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Tafenzi HA, Choulli F, Essaadi I, Belbaraka R. Real-World Outcomes of Combination Anthracycline and Taxane Adjuvant Therapies in Early Triple-Negative Breast Cancer: A Moroccan Retrospective Analysis. JCO Glob Oncol 2025; 11:e2400650. [PMID: 40344550 DOI: 10.1200/go-24-00650] [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: 12/23/2024] [Revised: 03/11/2025] [Accepted: 04/09/2025] [Indexed: 05/11/2025] Open
Abstract
PURPOSE Neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy is the gold standard for treating patients with higher risk early triple-negative breast cancer (TNBC); however, in some cases, these patients undergo surgery followed by chemotherapy-based anthracyclines and taxanes without adhering to the guidelines. METHODS Patients with previously untreated stage I, II, and III TNBC who received adjuvant therapy with either doxorubicin and cyclophosphamide (AC) + docetaxel (AC-D), AC + weekly paclitaxel (AC-WP), epirubicin and cyclophosphamide (EC) + docetaxel (EC-D), or EC + WP (EC-WP); older than 18 years; and diagnosed between January 1st, 2011, and December 31st, 2022, were eligible for the study. Disease-free survival (DFS) is the primary reported end point. Overall survival (OS) and safety were the secondary end points. RESULTS We included 272 female patients. At a prespecified event-driven data cutoff, with a median follow-up of 26.3 months, the 5-year DFS was 49% (95% CI, 38 to 63) in the AC-D group, 45% (95% CI, 29 to 70) in the AC-WP group, 73% (95% CI, 61 to 100) in the EC-D group, and 72% (95% CI, 44 to 100) in the EC-WP group (hazard ratio [HR], 0.2 [95% CI, 0.06 to 0.67]; P = .08). The 7-year OS was 52% (95% CI, 32 to 83) in the AC-D group, 88% (95% CI, 78 to 99) in the AC-WP group, 95% (95% CI, 88 to 100) in the EC-D group, and 83% (95% CI, 58 to 100) in the EC-WP group (HR, 0.19 [95% CI, 0.06 to 0.66]; P = .03). Most of the grade 3-4 adverse events occurred in the AC-D group, primarily neutropenia, nausea-vomiting, and alopecia. CONCLUSION EC-D was linked to a slightly longer survival free of invasive, noninvasive, or distant disease and a significantly longer OS with fewer adverse events. Further studies are needed to confirm and establish long-term clinical benefits.
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Affiliation(s)
- Hassan Abdelilah Tafenzi
- Medical Oncology Department, Mohammed VI University Hospital of Marrakech, Marrakech, Morocco
- Biosciences and Health Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech, Morocco
| | - Farah Choulli
- Medical Oncology Department, Mohammed VI University Hospital of Marrakech, Marrakech, Morocco
- Biosciences and Health Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech, Morocco
| | - Ismail Essaadi
- Biosciences and Health Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech, Morocco
- Medical Oncology Department, Avicenna Military Hospital of Marrakech, Marrakech, Morocco
| | - Rhizlane Belbaraka
- Medical Oncology Department, Mohammed VI University Hospital of Marrakech, Marrakech, Morocco
- Biosciences and Health Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech, Morocco
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Chen C, Pang X, Zhang M, Li F, Zhang W, Chen W. Long-Term and Sustained Remission of Advanced Triple-Negative Breast Cancer with Large Chest Wall Lesions after Transient Chemoimmunotherapy: A Case Report. Case Rep Oncol 2025; 18:198-205. [PMID: 39980521 PMCID: PMC11793911 DOI: 10.1159/000543292] [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: 08/24/2024] [Accepted: 12/18/2024] [Indexed: 02/22/2025] Open
Abstract
Introduction We report a case of advanced triple-negative breast cancer (TNBC) with special clinical manifestations, in which a durable remission was achieved after short-term administration of toripalimab combined with chemotherapy. The progress, advantages, and unique experience of chemoimmunotherapy in TNBC were examined. Case Presentation A patient with TNBC with local recurrence 2 years following surgery, with inoperable large chest wall lesions and positive PD-L1 as the main manifestations, was treated with toripalimab plus paclitaxel (albumin-bound) for 5 months and achieved a partial remission. Twenty-five months after the discontinuation of treatment, the chest wall lesions exhibited a slow but continuous decline, until they achieved a nearly complete remission; however, the patient eventually died from cancer progression. Conclusion Typically, chest wall recurrence in TNBC has a poor prognosis; however, recurrence was rapidly controlled, sustained remission was achieved after immunotherapy combined with chemotherapy, and the curative effect continued after drug withdrawal, which is a rare occurrence. Thus, the tailing effect of immune checkpoint inhibitors was confirmed in the treatment of TNBC.
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Affiliation(s)
- Chanjuan Chen
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaonan Pang
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mingjun Zhang
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fanfan Li
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wanying Zhang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Chen
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
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Khalid T, Cutress RI, Remer M, Copson ER. Clinical Impact of Somatic Genomic Testing on Breast Cancer Care. Clin Oncol (R Coll Radiol) 2025; 37:103665. [PMID: 39541893 DOI: 10.1016/j.clon.2024.10.037] [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: 10/04/2023] [Revised: 08/12/2024] [Accepted: 10/16/2024] [Indexed: 11/17/2024]
Abstract
Developments in our understanding of the molecular biology of breast cancer have had a direct impact on the investigations needed to provide optimal breast cancer care. Somatic genomic tests are now used routinely to inform decisions regarding adjuvant chemotherapy use in selected early breast cancer patients, and to identify patients with advanced disease who can potentially benefit from novel targeted agents. In this overview, we describe the somatic genomic tests currently available within the National Health Service (NHS) for early and advanced breast cancer patients. We review the underlying biology and the evidence base for clinical utility of these tests in routine clinical practice. In addition, we identify the somatic genomic biomarkers currently in use in breast cancer clinical trials that are most likely to influence future breast cancer management. We also consider the challenges associated with tissue-based genomic testing in advanced breast cancer and the role of circulating tumour deoxyribonucleic acid (ctDNA) testing.
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Affiliation(s)
- T Khalid
- University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK
| | - R I Cutress
- University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - M Remer
- Basingstoke and North Hampshire Hospitals, Hampshire Hospitals NHS Foundation Trust, Aldermaston Road, Basingstoke RG24 9NA, UK
| | - E R Copson
- University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
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Myers SP, Sevilimedu V, Barrio AV, Tadros AB, Mamtani A, Robson ME, Morrow M, Lee MK. Pathologic complete response after neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers. NPJ Breast Cancer 2024; 10:63. [PMID: 39060255 PMCID: PMC11282097 DOI: 10.1038/s41523-024-00674-y] [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: 11/17/2023] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
BRCA1 and BRCA2 pathogenic variant carriers develop breast cancers with distinct pathological characteristics and mutational signatures that may result in differential response to chemotherapy. We compared rates of pathologic complete response (pCR) after NAC between BRCA1/2 variant carriers and noncarriers in a cohort of 1426 women (92 [6.5%] BRCA1 and 73 [5.1%] BRCA2) with clinical stage I-III breast cancer treated with NAC followed by surgery from 11/2013 to 01/2022 at Memorial Sloan Kettering Cancer Center. The majority received doxorubicin/cyclophosphamide/paclitaxel therapy (93%); BRCA1/2 carriers were more likely to receive carboplatin (p < 0.001). Overall, pCR was achieved in 42% of BRCA1 carriers, 21% of BRCA2 carriers, and 26% of noncarriers (p = 0.001). Among clinically node-positive (cN+) patients, nodal pCR was more frequent in BRCA1/2 carriers compared to noncarriers (53/96 [55%] vs. 371/856 [43%], p = 0.015). This difference was seen in HR+/HER2- (36% vs. 20% of noncarriers; p = 0.027) and TN subtypes (79% vs. 45% of noncarriers; p < 0.001). In a multivariable analysis of the overall cohort, BRCA1 status, and TN and HER2+ subtypes were independently associated with pCR. These data indicate that BRCA1 carriers may be more likely to achieve overall and nodal pCR in response to NAC compared with BRCA2 carriers and patients with sporadic disease. Further studies with a larger cohort of BRCA1/2 mutation carriers are needed, as a small sample size may have a restricted ability to detect a significant association between mutational status and pCR in sensitivity analyses stratified by subtype and adjusted for clinically relevant factors.
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Affiliation(s)
- Sara P Myers
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Varadan Sevilimedu
- Biostatistical Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andrea V Barrio
- Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Audree B Tadros
- Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anita Mamtani
- Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mark E Robson
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Monica Morrow
- Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Minna K Lee
- Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Abdel-Razeq H, Tamimi F, Iweir S, Sharaf B, Abdel-Razeq S, Salama O, Edaily S, Bani Hani H, Azzam K, Abaza H. Genetic counseling and genetic testing for pathogenic germline mutations among high-risk patients previously diagnosed with breast cancer: a traceback approach. Sci Rep 2024; 14:12820. [PMID: 38834641 DOI: 10.1038/s41598-024-63300-8] [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: 11/10/2023] [Accepted: 05/27/2024] [Indexed: 06/06/2024] Open
Abstract
Genetic counseling and testing are more accessible than ever due to reduced costs, expanding indications and public awareness. Nonetheless, many patients missed the opportunity of genetic counseling and testing due to barriers that existed at that time of their cancer diagnoses. Given the identified implications of pathogenic mutations on patients' treatment and familial outcomes, an opportunity exists to utilize a 'traceback' approach to retrospectively examine their genetic makeup and provide consequent insights to their disease and treatment. In this study, we identified living patients diagnosed with breast cancer (BC) between July 2007 and January 2022 who would have been eligible for testing, but not tested. Overall, 422 patients met the eligibility criteria, 282 were reached and invited to participate, and germline testing was performed for 238, accounting for 84.4% of those invited. The median age (range) was 39.5 (24-64) years at BC diagnosis and 49 (31-75) years at the date of testing. Genetic testing revealed that 25 (10.5%) patients had pathogenic/likely pathogenic (P/LP) variants; mostly in BRCA2 and BRCA1. We concluded that long overdue genetic referral through a traceback approach is feasible and effective to diagnose P/LP variants in patients with history of BC who had missed the opportunity of genetic testing, with potential clinical implications for patients and their relatives.
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Affiliation(s)
- Hikmat Abdel-Razeq
- Department of Internal Medicine, King Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan.
- School of Medicine, The University of Jordan, Amman, Jordan.
| | - Faris Tamimi
- Department of Internal Medicine, King Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan
| | - Sereen Iweir
- Department of Internal Medicine, King Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan
- CRDF Global, Global Health Mission Area, Amman, Jordan
| | - Baha Sharaf
- Department of Internal Medicine, King Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan
| | | | - Osama Salama
- Department of Internal Medicine, King Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan
| | - Sarah Edaily
- Department of Internal Medicine, King Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan
| | - Hira Bani Hani
- Department of Internal Medicine, King Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan
| | - Khansa Azzam
- Department of Internal Medicine, King Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan
| | - Haneen Abaza
- Office of Scientific Affairs and Research, King Hussein Cancer Center, Amman, Jordan
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Saleh T, Al Shboul S, Awad H, El-Sadoni M, Alhesa A, Alsharaiah E, Abu Shahin N, Alotaibi MR, Battah A, Azab B. Characterization of BCL-X L , MCL-1, and BAX Protein Expression in Response to Neoadjuvant Chemotherapy in Breast Cancer. Appl Immunohistochem Mol Morphol 2024; 32:189-199. [PMID: 38426376 DOI: 10.1097/pai.0000000000001189] [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: 08/02/2023] [Accepted: 01/26/2024] [Indexed: 03/02/2024]
Abstract
The use of chemotherapy has improved the overall treatment of breast cancer, which is frequently administered in the form of neoadjuvant chemotherapy (NAC). Apoptosis is an established cell stress response to NAC in preclinical models; however, there is limited understanding of its role in clinical cancer, specifically, its contribution to favorable pathologic responses in breast cancer therapy. Here, we aimed to characterize the change in protein expression of 3 apoptosis-associated biomarkers, namely, BCL-X L , MCL-1, and BAX in breast cancer in response to NAC. For this, we utilized a set of 68 matched invasive breast cancer FFPE samples that were collected before (pre) and after (post) the exposure to NAC therapy that were characterized by incomplete pathologic response. Immunohistochemistry (IHC) analysis suggested that most of the samples show a decrease in the protein expression of all 3 markers following exposure to NAC as 90%, 69%, and 76% of the matched samples exhibited a decrease in expression for BCL-X L , MCL-1, and BAX, respectively. The median H-score of BCL-X L post-NAC was 150/300 compared with 225/300 pre-NAC ( P value <0.0001). The median H-score of MCL-1 declined from 200 pre-NAC to 160 post-NAC ( P value <0.0001). The median H-score of BAX protein expression decreased from 260 pre-NAC to 190 post-NAC ( P value <0.0001). There was no statistically significant association between the expression of these markers and stage, grade, and hormone receptor profiling (luminal status). Collectively, our data indicate that the expression of apoptosis regulatory proteins changes following exposure to NAC in breast cancer tissue, developing a partial pathologic response.
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Affiliation(s)
- Tareq Saleh
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa
| | - Sofian Al Shboul
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa
| | - Heyam Awad
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Mohammed El-Sadoni
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Ahmad Alhesa
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Elham Alsharaiah
- Department of Pathology, King Hussein Medical Center, Royal Medical Service, Amman, Jordan
| | - Nisreen Abu Shahin
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Moureq R Alotaibi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - AbdelKader Battah
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Bilal Azab
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
- Division of Pathology and Laboratory Medicine, Phoenix Children's Hospital, Phoenix, AZ
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Kuthethur R, Jerome MS, Subbannayya Y, Chakrabarty S. An integrated analysis of microRNAs regulating DNA damage response in triple-negative breast cancer. Breast Cancer 2023; 30:832-844. [PMID: 37344703 PMCID: PMC10404216 DOI: 10.1007/s12282-023-01477-y] [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: 01/07/2023] [Accepted: 06/09/2023] [Indexed: 06/23/2023]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive phenotype and limited treatment options for the patients. Many TNBC patients show an inherent defect in the DNA repair capacity primarily by acquiring germline mutations in BRCA1 and BRCA2 genes leading to Homologous Recombination Deficiency (HRD). Epigenetic modifications such as BRCA1 promoter methylation and miRNA expression targeting DNA repair pathway genes have contributed to the HRD phenotype in TNBC. Hence, we aimed to identify microRNAs that are associated with HRD status in the TCGA-BRCA project. MATERIALS AND METHODS We implemented a miRNA prediction strategy for identifying miRNAs targeting HR pathway genes using an in silico predicted and experimentally validated list from published literature for their association with genomic instability and factors affecting HRD. In silico analysis was performed to study miRNA expression patterns regulated by DNA methylation and TMB status in the TNBC patients from TCGA-BRCA project. Finally, we analysed selected miRNA expression with immune cell infiltration pattern in the TNBC patient cohort. RESULTS Our study identified miRNAs associated with HRD, tumour mutation burden (TMB), and immune cell infiltration. Identified miRNA signatures were associated with the miR-17 ~ 92 cluster, miR-106b ~ 25 cluster, and miR-200b ~ 429 cluster. Pathway analysis of selected miRNAs suggested their association with altered immune cell infiltration in TNBC. CONCLUSION Our study identified 6 'HRD associated miRNAs' such as miR-106b, miR-93, miR-17, miR-20a, miR-200b, and miR-429 as novel miRNA-based signatures associated with HR deficiency in TNBC.
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Affiliation(s)
- Raviprasad Kuthethur
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Maria Sona Jerome
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Yashwanth Subbannayya
- Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491, Trondheim, Norway
- School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH, UK
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
- Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Tsyganov MM, Sorokovikova SS, Lutzkaya EA, Ibragimova MK. Mutations of BRCA1, BRCA2, and PALB2 Genes in Breast Tumor Tissue: Relationship with the Effectiveness of Neoadjuvant Chemotherapy and Disease Prognosis. Genes (Basel) 2023; 14:1554. [PMID: 37628606 PMCID: PMC10454606 DOI: 10.3390/genes14081554] [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: 06/19/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
It has been shown that the loss of function of the BRCA1, BRCA2, and PALB2 genes due to a number of hereditary mutations or chromosomal aberrations can affect the effectiveness of chemotherapy treatment and disease prognosis in patients with various types of cancer, and in particular in breast cancer. Thus, the aim of the work was to evaluate the predictive and prognostic potential of DNA copy number aberrations and mutations in the BRCA1, BRCA2, and PALB2 genes in breast tumors. MATERIALS AND METHODS The study included 66 patients with breast cancer. DNA copy number aberrations (CNA) were assessed by high-density CytoScanHD™ Array micro matrix analysis. Gene mutations were assessed by sequencing on the MiSeq™ Sequencing System using the Accel-Amplicon BRCA1, BRCA2, and PALB2 Panel. RESULTS It has been established that the presence of a normal copy number of PALB2 is associated with a lack of response to chemotherapy in Taxotere-containing treatment regimens (p = 0.05). In addition, the presence of a PALB2 deletion is associated with 100% metastatic survival rates (log-rank test p = 0.04). As a result of sequencing, 25 mutations were found in the BRCA1 gene, 42 mutations in BRCA2, and 27 mutations in the PALB2 gene. The effect of mutations on the effectiveness of treatment is controversial, but an effect on the survival of patients with breast cancer has been shown. So, in the presence of pathogenic mutations in the BRCA2 gene, 100% metastatic survival is observed (log-rank test p = 0.05), as well as in the elimination of PALB2 mutations during treatment (log-rank test p = 0.07). CONCLUSION Currently, there is little data on the effect of chromosomal aberrations and mutations in the BRCA1/2 and PALB2 genes on the effectiveness of treatment and prognosis of the disease. At the same time, the study of these genes has great potential for testing focused on a personalized approach to the treatment of patients with breast cancer.
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Affiliation(s)
- Matvey M. Tsyganov
- Department of Experimental Oncology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (S.S.S.); (E.A.L.); (M.K.I.)
- Faculty of Medicine and Biology, Siberian State Medical University, 2, Moskovsky Trakt, 634050 Tomsk, Russia
| | - Sofia S. Sorokovikova
- Department of Experimental Oncology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (S.S.S.); (E.A.L.); (M.K.I.)
- Biological Institute, National Research Tomsk State University, 36, Lenin Avenue, 634050 Tomsk, Russia
| | - Elizaveta A. Lutzkaya
- Department of Experimental Oncology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (S.S.S.); (E.A.L.); (M.K.I.)
| | - Marina K. Ibragimova
- Department of Experimental Oncology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (S.S.S.); (E.A.L.); (M.K.I.)
- Faculty of Medicine and Biology, Siberian State Medical University, 2, Moskovsky Trakt, 634050 Tomsk, Russia
- Biological Institute, National Research Tomsk State University, 36, Lenin Avenue, 634050 Tomsk, Russia
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Wan A, Zhang G, Ma D, Zhang Y, Qi X. An overview of the research progress of BRCA gene mutations in breast cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188907. [PMID: 37172654 DOI: 10.1016/j.bbcan.2023.188907] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 04/14/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023]
Abstract
The breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene, including BRCA1 and BRCA2, a biomarker that assesses the risk of breast cancer and influences a patient's individualized treatment options. BRCA1/2 mutation (BRCAm) increases the risk of breast cancer. However, breast-conserving surgery is still an option for BRCAm, and prophylactic mastectomy and nipple-sparing mastectomy may also reduce the risk of breast cancer. BRCAm is sensitive to Poly (ADP-ribose) polymerase inhibitor (PARPi) therapy due to specific types of DNA repair defects, and its combination with other DNA damage pathway inhibitors and endocrine therapy and immunotherapy are also used for the treatment of BRCAm breast cancer. The current treatment and research progress of BRCA1/2 mutant breast cancer in this review provides a basis for the individualized treatment of patients with this type of breast cancer.
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Affiliation(s)
- Andi Wan
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Guozhi Zhang
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Dandan Ma
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yi Zhang
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Xiaowei Qi
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China.
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Chalertpet K, Sangkheereeput T, Somjit P, Bankeeree W, Yanatatsaneejit P. Effect of Smilax spp. and Phellinus linteus combination on cytotoxicity and cell proliferation of breast cancer cells. BMC Complement Med Ther 2023; 23:177. [PMID: 37264344 DOI: 10.1186/s12906-023-04003-x] [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: 07/29/2022] [Accepted: 05/18/2023] [Indexed: 06/03/2023] Open
Abstract
BACKGROUND Although the prevalence of breast cancer (BC) has been reduced in recent years, proficient therapeutic regimens should be further investigated with the aim of further reducing the mortality rate. To obtain more effective treatment, the present study aimed to observe the effects of PL synergistically combined with Smilax corbularia and S. glabra extracts (PSS) on BC cell lines, MCF7, T47D, MDA-MB-231, and MDA-MB-468. METHODS The half-maximal inhibition (IC50) concentrations of PSS and PL were determined in a dose- and time-dependent manner using MTT assay. The activity of PSS and PL on anti-BC proliferation was evaluated using BrdU assay, and colony formation assay. Moreover, cell cycle analysis and apoptosis induction as a result of PSS and PL exposure were investigated using propidium iodide (PI) staining and co-staining of annexin V DY634 and PI combined flow cytometric analysis, respectively. Finally, changes in the mRNA expression of genes involved in proliferative and apoptotic pathways (MKI67, HER2, EGFR, MDM2, TNFα, PI3KCA, KRAS, BAX, and CASP8) were explored using RT-qPCR following PSS and PL treatment. RESULTS The PSS and PL extracts exhibited significant potential in BC cytotoxicity which were in were in dose- and time-dependent response. This inhibition of cell growth was due to the suppression of cell proliferation, the cell cycle arrest, and the induction of apoptosis. Additionally, an investigation of the underlying molecular mechanism revealed that PSS and PL are involved in downregulation of the MKI67, HER2, EGFR, MDM2, TNFα, and PI3KCA expression. CONCLUSIONS This present study has suggested that PSS and PL possess anti-BC proliferative activity mediated via the downregulation of genes participating in the relevant pathways. PSS or PL may be combined with other agents to alleviate the adverse side effects resulted from conventional chemotherapeutic drugs.
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Affiliation(s)
- Kanwalat Chalertpet
- Department of Botany, Faculty of Science, Human Genetics Research Group, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Thanawitch Sangkheereeput
- Department of Botany, Faculty of Science, Human Genetics Research Group, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Prakaithip Somjit
- Department of Botany, Faculty of Science, Human Genetics Research Group, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Wichanee Bankeeree
- Department of Botany, Faculty of Science, Plant Biomass Utilization Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Pattamawadee Yanatatsaneejit
- Department of Botany, Faculty of Science, Human Genetics Research Group, Chulalongkorn University, Bangkok, 10330, Thailand.
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11
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Kung H, Yu J. Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study. MedComm (Beijing) 2023; 4:e216. [PMID: 36814688 PMCID: PMC9939368 DOI: 10.1002/mco2.216] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 02/21/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with a high rate of recurrence and a dismal 5-year survival rate. Contributing to the poor prognosis of PDAC is the lack of early detection, a complex network of signaling pathways and molecular mechanisms, a dense and desmoplastic stroma, and an immunosuppressive tumor microenvironment. A recent shift toward a neoadjuvant approach to treating PDAC has been sparked by the numerous benefits neoadjuvant therapy (NAT) has to offer compared with upfront surgery. However, certain aspects of NAT against PDAC, including the optimal regimen, the use of radiotherapy, and the selection of patients that would benefit from NAT, have yet to be fully elucidated. This review describes the major signaling pathways and molecular mechanisms involved in PDAC initiation and progression in addition to the immunosuppressive tumor microenvironment of PDAC. We then review current guidelines, ongoing research, and future research directions on the use of NAT based on randomized clinical trials and other studies. Finally, the current use of and research regarding targeted therapy for PDAC are examined. This review bridges the molecular understanding of PDAC with its clinical significance, development of novel therapies, and shifting directions in treatment paradigm.
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Affiliation(s)
- Heng‐Chung Kung
- Krieger School of Arts and SciencesJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Jun Yu
- Departments of Medicine and OncologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
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12
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Lang N, Ayme A, Ming C, Combes JD, Chappuis VN, Friedlaender A, Vuilleumier A, Sandoval JL, Viassolo V, Chappuis PO, Labidi-Galy SI. Chemotherapy-related agranulocytosis as a predictive factor for germline BRCA1 pathogenic variants in breast cancer patients: a retrospective cohort study. Swiss Med Wkly 2023; 153:40055. [PMID: 37011610 DOI: 10.57187/smw.2023.40055] [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] [Indexed: 04/03/2023] Open
Abstract
BACKGROUND Carriers of germline pathogenic variants of the BRCA1 gene (gBRCA1) tend to have a higher incidence of haematological toxicity upon exposure to chemotherapy. We hypothesised that the occurrence of agranulocytosis during the first cycle of (neo-)adjuvant chemotherapy (C1) in breast cancer (BC) patients could predict gBRCA1 pathogenic variants. PATIENTS AND METHODS The study population included non-metastatic BC patients selected for genetic counselling at Hôpitaux Universitaires de Genève (Jan. 1998 to Dec. 2017) with available mid-cycle blood counts performed during C1. The BOADICEA and Manchester scoring system risk-prediction models were applied. The primary outcome was the predicted likelihood of harbouring gBRCA1 pathogenic variants among patients presenting agranulocytosis during C1. RESULTS Three hundred seven BC patients were included: 32 (10.4%) gBRCA1, 27 (8.8%) gBRCA2, and 248 (81.1%) non-heterozygotes. Mean age at diagnosis was 40 years. Compared with non-heterozygotes, gBRCA1 heterozygotes more frequently had grade 3 BC (78.1%; p = 0.014), triple-negative subtype (68.8%; p <0.001), bilateral BC (25%; p = 0.004), and agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy (45.8%; p = 0.002). Agranulocytosis and febrile neutropenia that developed following the first cycle of chemotherapy were independently predictive for gBRCA1 pathogenic variants (odds ratio: 6.1; p = 0.002). The sensitivity, specificity, positive predictive value, and negative predictive value for agranulocytosis predicting gBRCA1 were 45.8% (25.6-67.2%), 82.8% (77.5-87.3%), 22.9% (6.1-37.3%), and 93.4% (88.9-96.4%), respectively. Agranulocytosis substantially improved the positive predictive value of the risk-prediction models used for gBRCA1 evaluation. CONCLUSION Agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy is an independent predictive factor for gBRCA1 detection in non-metastatic BC patients.
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Affiliation(s)
- Noémie Lang
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Aurélie Ayme
- Department of Diagnostics, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Chang Ming
- Department of Clinical Research, Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Jean-Damien Combes
- Infections and Cancer Epidemiology Group, International Agency for Research on Cancer, Lyon, France
| | - Victor N Chappuis
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Alex Friedlaender
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Aurélie Vuilleumier
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - José L Sandoval
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Valeria Viassolo
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Pierre O Chappuis
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
- Department of Diagnostics, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - S Intidhar Labidi-Galy
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
- Department of Diagnostics, Hôpitaux Universitaires de Genève, Geneva, Switzerland
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13
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Loboda AP, Adonin LS, Zvereva SD, Guschin DY, Korneenko TV, Telegina AV, Kondratieva OK, Frolova SE, Pestov NB, Barlev NA. BRCA Mutations-The Achilles Heel of Breast, Ovarian and Other Epithelial Cancers. Int J Mol Sci 2023; 24:ijms24054982. [PMID: 36902416 PMCID: PMC10003548 DOI: 10.3390/ijms24054982] [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: 02/11/2023] [Revised: 02/27/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Two related tumor suppressor genes, BRCA1 and BRCA2, attract a lot of attention from both fundamental and clinical points of view. Oncogenic hereditary mutations in these genes are firmly linked to the early onset of breast and ovarian cancers. However, the molecular mechanisms that drive extensive mutagenesis in these genes are not known. In this review, we hypothesize that one of the potential mechanisms behind this phenomenon can be mediated by Alu mobile genomic elements. Linking mutations in the BRCA1 and BRCA2 genes to the general mechanisms of genome stability and DNA repair is critical to ensure the rationalized choice of anti-cancer therapy. Accordingly, we review the literature available on the mechanisms of DNA damage repair where these proteins are involved, and how the inactivating mutations in these genes (BRCAness) can be exploited in anti-cancer therapy. We also discuss a hypothesis explaining why breast and ovarian epithelial tissues are preferentially susceptible to mutations in BRCA genes. Finally, we discuss prospective novel therapeutic approaches for treating BRCAness cancers.
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Affiliation(s)
- Anna P. Loboda
- Laboratory of Molecular Oncology, Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
| | | | - Svetlana D. Zvereva
- Laboratory of Molecular Oncology, Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
| | - Dmitri Y. Guschin
- School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan
| | - Tatyana V. Korneenko
- Group of Cross-Linking Enzymes, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
| | | | | | | | - Nikolay B. Pestov
- Institute of Biomedical Chemistry, 119121 Moscow, Russia
- Group of Cross-Linking Enzymes, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, 108819 Moscow, Russia
- Correspondence: (N.B.P.); (N.A.B.)
| | - Nick A. Barlev
- Institute of Biomedical Chemistry, 119121 Moscow, Russia
- School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, 108819 Moscow, Russia
- Institute of Cytology, Tikhoretsky ave 4, 194064 St-Petersburg, Russia
- Correspondence: (N.B.P.); (N.A.B.)
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14
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Akbari ME, Ghelichi-Ghojogh M, Nikeghbalian Z, Karami M, Akbari A, Hashemi M, Nooraei S, Ghiasi M, Fararouei M, Moradian F. Neoadjuvant VS adjuvant chemotherapy in patients with locally advanced breast cancer; a retrospective cohort study. Ann Med Surg (Lond) 2022; 84:104921. [PMID: 36536751 PMCID: PMC9758373 DOI: 10.1016/j.amsu.2022.104921] [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: 08/21/2022] [Revised: 11/07/2022] [Accepted: 11/13/2022] [Indexed: 11/17/2022] Open
Abstract
Background Breast cancer is one of the most common challenges for women's health. Until now, neoadjuvant chemotherapy is a standard approach in locally advanced breast cancer (LABC), as it increases the probability of breast-conserving surgery (BCS). This study aimed to compare the survival rate in neoadjuvant and adjuvant groups to suggest a better treatment strategy for locally advanced breast cancer. Methods The study was conducted between 2009 and 2019 on 845 LABC patients at the Cancer Research Center of Shahid Beheshti University of Medical Sciences in Iran. All patients with LABC at stages 3A, 3B, and two were evaluated for treatment with adjuvants (n = 520 female patients) and neoadjuvant (n = 320 female patients) treatment strategies. Patients were followed up for at least 120 months. The Kaplan-Meier method calculated the survival rate using SPSS version 23 software. Result The 5 and 10 years survival rates of neoadjuvant and adjuvant groups were 87 ± 0.04, 80 ± 0.07% and 87 ± 0.02, 83 ± 0.03%, respectively. Statistical analysis results with the mentioned treatment strategies did not show any significant difference in overall survival. Conclusion The result of this study on LABC patients demonstrated that compared to surgery first following adjuvant chemotherapy, the neoadjuvant chemotherapy has several benefits, including downstaging and more BCS, with no statistically significant difference in the overall survival rate of the patients.
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Affiliation(s)
| | - Mousa Ghelichi-Ghojogh
- Metabolic Disorders Research Center, Golestan University of Medical Science, Gorgan, Iran
| | - Zahra Nikeghbalian
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Karami
- School of Nursing & Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Akbari
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Islamic Azad University, Tehran Medical Sciences, Tehran, Iran
| | - Saghi Nooraei
- National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mohsen Ghiasi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Fararouei
- HIV/ADIS Research Center, Shiraz University of Medical Science, Shiraz, Iran
| | - Farid Moradian
- Department of General Surgery, Alborz University of Medical Science, Alborz, Iran
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15
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Gastric Cancer Risk and Pathogenesis in BRCA1 and BRCA2 Carriers. Cancers (Basel) 2022; 14:cancers14235953. [PMID: 36497436 PMCID: PMC9736932 DOI: 10.3390/cancers14235953] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/03/2022] Open
Abstract
Carriers of a pathogenic germline variant (PV) in BRCA1 or BRCA2 are at increased risk for a number of malignancies, including breast, ovarian, pancreatic, and prostate cancer. In this review, we discuss emerging evidence that BRCA2 PV carriers, and likely also BRCA1 PV carriers, are also at increased risk for gastric cancer (GC), highlighting that GC may be part of the BRCA1/2 cancer risk spectrum. While the pathogenesis of GC among BRCA1/2 PV carriers remains unclear, increasing evidence reveals that GCs are often enriched with mutations in homologous recombination-associated genes such as BRCA1/2, and that GC prognosis and response to certain therapies can depend on BRCA1/2 expression. Given the strength of data published to date, a risk management strategy for GC among BRCA1/2 PV carriers is needed, and herein we also propose a potential strategy for GC risk management in this population. Moving forward, further study is clearly warranted to define the mechanistic relationship between BRCA1/2 PVs and development of GC as well as to determine how GC risk management should be factored into the clinical care of BRCA1/2 carriers.
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16
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Arai H, Minami Y, Chi S, Utsu Y, Masuda S, Aotsuka N. Molecular-Targeted Therapy for Tumor-Agnostic Mutations in Acute Myeloid Leukemia. Biomedicines 2022; 10:3008. [PMID: 36551764 PMCID: PMC9775249 DOI: 10.3390/biomedicines10123008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/09/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022] Open
Abstract
Comprehensive genomic profiling examinations (CGPs) have recently been developed, and a variety of tumor-agnostic mutations have been detected, leading to the development of new molecular-targetable therapies across solid tumors. In addition, the elucidation of hereditary tumors, such as breast and ovarian cancer, has pioneered a new age marked by the development of new treatments and lifetime management strategies required for patients with potential or presented hereditary cancers. In acute myeloid leukemia (AML), however, few tumor-agnostic or hereditary mutations have been the focus of investigation, with associated molecular-targeted therapies remaining poorly developed. We focused on representative tumor-agnostic mutations such as the TP53, KIT, KRAS, BRCA1, ATM, JAK2, NTRK3, FGFR3 and EGFR genes, referring to a CGP study conducted in Japan, and we considered the possibility of developing molecular-targeted therapies for AML with tumor-agnostic mutations. We summarized the frequency, the prognosis, the structure and the function of these mutations as well as the current treatment strategies in solid tumors, revealed the genetical relationships between solid tumors and AML and developed tumor-agnostic molecular-targeted therapies and lifetime management strategies in AML.
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Affiliation(s)
- Hironori Arai
- Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Iidacho 286-0041, Japan
- Department of Hematology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - Yosuke Minami
- Department of Hematology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - SungGi Chi
- Department of Hematology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - Yoshikazu Utsu
- Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Iidacho 286-0041, Japan
| | - Shinichi Masuda
- Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Iidacho 286-0041, Japan
| | - Nobuyuki Aotsuka
- Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Iidacho 286-0041, Japan
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17
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van der Wiel AMA, Schuitmaker L, Cong Y, Theys J, Van Hoeck A, Vens C, Lambin P, Yaromina A, Dubois LJ. Homologous Recombination Deficiency Scar: Mutations and Beyond-Implications for Precision Oncology. Cancers (Basel) 2022; 14:cancers14174157. [PMID: 36077694 PMCID: PMC9454578 DOI: 10.3390/cancers14174157] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 02/05/2023] Open
Abstract
Homologous recombination deficiency (HRD) is a prevalent in approximately 17% of tumors and is associated with enhanced sensitivity to anticancer therapies inducing double-strand DNA breaks. Accurate detection of HRD would therefore allow improved patient selection and outcome of conventional and targeted anticancer therapies. However, current clinical assessment of HRD mainly relies on determining germline BRCA1/2 mutational status and is insufficient for adequate patient stratification as mechanisms of HRD occurrence extend beyond functional BRCA1/2 loss. HRD, regardless of BRCA1/2 status, is associated with specific forms of genomic and mutational signatures termed HRD scar. Detection of this HRD scar might therefore be a more reliable biomarker for HRD. This review discusses and compares different methods of assessing HRD and HRD scar, their advances into the clinic, and their potential implications for precision oncology.
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Affiliation(s)
- Alexander M. A. van der Wiel
- The M-Lab, Department of Precision Medicine, GROW—School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Lesley Schuitmaker
- The M-Lab, Department of Precision Medicine, GROW—School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Ying Cong
- The M-Lab, Department of Precision Medicine, GROW—School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Jan Theys
- The M-Lab, Department of Precision Medicine, GROW—School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Arne Van Hoeck
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
| | - Conchita Vens
- Institute of Cancer Science, University of Glasgow, Glasgow G61 1BD, Scotland, UK
- Department of Radiation Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Philippe Lambin
- The M-Lab, Department of Precision Medicine, GROW—School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Ala Yaromina
- The M-Lab, Department of Precision Medicine, GROW—School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Ludwig J. Dubois
- The M-Lab, Department of Precision Medicine, GROW—School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
- Correspondence:
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18
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Abdel-Razeq H, Khalil H, Assi HI, Dargham TB. Treatment Strategies for Residual Disease following Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer. Curr Oncol 2022; 29:5810-5822. [PMID: 36005196 PMCID: PMC9406771 DOI: 10.3390/curroncol29080458] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally advanced disease and patients with poor pathological features, such as triple-negative (TN) or human epidermal growth factor receptor-2 (HER2)-positive subtypes. Neoadjuvant therapy offers several advantages, including better surgical outcomes, early systemic treatment for micro-metastases, and accurate tumor biology and chemosensitivity assessment. Multiple studies have shown that achieving pathological complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis and better treatment outcomes; almost half of such patients may fail to achieve pCR. Tumor proliferative index, hormone receptor (HR) status, and HER2 expression are the major predictors of pCR. Strategies to improve pCR have been dependent on augmenting neoadjuvant chemotherapy with the addition of taxanes and dual anti-HER2 targeted therapy in patients with HER2-positive tumor, and more recently, immunotherapy for patients with TN disease. The clinical management of patients with residual disease following neoadjuvant chemotherapy varies and depends mostly on the level of HR expression and HER2 status. Recent data have suggested that switching trastuzumab to trastuzumab-emtansine (T-DM1) in patients with HER2-positive disease and the addition of capecitabine for patients with HER2-negative and HR-negative subtype is associated with a better outcome; both strategies are incorporated into current clinical practice guidelines. This paper reviews available and ongoing studies addressing strategies to better manage patients who continue to have residual disease following neoadjuvant chemotherapy.
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Affiliation(s)
- Hikmat Abdel-Razeq
- Department of Internal Medicine, King Hussein Cancer Center, Amman 11941, Jordan
- School of Medicine, University of Jordan, Amman 11941, Jordan
| | - Hanan Khalil
- Department of Internal Medicine, King Hussein Cancer Center, Amman 11941, Jordan
| | - Hazem I. Assi
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut 1107, Lebanon
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Pinilla K, Drewett LM, Lucey R, Abraham JE. Precision Breast Cancer Medicine: Early Stage Triple Negative Breast Cancer-A Review of Molecular Characterisation, Therapeutic Targets and Future Trends. Front Oncol 2022; 12:866889. [PMID: 36003779 PMCID: PMC9393396 DOI: 10.3389/fonc.2022.866889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 05/23/2022] [Indexed: 11/29/2022] Open
Abstract
Personalised approaches to the management of all solid tumours are increasing rapidly, along with wider accessibility for clinicians. Advances in tumour characterisation and targeted therapies have placed triple-negative breast cancers (TNBC) at the forefront of this approach. TNBC is a highly heterogeneous disease with various histopathological features and is driven by distinct molecular alterations. The ability to tailor individualised and effective treatments for each patient is of particular importance in this group due to the high risk of distant recurrence and death. The mainstay of treatment across all subtypes of TNBC has historically been cytotoxic chemotherapy, which is often associated with off-target tissue toxicity and drug resistance. Neoadjuvant chemotherapy is commonly used as it allows close monitoring of early treatment response and provides valuable prognostic information. Patients who achieve a complete pathological response after neoadjuvant chemotherapy are known to have significantly improved long-term outcomes. Conversely, poor responders face a higher risk of relapse and death. The identification of those subgroups that are more likely to benefit from breakthroughs in the personalised approach is a challenge of the current era where several targeted therapies are available. This review presents an overview of contemporary practice, and promising future trends in the management of early TNBC. Platinum chemotherapy, DNA damage response (DDR) inhibitors, immune checkpoint inhibitors, inhibitors of the PI3K-AKT-mTOR, and androgen receptor (AR) pathways are some of the increasingly studied therapies which will be reviewed. We will also discuss the growing evidence for less-developed agents and predictive biomarkers that are likely to contribute to the forthcoming advances in this field. Finally, we will propose a framework for the personalised management of TNBC based upon the integration of clinico-pathological and molecular features to ensure that long-term outcomes are optimised.
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Affiliation(s)
- Karen Pinilla
- Precision Breast Cancer Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
- Cancer Research UK Cambridge Centre, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
| | - Lynsey M. Drewett
- Precision Breast Cancer Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Rebecca Lucey
- Precision Breast Cancer Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Jean E. Abraham
- Precision Breast Cancer Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
- Cancer Research UK Cambridge Centre, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
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20
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Xie K, Ren X, Hong X, Zhu S, Wang D, Ye X, Ren X. Platinum-based adjuvant therapy was efficient for triple-negative breast cancer: a meta-analysis from randomized controlled trials. Bioengineered 2022; 13:14827-14839. [PMID: 36278891 PMCID: PMC9601551 DOI: 10.1080/21655979.2022.2115616] [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] [Indexed: 11/02/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer. Neoadjuvant chemotherapy was widely accepted for treating TNBC. This systematic review and meta-analysis aimed to evaluate the efficacy, safety, and survival benefit of platinum-based adjuvant therapy (PBAT) in treating TNBC. The keywords were searched in Medline, Embase, Pubmed, and Cochrane Library database up to July 24, 2022. All the randomized control trials (RCTs) comparing PBAT and non-PBAT in treating TNBC were included in our study. The pathological complete remission (pCR) and complications were compared by odds ratio (OR) and 95% confidence intervals (CIs). The overall survival (OS) and relapse-free survival (RFS) were compared by hazard ratio (HR) and 95% CIs. A total of 19 RCTs were included in our meta-analysis, among which 2,501 patients were treated with PBAT and 2,290 with non-PBAT. The patients treated with PBAT combined a significantly higher pCR rate compared to those patients treated with non-PBAT (49.8% versus 36.4%, OR = 1.27, 95%CI = 1.14-1.43, P < 0.001). Besides, patients treated with PBAT had a significantly better RFS (HR = 0.78, 95%CI = 0.63-0.95, P = 0.016), but not in OS (HR = 0.84, P = 0.304). Although the occurrence of neutropenia and nausea were slightly different between the PBAT group (51.5% and 24.4%) and the non-PBAT group (47.0% and 29.4%), the complications were acceptable in the two treatments groups. Our results demonstrated that TNBC patients treated with PBAT could achieve a higher pCR rate and better RFS benefit without a higher complication rate.Highlights Platinum-based adjuvant therapy provided a higher pCR rate for TNBC.Platinum-based adjuvant therapy prolonged the RFS but without prolongingthe OS.Neutropenia and nausea rate was different between group PBAT and non-PBAT.
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Affiliation(s)
- Kaigang Xie
- Department of General Surgery, the Yinzhou Second Hospital, Ningbo, China
| | - Xuanlei Ren
- Department of General Surgery, the Yinzhou Second Hospital, Ningbo, China
| | - Xiaoming Hong
- Department of General Surgery, the Yinzhou Second Hospital, Ningbo, China,CONTACT Xiaoming Hong Department of General Surgery, the Yinzhou Second Hospital, 998 Qianhe Road, Ningbo, Zhejiang Province315192, China
| | - Shuiyin Zhu
- Department of General Surgery, the Yinzhou Second Hospital, Ningbo, China
| | - Dongjie Wang
- Department of General Surgery, the Yinzhou Second Hospital, Ningbo, China
| | - Xiaoming Ye
- Department of General Surgery, the Yinzhou Second Hospital, Ningbo, China
| | - Xiaoting Ren
- Department of General Surgery, the Yinzhou Second Hospital, Ningbo, China
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21
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Li J, Xu X, Peng X. NDC80 Enhances Cisplatin-resistance in Triple-negative Breast Cancer. Arch Med Res 2022; 53:378-387. [PMID: 35346500 DOI: 10.1016/j.arcmed.2022.03.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/28/2021] [Accepted: 03/04/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUNDS Chemotherapy is a standard systemic treatment option for triple-negative breast cancer (TNBC). Cisplatin has been used to treat TNBC, but frequently leads to cisplatin resistance in patients. The aim of our study was to investigate cisplatin-resistant mechanism in TNBC. MATERIALS AND METHODS To identify the potential genes and pathways relative to cisplatin resistance, GSE103115 data were analyzed by the Limma package and Gene set enrichment analysis (GSEA). TNBC data from TCGA, GSE76250 and GSE115275 datasets were used to calculate NDC80 expression. Immunohistochemistry detected NDC80 protein expression in TNBC tissues from patients before and after cisplatin treatment. After expose to cisplatin treatment, the viability and proliferation of TNBC cells were measured by CCK-8 and colony formation assays, respectively. RESULTS NDC80 was regarded as a cisplatin-resistant gene because after cisplatin treatment NDC80 was downregulated in cisplatin-sensitive cells but was upregulated in cisplatin-resistant cells. NDC80 was over-expressed in TNBC tissues compared to normal tissues. Furthermore, NDC80 expression in TNBC patients was increased after cisplatin treatment. Cisplatin-sensitive TNBC patients showed lower NDC80 expression than cisplatin-resistant patients. Additionally, NDC80 expression was correlated with clinical stages, tumor size and chemotherapy of TNBC patients. Moreover, NDC80 overexpression promoted the viability and proliferation of TNBC cells and enhanced the cells resistance to cisplatin. The potential pathways relative to cisplatin resistance were obtained, such as p53 signaling pathway and Oxidative phosphorylation. CONCLUSION These findings provide new insights for understanding the mechanism of cisplatin resistance in TNBC, and NDC80 may be a potential therapeutic target for TNBC treatment.
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22
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Ryu JM, Choi HJ, Park EH, Kim JY, Lee YJ, Park S, Lee J, Park HK, Nam SJ, Kim SW, Lee JH, Lee JE. Relationship Between Breast and Axillary Pathologic Complete Response According to Clinical Nodal Stage: A Nationwide Study From Korean Breast Cancer Society. J Breast Cancer 2022; 25:94-105. [PMID: 35506578 PMCID: PMC9065358 DOI: 10.4048/jbc.2022.25.e17] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 01/27/2022] [Accepted: 04/03/2022] [Indexed: 12/02/2022] Open
Abstract
Purpose We evaluated the relationship between breast pathologic complete response (BpCR) and axillary pathologic complete response (ApCR) after neoadjuvant chemotherapy (NACT) according to nodal burden at presentation. As the indications for NACT have expanded, clinicians have started clinical trials for the omission of surgery from the treatment plan in patients with excellent responses to NACT. However, the appropriate indications for axillary surgery omission after excellent NACT response remain unclear. Methods Data were collected from patients in the Korean Breast Cancer Society Registry who underwent NACT followed by surgery between 2010 and 2020. We analyzed pathologic axillary nodal positivity after NACT according to BpCR stratified by tumor subtype in patients with cT1-3/N0-2 disease at diagnosis. Results A total of 6,597 patients were identified. Regarding cT stage, 528 (9.5%), 3,778 (67.8%), and 1,268 (22.7%) patients had cT1, cT2, and cT3 disease, respectively. Regarding cN stage, 1,539 (27.7%), 2,976 (53.6%), and 1,036 (18.7%) patients had cN0, cN1, and cN2 disease, respectively. BpCR occurred in 21.6% (n = 1,427) of patients, while ApCR and pathologic complete response (ypCR) occurred in 59.7% (n = 3,929) and ypCR 19.4% (n = 1,285) of patients, respectively. The distribution of biologic subtypes included 2,329 (39.3%) patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative disease, 1,122 (18.9%) with HR-positive/HER2-positive disease, 405 (6.8%) with HR-negative/HER2-positive disease, and 2,072 (35.0%) with triple-negative breast cancer . Among the patients with BpCR, 89.6% (1,122/1,252) had ApCR. Of those with cN0 disease, most (99.0%, 301/304) showed ApCR. Among patients with cN1-2 disease, 86.6% (821/948) had ApCR. Conclusion BpCR was highly correlated with ApCR after NACT. In patients with cN0 and BpCR, the risk of missing axillary nodal metastasis was low after NACT. Further research on axillary surgery omission in patients with cN0 disease is needed.
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Affiliation(s)
- Jai Min Ryu
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Jun Choi
- Department of Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Eun Hwa Park
- Department of Surgery, Dong-A University Hospital, Dong-A University College of Medicine, Busan, Korea
| | - Ji Young Kim
- Department of Surgery, Ajou University Hospital, Suwon, Korea
| | - Young Joo Lee
- Department of Surgery, Asan Medical Center, Seoul, Korea
| | - Seho Park
- Division of Breast Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jeeyeon Lee
- Division of Breast Surgery, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Heung Kyu Park
- Department of Breast Cancer Surgery, Gachon University Gil Medical Center, Incheon, Korea
| | - Seok Jin Nam
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seok Won Kim
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jun-Hee Lee
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeong Eon Lee
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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23
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Shafaee MN, Makawita S, Lim B, Ellis MJ, Ducan DL, Ludwig MS, Duncan DL. Concurrent Chemo-radiation As a Means of Achieving Pathologic Complete Response in Triple Negative Breast Cancer. Clin Breast Cancer 2021; 22:e536-e543. [DOI: 10.1016/j.clbc.2021.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 11/16/2021] [Accepted: 12/03/2021] [Indexed: 11/03/2022]
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24
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Metzger-Filho O, Collier K, Asad S, Ansell PJ, Watson M, Bae J, Cherian M, O'Shaughnessy J, Untch M, Rugo HS, Huober JB, Golshan M, Sikov WM, von Minckwitz G, Rastogi P, Li L, Cheng L, Maag D, Wolmark N, Denkert C, Symmans WF, Geyer CE, Loibl S, Stover DG. Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness. NPJ Breast Cancer 2021; 7:142. [PMID: 34764307 PMCID: PMC8586340 DOI: 10.1038/s41523-021-00349-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 10/11/2021] [Indexed: 12/31/2022] Open
Abstract
In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.
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Affiliation(s)
| | - Katharine Collier
- Department of Medicine, The Ohio State University College of Medicine, Columbus, OH, USA
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Sarah Asad
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | | | - Mark Watson
- Washington University School of Medicine, St. Louis, MO, USA
| | - Junu Bae
- Department of Medicine, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Mathew Cherian
- Department of Medicine, The Ohio State University College of Medicine, Columbus, OH, USA
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Joyce O'Shaughnessy
- Baylor University Medical Center, Texas Oncology, U.S. Oncology, Dallas, TX, USA
| | | | - Hope S Rugo
- University of California, San Francisco, San Francisco, CA, USA
| | | | - Mehra Golshan
- Department of Surgery, Yale Cancer Center, New Haven, CT, USA
| | - William M Sikov
- Women and Infants Hospital of Rhode Island, Providence, RI, USA
| | | | - Priya Rastogi
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Lang Li
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA
| | - Lijun Cheng
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA
| | | | | | - Carsten Denkert
- Institute of Pathology, Philipps-University Marburg and University Hospital Marburg (UKGM), Marburg, Germany
| | - W Fraser Symmans
- University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Charles E Geyer
- Virginia Commonwealth University Massey Cancer Center, Richmond, VA, USA
- Houston Methodist, Houston, TX, USA
| | | | - Daniel G Stover
- Department of Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
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25
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Chowdhury P, Ghosh U, Samanta K, Jaggi M, Chauhan SC, Yallapu MM. Bioactive nanotherapeutic trends to combat triple negative breast cancer. Bioact Mater 2021; 6:3269-3287. [PMID: 33778204 PMCID: PMC7970221 DOI: 10.1016/j.bioactmat.2021.02.037] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 02/27/2021] [Accepted: 02/28/2021] [Indexed: 02/09/2023] Open
Abstract
The management of aggressive breast cancer, particularly, triple negative breast cancer (TNBC) remains a formidable challenge, despite treatment advancement. Although newer therapies such as atezolizumab, olaparib, and sacituzumab can tackle the breast cancer prognosis and/or progression, but achieved limited survival benefit(s). The current research efforts are aimed to develop and implement strategies for improved bioavailability, targetability, reduce systemic toxicity, and enhance therapeutic outcome of FDA-approved treatment regimen. This review presents various nanoparticle technology mediated delivery of chemotherapeutic agent(s) for breast cancer treatment. This article also documents novel strategies to employ cellular and cell membrane cloaked (biomimetic) nanoparticles for effective clinical translation. These technologies offer a safe and active targeting nanomedicine for effective management of breast cancer, especially TNBC.
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Affiliation(s)
- Pallabita Chowdhury
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Upasana Ghosh
- Department of Biomedical Engineering, School of Engineering, Rutgers University, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Kamalika Samanta
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Meena Jaggi
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C. Chauhan
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Murali M. Yallapu
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
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Saleh RR, Nadler MB, Desnoyers A, Meti N, Fazelzad R, Amir E. Platinum-based chemotherapy in early-stage triple negative breast cancer: A meta-analysis. Cancer Treat Rev 2021; 100:102283. [PMID: 34530283 DOI: 10.1016/j.ctrv.2021.102283] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 08/11/2021] [Accepted: 08/16/2021] [Indexed: 12/23/2022]
Abstract
PURPOSE The addition of platinum agents to anthracycline and taxane-based chemotherapy in early-stage triple negative breast cancer (TNBC) patients improves pathological complete response (pCR). Long-term outcomes, such as disease-free survival (DFS) and overall survival (OS), have not been well-established. METHODS A systematic literature review identified studies using platinum-based treatment in TNBC patients in the neoadjuvant or adjuvant setting with reportable long-term outcomes. Hazard ratios (HR) from collected data were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on treatment setting and study design. RESULTS Fourteen studies comprising 3518 patients met the inclusion criteria. Median follow up was 56.2 months. All studies reported DFS and 9 studies (64%) reported OS. DFS was significantly better in platinum-based treatment (HR 0.71, 95% confidence interval (CI) 0.56-0.89; p = 0.03). However, OS was no different (HR 0.98, 95% CI 0.75-1.27; p = 0.87). There was a non-significant difference between platinum exposure in the adjuvant compared to neoadjuvant setting for both DFS (HR 0.75 vs 0.62, p = 0.43) and for OS (HR 0.90 vs 1.10, p = 0.58). The addition of platinum was associated with more thrombocytopenia and all-grade neuropathy and non-significant increases in neutropenia and grade 3-4 neuropathy. CONCLUSIONS Platinum-based treatment improves DFS but not OS. The reporting of toxicity was suboptimal, but in general adding platinum increased toxicity. The discordant effect of platinum-based treatment on DFS and OS suggest the potential development of platinum resistance and worse outcomes after recurrence. Platinum-based chemotherapy cannot be recommended in unselected patients with early TNBC.
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Affiliation(s)
- Ramy R Saleh
- Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada
| | - Michelle B Nadler
- Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada
| | - Alexandra Desnoyers
- Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada
| | - Nicholas Meti
- Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada
| | - Rouhi Fazelzad
- Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada; Information Specialist, Library and Information Services, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Eitan Amir
- Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada.
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27
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Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer. Breast Cancer Res Treat 2021; 189:187-202. [PMID: 34173924 DOI: 10.1007/s10549-021-06307-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 06/18/2021] [Indexed: 12/31/2022]
Abstract
PURPOSE Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin and to identify molecular alterations and/or immune gene signatures predicting pCR. EXPERIMENTAL DESIGN Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole-exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles. RESULTS Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend toward higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80 versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteasome were upregulated in pre-treatment samples from patients who achieved pCR. CONCLUSION Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR. TRIAL REGISTRATION Clinical trial information: NCT02124902, Registered 24 April 2014 & NCT02547987, Registered 10 September 2015.
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28
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Lou SK, Grenier S, Care M, McCuaig J, Stockley TL, Clarke B, Ruff HM, Boerner SL. Validation of BRCA testing on cytologic samples of high-grade serous carcinoma. Cancer Cytopathol 2021; 129:907-913. [PMID: 34157791 DOI: 10.1002/cncy.22484] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/22/2021] [Accepted: 05/26/2021] [Indexed: 01/30/2023]
Abstract
BACKGROUND Testing for BRCA1/2 gene alterations in patients with high-grade serous carcinoma (HGSC) is a critical determinant of treatment eligibility for poly(adenosine diphosphate-ribose) polymerase inhibitors in addition to providing vital information for genetic counselling. Many patients present with effusions necessitating therapeutic drainage, and this makes cytologic specimens (CySs) the initial diagnostic material for HGSC, often before histologic sampling. Initiating somatic BRCA testing on a CyS allows the BRCA status to be determined sooner, and this affects clinical management. METHODS Retrospectively, 8 cases of formalin-fixed, paraffin-embedded (FFPE) CySs of peritoneal or pleural fluid from patients with HGSC and known BRCA1/2 alterations previously established by the testing of FFPE surgical specimens (SpSs) underwent next-generation sequencing (NGS). Prospectively, 11 cases of peritoneal or pleural fluid from patients with HGSC but an unknown BRCA1/2 status underwent NGS with fresh, alcohol-fixed, and FFPE CySs, and they were compared with subsequent NGS on 4 SpSs. RESULTS CySs yielded high-quantity and high-quality DNA for NGS analysis when sufficient tumor cellularity was present. Fresh, alcohol-fixed, and FFPE CySs were all suitable for NGS and provided identical NGS results. SpS and CyS BRCA testing was concordant in 10 of 12 cases. The 2 discordant cases showed low tumor cellularity and quality in the CyS and the SpS, respectively. CONCLUSION Effusion CySs of HGSC are excellent sources for NGS testing for BRCA1/2 genetic alterations when sufficient tumor cellularity is present. Fresh, alcohol-fixed, and FFPE CySs are equivalent for NGS of BRCA1/2. NGS testing of HGSC CySs demonstrates good concordance with SpSs for the BRCA1/2 status.
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Affiliation(s)
- Si Kei Lou
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Sylvie Grenier
- Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Melanie Care
- Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Jeanna McCuaig
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.,Familial Cancer Clinic, Princess Margaret Hospital Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada
| | - Tracy L Stockley
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Blaise Clarke
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Heather M Ruff
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Scott L Boerner
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
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29
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Koh MZ, Ho WY, Yeap SK, Ali NM, Boo L, Alitheen NB. Regulation of Cellular and Cancer Stem Cell-Related Putative Gene Expression of Parental and CD44 +CD24 - Sorted MDA-MB-231 Cells by Cisplatin. Pharmaceuticals (Basel) 2021; 14:ph14050391. [PMID: 33919109 PMCID: PMC8143088 DOI: 10.3390/ph14050391] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/04/2021] [Accepted: 04/13/2021] [Indexed: 01/16/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that promotes a higher risk of metastasis and cancer reoccurrence. Cisplatin is one of the potential anticancer drugs for treating TNBC. However, the occurrence of cisplatin resistance still remains one of the challenges in fully eradicating TNBC. The presence of cancer stem cells (CSCs) has been proposed as one of the factors contributing to the development of cisplatin resistance. In this study, we aimed to characterize the cellular properties and reveal the corresponding putative target genes involved in cisplatin resistance associated with CSCs using the TNBC cell line (MDA-MB-231). CSC-like cells were isolated from parental cells and the therapeutic effect of cisplatin on CSC-like cells was compared to that of the parental cells via cell characterization bioassays. A PCR array was then conducted to study the expression of cellular mRNA for each subpopulation. As compared to treated parental cells, treated CSCs displayed lower events of late apoptosis/necrosis and G2/M phase cell arrest, with higher mammosphere formation capacity. Furthermore, a distinct set of putative target genes correlated to the Hedgehog pathway and angiogenesis were dysregulated solely in CSC-like cells after cisplatin treatment, which were closely related to the regulation of chemoresistance and self-renewability in breast cancer. In summary, both cellular and gene expression studies suggest the attenuated cytotoxicity of cisplatin in CSC-like cells as compared to parental cells. Understanding the role of dysregulated putative target genes induced by cisplatin in CSCs may aid in the potential development of therapeutic targets for cisplatin-resistant breast cancer.
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Affiliation(s)
- May Zie Koh
- Faculty of Sciences and Engineering, University of Nottingham Malaysia, Semenyih 43500, Malaysia;
| | - Wan Yong Ho
- Faculty of Sciences and Engineering, University of Nottingham Malaysia, Semenyih 43500, Malaysia;
- Correspondence: (W.Y.H.); (S.K.Y.)
| | - Swee Keong Yeap
- China-ASEAN College of Marine Sciences, Xiamen University Malaysia, Sepang 43900, Malaysia
- Correspondence: (W.Y.H.); (S.K.Y.)
| | - Norlaily Mohd Ali
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras 43000, Malaysia; (N.M.A.); (L.B.)
| | - Lily Boo
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras 43000, Malaysia; (N.M.A.); (L.B.)
| | - Noorjahan Banu Alitheen
- Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia;
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Riis M. Management of patients with BRCA mutation from the point of view of a breast surgeon. Ann Med Surg (Lond) 2021; 65:102311. [PMID: 33996049 PMCID: PMC8091883 DOI: 10.1016/j.amsu.2021.102311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 12/24/2022] Open
Abstract
Germ-line mutation in BRCA (BReast CAncer gene) 1 or BRCA2 are found in 3–4% of all women with breast cancer. These patients have a significant increased risk of breast and ovarian cancer. They are often younger when diagnosed with the mutation, and the possible breast cancer they get is often aggressive with inferior outcome. There are risk reducing strategies, and the most powerful strategy is risk reducing surgery, both risk reducing bilateral mastectomy (RRM) and risk reducing bilateral salpino-oophorectomy (PBSO). This review is meant to address breast surgery in patients with germline BRCA mutation. The guidelines and techniques applied is under continuous change and it is important for the clinicians to be well informed to provide the patient with the information needed for them to make an informed decision on what risk strategy to choose.
Patients with germ-line mutation in BRCA1 or BRCA2 have a significant increased risk of breast and ovarian cancer. There are different risk reducing strategies and the most powerful strategy is risk-reducing surgery, both risk reducing bilateral mastectomy and risk reducing bilateral salpingo-oophorectomy. Guidelines and techniques for the risk reducing surgery of the breast are under continuous change and improvement. Breast conserving therapy is not associated with worse survival and is a good option for a BRCA mutation carrier diagnosed with breast cancer. Risk-reducing mastectomy can be performed in a later setting. The management of BRCA mutation carriers, both affected and unaffected, should be performed in a multidisciplinary team. Physicians need to be systematically educated and updated on the most recent literature.
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Clinical utility of ABCB1 and ABCG2 genotyping for assessing the clinical and pathological response to FAC therapy in Mexican breast cancer patients. Cancer Chemother Pharmacol 2021; 87:843-853. [PMID: 33740100 DOI: 10.1007/s00280-021-04244-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 02/05/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Resistance to neoadjuvant chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) in some patients with locally advanced breast cancer remains one of the main obstacles to first-line treatment. We investigated clinical and pathological responses to FAC neoadjuvant chemotherapy in Mexican women with breast cancer and their possible association with SNPs present in ABC transporters as predictors of chemoresistance. MATERIALS A total of 102 patients undergoing FAC neoadjuvant chemotherapy were included in the study. SNP analysis was performed by RT-PCR from genomic DNA. Two SNPs were analyzed: ABCB1 rs1045642 (3435 C > T) and ABCG2 rs2231142 (421 G > T). RESULTS In clinical response evaluation, significant associations were found between the ABCB1 C3435T genotype and breast cancer chemoresistant and chemosensitive patients (p < 0.05). In the early clinical response, patients with genotype C/C or C/T were more likely to be chemosensitive to neoadjuvant therapy than patients with genotype T/T (OR = 4.055; p = 0.0064). Association analysis between the ABCB1 gene polymorphism and the pathologic response to FAC chemotherapy showed that the C/C + C/T genotype was a protective factor against chemoresistance (OR = 3.714; p = 0.0104). Polymorphisms in ABCG2 indicated a lack of association with resistance to chemotherapy (p = 0.2586) evaluating the clinical or pathological response rate to FAC neoadjuvant chemotherapy. CONCLUSION The early clinical response and its association with SNPs in the ABCB1 transporter are preserved until the pathological response to neoadjuvant chemotherapy; therefore, it could be used as a predictor of chemoresistance in locally advanced breast cancer patients of the Mexican population.
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Ali RMM, McIntosh SA, Savage KI. Homologous recombination deficiency in breast cancer: Implications for risk, cancer development, and therapy. Genes Chromosomes Cancer 2020; 60:358-372. [DOI: 10.1002/gcc.22921] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 11/23/2020] [Indexed: 12/19/2022] Open
Affiliation(s)
- Rayhaan M. M. Ali
- Patrick G Johnston Centre for Cancer Research Queen's University Belfast Belfast UK
| | - Stuart A. McIntosh
- Patrick G Johnston Centre for Cancer Research Queen's University Belfast Belfast UK
| | - Kienan I. Savage
- Patrick G Johnston Centre for Cancer Research Queen's University Belfast Belfast UK
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Mutations of Brca1 gene in a tumor tissue and effectiveness of preoperative taxotere therapy in patients with luminal B breast cancer. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Trusler O, Goodwin J, Laslett AL. BRCA1 and BRCA2 associated breast cancer and the roles of current modelling systems in drug discovery. Biochim Biophys Acta Rev Cancer 2020; 1875:188459. [PMID: 33129865 DOI: 10.1016/j.bbcan.2020.188459] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 10/18/2020] [Accepted: 10/20/2020] [Indexed: 02/08/2023]
Abstract
For a drug candidate to be fully developed takes years and investment of hundreds of millions of dollars. There is no doubt that drug development is difficult and risky, but vital to protecting against devastating disease. This difficulty is clearly evident in BRCA1 and BRCA2 related breast cancer, with current treatment options largely confined to invasive surgical procedures, as well as chemotherapy and radiotherapy regimes which damage healthy tissue and can leave remnant disease. Consequently, patient survival and relapse rates are far from ideal, and new candidate treatments are needed. The preclinical stages of drug discovery are crucial to get right for translation to hospital beds. Disease models must take advantage of current technologies and be accurate for rapid and translatable treatments. Careful selection of cell lines must be coupled with high throughput techniques, with promising results trialled further in highly accurate humanised patient derived xenograft models. Traditional adherent drug screening should transition to 3D culture systems amenable to high throughput techniques if the gap between in vitro and in vivo studies is to be partially bridged. The possibility of organoid, induced pluripotent stem cell, and conditionally reprogrammed in vitro models is tantalising, however protocols are yet to be fully established. This review of BRCA1 and BRCA2 cancer biology and current modelling systems will hopefully guide the design of future drug discovery endeavours and highlight areas requiring improvement.
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Affiliation(s)
- Oliver Trusler
- CSIRO Manufacturing, Clayton, Victoria 3168, Australia; Australian Regenerative Medicine Institute, Monash University, Victoria 3800, Australia
| | - Jacob Goodwin
- CSIRO Manufacturing, Clayton, Victoria 3168, Australia; Australian Regenerative Medicine Institute, Monash University, Victoria 3800, Australia
| | - Andrew L Laslett
- CSIRO Manufacturing, Clayton, Victoria 3168, Australia; Australian Regenerative Medicine Institute, Monash University, Victoria 3800, Australia.
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El Adoui M, Drisis S, Benjelloun M. Multi-input deep learning architecture for predicting breast tumor response to chemotherapy using quantitative MR images. Int J Comput Assist Radiol Surg 2020; 15:1491-1500. [DOI: 10.1007/s11548-020-02209-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/01/2020] [Indexed: 12/13/2022]
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The circadian clock gene Bmal1 facilitates cisplatin-induced renal injury and hepatization. Cell Death Dis 2020; 11:446. [PMID: 32522976 PMCID: PMC7287064 DOI: 10.1038/s41419-020-2655-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 05/26/2020] [Accepted: 05/27/2020] [Indexed: 12/13/2022]
Abstract
Cisplatin is one of the most potent chemotherapy drugs to treat cancers, but its clinical application remains limited due to severe nephrotoxicity. Several approaches have been developed to minimize such side effects, notably including chronotherapy, a well-known strategy based on the circadian clock. However, the component of the circadian clock machinery that particularly responses to the cisplatin stimulation remains unknown, including its functions in cisplatin-induced renal injury. In our present study, we demonstrated that Bmal1, as a key clock gene, was induced by the cisplatin stimulation in the mouse kidney and cultured human HK-2 renal cells. Gain- and loss-of-function studies indicated that Bmal1 facilitated cisplatin-induced renal injury both in vivo and in vitro, by aggravating the cell apoptotic process. More importantly, RNA-seq analysis revealed that Bmal1 triggered the expression of hallmark genes involved in renal hepatization, a critical event accompanied by the injury. At the molecular level, Bmal1 activated the transcription of hepatization-associated genes through direct recruitment to the E-box motifs of their promoters. Our findings suggest that Bmal1, a pivotal mediator induced renal injury in response to cisplatin treatment, and the therapeutic intervention targeting Bmal1 in the kidney may be a promising strategy to minimize the toxic side-effects of cisplatin in its clinical applications.
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Vidula N, Rich TA, Sartor O, Yen J, Hardin A, Nance T, Lilly MB, Nezami MA, Patel SP, Carneiro BA, Fan AC, Brufsky AM, Parker BA, Bridges BB, Agarwal N, Maughan BL, Raymond VM, Fairclough SR, Lanman RB, Bardia A, Cristofanilli M. Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion BRCA Mutations among Patients with Advanced Solid Tumors. Clin Cancer Res 2020; 26:2546-2555. [DOI: 10.1158/1078-0432.ccr-19-2933] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 12/17/2019] [Accepted: 02/03/2020] [Indexed: 11/16/2022]
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Klinakis A, Karagiannis D, Rampias T. Targeting DNA repair in cancer: current state and novel approaches. Cell Mol Life Sci 2020; 77:677-703. [PMID: 31612241 PMCID: PMC11105035 DOI: 10.1007/s00018-019-03299-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 08/06/2019] [Accepted: 09/09/2019] [Indexed: 12/12/2022]
Abstract
DNA damage response, DNA repair and genomic instability have been under study for their role in tumor initiation and progression for many years now. More recently, next-generation sequencing on cancer tissue from various patient cohorts have revealed mutations and epigenetic silencing of various genes encoding proteins with roles in these processes. These findings, together with the unequivocal role of DNA repair in therapeutic response, have fueled efforts toward the clinical exploitation of research findings. The successful example of PARP1/2 inhibitors has also supported these efforts and led to numerous preclinical and clinical trials with a large number of small molecules targeting various components involved in DNA repair singularly or in combination with other therapies. In this review, we focus on recent considerations related to DNA damage response and new DNA repair inhibition agents. We then discuss how immunotherapy can collaborate with these new drugs and how epigenetic drugs can rewire the activity of repair pathways and sensitize cancer cells to DNA repair inhibition therapies.
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Affiliation(s)
- Apostolos Klinakis
- Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece.
| | - Dimitris Karagiannis
- Department of Genetics and Development, Columbia University Medical Center, New York, NY, 10032, USA
| | - Theodoros Rampias
- Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece.
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Azim HA, Ghosn M, Oualla K, Kassem L. Personalized treatment in metastatic triple-negative breast cancer: The outlook in 2020. Breast J 2019; 26:69-80. [PMID: 31872557 DOI: 10.1111/tbj.13713] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 12/04/2019] [Indexed: 12/15/2022]
Abstract
Compared with other breast cancer subtypes, patients with triple-negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This-in return-has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti-PD-L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key-practice changing-clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.
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Affiliation(s)
- Hamdy A Azim
- Clinical Oncology Department, Kasr Alainy School of Medicine, Cairo University, Giza, Egypt.,Clinical Oncology Department, Cairo Oncology Center, Cairo, Egypt
| | - Marwan Ghosn
- Hotel Dieu de France University Hospital and Saint Joseph University, Beirut, Lebanon
| | - Karima Oualla
- Medical Oncology Department, Hassan II University Hospital, Fes, Morocco
| | - Loay Kassem
- Clinical Oncology Department, Kasr Alainy School of Medicine, Cairo University, Giza, Egypt.,Clinical Oncology Department, Cairo Oncology Center, Cairo, Egypt
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Díaz-Casas SE, Castilla-Tarra JA, Pena-Torres E, Orozco-Ospino M, Mendoza-Diaz S, Nuñez-Lemus M, Garcia-Angulo O, Garcia-Mora M, Guzman-AbiSaab L, Lehmann-Mosquera C, Angel-Aristizabal J, Duarte-Torres C, Vergel-Martinez JC. Pathological Response to Neoadjuvant Chemotherapy and the Molecular Classification of Locally Advanced Breast Cancer in a Latin American Cohort. Oncologist 2019; 24:e1360-e1370. [PMID: 31346133 PMCID: PMC6975950 DOI: 10.1634/theoncologist.2019-0300] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 06/27/2019] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND The majority of patients with breast cancer in Colombia are admitted into oncological centers at locally advanced stages of the disease (53.9%). The aim of this study was to describe the pathological response obtained with neoadjuvant chemotherapy (NACT) according to the molecular classification of breast cancer in patients with locally advanced tumors treated within the National Cancer Institute (NCI) Functional Breast Cancer Unit (FBCU) in Bogotá, Colombia. MATERIALS AND METHODS This was an observational, descriptive, historical cohort study of patients with locally advanced breast cancer treated within the NCI FBCU. RESULTS We included 414 patients who received NACT and surgical management. Most patients had luminal B HER2-negative tumors (n = 134, 32.4%). The overall rate of pathological complete response (pCR) ypT0/ypN0 was 15.2% (n = 63). Tumors that presented the highest rate of pCR were pure HER2, at 40.5% (n = 15; odds ratio [OR], 6.7); however, with a follow-up of 60 months, only the triple negative tumors presented a statistically significant difference for event-free survival (EFS; median recurrence time, 18 months; range, 1-46) and overall survival (OS; median follow-up, 31 months; range 10-57). The molecular subtype that most recurrences presented was luminal B HER2 negative, at 38.3% (n = 28). The majority of recurrences (93.2 %; n = 68; OR, 5.9) occurred in patients in whom no pathological response was obtained (Chevallier 3 and 4). CONCLUSION Pathological response in locally advanced tumors is related to the molecular subtype of breast cancer, finding higher pCR rates in pure HER2 and triple-negative tumors. A direct relationship was found between disease recurrences and the pathological response, evidencing greater tumor recurrence in patients who did not respond to NACT (Chevallier 3 and 4). EFS and OS were greater in patients with pCR, with statistical significance only in triple-negative tumors. IMPLICATIONS FOR PRACTICE This research article is of scientific interest, because it describes the clinical and pathological features and analyzes the correlation between pathological response to neoadjuvant chemotherapy and the molecular classification of locally advanced breast cancer in patients treated in the National Cancer Institute in Bogotá, Colombia. It was found that pathological response is related to the molecular subtype of breast cancer. In addition, there is a direct relationship between disease recurrences and pathological response. The survival results were greater in patients with pathological complete response.
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Affiliation(s)
| | | | - Esperanza Pena-Torres
- Office of the Deputy Director for Research, Epidemiological Surveillance, Promotion and Prevention, National Cancer Institute, Bogotá, D.C., Colombia
| | - Martha Orozco-Ospino
- Breast and Soft Tissue Clinic, National Cancer Institute, Bogotá, D.C., Colombia
| | - Sara Mendoza-Diaz
- Breast and Soft Tissue Clinic, National Cancer Institute, Bogotá, D.C., Colombia
| | - Marcela Nuñez-Lemus
- Office of the Deputy Director for Research, Epidemiological Surveillance, Promotion and Prevention, National Cancer Institute, Bogotá, D.C., Colombia
| | - Oscar Garcia-Angulo
- Breast and Soft Tissue Clinic, National Cancer Institute, Bogotá, D.C., Colombia
| | - Mauricio Garcia-Mora
- Breast and Soft Tissue Clinic, National Cancer Institute, Bogotá, D.C., Colombia
| | - Luis Guzman-AbiSaab
- Breast and Soft Tissue Clinic, National Cancer Institute, Bogotá, D.C., Colombia
| | | | | | - Carlos Duarte-Torres
- Breast and Soft Tissue Clinic, National Cancer Institute, Bogotá, D.C., Colombia
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Scott D, Friedman S, Telli ML, Kurian AW. Decision Making About Genetic Testing Among Women With a Personal and Family History of Breast Cancer. JCO Oncol Pract 2019; 16:e37-e55. [PMID: 31613719 DOI: 10.1200/jop.19.00221] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE To understand genetic testing use and decision making among patients with high genetic risk. MATERIALS AND METHODS A survey of breast cancer survivors was administered online by a hereditary cancer nonprofit organization, Facing Our Risk of Cancer Empowered, from October 2017 to March 2018. RESULTS Of 1,322 respondents, 46% had breast cancer at age < 45 years, 61% had a first-degree relative with cancer, and 84% underwent genetic testing, of whom 56% had a risk-associated pathogenic variant. Most (86%; 95% CI, 84% to 88%) tested respondents were very satisfied with their testing decision, versus 34% (95% CI, 27% to 41%) of untested respondents. Factors that encouraged testing included relatives' cancer risk (75%; 95% CI, 73% to 78%), clinicians' recommendations (68%; 95% CI, 66% to 71%), and potential treatment implications (67%; 95% CI, 64% to 69%). Factors that discouraged testing included insurance concerns (14%; 95% CI, 12% to 16%), cost (14%; 95% CI, 12% to 16%), and discrimination (9%; 95% CI, 7% to 11%). Thirty-nine percent (95% CI, 36% to 41%) recalled hearing from a clinician that genetic discrimination is illegal. Respondents often recalled clinicians informing them about inheritance patterns (65%; 95% CI, 62% to 67%), surgical implications (65%; 95% CI, 63% to 68%), and other cancer risks (66%; 95% CI, 63% to 68%) but less often that results could have potential implications for clinical trial eligibility (38%; 95% CI, 36% to 42%) or targeted therapies (14%; 95% CI, 12% to 16%). Patients who had genetic counseling were twice as likely to recall clinicians informing them about all queried topics. Results did not vary by diagnosis year. CONCLUSION Among patients with high genetic risk, clinicians' recommendations, potential treatment implications, and protections against discrimination were motivating factors to undergo genetic testing, but fewer than half recalled clinicians providing all this information, and this did not improve over time. Clinicians influence testing decisions and should inform patients about legal protections and treatment implications.
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Affiliation(s)
- Danika Scott
- Stanford University School of Medicine, Stanford, CA
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Abstract
Triple-negative breast cancer (TNBC) is a breast cancer subtype renowned for its capacity to affect younger women, metastasise early despite optimal adjuvant treatment and carry a poor prognosis. Neoadjuvant therapy has focused on combinations of systemic agents to optimise pathological complete response. Treatment algorithms now guide the management of patients with or without residual disease, but metastatic TNBC continues to harbour a poor prognosis. Innovative, multi-drug combination systemic therapies in the neoadjuvant and adjuvant settings have led to significant improvements in outcomes, particularly over the past decade. Recently published advances in the treatment of metastatic TNBC have shown impressive results with poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy agents. Immunotherapy agents in combination with traditional systemic chemotherapy have been shown to alter the natural history of this devastating condition, particularly in patients whose tumours are positive for programmed cell death ligand 1 (PD-L1).
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Affiliation(s)
| | - Sherene Loi
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
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43
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Wang D, Feng J, Xu B. A meta-analysis of platinum-based neoadjuvant chemotherapy versus standard neoadjuvant chemotherapy for triple-negative breast cancer. Future Oncol 2019; 15:2779-2790. [PMID: 31293180 DOI: 10.2217/fon-2019-0165] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 06/20/2019] [Indexed: 01/19/2023] Open
Abstract
Aim: Platinum agents are DNA damaging agents with promising activity in breast cancers, especially in triple-negative subgroup. This meta-analysis was conducted to compare the treatments of platinum-based neoadjuvant chemotherapy (NAC) and standard NAC for triple-negative breast cancers (TNBCs). Materials & methods: Diverse electronic databases were searched to identify the randomized clinical trials that directly compared the treatments of platinum-based NAC versus NAC in TNBC patients. Toxicity of platinum-based regimens was further evaluated. Results: Addition of platinum agents significantly improved the pathological complete response rates in TNBC patients compared with the standard NAC. Unfortunately, platinum-based regimens were more likely to develop higher incidence of hematologic toxicities. Conclusion: Platinum-based NAC regimens could achieve significant pathological complete response improvement with well-tolerated toxicity in TNBC patients.
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Affiliation(s)
- Dong Wang
- Department of General Surgery, Mianyang Central Hospital, Affiliated to Southwest Medical University, Mianyang 621000, Sichuan, PR China
| | - Jiafu Feng
- Department of Clinical Laboratory, Mianyang Central Hospital, Affiliated to Southwest Medical University, Mianyang 621000, Sichuan, PR China
| | - Bei Xu
- Department of Clinical Laboratory, Mianyang Central Hospital, Affiliated to Southwest Medical University, Mianyang 621000, Sichuan, PR China
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Morovati A, Ahmadian S, Jafary H. Cytotoxic effects and apoptosis induction of cisplatin-loaded iron oxide nanoparticles modified with chitosan in human breast cancer cells. Mol Biol Rep 2019; 46:5033-5039. [PMID: 31278563 DOI: 10.1007/s11033-019-04954-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 06/27/2019] [Indexed: 12/01/2022]
Abstract
Cisplatin is widely used as an anticancer drug in chemotherapy of human cancers. In the field of cancer therapy, nanoparticles modified with biocompatible copolymers are suitable vehicles to effectively deliver smaller doses of hydrophobic drugs such as cisplatin in the body. In this study, we investigated whether cisplatin-loaded iron oxide nanoparticles (IONPs) modified with chitosan can exert cytotoxic effects in the human breast cancer cell line MDA-MB-231. IONPs was synthesized using eucalyptus leaf extract as a reducing and stabilizing agent. MDA-MB-231 cells were treated with different concentrations of cisplatin, cisplatin-IONPs and cisplatin-IONPs-chitosan for 24 h. Apoptosis was confirmed by flow cytometry, whereas The mRNA and protein expression of pro- and anti-apoptotic molecules were measured using Real time RT-PCR and western blotting. Treatment with both cisplatin-IONPs and cisplatin-IONPs-chitosan showed a significantly higher cytotoxic effect in comparison to the free drug alone in MDA-MB-231 cells. The levels of apoptosis in cells treated with a combination of cisplatin-IONPs-chitosan were significantly higher compared with cisplatin-IONPs and cisplatin alone. The results of this study showed that the interaction between cisplatin and iron oxide nanoparticles modified with chitosan could enhance responsiveness to cisplatin in breast cancer cells.
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Affiliation(s)
- Ali Morovati
- Department of Biology, Science and Research Branch, Islamic Azad University, P.O. Box 14515-775, Tehran, Iran
| | - Shahin Ahmadian
- Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran.
| | - Hanieh Jafary
- Department of Biology, Science and Research Branch, Islamic Azad University, P.O. Box 14515-775, Tehran, Iran.
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Tacconi EMC, Badie S, De Gregoriis G, Reisländer T, Lai X, Porru M, Folio C, Moore J, Kopp A, Baguña Torres J, Sneddon D, Green M, Dedic S, Lee JW, Batra AS, Rueda OM, Bruna A, Leonetti C, Caldas C, Cornelissen B, Brino L, Ryan A, Biroccio A, Tarsounas M. Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance. EMBO Mol Med 2019; 11:e9982. [PMID: 31273933 PMCID: PMC6609913 DOI: 10.15252/emmm.201809982] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 04/30/2019] [Accepted: 05/03/2019] [Indexed: 01/03/2023] Open
Abstract
Due to compromised homologous recombination (HR) repair, BRCA1- and BRCA2-mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2-deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2-deficient cells, including olaparib-resistant and cisplatin-resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2-deficient xenografts and inhibits growth of olaparib-resistant patient-derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication-associated DNA double-strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2-compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA-deficient tumours.
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MESH Headings
- Animals
- BRCA1 Protein/deficiency
- BRCA2 Protein/deficiency
- Cell Line, Tumor
- Chlorambucil/pharmacology
- Cricetinae
- Drug Delivery Systems
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Male
- Mice
- Mice, SCID
- Peroxisome Proliferator-Activated Receptors/antagonists & inhibitors
- Peroxisome Proliferator-Activated Receptors/metabolism
- Phthalazines/pharmacology
- Piperazines/pharmacology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Eliana MC Tacconi
- Genome Stability and Tumorigenesis GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Sophie Badie
- Genome Stability and Tumorigenesis GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Giuliana De Gregoriis
- Genome Stability and Tumorigenesis GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Timo Reisländer
- Genome Stability and Tumorigenesis GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Xianning Lai
- Genome Stability and Tumorigenesis GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Manuela Porru
- Area of Translational ResearchIRCCS Regina Elena National Cancer InstituteRomeItaly
| | - Cecilia Folio
- Genome Stability and Tumorigenesis GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - John Moore
- Lung Cancer Translational Science Research GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Arnaud Kopp
- Institut de Génétique et de Biologie Cellulaire et Moléculaire (IGBMC)Inserm U1258, CNRS (UMR 7104)Université de StrasbourgIllkirchFrance
| | - Júlia Baguña Torres
- Radiopharmaceuticals and Molecular Imaging GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Deborah Sneddon
- Radiopharmaceuticals and Molecular Imaging GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Marcus Green
- Lung Cancer Translational Science Research GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Simon Dedic
- Genome Stability and Tumorigenesis GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Jonathan W Lee
- Genome Stability and Tumorigenesis GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Ankita Sati Batra
- Department of OncologyCancer Research UK Cambridge InstituteUniversity of CambridgeCambridgeUK
| | - Oscar M Rueda
- Department of OncologyCancer Research UK Cambridge InstituteUniversity of CambridgeCambridgeUK
| | - Alejandra Bruna
- Department of OncologyCancer Research UK Cambridge InstituteUniversity of CambridgeCambridgeUK
| | - Carlo Leonetti
- Area of Translational ResearchIRCCS Regina Elena National Cancer InstituteRomeItaly
| | - Carlos Caldas
- Department of OncologyCancer Research UK Cambridge InstituteUniversity of CambridgeCambridgeUK
| | - Bart Cornelissen
- Radiopharmaceuticals and Molecular Imaging GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Laurent Brino
- Institut de Génétique et de Biologie Cellulaire et Moléculaire (IGBMC)Inserm U1258, CNRS (UMR 7104)Université de StrasbourgIllkirchFrance
| | - Anderson Ryan
- Lung Cancer Translational Science Research GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Annamaria Biroccio
- Area of Translational ResearchIRCCS Regina Elena National Cancer InstituteRomeItaly
| | - Madalena Tarsounas
- Genome Stability and Tumorigenesis GroupDepartment of OncologyThe CR‐UK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
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Aktas BY, Guner G, Guven DC, Arslan C, Dizdar O. Exploiting DNA repair defects in breast cancer: from chemotherapy to immunotherapy. Expert Rev Anticancer Ther 2019; 19:589-601. [PMID: 31181965 DOI: 10.1080/14737140.2019.1631162] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 06/10/2019] [Indexed: 02/08/2023]
Abstract
Introduction: Impaired DNA damage response (DDR) and subsequent genomic instability are associated with the carcinogenic process itself, but it also results in sensitivity of tumor cells to certain drugs and can be exploited to treat cancer by inducing deadly mutations or mitotic catastrophe. Exploiting DDR defects in breast cancer cells has been one of the main strategies in both conventional chemotherapy, targeted therapies, or immunotherapies. Areas covered: In this review, the authors first discuss DDR mechanisms in healthy cells and DDR defects in breast cancer, then focus on current therapies and developments in the treatment of DDR-deficient breast cancer. Expert opinion: Among conventional chemotherapeutics, platinum-based regimens, in particular, seem to be effective in DDR-deficient patients. PARP inhibitors represent one of the successful models of translational research in this area and clinical data showed high efficacy and reasonable toxicity with these agents in patients with breast cancer and BRCA mutation. Recent studies have underlined that some subtypes of breast cancer are highly immunogenic. Promising activity has been shown with immunotherapeutic agents, particularly in DDR-deficient breast cancers. Chemotherapeutics, DNA-repair pathway inhibitors, and immunotherapies might result in further improved outcomes in certain subsets of patients with breast cancer and DDR.
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Affiliation(s)
- Burak Yasin Aktas
- a Department of Medical Oncology , Hacettepe University Cancer Institute , Ankara , Turkey
| | - Gurkan Guner
- a Department of Medical Oncology , Hacettepe University Cancer Institute , Ankara , Turkey
| | - Deniz Can Guven
- a Department of Medical Oncology , Hacettepe University Cancer Institute , Ankara , Turkey
| | - Cagatay Arslan
- b Bahcesehir University , Faculty of Medicine, Department of Internal Medicine and Medical Oncology , Istanbul , Turkey
| | - Omer Dizdar
- a Department of Medical Oncology , Hacettepe University Cancer Institute , Ankara , Turkey
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Cancer Genomics for Oncologists: Cancer Risk and Management of BRCA1 and BRCA2 Carriers. CURRENT GENETIC MEDICINE REPORTS 2019. [DOI: 10.1007/s40142-019-00167-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Deng M, Chen H, Zhu X, Luo M, Zhang K, Xu C, Hu K, Cheng P, Zhou J, Zheng S, Chen Y. Prevalence and clinical outcomes of germline mutations in
BRCA1/2
and
PALB2
genes in 2769 unselected breast cancer patients in China. Int J Cancer 2019; 145:1517-1528. [PMID: 30720863 DOI: 10.1002/ijc.32184] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 12/30/2018] [Accepted: 01/22/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Mei Deng
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
- Department of RadiotherapyAffiliated Hospital, Guilin Medical University Guilin Guangxi China
| | - Hui‐Hui Chen
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
- The Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education Zhejiang Hangzhou China
| | - Xuan Zhu
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
- The Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education Zhejiang Hangzhou China
| | - Meng Luo
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
- The Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education Zhejiang Hangzhou China
| | - Kun Zhang
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
- The Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education Zhejiang Hangzhou China
| | - Chun‐Jing Xu
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
- The Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education Zhejiang Hangzhou China
| | - Kai‐Min Hu
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
| | - Pu Cheng
- Department of GynecologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Hangzhou China
| | - Jiao‐Jiao Zhou
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
- The Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education Zhejiang Hangzhou China
| | - Shu Zheng
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
- The Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education Zhejiang Hangzhou China
| | - Yi‐Ding Chen
- Department of Surgical OncologyThe Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang Hangzhou China
- The Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education Zhejiang Hangzhou China
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Synchronous Ovarian and Breast Cancers with a Novel Variant in BRCA2 Gene: A Case Report. Case Rep Oncol Med 2019; 2019:6958952. [PMID: 30723561 PMCID: PMC6339711 DOI: 10.1155/2019/6958952] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 09/10/2018] [Accepted: 12/09/2018] [Indexed: 11/25/2022] Open
Abstract
We report a case of a 52-year-old female with a family history of pancreatic and colon cancers who presented with a right breast mass positive for high-grade medullar carcinoma with triple-negative biomolecular profile. Further workup was performed finding a left ovarian mass. The patient underwent laparotomy performing optimal cytoreduction on bilateral ovarian tumors; the pathology and immunohistochemistry confirmed bilateral ovary adenocarcinoma with positive peritoneal malignancy. Due to her synchronic breast and ovarian cancers, a genetic profile was performed detecting a new pathogenic variant in the BRCA2 gene: c.3606_3607del (p.Ser1203Cysfs). She was given chemotherapy with carboplatin and paclitaxel obtaining complete clinical response. Regarding her breast cancer, she had a right modified radical mastectomy and prophylactic left mastectomy obtaining complete clinical response. This case presents with an unusual subtype and difficult histologic diagnosis of a synchronic medullar breast cancer and ovary carcinoma associated with a new mutation of the BRCA2 gene.
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Evaluation of site-specific homologous recombination activity of BRCA1 by direct quantitation of gene editing efficiency. Sci Rep 2019; 9:1644. [PMID: 30733539 PMCID: PMC6367331 DOI: 10.1038/s41598-018-38311-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 12/18/2018] [Indexed: 02/03/2023] Open
Abstract
Homologous recombination (HR) contributes to the repair of DNA double-strand breaks (DSBs) and inter-strand crosslinks. The HR activity in cancer cells can be used to predict their sensitivity to DNA-damaging agents that cause these damages. To evaluate HR activity, we developed a system called Assay for Site-specific HR Activity (ASHRA), in which cells are transiently transfected with an expression vector for CRISPR/Cas9 and a HR donor sequence containing a marker gene. DSBs are created by Cas9 and then repaired by HR using donor vector sequences homologous to the target gene. The level of genomic integration of the marker gene is quantified by Western blotting, flowcytometry, or quantitative PCR (qPCR). ASHRA detected HR deficiency caused by BRCA1, BARD1, or RAD51 knockdown or introduction of BRCA1 variants. The influence of BRCA1 variants on HR, as determined by qPCR, was consistent with the chemosensitivities of the transfected cells. The qPCR format of ASHRA could measure HR activity in both transcribed and un-transcribed regions. Knockdown of BRCA1 nor BARD1 did not affect HR activity in a transcriptionally inactive site. ASHRA can evaluate HR activity and will be useful for predicting sensitivity to chemotherapy, screening drugs that affect HR, and investigating the mechanisms of HR.
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