Network, Dallas, Texas
- Invitae, San Francisco, California
| | | | | | | | - Rache Simmons
- Department of Surgery, Weill Cornell Medicine, New York, New York
| | - Eric A. Brown
- Comprehensive Breast Care, A Division of Michigan Healthcare Professionals, Troy
| | - Linsey Gold
- Comprehensive Breast Care, A Division of Michigan Healthcare Professionals, Troy
| | | | | | - Michael Kinney
- Center for Advanced Breast Care, Arlington Heights, Illinois
| | - Ian Grady
- North Valley Breast Clinic, Redding, California
| | - Patricia Clark
- Ironwood Cancer and Research Centers, Scottsdale, Arizona
| | | | | | - Lee Riley
- St Luke’s University Health Network, Easton, Pennsylvania
| | - Cynara Coomer
- Department of Surgery, Northwell Staten Island University Hospital, Staten Island, New York
| | | | - Antonio Ruiz
- Chesapeake Regional Medical Center, Chesapeake, Virginia
| | - Sadia Khan
- Hoag Hospital Newport Beach, Newport Beach, California
| | | | - Kevin Hughes
- Department of Surgery, Medical University of South Carolina, Charleston
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McNamara N, Feeney M, Giltenane M, Dowling M. Breast cancer genetic mutation: Synthesis of women's experience. J Clin Nurs 2022. [PMID: 36016506 DOI: 10.1111/jocn.16498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 11/28/2022]
Abstract
AIMS AND OBJECTIVES To systematically identify and synthesise the experiences reported by women with a breast cancer mutation who do not have cancer as reported in qualitative research published between 2013 and 2020. BACKGROUND Women carrying a BReast CAncer (BRC) genetic mutation have an increased risk for breast and ovarian cancer. They must engage in emotional decision-making regarding risk management strategies to prevent cancer, including risk-reducing bilateral mastectomy and bilateral salpingo-oophorectomy. DESIGN AND METHODS The ENTREQ statement guided this review. Eight databases were systematically searched (CINAHL, Pubmed, Embase, Psychinfo [Ovid], Web of Science, Scopus, Proquest and Lenus). Synthesis was guided by "best fit" framework. The Critical Appraisal Skills Programme guided assessment of methodological limitations and confidence in the review findings was informed by GRADE-CERQual. RESULTS Twenty studies met the inclusion criteria for synthesis. Six themes were synthesised from the included studies (anxiety; family planning; it's a family affair; empowerment; actions; pragmatic adjustments). CONCLUSIONS The multidimensional experiences of women living with a BRCA1/2 mutation require an individualised response based on women's needs at their life stages. A decision coaching model adopted during consultations could support women to guide decision-making regarding cancer risk-reducing strategies.
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Affiliation(s)
- Nichola McNamara
- Symptomatic Breast Unit, University Hospital Limerick, Limerick, Ireland
| | - Meghan Feeney
- Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Martina Giltenane
- Department of Nursing and Midwifery, University of Limerick, Limerick, Ireland
| | - Maura Dowling
- School of Nursing and Midwifery, National University of Ireland Galway, Galway, Ireland
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50
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Ceyhan-Birsoy O, Jayakumaran G, Kemel Y, Misyura M, Aypar U, Jairam S, Yang C, Li Y, Mehta N, Maio A, Arnold A, Salo-Mullen E, Sheehan M, Syed A, Walsh M, Carlo M, Robson M, Offit K, Ladanyi M, Reis-Filho JS, Stadler ZK, Zhang L, Latham A, Zehir A, Mandelker D. Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients. Genome Med 2022; 14:92. [PMID: 35971132 PMCID: PMC9377129 DOI: 10.1186/s13073-022-01101-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 08/03/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Genetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary cancer gene panels uncovered hereditary predisposition in a greater proportion of patients than previously anticipated. We sought to define the diagnostic yield of eGT and its clinical relevance in a broad cancer patient population over a 5-year period. METHODS A total of 17,523 cancer patients with a broad range of solid tumors, who received eGT at Memorial Sloan Kettering Cancer Center between July 2015 to April 2020, were included in the study. The patients were unselected for current GT criteria such as cancer type, age of onset, and/or family history of disease. The diagnostic yield of eGT was determined for each cancer type. For 9187 patients with five common cancer types frequently interrogated for hereditary predisposition (breast, colorectal, ovarian, pancreatic, and prostate cancer), the rate of pathogenic/likely pathogenic (P/LP) variants in genes that have been associated with each cancer type was analyzed. The clinical implications of additional findings in genes not known to be associated with a patients' cancer type were investigated. RESULTS 16.7% of patients in a broad cancer cohort had P/LP variants in hereditary cancer predisposition genes identified by eGT. The diagnostic yield of eGT in patients with breast, colorectal, ovarian, pancreatic, and prostate cancer was 17.5%, 15.3%, 24.2%, 19.4%, and 15.9%, respectively. Additionally, 8% of the patients with five common cancers had P/LP variants in genes not known to be associated with the patient's current cancer type, with 0.8% of them having such a variant that confers a high risk for another cancer type. Analysis of clinical and family histories revealed that 74% of patients with variants in genes not associated with their current cancer type but which conferred a high risk for another cancer did not meet the current GT criteria for the genes harboring these variants. One or more variants of uncertain significance were identified in 57% of the patients. CONCLUSIONS Compared to targeted testing approaches, eGT can increase the yield of detection of hereditary cancer predisposition in patients with a range of tumors, allowing opportunities for enhanced surveillance and intervention. The benefits of performing eGT should be weighed against the added number of VUSs identified with this approach.
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Affiliation(s)
- Ozge Ceyhan-Birsoy
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Gowtham Jayakumaran
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yelena Kemel
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maksym Misyura
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Umut Aypar
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sowmya Jairam
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ciyu Yang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yirong Li
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikita Mehta
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anna Maio
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Angela Arnold
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Erin Salo-Mullen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Margaret Sheehan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Aijazuddin Syed
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Walsh
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria Carlo
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mark Robson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kenneth Offit
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marc Ladanyi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jorge S Reis-Filho
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Liying Zhang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Present Address: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Alicia Latham
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ahmet Zehir
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Present Address: Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, New York, NY, USA.
| | - Diana Mandelker
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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