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Bjelic-Radisic V, Cardoso F, Weis J, Pogoda K, Arraras JI, Greimel E, Bottomley A, Cameron D, Brain E, Hartup S, da Costa Vieira RA, Hoefnagels N, Huang CC, Shamieh O, Pinto M, Belay YB, Serpentini S, Bleiker E, Nookala Krishnamurthy M, Shimomura A, Sturm-Inwald EC, Getu MA, Bliem B, Astrup G, Morag O, Kikawa Y, Kuljanic K, Nevries N, Sprangers M, Aaronson NK, Sinai P, Tomaszewski K, Galalae R, Conroy T, Duhoux F, Chie WC, Velikova G. An international Phase IV field study - psychometric properties of the updated module on assessing quality of life of patients with breast cancer EORTC QLQ-BR42. Breast 2025; 80:103890. [PMID: 39947087 PMCID: PMC11867226 DOI: 10.1016/j.breast.2025.103890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 01/21/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND The EORTC QLQ-BR23, published in 1996, was one of the first disease-specific questionnaires to assess health-related quality of life (HRQoL) in patients with breast cancer (BC). In the last decades, major changes in BC treatment have occurred, requiring an update of this module. The results of the Phase 1-3 of the study were published in 2019. The aim of study was to examine the psychometric properties of the provisional EORTC-QLQ-BR45.questionnaire. METHODS Patients with a diagnosis of BC, age ≥18 years, and cognitive able to fill the questionnaire were included in the study and completed the provisional questionnaire during a visit at each participating centre. Psychometric analyses included the evaluation of the scale structure, internal consistency, test-retest reliability, convergent, discriminant, and clinical validity, and responsiveness to change. RESULTS Between May 2019 and September 2021, 576 patients from 22 centers (17 countries, 16 languages) were enrolled in the study. The psychometric analyses resulted in a final questionnaire containing 42 items divided into 10 scales: Breast Symptoms, Body Image, Sexual Functioning, Arm Symptoms, Systemic Chemotherapy Side Effects, Hand/Feet Symptoms/Neuropathy, Skeletal Symptoms, Endocrine Symptoms, Breast Satisfaction, Vaginal Symptoms, and 3 single items: Weight Gain, Sexual Enjoyment and Future Perspective. CONCLUSION The revised EORTC QLQ-BR42 questionnaire incorporates the EORTC-QLQ-BR23 original items, combined with 19 new items that address the new therapies developed over the past 20 years. This comprehensive module is a valid instrument to assess the HRQoL of BC patients and can be used in place of the BR23 in future trials.
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Affiliation(s)
| | - Fatima Cardoso
- Breast Unit Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon, Portugal
| | - Joachim Weis
- Comprehensive Cancer Center, Medical Faculty, University Medical Center Freiburg, Freiburg, Germany
| | - Katarzyna Pogoda
- Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Elfriede Greimel
- Department of Obstetrics and Gynecology, Medical University Graz, Graz, Austria
| | | | - David Cameron
- Cancer Research UK Edinburgh Centre, University of Edinburgh, Edinburgh, UK
| | - Etienne Brain
- Department of Medical Oncology, Institut Curie, Saint-Cloud, France
| | - Sue Hartup
- Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | | | - Nicolette Hoefnagels
- Tumor- and Breast Center of Eastern Switzerland, (TBZO, St. Gallen site), Switzerland
| | - Chi-Cheng Huang
- Taipei Veterans General Hospital, Comprehensive Breast Health Center and Division of Breast Surgery, Taipei, Taiwan; National Taiwan University, Institute of Epidemiology and Preventive Medicine, Taipei, Taiwan
| | - Omar Shamieh
- King Hussein Cancer Center, Department of Palliative Medicine, Amman, Jordan
| | - Monica Pinto
- Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy
| | - Yared Belete Belay
- Mekelle University, School of Pharmacy, Mekelle, Ethiopia; School of Public Health and Preventive Medicine, Monash University, VIC, Australia
| | - Samantha Serpentini
- Unit for Psychooncology, Veneto Institute of Oncology IOV e IRCCS, Padua, Italy
| | - Eveline Bleiker
- Netherlands Cancer Institute, Psychosocial Research and Epidemiology, Amsterdam, the Netherlands
| | - Manjunath Nookala Krishnamurthy
- Dept. of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India
| | - Akihiko Shimomura
- Department of Breast and Medical Oncology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Elisabeth C Sturm-Inwald
- Department of Gynecology and Obstetrics, University Medical Center Regensburg, Regensburg, Germany
| | | | - Brigitte Bliem
- Department of Obstetrics and Gynecology, Medical University Graz, Graz, Austria
| | - Guro Astrup
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Ofir Morag
- Cancer Pain Service, Chaim Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
| | - Yuichiro Kikawa
- Kansai Medical University, Dept. of Breast Surgery, Osaka, Japan
| | - Karin Kuljanic
- Department of Obstetrics and Gynecology, Clinical Center Rijeka, Rijeka, Croatia
| | - Nora Nevries
- Breast Unit, Helios University Clinic Wuppertal, Germany
| | - Mirjam Sprangers
- Netherlands Cancer Institute, Psychosocial Research and Epidemiology, Amsterdam, the Netherlands
| | - Neil K Aaronson
- Netherlands Cancer Institute, Psychosocial Research and Epidemiology, Amsterdam, the Netherlands
| | - Parisa Sinai
- Southmead Hospital, University of Bristol, Bristol, UK
| | - Krzysztof Tomaszewski
- Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland
| | | | - Thierry Conroy
- Département d'oncologie médicale, Institut de Cancérologie de Lorraine, Vandoeuvre-lès-Nancy, France
| | - Francois Duhoux
- Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc (UCLouvain), Brussels, Belgium
| | - Wei-Chu Chie
- National Taiwan University, Institute of Epidemiology and Preventive Medicine, Taipei, Taiwan
| | - Galina Velikova
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; Leeds Cancer Centre, St James's University Hospital, Leeds, UK
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Gannon MR, Dodwell D, Miller K, Medina J, Clements K, Horgan K, Park MH, Cromwell DA. Survival following adjuvant trastuzumab-based treatment among older patients with HER2-positive early invasive breast cancer: A national population-based cohort study using routine data. Eur J Cancer 2024; 211:114309. [PMID: 39293345 DOI: 10.1016/j.ejca.2024.114309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/06/2024] [Accepted: 08/22/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND Randomised controlled trials (RCTs) reported adjuvant trastuzumab-based treatment improved overall survival (OS) among patients with HER2-positive early invasive breast cancer (EIBC). Few RCTs included older patients or those with comorbidity/frailty. This study aimed to determine whether the effect of adjuvant trastuzumab-based treatment on survival outcomes varies by patient age and fitness, using national data from routine care. METHODS Women (50+ years) newly-diagnosed with HER2-positive EIBC between 2014 and 2019 were identified from England Cancer Registry data. Registration records were linked to Systemic Anti-Cancer Therapy data for treatment details and ONS death register for mortality details. A propensity score analysis employing the inverse probability of treatment weighting method was used to balance the patient variables across treatment groups. Cox models were used to evaluate whether the effect of treatment on OS was associated with patient age and fitness; competing risks regression models were used for breast cancer-specific survival (BCSS). RESULTS 5238 women initiated adjuvant trastuzumab-based treatment. Median follow-up was 56.7 months. Comparison with 3421 women who did not receive adjuvant trastuzumab highlighted differences at diagnosis in relation to age, fitness, grade, nodal involvement, surgery type and use of radiotherapy. Weighted survival analysis found trastuzumab was associated with improved OS (hazard ratio HR 0.56, 95 %CI: 0.45-0.70) and improved BCSS (subHR 0.62, 95 %CI: 0.47-0.82). We found no evidence of a difference in effect by age or patient fitness for either outcome. CONCLUSION In this national dataset, adjuvant trastuzumab was associated with improvements in survival, with an OS effect size similar to RCT evidence. The effect size was not found to vary by patient age or fitness. Chronological age and fitness alone should not be barriers to receipt of effective adjuvant targeted treatment.
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Affiliation(s)
- Melissa Ruth Gannon
- Clinical Effectiveness Unit, The Royal College of Surgeons of England, London, UK; Department of Health Services Research & Policy, London School of Hygiene & Tropical Medicine, London, UK.
| | - David Dodwell
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Katie Miller
- Clinical Effectiveness Unit, The Royal College of Surgeons of England, London, UK; Department of Health Services Research & Policy, London School of Hygiene & Tropical Medicine, London, UK
| | - Jibby Medina
- Clinical Effectiveness Unit, The Royal College of Surgeons of England, London, UK; Department of Health Services Research & Policy, London School of Hygiene & Tropical Medicine, London, UK
| | - Karen Clements
- National Cancer Registration and Analysis Service, NHS England, 5th Floor, 23 Stephenson Street, Birmingham, UK
| | - Kieran Horgan
- Department of Breast Surgery, St James's University Hospital, Leeds, UK
| | - Min Hae Park
- Clinical Effectiveness Unit, The Royal College of Surgeons of England, London, UK; Department of Health Services Research & Policy, London School of Hygiene & Tropical Medicine, London, UK
| | - David Alan Cromwell
- Clinical Effectiveness Unit, The Royal College of Surgeons of England, London, UK; Department of Health Services Research & Policy, London School of Hygiene & Tropical Medicine, London, UK
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Tu Y, Renfro LA. Latest Developments in "Adaptive Enrichment" Clinical Trial Designs in Oncology. Ther Innov Regul Sci 2024; 58:1201-1213. [PMID: 39271644 PMCID: PMC11530510 DOI: 10.1007/s43441-024-00698-3] [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: 03/20/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024]
Abstract
As cancer has become better understood on the molecular level with the evolution of gene sequencing techniques, considerations for individualized therapy using predictive biomarkers (those associated with a treatment's effect) have shifted to a new level. In the last decade or so, randomized "adaptive enrichment" clinical trials have become increasingly utilized to strike a balance between enrolling all patients with a given tumor type, versus enrolling only a subpopulation whose tumors are defined by a potential predictive biomarker related to the mechanism of action of the experimental therapy. In this review article, we review recent innovative design extensions and adaptations to adaptive enrichment designs proposed during the last few years in the clinical trial methodology literature, both from Bayesian and frequentist perspectives.
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Affiliation(s)
- Yue Tu
- Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - Lindsay A Renfro
- Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
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Abdel-Razeq H. De-Escalating Treatment Strategies for Patients with Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Early-Stage Breast Cancer. Cancers (Basel) 2024; 16:3478. [PMID: 39456572 PMCID: PMC11506701 DOI: 10.3390/cancers16203478] [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: 08/31/2024] [Revised: 09/28/2024] [Accepted: 10/12/2024] [Indexed: 10/28/2024] Open
Abstract
Almost one-fifth of breast cancer cases express Human Epidermal Growth Factor-2 (HER2), and such expression is associated with highly proliferative tumors and poor prognosis. The introduction of anti-HER2 therapies has dramatically changed the natural course of this aggressive subtype of breast cancer. However, anti-HER2 therapy can be associated with substantial toxicities, mostly cardiac, and high cost. Over the past few years, there has been growing interest in de-escalation of anti-HER2 therapies to minimize adverse events and healthcare costs, while maintaining the efficacy of treatment. Data from clinical observations and single-arm studies have eluted to the minimal impact of anti-HER2 therapy in low-risk patients, like those with node-negative and small tumors. Though single-arm, the APT trial, in which patients with node-negative, small tumors received single-agent paclitaxel for 12 cycles plus trastuzumab for 1 year, was a practice-changing study. Several other recently published studies, like the PERSEPHONE trial, have shown more convincing data that 6 months of trastuzumab is not inferior to 12 months, in terms of disease-free survival (DFS), suggesting that de-escalating strategies with shorter treatment may be appropriate for some low-risk patients. Other de-escalating strategies involved an adaptive, response-directed approach, and personalized therapy that depends on tumor genomic profiling.
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Affiliation(s)
- Hikmat Abdel-Razeq
- Section of Hematology and Medical Oncology, Department of Internal Medicine, King Hussein Cancer Center, Amman 11941, Jordan; ; Tel.: +962-6-5300460 (ext. 1000)
- School of Medicine, University of Jordan, Amman 11941, Jordan
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Gagliato D, Reinert T, Rocha C, Tavares M, Pimentel S, Fuzita W, Araújo M, Matias D, Aleixo S, França B, Magaton É, Brito N, Cardoso AC, Castilho V. Real-World Study of Adjuvant Biosimilar Trastuzumab-dkst for HER2-Positive Breast Cancer Treatment in a Brazilian Population. Oncol Ther 2024; 12:437-449. [PMID: 38836997 PMCID: PMC11333778 DOI: 10.1007/s40487-024-00284-5] [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: 02/29/2024] [Accepted: 05/21/2024] [Indexed: 06/06/2024] Open
Abstract
INTRODUCTION Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse setting, real-world evidence is crucial for assessing the effectiveness and applicability of these therapies in routine clinical practice. METHODS We performed a multicentric, observational, prospective real-world study on biosimilar trastuzumab-dkst for adjuvant treatment of early HER2-positive breast cancer in Brazilian patients. Data were collected using a case-report form. RESULTS Of the 176 recruited, we present data from the first 59 patients (mean age 51.7 ± 12.9 years) who had completed treatment with trastuzumab-dkst. The mean time from diagnosis to the first adjuvant treatment with trastuzumab-dkst was 5.5 ± 2.7 months. Of the patients, 59% of patients achieved at least a 30-month follow-up. The 31.7-month invasive disease-free survival rate (IDFS) was 94.5% (95% CI 83.9-98.2%) and median IDFS was not achieved, since only three patients had invasive disease recurrence. The overall survival rate was 100% until the last assessment. The observed adverse events were similar to those presented by other studies using biosimilar or reference trastuzumab. Four serious adverse events (8.5%) were observed. A reduction in left ventricular ejection fraction of at least 10% was observed in 16.9% of participants. There was no treatment interruption, and three participants (5.1%) had their trastuzumab-dkst dose reduced. CONCLUSION Our study reinforces the existing pivotal data, underscoring the real-world efficacy and safety of biosimilar trastuzumab-dkst in the adjuvant treatment for early HER2-positive breast cancer. The preliminary long-term effectiveness and safety data we present further validate trastuzumab-dkst's role as a cost-saving alternative in oncological care. These findings have important implications for improving patient access to crucial treatments and for the more efficient use of healthcare resources. CLINICALTRIALS GOV REGISTRATION NCT03892655.
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Affiliation(s)
- Debora Gagliato
- Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, 637-Bela Vista, São Paulo, SP, 01323-001, Brazil
| | - Tomás Reinert
- Centro de Pesquisa da Serra Gaúcha (CEPESG), Rua Vinte de Setembro, 2304, Bairro Centro, Caxias do Sul, RS, 95020-450, Brazil
| | - Cláudio Rocha
- Vencer e Oncoclínica Centro de Pesquisa, Rua Gardênia, 710-Jóquei, Teresina, PI, 64049-200, Brazil
| | - Monique Tavares
- A.C. Camargo Cancer Center, Rua Tamandaré, 753-Liberdade, São Paulo, SP, 01525-001, Brazil
| | - Sâmio Pimentel
- Ser Clínica Oncológica, Rua Passagem Euclídes da Cunha, 50-Batista Campos, Belém, PA, 66035-265, Brazil
| | - William Fuzita
- Instituto Sensumed de Ensino e Pesquisa (ISENP), Rua São Luíz, 510-Adrianópolis, Manaus, AM, 69029-520, Brazil
| | - Márcia Araújo
- Centro de Oncologia Leonardo da Vinci Ltda, Rua Rocha Lima, 1563-Aldeota, Fortaleza, CE, 60135-285, Brazil
| | - Danielli Matias
- Liga Norte Riograndense Contra O Câncer, Avenida Miguel Castro, 1355-Nossa Senhora de Nazaré, Natal, RN, 59062-000, Brazil
| | - Sabina Aleixo
- Hospital Evangélico de Cachoeiro de Itapemirim (CPCO/HECI), Rua Manoel Braga Machado, 2-Nossa Sra. da Penha, Cachoeiro de Itapemirim, ES, 29308-020, Brazil
| | - Bruno França
- Oncologia|Hematologia|Centro de Infusão, Av. das Américas, 2251-Barra da Tijuca, Rio de Janeiro, RJ, 22,631-001, Brazil
| | - Érida Magaton
- Libbs Farmacêutica, Av. Marquês de São Vicente, 2219-Jardim das Perdizes, São Paulo, SP, 05036-040, Brazil
| | - Natália Brito
- Libbs Farmacêutica, Av. Marquês de São Vicente, 2219-Jardim das Perdizes, São Paulo, SP, 05036-040, Brazil.
| | - Ana Carolina Cardoso
- Libbs Farmacêutica, Av. Marquês de São Vicente, 2219-Jardim das Perdizes, São Paulo, SP, 05036-040, Brazil
| | - Vivienne Castilho
- Libbs Farmacêutica, Av. Marquês de São Vicente, 2219-Jardim das Perdizes, São Paulo, SP, 05036-040, Brazil
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Sakai K, Kato D, Yoshinaka J, Takahashi Y, Ikeda N, Aoki S, Iguchi T, Ishikawa S, Yamagishi N, Shimamura S, Nakagawa T. Effects of trastuzumab emtansine on canine urothelial carcinoma cells in vitro and in vivo. Vet Comp Oncol 2024; 22:230-238. [PMID: 38502572 DOI: 10.1111/vco.12970] [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: 12/08/2023] [Revised: 02/16/2024] [Accepted: 02/17/2024] [Indexed: 03/21/2024]
Abstract
Urothelial carcinoma (UC) is the most common malignancy of the urinary tract in dogs and has aggressive behaviour. Although human epidermal growth factor receptor 2 (HER2) is a known therapeutic target with evidence in canine UC, the efficacy of anti-HER2 antibody drugs remains unknown. This study aimed to investigate the effects of anti-HER2 antibody drugs including trastuzumab and trastuzumab emtansine (T-DM1) on canine UC cell lines in vitro and in vivo. Four canine UC cell lines (Nene, TCCUB, Love, and Sora) were used. In western blotting, HER2 protein expression was observed in all the cell lines. Although both trastuzumab and T-DM1 showed dose-dependent growth inhibitory activity in the cell lines, T-DM1 showed much stronger activity than that of trastuzumab. In flow cytometry analyses with the canine UC cell line (Sora), T-DM1 but not trastuzumab significantly increased the percentages of early and late apoptotic cells in annexin V apoptotic assays and the sub-G1 phase fraction in cell cycle analyses. For the in vivo experiment, the canine UC cells (Sora) were subcutaneously injected into nude mice. Four days after inoculation, trastuzumab, T-DM1, or vehicle was administered intraperitoneally once a week for three times. Tumour volumes were significantly smaller in the T-DM1 group compared to the trastuzumab and vehicle control groups. These findings indicate that T-DM1 exerts a stronger antitumour effect than that of trastuzumab on canine UC cells in vitro and in vivo, possibly by inducing apoptosis due to DM1.
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Affiliation(s)
- Kosei Sakai
- Laboratory of Small Animal Clinical Medicine, Graduate School of Veterinary Sciences, Osaka Metropolitan University, Osaka, Japan
| | - Daiki Kato
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Junka Yoshinaka
- Laboratory of Small Animal Clinical Medicine, Graduate School of Veterinary Sciences, Osaka Metropolitan University, Osaka, Japan
| | - Yosuke Takahashi
- Veterinary Medical Centre, The University of Tokyo, Tokyo, Japan
| | - Namiko Ikeda
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Susumu Aoki
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Takaaki Iguchi
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Shingo Ishikawa
- Laboratory of Large Animal Clinical Medicine, Graduate School of Veterinary Sciences, Osaka Metropolitan University, Osaka, Japan
| | - Norio Yamagishi
- Laboratory of Large Animal Clinical Medicine, Graduate School of Veterinary Sciences, Osaka Metropolitan University, Osaka, Japan
| | - Shunsuke Shimamura
- Laboratory of Small Animal Clinical Medicine, Graduate School of Veterinary Sciences, Osaka Metropolitan University, Osaka, Japan
| | - Takayuki Nakagawa
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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Khoirunnisa SM, Suryanegara FDA, Setiawan D, Postma MJ, de Jong LA. Economic evaluation of trastuzumab in HER2-positive early breast cancer in Indonesia: A cost-effectiveness analysis. PLoS One 2024; 19:e0304483. [PMID: 38787899 PMCID: PMC11125485 DOI: 10.1371/journal.pone.0304483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Trastuzumab has significantly enhanced the survival and prognosis of individuals diagnosed with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. Considering its relatively high costs, we aimed to examine the cost-effectiveness of trastuzumab plus chemotherapy compared with chemotherapy alone in HER2-positive early breast cancer from an Indonesian healthcare payer's perspective. METHODS A Markov model was developed to project the lifetime health benefits and costs associated with trastuzumab treatment for a cohort of women with HER2-positive early breast cancer. Efficacy data and baseline characteristics in the base-case analysis were primarily derived from the 11-year results of the HERA trial. Costs were based on verified reimbursement data from Indonesia's Health and Social Security Agency (BPJS Kesehatan) of the year 2020. A scenario analysis was conducted with efficacy data based on the joint analysis from the NSABP B-31 and NCCTG N9831 trials, allowing for subgroup analysis by age at diagnosis. Univariate and probabilistic sensitivity analyses were conducted to assess the influence of parameter uncertainty. RESULTS In the base-case analysis, the results indicated that the lifetime costs for trastuzumab plus chemotherapy and chemotherapy alone were US$33,744 and US$22,720, respectively, resulting in substantial incremental savings of US$11,024 per patient for the former. Trastuzumab plus chemotherapy also led to higher total quality-adjusted life years (QALYs) and life years gained (LYG), resulting in incremental cost-effectiveness ratios (ICERs) of US$6,842 per QALY and US$5,510 per LYG. In scenario analysis, the subgroup with an age at diagnosis <40 years old reflected the most cost-effective subgroup. Both the base-case and scenario analyses demonstrated cost-effectiveness with a willingness-to-pay threshold of three-times Gross Domestic Product (GDP). Sensitivity analyses confirmed the robustness of the findings and conclusions. CONCLUSION In Indonesia, trastuzumab plus chemotherapy can be considered cost-effective compared to chemotherapy alone at a willingness-to-pay threshold of three times GDP, and it is likely most cost-effective in women <40 years of age.
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Affiliation(s)
- Sudewi Mukaromah Khoirunnisa
- Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Pharmacy, Institut Teknologi Sumatera, Lampung Selatan, Indonesia
| | - Fithria Dyah Ayu Suryanegara
- Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Pharmacy, Universitas Islam Indonesia, Yogyakarta, Indonesia
| | - Didik Setiawan
- Faculty of Pharmacy, Universitas Muhammadiyah Purwokerto, Banyumas, Indonesia
- Centre for Health Economic Studies, Universitas Muhammadiyah Purwokerto, Banyumas, Indonesia
| | - Maarten Jacobus Postma
- Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Faculty of Economics & Business, Department of Economics, Econometrics and Finance, University of Groningen, Groningen, The Netherlands
- Faculty of Medicine, Department of Pharmacology and Therapy, Universitas Airlangga, Surabaya, Indonesia
- Centre of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Bandung, Indonesia
| | - Lisa Aniek de Jong
- Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Xu Z, Tao D, Zhou Z, Jiang Q, Wei W. Evaluation of the Efficacy of Postoperative Adjuvant Therapy for HER2-Positive Ductal Carcinoma in Situ with Microinvasion. Cancer Invest 2024; 42:408-415. [PMID: 38785094 DOI: 10.1080/07357907.2024.2355320] [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: 03/03/2023] [Revised: 03/28/2024] [Accepted: 05/10/2024] [Indexed: 05/25/2024]
Abstract
A retrospective study on 90 eligible HER2+ ductal carcinoma in situ with microinvasion (DCIS-MI) patients was performed with a median follow-up time of 57 months. The baseline was consistent between the 4-cycle and 6-cycle chemotherapy groups. There were more patients with multiple foci of micrometastasis in the target therapy group in the two groups with or without target therapy (p < 0.01). Postoperative chemotherapy with a 4-cycle regimen can achieve the expected therapeutic effect in patients with HER2+ DCIS-MI, but the role of target therapy in HER2+ DCIS-MI patients has not been confirmed.
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MESH Headings
- Humans
- Female
- Receptor, ErbB-2/metabolism
- Breast Neoplasms/pathology
- Breast Neoplasms/drug therapy
- Breast Neoplasms/surgery
- Breast Neoplasms/metabolism
- Middle Aged
- Retrospective Studies
- Chemotherapy, Adjuvant
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Carcinoma, Intraductal, Noninfiltrating/drug therapy
- Carcinoma, Intraductal, Noninfiltrating/surgery
- Carcinoma, Intraductal, Noninfiltrating/metabolism
- Adult
- Aged
- Neoplasm Invasiveness
- Treatment Outcome
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
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Affiliation(s)
- Zhihong Xu
- Department of Breast Surgery, the Third Hospital of Nanchang, Nanchang City, China
| | - Dan Tao
- Department of Breast Surgery, the Third Hospital of Nanchang, Nanchang City, China
| | - Zhibing Zhou
- Department of Breast Surgery, the Third Hospital of Nanchang, Nanchang City, China
| | - Qihua Jiang
- Department of Breast Surgery, the Third Hospital of Nanchang, Nanchang City, China
| | - Wensong Wei
- Department of Breast Surgery, the Third Hospital of Nanchang, Nanchang City, China
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de Mello RA, Perez KR, Haris PA. What is the future of immune checkpoints inhibitors for metastatic triple negative breast cancers? Immunotherapy 2024; 16:497-500. [PMID: 38686830 DOI: 10.2217/imt-2024-0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 04/09/2024] [Indexed: 05/02/2024] Open
Affiliation(s)
- Ramon Andrade de Mello
- Department of Oncology, Oxford Cancer Center, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, OX3 7LE, Oxford, UK
- Department of Oncology, University of Oxford, OX3 7DR, Oxford, UK
- Master in Science Post-Graduate Program in Medical Oncology, University of Buckingham, MK18 1EG, Buckingham, UK
- Post Graduation Program in Medicine, Faculty of Medicine, Nine of July University (UNINOVE), Rua Vergueiro, 235, 12o andar, 015250-000, São Paulo, Brazil
| | - Kátia Roque Perez
- Post Graduation Program in Medicine, Faculty of Medicine, Nine of July University (UNINOVE), Rua Vergueiro, 235, 12o andar, 015250-000, São Paulo, Brazil
- Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
| | - Puteri Abdul Haris
- Department of Oncology, Oxford Cancer Center, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, OX3 7LE, Oxford, UK
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10
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Pang J, Ding N, Yin N, Xiao Z. Systemic immune-inflammation index as a prognostic marker in HER2-positive breast cancer patients undergoing trastuzumab therapy. Sci Rep 2024; 14:6578. [PMID: 38503890 PMCID: PMC10951263 DOI: 10.1038/s41598-024-57343-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/18/2024] [Indexed: 03/21/2024] Open
Abstract
The prognostic value of SII (Systemic Immune-Inflammation Index) in HER-2-positive breast cancer (BC) patients, regardless of whether they receive trastuzumab treatment, and its potential value to distinguish patients who may benefit from trastuzumab therapy, warrant further investigation. Clinical data was collected from 797 HER-2-positive BC patients between July 2013 and March 2018. Baseline data differences were adjusted with propensity score matching. Univariate and multivariate analyses explored the correlation between clinical pathological factors, SII, and DFS. Four groups were established. Based on the baseline SII values of the participants, patients who did not receive trastuzumab treatment were divided into Group 1 (Low-SII) and Group 2 (High-SII), where SII had no predictive value for prognosis between groups. Participants who received trastuzumab treatment were also divided into two groups: the Low-SII group (Group 3) and the High-SII group (Group 4). The 5-year DFS was significantly higher in Group 3 than in Group 4 (91.76% vs. 82.76%, P = 0.017). Furthermore, multivariate analysis demonstrated a significant association between high SII and shorter DFS (HR = 3.430, 95% CI = 1.830-6.420, P < 0.001). In HER-2-positive BC patients treated with trastuzumab, those with lower SII showed a longer DFS, suggesting that SII may help in identifying patients who benefit from trastuzumab therapy.
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Affiliation(s)
- Jian Pang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Nianhua Ding
- Department of Clinical Laboratory, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Nana Yin
- Department of Operating Room, First People's Hospital of Changde, Changde, China
| | - Zhi Xiao
- Department of Breast Surgery, Xiangya Hospital, Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, China.
- Clinical Research Center for Breast Cancer in Hunan Province, Changsha, China.
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11
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Lim EH, Lim A, Khara JS, Cheong J, Fong J, Sivanesan S, Griffiths M, New E, Lee SC. Cost-effectiveness analysis of add-on pertuzumab to trastuzumab biosimilar and chemotherapy as neoadjuvant treatment for human epidermal growth receptor 2-positive early breast cancer patients in Singapore. Expert Rev Pharmacoecon Outcomes Res 2024; 24:413-426. [PMID: 38289042 DOI: 10.1080/14737167.2023.2295474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 12/10/2023] [Indexed: 02/16/2024]
Abstract
OBJECTIVES The Asian PEONY trial showed that add-on pertuzumab to trastuzumab and chemotherapy significantly improved pathological complete response in the neoadjuvant treatment of patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). This study evaluated the cost-effectiveness of pertuzumab as an add-on therapy to trastuzumab and chemotherapy for neoadjuvant treatment of patients with HER2+ EBC in Singapore. METHODS A six-state Markov model was developed from the Singapore healthcare system perspective, with a lifetime time horizon. Model outputs were: costs; life-years (LYs); quality-adjusted LYs (QALYs); incremental cost-effectiveness ratios (ICERs). Sensitivity/scenario analyses explored model uncertainties. RESULTS The base case projected the addition of pertuzumab to be associated with improved outcomes by 0.277 LYs and 0.271 QALYs, increased costs by S$1,387, and an ICER of S$5,121/QALY. The ICER was most sensitive to the pCR rate, and the probabilistic sensitivity analysis showed that add-on pertuzumab had an 81.3% probability of being cost-effective at a willingness-to-pay threshold of S$45,000/QALY gained. CONCLUSIONS This model demonstrated that the long-term clinical impact of early pertuzumab use, particularly the avoidance of metastatic disease and thus avoidance of higher costs and mortality rates, make neoadjuvant pertuzumab a cost-effective option in the management of patients with HER2+ breast cancer in Singapore.
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Affiliation(s)
- Elaine Hsuen Lim
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Andrew Lim
- Asia-Pacific Evidence Development, Costello Medical Singapore Pte Ltd, Singapore, Singapore
| | | | - John Cheong
- Market Access, Roche Singapore Pte Ltd, Singapore, Singapore
| | - Jek Fong
- Market Access, Roche Singapore Pte Ltd, Singapore, Singapore
| | | | | | - Emma New
- Health Economics, Costello Medical Consulting Ltd, London, UK
| | - Soo Chin Lee
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
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12
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Ding N, Pang J, Liu X, He X, Zhou W, Xie H, Feng J, Wang G, Tang J, Cao J, He L, He Y, Wang S, Xiao Z. Prognostic value of baseline neutrophil/lymphocyte ratio in HER2-positive metastatic breast cancer: exploratory analysis of data from the CLEOPATRA trial. Breast Cancer Res 2024; 26:9. [PMID: 38212845 PMCID: PMC10785455 DOI: 10.1186/s13058-023-01761-x] [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: 07/24/2023] [Accepted: 12/27/2023] [Indexed: 01/13/2024] Open
Abstract
PURPOSE This study aimed to evaluate the prognostic role of the baseline neutrophil/lymphocyte ratio (NLR) in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab/pertuzumab. EXPERIMENTAL DESIGN Data from 780 patients from the CLEOPATRA trial and 248 local patients were collected. Patients were divided into the low and high NLR subgroups by the NLR cutoff value. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methods were used to control bias. Associations between the NLR and progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS The baseline characteristics of the subgroups were well balanced after PSM and IPTW. A low baseline NLR was associated with better PFS and OS in the trastuzumab and docetaxel (TH) group in the unadjusted, PSM and IPTW models. After IPTW, a low NLR, versus a high NLR, was associated with improved PFS (HR 1.35, 95% CI 1.07-1.70, P = 0.012) and OS (HR 1.47, 95% CI 1.12-1.94, P = 0.006) in the TH group. In patients undergoing treatment with trastuzumab and pertuzumab and docetaxel (THP), a low baseline NLR was also correlated with better PFS but not OS across the three models. After IPTW, a low NLR was associated with better PFS (HR 1.52, 95% CI 1.20-1.93, P = 0.001) than a high NLR in the THP group. Multivariate analyses showed that a low baseline NLR was a predictor for PFS and OS in the TH group and for PFS in the THP group in all three models. In the real-world setting, a low baseline NLR was a predictor of better PFS among patients treated with docetaxel plus trastuzumab without or with pertuzumab in the multivariate model (P = 0.015 and 0.008, respectively). CONCLUSIONS A low baseline NLR is associated with better survival outcomes among HER2-positive MBC patients receiving docetaxel plus trastuzumab/pertuzumab as first-line therapy.
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Affiliation(s)
- Nianhua Ding
- Department of Clinical Laboratory, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Jian Pang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Xuan Liu
- Department of General Surgery, The First People's Hospital of Xiangtan, Xiangtan, People's Republic of China
| | - Xiongbin He
- Department of Breast and Thyroid Surgery, The First People's Hospital of Chenzhou, Chenzhou, People's Republic of China
| | - Wei Zhou
- Department of Breast Surgery, The Affiliated Zhuzhou Hospital of Xiangya School of Medicine, Zhuzhou, People's Republic of China
| | - Haiqing Xie
- Department of Breast and Thyroid Surgery, The Third People's Hospital of Chenzhou, Chenzhou, People's Republic of China
| | - Jianqi Feng
- Department of Breast and Thyroid Surgery, The First People's Hospital of Huaihua, Huaihua, People's Republic of China
| | - Guo Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Jie Tang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Jing Cao
- Department of Breast SurgeryXiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Liying He
- Department of Clinical Laboratory, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yingjian He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Shouman Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Zhi Xiao
- Department of Breast Surgery, General Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China.
- Clinical Research Center for Breast Cancer in Hunan Province, Changsha, People's Republic of China.
- Multidisciplinary Breast Cancer Center, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
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13
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Royle KL, Meads D, Visser-Rogers JK, White IR, Cairns DA. How is overall survival assessed in randomised clinical trials in cancer and are subsequent treatment lines considered? A systematic review. Trials 2023; 24:708. [PMID: 37926806 PMCID: PMC10626781 DOI: 10.1186/s13063-023-07730-1] [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: 06/29/2023] [Accepted: 10/13/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND Overall survival is the "gold standard" endpoint in cancer clinical trials. It plays a key role in determining the clinical- and cost-effectiveness of a new intervention and whether it is recommended for use in standard of care. The assessment of overall survival usually requires trial participants to be followed up for a long period of time. In this time, they may stop receiving the trial intervention and receive subsequent anti-cancer treatments, which also aim to extend survival, during trial follow-up. This can potentially change the interpretation of overall survival in the context of the clinical trial. This review aimed to determine how overall survival has been assessed in cancer clinical trials and whether subsequent anti-cancer treatments are considered. METHODS Two searches were conducted using MEDLINE within OVID© on the 9th of November 2021. The first sought to identify papers publishing overall survival results from randomised controlled trials in eight reputable journals and the second to identify papers mentioning or considering subsequent treatments. Papers published since 2010 were included if presenting or discussing overall survival in the context of treating cancer. RESULTS One hundred and thirty-four papers were included. The majority of these were presenting clinical trial results (98, 73%). Of these, 45 (46%) reported overall survival as a (co-) primary endpoint. A lower proportion of papers including overall survival as a (co-) primary endpoint compared to a secondary endpoint were published in recent years. The primary analysis of overall survival varied across the papers. Fifty-nine (60%) mentioned subsequent treatments. Seven papers performed additional analysis, primarily when patients in the control arm received the experimental treatment during trial follow-up (treatment switching). DISCUSSION Overall survival has steadily moved from being the primary to a secondary endpoint. However, it is still of interest with papers presenting overall survival results with the caveat of subsequent treatments, but little or no investigation into their effect. This review shows that there is a methodological gap for what researchers should do when trial participants receive anti-cancer treatment during trial follow-up. Future research will identify the stakeholder opinions, on how this methodological gap should be addressed.
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Affiliation(s)
- Kara-Louise Royle
- Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
| | - David Meads
- Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | | | | | - David A Cairns
- Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
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14
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Liu J, Huang S, Bi Z, Zhang X, He Z, Lan X, Tan Y, Lin X, Zhou W, Huang X. De-escalated radiotherapy for HER2-overexpressing breast cancer patients with 1-3 positive lymph nodes undergoing anti-HER2 targeted therapy. Front Oncol 2023; 13:1280900. [PMID: 38023183 PMCID: PMC10646411 DOI: 10.3389/fonc.2023.1280900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 10/19/2023] [Indexed: 12/01/2023] Open
Abstract
Background In the era of anti-HER2 targeted therapy, the potential clinical feasibility of considering HER2-overexpressing breast cancer cases presenting with 1-3 positive axillary lymph nodes as low-risk, and thereby contemplating postoperative radiotherapy reduction, remains an important subject for in-depth examination. The aim of this retrospective study was to evaluate the effectiveness of de-escalated radiotherapy in T1-2N1M0 HER2-overexpressing breast cancer patients receiving anti-HER2 targeted therapy. Specifically, omitting regional lymph node irradiation (RNI) after breast-conserving surgery and only performing whole-breast irradiation or omitting postmastectomy radiation therapy. Methods A retrospective analysis was conducted on 429 patients with stage T1-2N1M0 primary invasive HER2-overexpressing breast cancer from our center between 2004 and 2018. Patients who received anti-HER2 targeted therapy were divided into an RNI group and a no RNI group to assess the role of RNI. The prognostic role of RNI was investigated via the Kaplan-Meier method and Cox proportional hazards modeling. Results The median follow-up time was 46.8 months (range 7.1-225.8 months). In the anti-HER2 targeted therapy group RNI yielded no significant improvements in invasive disease-free survival (IDFS) (p = 0.940), local-regional recurrence-free survival (p = 0.380), distant metastases-free survival (p = 0.698), or overall survival (p = 0.403). Estrogen receptor (ER) status (hazard ratio [HR] 0.105, 95% confidence interval [CI] 0.023-0.749, p = 0.004) and lymph vascular invasion status (LVI) (HR 5.721, 95% CI 1.586-20.633, p = 0.008) were identified as independent prognostic factors for IDFS, and ER-positive and LVI-negative patients exhibited better prognoses. Conclusion Omitting RNI may be a safe option in T1-2N1 HER2-overexpressing breast cancer patients receiving standardized anti-HER2 targeted therapy; particularly in ER-positive or LVI-negative subgroups.
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Affiliation(s)
- Jing Liu
- Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Yat-Sen Breast Tumor Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Suning Huang
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Zhuofei Bi
- Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoxue Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Yat-Sen Breast Tumor Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ziqing He
- Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Yat-Sen Breast Tumor Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaowen Lan
- Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Yat-Sen Breast Tumor Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yuting Tan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Yat-Sen Breast Tumor Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiao Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Yat-Sen Breast Tumor Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wenyi Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Yat-Sen Breast Tumor Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaobo Huang
- Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Centre, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Yat-Sen Breast Tumor Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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15
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Atallah NM, Alsaleem M, Toss MS, Mongan NP, Rakha E. Differential response of HER2-positive breast cancer to anti-HER2 therapy based on HER2 protein expression level. Br J Cancer 2023; 129:1692-1705. [PMID: 37740038 PMCID: PMC10646129 DOI: 10.1038/s41416-023-02426-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 08/25/2023] [Accepted: 09/05/2023] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Increasing data indicate that HER2-positive (HER2 + ) breast cancer (BC) subtypes exhibit differential responses to targeted anti-HER2 therapy. This study aims to investigate these differences and the potential underlying molecular mechanisms. METHODS A large cohort of BC patients (n = 7390) was utilised. The clinicopathological characteristics and differential gene expression (DGE) of HER2+ immunohistochemical (IHC) subtypes, specifically HER2 IHC 3+ and IHC 2 + /Amplified, were assessed and correlated with pathological complete response (pCR) and survival in the neoadjuvant and adjuvant settings, respectively. The role of oestrogen receptor (ER) status was also investigated. RESULTS Compared to HER2 IHC 3+ tumours, BC patients with IHC 2 + /Amplified showed a significantly lower pCR rate (22% versus 57%, P < 0.001), shorter survival regardless of HER2 gene copy number, were less classified as HER2 enriched, and enriched for trastuzumab resistance and ER signalling pathway genes. ER positivity significantly decreased response to anti-HER2 therapy in IHC 2 + /Amplified, but not in IHC 3 + BC patients. CONCLUSION In HER2 + BC, overexpression of HER2 protein is the driver of the oncogenic pathway, and it is the main predictor of response to anti-HER2 therapy. ER signalling pathways are more dominant in BC with equivocal HER2 expression. personalised anti-HER2 therapy based on IHC classes should be considered.
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Affiliation(s)
- N M Atallah
- Division of Cancer and Stem Cells, School of Medicine, the University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK
- Department of Pathology, Faculty of Medicine, Menoufia University, Shibin el Kom, Egypt
| | - M Alsaleem
- Unit of Scientific Research, Applied College, Qassim University, Buraydah, Saudi Arabia
| | - M S Toss
- Histopathology Department, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - N P Mongan
- School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, UK
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - E Rakha
- Division of Cancer and Stem Cells, School of Medicine, the University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK.
- Department of Pathology, Faculty of Medicine, Menoufia University, Shibin el Kom, Egypt.
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16
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Epstein N, Simon-Tuval T, Berchenko Y. Context-Specific Estimation of Future Unrelated Medical Costs and Their Impact on Cost-Effectiveness Analyses. PHARMACOECONOMICS 2023; 41:1275-1286. [PMID: 37329391 DOI: 10.1007/s40273-023-01290-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/30/2023] [Indexed: 06/19/2023]
Abstract
OBJECTIVES This study constructed and applied procedures for the estimation of unrelated future medical costs (UFMC) of women with breast cancer in Israel (as a case study) and examined the influence of including UFMC in cost-effectiveness analyses (CEAs). METHODS Part I consisted of a retrospective cohort study based on patient-level claims data of both patients with breast cancer and matched controls during 14 years of follow-up. UFMC were estimated as (a) the annual average all-cause healthcare costs of the control subjects, and (b) as predicted values based on a generalized linear model (GLM) adjusted to patients' characteristics. Part II consisted of a CEA performed using a Markov simulation model comparing regimens of chemotherapy with/without trastuzumab, both excluding and including UFMC and for each of the UFMC estimates separately. All costs were adjusted to 2019 prices. Costs and QALYs were discounted at a yearly rate of 3%. RESULTS The average annual healthcare costs in the control group were $2328 (± $5662). The corresponding incremental cost-effectiveness ratio (ICER) was $53,411/QALY and $55,903/QALY, when UFMC were excluded or included, respectively. Hence, trastuzumab was not considered cost-effective compared with a threshold of willingness-to-pay of $37,000 per QALY, regardless of the inclusion of UFMC. When UFMC were estimated on the basis of the prediction model, the ICERs were $37,968/QALY and $39,033/QALY, when UFMC were excluded or included, respectively. Thus, in this simulation, trastuzumab was not considered cost-effective, independent of the inclusion of UFMC. CONCLUSION Our case study revealed that the inclusion of UFMC had modest effect on the ICERs, and thus did not alter the conclusion. Thus, we should estimate context-specific UFMC if they are expected to change the ICERs significantly, and transparently report the corresponding assumptions to uphold the integrity and reliability of the economic evaluation.
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Affiliation(s)
- Noga Epstein
- Department of Industrial Engineering and Management, Faculty of Engineering Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Tzahit Simon-Tuval
- Department of Health Policy and Management, Guilford Glazer Faculty of Business and Management and Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O Box 653, 8410501, Beer-Sheva, Israel.
| | - Yakir Berchenko
- Department of Industrial Engineering and Management, Faculty of Engineering Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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17
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McDonald SJ, Bullard BM, VanderVeen BN, Cardaci TD, Chatzistamou I, Fan D, Murphy EA. Emodin reduces surgical wounding-accelerated tumor growth and metastasis via macrophage suppression in a murine triple-negative breast cancer model. Physiol Rep 2023; 11:e15813. [PMID: 37821408 PMCID: PMC10567645 DOI: 10.14814/phy2.15813] [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: 07/11/2023] [Revised: 08/23/2023] [Accepted: 08/23/2023] [Indexed: 10/13/2023] Open
Abstract
It has been suspected that tumor resection surgery itself may accelerate breast cancer (BC) lung metastasis in some patients. Emodin, a natural anthraquinone found in the roots and rhizomes of various plants, exhibits anticancer activity. We examined the perioperative use of emodin in our established surgery wounding murine BC model. Emodin reduced primary BC tumor growth and metastasis in the lungs in both sham and surgical wounded mice, consistent with a reduction in proliferation and enhanced apoptosis (primary tumor and lungs). Further, emodin reduced systemic inflammation, most notably the number of monocytes in the peripheral blood and reduced pro-tumoral M2 macrophages in the primary tumor and the lungs. Consistently, we show that emodin reduces gene expression of select macrophage markers and associated cytokines in the primary tumor and lungs of wounded mice. Overall, we demonstrate that emodin is beneficial in mitigating surgical wounding accelerated lung metastasis in a model of triple-negative BC, which appears to be mediated, at least in part, by its actions on macrophages. These data support the development of emodin as a safe, low-cost, and effective agent to be used perioperatively to alleviate the surgery triggered inflammatory response and consequential metastasis of BC to the lungs.
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Affiliation(s)
- Sierra J. McDonald
- Department of Pathology, Microbiology & Immunology, School of MedicineUniversity of South CarolinaColumbiaSouth CarolinaUSA
| | - Brooke M. Bullard
- Department of Pathology, Microbiology & Immunology, School of MedicineUniversity of South CarolinaColumbiaSouth CarolinaUSA
| | - Brandon N. VanderVeen
- Department of Pathology, Microbiology & Immunology, School of MedicineUniversity of South CarolinaColumbiaSouth CarolinaUSA
| | - Thomas D. Cardaci
- Department of Pathology, Microbiology & Immunology, School of MedicineUniversity of South CarolinaColumbiaSouth CarolinaUSA
| | - Ioulia Chatzistamou
- Department of Pathology, Microbiology & Immunology, School of MedicineUniversity of South CarolinaColumbiaSouth CarolinaUSA
| | - Daping Fan
- Department of Cell Biology and Anatomy, School of MedicineUniversity of South CarolinaColumbiaSouth CarolinaUSA
- AcePre, LLCColumbiaSouth CarolinaUSA
| | - E. Angela Murphy
- Department of Pathology, Microbiology & Immunology, School of MedicineUniversity of South CarolinaColumbiaSouth CarolinaUSA
- AcePre, LLCColumbiaSouth CarolinaUSA
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Batista JDL, Alves RJV, Cardoso TB, Moreno M, Tiscoski KA, Polanczyk CA. Effectiveness of adjuvant trastuzumab in women with HER-2+ breast cancer in the SUS. CIENCIA & SAUDE COLETIVA 2023; 28:1819-1830. [PMID: 37255158 DOI: 10.1590/1413-81232023286.15092022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 11/04/2022] [Indexed: 06/01/2023] Open
Abstract
The aim of this study was to evaluate the effectiveness in a real-world study of adjuvant trastuzumab in women with HER-2+ initial breast cancer in overall survival and recurrence-free survival. A retrospective cohort study was conducted with women who had HER-2+ breast cancer treated with trastuzumab from July 2012 to May 2017 and followed up until July 2021. The death rate was 2.62 per 100 persons/year, and the incidence rate of recurrence was 7.52 per 100 persons/year. The probability of survival at 8.7 years was 85.9%, while the probability of recurrence-free survival in the same period was 62.8%. The use of trastuzumab proved to be effective in the adjuvant treatment of breast cancer in a public health service in southern Brazil. Prognostic factors associated with worse overall survival or relapse did not influence the natural history of the disease, except locally advanced disease at the beginning of treatment. The data presented may prove to be useful in helping to make decisions about whether to use trastuzumab in the treatment of initial or locally advanced breast cancer in the Brazilian SUS.
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Affiliation(s)
- Joanna d'Arc Lyra Batista
- Universidade Federal da Fronteira Sul. Rodovia SC 459, Km 02, Sala 317, Fronteira Sul. 89801-001 Chapecó SC Brasil.
- Instituto de Avaliação de Tecnologia em Saúde. Porto Alegre RS Brasil
| | | | | | - Marcelo Moreno
- Universidade Federal da Fronteira Sul. Rodovia SC 459, Km 02, Sala 317, Fronteira Sul. 89801-001 Chapecó SC Brasil.
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Teruya N, Inoue H, Horii R, Akiyama F, Ueno T, Ohno S, Takahashi S. Intratumoral heterogeneity, treatment response, and survival outcome of ER-positive HER2-positive breast cancer. Cancer Med 2023; 12:10526-10535. [PMID: 36934442 PMCID: PMC10225233 DOI: 10.1002/cam4.5788] [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: 10/27/2022] [Revised: 02/03/2023] [Accepted: 02/27/2023] [Indexed: 03/20/2023] Open
Abstract
BACKGROUND ER+HER2+ breast cancer requires most types of systemic therapies perioperatively. However, treatment resistance is often experienced. The current study investigated the predictive and prognostic value of intratumoral heterogeneity and conventional clinicopathological factors in patients with ER+HER2+ breast cancer. METHODS This research included two patient cohorts with ER+HER2+ breast cancer. Cohort A included patients who underwent surgery without neoadjuvant chemotherapy (NAC). Cohort B comprised patients who received NAC followed by surgery. Intratumoral heterogeneity was assessed via ER and HER2 double staining, and the number of cells stained with different patterns of ER and HER2 was counted. RESULTS In total, 11 of 92 tumors in cohort A and four of 45 tumors in cohort B consisted exclusively of double-positive (ER+ and HER2+) cells (homogeneous). The rest had different combinations of cells (heterogeneous). The pathological complete response (pCR) rates differed based on tumoral cell components but not intratumoral heterogeneity. The pCR rate of tumors with ER-HER2+ cells but without HER2- cells was higher than that of others (45.5% vs 4.3%; p = 0.0013). Low ER and PgR Allred scores indicated better pCR rates than high scores (p = 0.0005 and 0.024, respectively). Multivariate analysis showed that the ER Allred score and cell component of ER-HER2+ cells without HER2- cells were independent predictors of pCR (p = 0.0055 and 0.0081, respectively). In cohort B, posttreatment Ki67, but not pCR, was a prognostic factor of DFS and OS (p = 0.028 and 0.017, respectively). The prognostic value of combined posttreatment Ki67 and pCR was superior to that of either alone. Combined pCR and posttreatment Ki67 had an independent prognostic value for DFS and OS (p = 0.0068 and 0.0101, respectively). CONCLUSIONS In ER+HER2+ breast cancer, the presence of ER-HER2+ cells without HER2- cells was independently associated with pCR. Combined posttreatment Ki67 and pCR can be more precise in predicting prognosis than pCR alone.
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Affiliation(s)
- Natsuki Teruya
- Breast Surgical Oncology, Breast Oncology CenterCancer Institute Hospital, Japanese Foundation for Cancer ResearchTokyoJapan
- Department of Oncotherapeutic Medicine, Graduate School of MedicineTohoku UniversitySendaiJapan
| | - Hiroaki Inoue
- Department of Thoracic, Endocrine Surgery and OncologyTokushima Graduate School of Biomedical SciencesTokushima CityJapan
| | - Rie Horii
- Department of PathologySaitama Cancer CenterSaitamaJapan
- Department of PathologyCancer Institute Hospital, Japanese Foundation for Cancer ResearchTokyoJapan
- Department of PathologyCancer Institute, Japanese Foundation for Cancer ResearchTokyoJapan
| | - Futoshi Akiyama
- Department of PathologyCancer Institute Hospital, Japanese Foundation for Cancer ResearchTokyoJapan
- Department of PathologyCancer Institute, Japanese Foundation for Cancer ResearchTokyoJapan
| | - Takayuki Ueno
- Breast Surgical Oncology, Breast Oncology CenterCancer Institute Hospital, Japanese Foundation for Cancer ResearchTokyoJapan
| | - Shinji Ohno
- Breast Oncology CenterCancer Institute Hospital, Japanese Foundation for Cancer ResearchTokyoJapan
| | - Shunji Takahashi
- Department of Oncotherapeutic Medicine, Graduate School of MedicineTohoku UniversitySendaiJapan
- Department of Medical OncologyCancer Institute Hospital, Japanese Foundation for Cancer ResearchTokyoJapan
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20
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Holmes FA, Moy B, Delaloge S, Chia SKL, Ejlertsen B, Mansi J, Iwata H, Gnant M, Buyse M, Barrios CH, Silovski T, Šeparović R, Bashford A, Zotano AG, Denduluri N, Patt D, Gokmen E, Gore I, Smith JW, Loibl S, Masuda N, Tomašević Z, Petráková K, DiPrimeo D, Wong A, Martin M, Chan A. Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial. Eur J Cancer 2023; 184:48-59. [PMID: 36898233 DOI: 10.1016/j.ejca.2023.02.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/12/2023]
Abstract
BACKGROUND ExteNET showed that neratinib, an irreversible pan-HER tyrosine kinase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved invasive disease-free survival in women with early-stage HER2-positive breast cancer. We report the final analysis of overall survival in ExteNET. METHODS In this international, randomised, double-blind, placebo-controlled, phase 3 trial, women aged 18 years or older with stage 1-3c (amended to stage 2-3c) HER2-positive breast cancer who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab were eligible. Patients were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year. Randomisation was stratified according to hormone receptor (HR) status (HR-positive vs. HR-negative), nodal status (0, 1-3 or 4+), and trastuzumab regimen (sequentially vs. concurrently with chemotherapy). Overall survival was analysed by intention to treat. ExteNET is registered (Clinicaltrials.gov: NCT00878709) and is complete. RESULTS Between July 9, 2009, and October 24, 2011, 2840 women received neratinib (n = 1420) or placebo (n = 1420). After a median follow-up of 8.1 (IQR, 7.0-8.8) years, 127 patients (8.9%) in the neratinib group and 137 patients (9.6%) in the placebo group in the intention-to-treat population had died. Eight-year overall survival rates were 90.1% (95% CI 88.3-91.6) with neratinib and 90.2% (95% CI 88.4-91.7) with placebo (stratified hazard ratio 0.95; 95% CI 0.75-1.21; p = 0.6914). CONCLUSIONS Overall survival in the extended adjuvant setting was comparable for neratinib and placebo after a median follow-up of 8.1 years in women with early-stage HER2-positive breast cancer.
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Affiliation(s)
| | - Beverly Moy
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | | | | | | | - Janine Mansi
- Guy's and St Thomas Hospital NHS Foundation Trust and Biomedical Research Centre, King's College, London, United Kingdom
| | | | - Michael Gnant
- Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria
| | - Marc Buyse
- International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium
| | | | | | - Robert Šeparović
- University Hospital for Tumors, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | | | | | - Neelima Denduluri
- Virginia Cancer Specialists, US Oncology Research, Arlington, VA, USA
| | - Debra Patt
- Texas Oncology - Round Rock, US Oncology Research, Austin, TX, USA
| | - Erhan Gokmen
- Ege University Faculty of Medicine, Izmir, Turkey
| | - Ira Gore
- Alabama Oncology, Birmingham, AL, USA
| | - John W Smith
- Northwest Cancer Specialists, P.C., US Oncology Research, Vancouver, VA, USA
| | - Sibylle Loibl
- Center for Hematology and Oncology Bethanien, Frankfurt, Germany and German Breast Group, Neu-Isenburg, Germany
| | - Norikazu Masuda
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Zorica Tomašević
- Daily Chemotherapy Hospital, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
| | | | | | - Alvin Wong
- Puma Biotechnology Inc., Los Angeles, CA, USA
| | - Miguel Martin
- Instituto de Investigación Sanitaria Gregorio Marañón, CIBERONC, GEICAM, Universidad Complutense, Madrid, Spain
| | - Arlene Chan
- Breast Cancer Research Centre-WA & Curtin University, Perth, Australia
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21
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Méndez-Valdés G, Gómez-Hevia F, Bragato MC, Lillo-Moya J, Rojas-Solé C, Saso L, Rodrigo R. Antioxidant Protection against Trastuzumab Cardiotoxicity in Breast Cancer Therapy. Antioxidants (Basel) 2023; 12:antiox12020457. [PMID: 36830015 PMCID: PMC9952697 DOI: 10.3390/antiox12020457] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/31/2023] [Accepted: 02/06/2023] [Indexed: 02/15/2023] Open
Abstract
Breast cancer is the most frequent malignant neoplastic disease in women, with an estimated 2.3 million cases in 2020 worldwide. Its treatment depends on characteristics of the patient and the tumor. In the latter, characteristics include cell type and morphology, anatomical location, and immunophenotype. Concerning this latter aspect, the overexpression of the HER2 receptor, expressed in 15-25% of tumors, is associated with greater aggressiveness and worse prognosis. In recent times some monoclonal antibodies have been developed in order to target HER2 receptor overexpression. Trastuzumab is part of the monoclonal antibodies used as targeted therapy against HER2 receptor, whose major problem is its cardiac safety profile, where it has been associated with cardiotoxicity. The appearance of cardiotoxicity is an indication to stop therapy. Although the pathophysiological mechanism is poorly known, evidence indicates that oxidative stress plays a fundamental role causing DNA damage, increased cytosolic and mitochondrial ROS production, changes in mitochondrial membrane potential, intracellular calcium dysregulation, and the consequent cell death through different pathways. The aim of this review was to explore the use of antioxidants as adjuvant therapy to trastuzumab to prevent its cardiac toxicity, thus leading to ameliorate its safety profile in its administration.
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Affiliation(s)
- Gabriel Méndez-Valdés
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380000, Chile
| | - Francisca Gómez-Hevia
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380000, Chile
| | | | - José Lillo-Moya
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380000, Chile
| | - Catalina Rojas-Solé
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380000, Chile
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Faculty of Pharmacy and Medicine, Sapienza University, P.Le Aldo Moro 5, 00185 Rome, Italy
| | - Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380000, Chile
- Correspondence: ; Tel.: +56-229786126
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22
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Khoirunnisa SM, Suryanegara FDA, Setiawan D, Postma MJ. Health-related quality of life in Her2-positive early breast cancer woman using trastuzumab: A systematic review and meta-analysis. Front Pharmacol 2023; 14:1090326. [PMID: 37124232 PMCID: PMC10140570 DOI: 10.3389/fphar.2023.1090326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 03/31/2023] [Indexed: 05/02/2023] Open
Abstract
Background: Despite the benefits of trastuzumab in many trials, evidence of its impact on health-related quality of life (HRQoL) in early treatment has not been summarized. This study explored the effects of trastuzumab treatment on HRQoL, including pooled meta-analysis, in an effort to provide an integrated assessment of HRQoL for Her2-positive early breast cancer patients. Methods: A comprehensive literature review to February 2023 using three databases, focusing on treatment using trastuzumab during the early stage, was performed. The mean changes from baseline during and after treatment were extracted from the included randomized control trials (RCTs) papers and total HRQoL scores were obtained from cross-sectional studies included. Mean difference (MD) and 95% confidence intervals were assessed by a random effect or fixed effect model based on heterogeneity (I2). Results: A total of ten studies were identified and reviewed, consisting of seven RCTs and three cross-sectional studies. The pooled analysis of the mean change from baseline during treatment resulted in an MD of 1.92 (95% CI = 1.59 to 2.25, p < 0.05, I2 = 0%), favoring the trastuzumab group. A non-significant result of the mean change from baseline after treatment appeared in the analysis of 12-month follow-up. In the cross-sectional studies, pooled analyses of HRQoL showed that trastuzumab meaningfully demonstrated an improved HRQoL profile (MD = 9.29, 95% CI = 1.31 to 17.27, p = 0.02, I2 = 0%). Conclusion: Trastuzumab as a targeted therapy resulted in a favorable effect on HRQoL in the early stages of Her2-positive breast cancer. The findings of significant improvements in patients' HRQoL and less clinically meaningful deterioration in side effects of trastuzumab-containing regimen during treatment were supported by prolonged survival.
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Affiliation(s)
- Sudewi Mukaromah Khoirunnisa
- Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
- Department of Pharmacy, Institut Teknologi Sumatera, Lampung Selatan, Indonesia
- *Correspondence: Sudewi Mukaromah Khoirunnisa, ,
| | - Fithria Dyah Ayu Suryanegara
- Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
- Department of Pharmacy, Universitas Islam Indonesia, Yogyakarta, Indonesia
| | - Didik Setiawan
- Faculty of Pharmacy, Universitas Muhammadiyah Purwokerto, Banyumas, Indonesia
- Center for Health Economic Studies, Universitas Muhammadiyah Purwokerto, Banyumas, Indonesia
| | - Maarten Jacobus Postma
- Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
- Department of Economics, Econometrics and Finance, University of Groningen, Groningen, Netherlands
- Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Centre of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Bandung, Indonesia
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23
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Jackson C, Finikarides L, Freeman ALJ. The adverse effects of trastuzumab-containing regimes as a therapy in breast cancer: A piggy-back systematic review and meta-analysis. PLoS One 2022; 17:e0275321. [PMID: 36454979 PMCID: PMC9714930 DOI: 10.1371/journal.pone.0275321] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/14/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Trastuzumab is a valuable therapy option for women with ERBB2(HER2)+ breast cancer tumours, often used in combination with chemotherapy and alongside other therapies. It is known to have adverse effects, but these have proved difficult to separate from the effects of other concurrent therapies patients are usually taking. This study aims to assess the adverse effects specifically attributable to trastuzumab, and whether they vary by patient subgroup or concurrent therapies. METHODS As registered on PROSPERO (CRD42019146541), we used previous systematic reviews as well as the clinicaltrials.gov registry to identify randomised controlled trials in breast cancer which compared treatment regimes with and without trastuzumab. Neoadjuvant, adjuvant and metastatic settings were examined. Data was extracted from those which had, as of July 2022, reported adverse events. Risk of bias was assessed using ROB2. Primary outcomes were adverse events of any type or severity (excluding death). A standard random-effects meta-analysis was performed for each outcome independently. In order to ascertain whether adverse effects differed by individual factors such as age or tumour characteristics, or by use of trastuzumab concurrently with hormone therapy, we examined individual-level patient data for one large trial, HERA. RESULTS 79 relevant trials were found, of which 20 contained comparable arms of trastuzumab-containing therapy and corresponding matched therapy without trastuzumab. This allowed a comparison of 8669 patients receiving trastuzumab versus 9556 receiving no trastuzumab, which gave a list of 25 statistically and clinically significant adverse effects related to trastuzumab alone: unspecified pain, asthenia, nasopharyngitis, skin disorders (mainly rash), dyspepsia, paraesthesia, infections (often respiratory), increased lacrimation, diarrhoea, myalgia, oedema (limb/peripheral), fever, nose bleeds, cardiac events, insomnia, cough, back pain, dyspnoea, chills, dizziness or vertigo, hypertension, congestive heart failure, increased levels of aspartate aminotransferase, gastrointestinal issues and dehydration. Analysis of individual patient-level data from 5102 patients suggested that nausea is slightly more likely for women taking trastuzumab who are ER+ /also taking hormone therapy than for those who are ER-/not taking hormone therapy; no other potential treatment-subgroup interactions were detected. We found no evidence for significantly increased rates of neutropenia, anaemia or lymphopenia in patients on trastuzumab-containing regimes compared to those on comparable regimes without trastuzumab. CONCLUSIONS This meta-analysis should allow clinicians and patients to better identify and quantify the potential adverse effects of adding trastuzumab to their treatment regime for breast cancer, and hence inform their decision-making. However, limitations include serious risk of bias due to heterogeneity in reporting of the outcomes and the open-label nature of the trials.
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Affiliation(s)
| | - Leila Finikarides
- Winton Centre for Risk & Evidence Communication, Department of Pure Mathematics & Mathematical Statistics, University of Cambridge, Cambridge, United Kingdom
| | - Alexandra L. J. Freeman
- Winton Centre for Risk & Evidence Communication, Department of Pure Mathematics & Mathematical Statistics, University of Cambridge, Cambridge, United Kingdom
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24
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Complete response in patient with liver metastasis of HER2-positive breast cancer following therapy with margetuximab: a case report. Anticancer Drugs 2022:00001813-990000000-00114. [PMID: 36730303 PMCID: PMC10344431 DOI: 10.1097/cad.0000000000001466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer has a poor prognosis and few effective targeted therapies. However, several anti-HER2 agents are emerging in conjunction with chemotherapy, which may lead to increased rates of pathological complete response in patients with HER2-positive metastatic breast cancer. Among them, margetuximab demonstrated a significant improvement in progression-free survival compared with trastuzumab, when combined with chemotherapy in pretreated patients. Here we present a case of a 67-year-old female patient who was diagnosed with HER2-positive, histological grade III and invasive ductal carcinoma of the left breast in September 2018. She received postoperative adjuvant therapy with EC-TH plus radiotherapy, followed by therapy with HER2-targeted trastuzumab for 1 year (till December 2019). In May 2020, routine reexamination showed a supraclavicular lymph node and bone metastasis. Patient was then treated with pyrotinib, capecitabine and bisphosphonate for a period of 3 months. In December 2020, liver MRI revealed multiple liver metastases. The patient received eight cycles of second-line therapy (vinorelbine plus margetuximab) from January 2021. Since the ninth cycle, the patient was continued with only margetuximab. In March 2021, MRI showed a 70% decrease in the liver metastasis lesions. By June 2021, liver lesions were totally disappeared. During therapy, patient experienced only grade-1 anemia. This case demonstrates that margetuximab plus chemotherapy is safe and might bring clinical benefits for patients with HER2-positive breast cancer with liver metastasis. Further studies evaluating the efficacy and safety of margetuximab in Chinese HER2-positive breast cancer patients are needed.
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25
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McDonald SJ, VanderVeen BN, Bullard BM, Cardaci TD, Madero SS, Chatzistamou I, Fan D, Murphy EA. Surgical wounding enhances pro-tumor macrophage responses and accelerates tumor growth and lung metastasis in a triple negative breast cancer mouse model. Physiol Rep 2022; 10:e15497. [PMID: 36325601 PMCID: PMC9630756 DOI: 10.14814/phy2.15497] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/12/2022] [Accepted: 09/16/2022] [Indexed: 11/06/2022] Open
Abstract
Approximately one-third of all breast cancer mortality results from metastatic recurrence after initial success of surgery and/or therapy. Although primary tumor removal is widely accepted as beneficial, it has long been suspected that surgery itself contributes to accelerated metastatic recurrence. We investigated surgical wounding's impact on tumor progression and lung metastasis in a murine model of triple negative breast cancer (TNBC). Ten-week-old female mice were inoculated with 4 T1 cells (week 0) and were either subjected to a 2 cm long cutaneous contralateral incision (wounded) or control (non-wounded) on week 2 and monitored for 3 weeks (week 5). Mice with surgical wounding displayed significantly accelerated tumor growth observable as early as 1-week post wounding. This was confirmed by increased tumor volume and tumor weight, post-mortem. Further, surgical wounding increased metastasis to the lungs, as detected by IVIS imaging, in vivo and ex vivo (week 5). As expected then, wounded mice displayed decreased apoptosis and increased proliferation in both the primary tumor and in the lungs. Flow cytometry revealed that primary tumors from wounded mice exhibited increased tumor associated macrophages and specifically M2-like macrophages, which are important in promoting tumor development, maintenance, and metastasis. Immunofluorescence staining and gene expression data further confirms an increase in macrophages in both the primary tumor and the lungs of wounded mice. Our data suggests that surgical wounding accelerates tumor progression and lung metastasis in a mouse model of TNBC, which is likely mediated, at least in part by an increase in macrophages.
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Affiliation(s)
- Sierra J. McDonald
- Department of Pathology, Microbiology & ImmunologyUniversity of South Carolina School of MedicineColumbiaSouth CarolinaUSA
| | - Brandon N. VanderVeen
- Department of Pathology, Microbiology & ImmunologyUniversity of South Carolina School of MedicineColumbiaSouth CarolinaUSA
- AcePre, LLCColumbiaSouth CarolinaUSA
| | - Brooke M. Bullard
- Department of Pathology, Microbiology & ImmunologyUniversity of South Carolina School of MedicineColumbiaSouth CarolinaUSA
| | - Thomas D. Cardaci
- Department of Pathology, Microbiology & ImmunologyUniversity of South Carolina School of MedicineColumbiaSouth CarolinaUSA
| | - Sarah S. Madero
- Department of Pathology, Microbiology & ImmunologyUniversity of South Carolina School of MedicineColumbiaSouth CarolinaUSA
| | - Ioulia Chatzistamou
- Department of Pathology, Microbiology & ImmunologyUniversity of South Carolina School of MedicineColumbiaSouth CarolinaUSA
| | - Daping Fan
- AcePre, LLCColumbiaSouth CarolinaUSA
- Department of Cell Biology and AnatomyUniversity of South Carolina School of MedicineColumbiaSouth CarolinaUSA
| | - E. Angela Murphy
- Department of Pathology, Microbiology & ImmunologyUniversity of South Carolina School of MedicineColumbiaSouth CarolinaUSA
- AcePre, LLCColumbiaSouth CarolinaUSA
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Chen N, Li CL, Peng YF, Yao YF. Long-term follow-up of HER2 overexpression in patients with rectal cancer after preoperative radiotherapy: A prospective cohort study. World J Gastrointest Oncol 2022; 14:2048-2060. [PMID: 36310698 PMCID: PMC9611427 DOI: 10.4251/wjgo.v14.i10.2048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/17/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The role of HER2 overexpression in rectal cancer is controversial.
AIM To assess the role of HER2 overexpression in the long-term prognosis of rectal cancer.
METHODS Data from patients with locally advanced rectal cancer who underwent total mesorectal excision after short-course radiotherapy at Beijing Cancer Hospital between May 2002 and October 2005 were collected. A total of 151 tissue samples of rectal cancer were obtained using rigid proctoscopy before neoadjuvant radiotherapy, followed by immunohistochemistry and fluorescence in situ hybridisation to determine the patients’ HER2 expression status. Univariate and multivariate analyses of the associations between the clinicopathological factors and HER2 status were performed. Survival was estimated and compared using the Kaplan-Meier method based on HER2 expression status, and the differences between groups were verified using the log-rank test.
RESULTS A total of 151 patients were enrolled in this study. A total of 27 (17.9%) patients were ultimately confirmed to be HER2-positive. The follow-up duration ranged from 9 mo to 210 mo, with a median of 134 mo. Distant metastasis and local recurrence occurred in 60 (39.7%) and 24 (15.9%) patients, respectively. HER2 positivity was significantly associated with the pre-treatment lymph node stage (pre-N) (P = 0.040), while there were no differences between HER2 status and age, sex, preoperative CEA levels (pre-CEA), T stage, and lympho-vascular invasion. In terms of prognosis, HER2 overexpression was correlated with distant metastasis (P = 0.002) rather than local recurrence (P > 0.05). The multivariate analysis demonstrated that elevated pre-CEA [P = 0.002, odds ratio (OR) = 3.277, 97.5% confidence interval (CI): 1.543-7.163], post N(+) (P = 0.022, OR = 2.437, 97.5%CI: 1.143-5.308) and HER2(+) (P = 0.003, OR = 4.222, 97.5%CI: 1.667-11.409) were risk factors for distant metastasis. The survival analysis showed that there were significant differences between rectal cancer patients in terms of disease-free survival (DFS) [hazard ratio: 1.69 (95%CI: 0.91-3.14); P = 0.048] and overall survival (OS) [1.95 (1.05-3.63); P = 0.0077].
CONCLUSION HER2 overexpression is a potential biomarker for predicting lymph node metastasis and distant metastasis, which are associated with worse long-term DFS and OS in rectal cancer patients with locally advanced disease.
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Affiliation(s)
- Nan Chen
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Chang-Long Li
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yi-Fan Peng
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yun-Feng Yao
- Department of Gastrointestinal Surgery, Ward III, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
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27
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Tuia JE, Olivier T, Prasad VK. Crossover in Adjuvant Trastuzumab Trials: Sparing Toxicity in Patient Care. Am J Clin Oncol 2022; 45:438-441. [PMID: 36073967 DOI: 10.1097/coc.0000000000000938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
OBJECTIVES Design and reporting of randomized control trials for drug therapies in the adjuvant setting require a nuanced consideration of patient crossover. Adjuvant trials can be susceptible to the misuse of crossover and may distort the interpretation of findings. We sought to investigate and describe crossover and/or postprogression access to trastuzumab within adjuvant trastuzumab randomized control trials for human epidermal growth factor receptor 2-positive breast cancer patients. METHODS Seven clinical trials for adjuvant trastuzumab in human epidermal growth factor receptor 2-positive breast cancer were identified through a meta-analysis published in the Lancet . Primary study publications were located through MEDLINE, Google Scholar, and trials were identified, when possible, using Clincialtrials.gov. RESULTS Sixteen publications, describing 7 studies, were reviewed. Four (57%) trials reported offering patients within the control arm the opportunity to crossover and receive trastuzumab in the adjuvant setting. Two (29%) trials did not report nor discuss crossover within the publication. Five (71%) trials reported the total number of patients who crossed over among the control arms. No trials specified the proportion of control patients who received trastuzumab at recurrence. CONCLUSIONS Trials for adjuvant trastuzumab did not disambiguate between crossover (1) in the adjuvant setting or (2) at recurrence. Due to the low reported rate of crossover, it is questionable if participants received the standard of care.
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Affiliation(s)
| | - Timothée Olivier
- Departments of Epidemiology and Biostatistics
- Department of Oncology, Geneva University Hospital, Geneva, Switzerland
| | - Vinay K Prasad
- Departments of Epidemiology and Biostatistics
- Medicine, University of California San Francisco, San Francisco, CA
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Fedele P, Sanna V, Santoro AN, Iaia ML, Fancellu A. Tailoring antiHer2 treatment strategies in breast cancer and beyond. Curr Probl Cancer 2022; 46:100892. [DOI: 10.1016/j.currproblcancer.2022.100892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/04/2022] [Accepted: 05/23/2022] [Indexed: 11/03/2022]
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Hossain MS, Syeed MMM, Fatema K, Hossain MS, Uddin MF. Singular Nuclei Segmentation for Automatic HER2 Quantification Using CISH Whole Slide Images. SENSORS (BASEL, SWITZERLAND) 2022; 22:7361. [PMID: 36236459 PMCID: PMC9571354 DOI: 10.3390/s22197361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 09/20/2022] [Accepted: 09/22/2022] [Indexed: 06/16/2023]
Abstract
Human epidermal growth factor receptor 2 (HER2) quantification is performed routinely for all breast cancer patients to determine their suitability for HER2-targeted therapy. Fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH) are the US Food and Drug Administration (FDA) approved tests for HER2 quantification in which at least 20 cancer-affected singular nuclei are quantified for HER2 grading. CISH is more advantageous than FISH for cost, time and practical usability. In clinical practice, nuclei suitable for HER2 quantification are selected manually by pathologists which is time-consuming and laborious. Previously, a method was proposed for automatic HER2 quantification using a support vector machine (SVM) to detect suitable singular nuclei from CISH slides. However, the SVM-based method occasionally failed to detect singular nuclei resulting in inaccurate results. Therefore, it is necessary to develop a robust nuclei detection method for reliable automatic HER2 quantification. In this paper, we propose a robust U-net-based singular nuclei detection method with complementary color correction and deconvolution adapted for accurate HER2 grading using CISH whole slide images (WSIs). The efficacy of the proposed method was demonstrated for automatic HER2 quantification during a comparison with the SVM-based approach.
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Affiliation(s)
- Md Shakhawat Hossain
- Department of CS, American International University-Bangladesh, Dhaka 1229, Bangladesh
- RIoT Research Center, Independent University, Bangladesh, Dhaka 1229, Bangladesh
| | - M. M. Mahbubul Syeed
- RIoT Research Center, Independent University, Bangladesh, Dhaka 1229, Bangladesh
- Department of CSE, Independent University, Bangladesh, Dhaka 1229, Bangladesh
| | - Kaniz Fatema
- RIoT Research Center, Independent University, Bangladesh, Dhaka 1229, Bangladesh
- Department of CSE, Independent University, Bangladesh, Dhaka 1229, Bangladesh
| | - Md Sakir Hossain
- Department of CS, American International University-Bangladesh, Dhaka 1229, Bangladesh
| | - Mohammad Faisal Uddin
- RIoT Research Center, Independent University, Bangladesh, Dhaka 1229, Bangladesh
- Department of CSE, Independent University, Bangladesh, Dhaka 1229, Bangladesh
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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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Yuan Y, Zhou S, Li C, Zhang X, Mao H, Chen W, Jiang X. Cascade Downregulation of the HER Family by a Dual-Targeted Recombinant Protein-Drug Conjugate to Inhibit Tumor Growth and Metastasis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2201558. [PMID: 35365900 DOI: 10.1002/adma.202201558] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/30/2022] [Indexed: 06/14/2023]
Abstract
Human epidermal growth factor receptor type 2 (HER2)-targeted therapy can significantly improve the outcome of patients with HER2 positive cancer. However, relapse after this treatment remains a great challenge in the clinic due to tumor resistance, in which the HER network induces constitutive signal transduction. In addition, integrin receptors in the tumor extracellular matrix can mitigate the therapeutic effect of inhibitors to the growth factors receptors and tyrosine kinases. Here, the development of a recombinant protein (RP-HI) and its drug conjugates (RPDC-HI) to target both HER2 and integrin is reported. When simultaneously blocking HER2 and integrin by RP-HI, functions of the HER family and their interactions with the integrin are disrupted by downregulated expressions of HER family members, leading to inhibition of several downstream signal pathways. In combination with targeted delivery of the anticancer agent, doxorubicin (DOX), RPDC-HI significantly improves the tumor inhibition efficacy to 97.5% in treating HER2-positive breast cancer, comparing to 34.3% for free DOX. RPDC-HI shows even better antitumor efficiency than a monoclonal antibody, trastuzumab, when treating larger tumors. The developed dual-targeted RPDC platform offers a new and promising strategy for treating HER2-positive patients with synergistic therapeutic effects against tumor resistance to the conventional HER2-targeted treatment.
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Affiliation(s)
- Yang Yuan
- MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
| | - Sensen Zhou
- MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
| | - Cheng Li
- MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
| | - Xiaoke Zhang
- MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
| | - Hui Mao
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, 30322, USA
| | - Weizhi Chen
- MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
| | - Xiqun Jiang
- MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
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Cultural Adaptation and Validation of the EORTC QLQ-BR45 to Assess Health-Related Quality of Life of Breast Cancer Patients. EUROPEAN PHARMACEUTICAL JOURNAL 2022. [DOI: 10.2478/afpuc-2021-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Abstract
Background
The European Organization for Research and Treatment of Cancer (EORTC) QLQ-BR23 is considered a premier module for breast cancer patients that is utilised synchronously with the core questionnaire. However, new and scalable treatments on breast cancer patients’ quality of life (QoL) need a more accurate and comprehensive tool to be assessed. Therefore, the EORTC introduced the newly updated module EORTC QLQ-BR45. Hence, the current study aims to perform cultural adaptation, pilot testing and assessment of the psychometric properties of the Egyptian Arabic translation of the EORTC QLQ-BR45 module on Egyptian breast cancer patients.
Patients and Methods
First, a review of the existing Arabic translation and the modified preliminary translation was sent to a professional proofreader. Then, comprehensibility of the Egyptian Arabic translation was pilot tested on a sample of 13 breast cancer patients. Afterwards, 74 patients with proven locally advanced breast cancer receiving neoadjuvant chemotherapy at Beni-Suef University Hospital, Beni-Suef, Egypt were interviewed. A second interview was conducted post-surgery for patients receiving target therapy, endocrine therapy or radiotherapy. The psychometric properties of the EORTC QLQ-BR45 were assessed in terms of reliability, convergent and divergent validity.
Results
Adequate internal consistency reliability (Cronbach’s α coefficients >0.7) was demonstrated for the questionnaire, except for body image scale (α = 0.51) and systemic therapy side effects scale (α = 0.63). Multi-trait scaling analysis exhibited acceptable convergent and divergent validity, and scaling success was observed for all questionnaire items.
Conclusion
The Egyptian Arabic version of the EORTC QLQ-BR45 module is valid and adequately reliable. These results support using the EORTC QLQ-BR45 in future breast cancer clinical trials.
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HER2 testing in metastatic breast cancer – Is reflex ISH testing necessary on HER2 IHC-equivocal (2+) cases? Ann Diagn Pathol 2022; 59:151953. [DOI: 10.1016/j.anndiagpath.2022.151953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/18/2022] [Indexed: 11/20/2022]
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Venetis K, Crimini E, Sajjadi E, Corti C, Guerini-Rocco E, Viale G, Curigliano G, Criscitiello C, Fusco N. HER2 Low, Ultra-low, and Novel Complementary Biomarkers: Expanding the Spectrum of HER2 Positivity in Breast Cancer. Front Mol Biosci 2022; 9:834651. [PMID: 35372498 PMCID: PMC8965450 DOI: 10.3389/fmolb.2022.834651] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/21/2022] [Indexed: 12/16/2022] Open
Abstract
HER2 status in breast cancer is assessed to select patients eligible for targeted therapy with anti-HER2 therapies. According to the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), the HER2 test positivity is defined by protein overexpression (score 3+) at immunohistochemistry (IHC) and/or gene amplification at in situ hybridization (ISH). The introduction of novel anti-HER2 compounds, however, is changing this paradigm because some breast cancers with lower levels of protein expression (i.e. score 1+/2+ with no gene amplification) benefited from HER2 antibody-drug conjugates (ADC). Recently, a potential for HER2 targeting in HER2 "ultra-low" (i.e. score 0 with incomplete and faint staining in ≤10% of tumor cells) and MutL-deficient estrogen receptor (estrogen receptor)-positive/HER2-negative breast cancers has been highlighted. All these novel findings are transforming the traditional dichotomy of HER2 status and have dramatically raised the expectations in this field. Still, a more aware HER2 status assessment coupled with the comprehensive characterization of the clinical and molecular features of these tumors is required. Here, we seek to provide an overview of the current state of HER2 targeting in breast cancers beyond the canonical HER2 positivity and to discuss the practical implications for pathologists and oncologists.
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Affiliation(s)
- Konstantinos Venetis
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Edoardo Crimini
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology, IRCCS, Milan, Italy
| | - Elham Sajjadi
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Chiara Corti
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology, IRCCS, Milan, Italy
| | - Elena Guerini-Rocco
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Giuseppe Viale
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Giuseppe Curigliano
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology, IRCCS, Milan, Italy
| | - Carmen Criscitiello
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology, IRCCS, Milan, Italy
| | - Nicola Fusco
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Krop IE, Im SA, Barrios C, Bonnefoi H, Gralow J, Toi M, Ellis PA, Gianni L, Swain SM, Im YH, De Laurentiis M, Nowecki Z, Huang CS, Fehrenbacher L, Ito Y, Shah J, Boulet T, Liu H, Macharia H, Trask P, Song C, Winer EP, Harbeck N. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J Clin Oncol 2022; 40:438-448. [PMID: 34890214 PMCID: PMC8824393 DOI: 10.1200/jco.21.00896] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
PURPOSE We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1). METHODS The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing. RESULTS The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ≥ 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80). CONCLUSION The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC.
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Affiliation(s)
- Ian E. Krop
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA,Ian E. Krop, MD, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215; e-mail:
| | - Seock-Ah Im
- Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Carlos Barrios
- Oncology Research Unit, Oncoclínicas, HSL, PUCRS, Porto Alegre, Brazil
| | - Hervé Bonnefoi
- Institut Bergonié Unicancer and Bordeaux University, Bordeaux, France
| | | | - Masakazu Toi
- Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Paul A. Ellis
- Guy's Hospital and Sarah Cannon Research Institute, London, UK
| | | | - Sandra M. Swain
- Georgetown University Medical Center and MedStar Health, Washington, DC
| | - Young-Hyuck Im
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - Zbigniew Nowecki
- Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Chiun-Sheng Huang
- National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Yoshinori Ito
- Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | | | | | | | | | | | | | - Eric P. Winer
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Nadia Harbeck
- Breast Center, Dept. OB&GYN, LMU University Hospital, Munich, Germany
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Chang CH, Jung CJ, Huang YM, Chiao L, Chang YL, Hsieh SC, Lin CH, Kuo YM. The first reported case of trastuzumab induced interstitial lung disease associated with anti-neutrophil cytoplasmic antibody vasculitis - A case report and a prospective cohort study on the usefulness of neutrophil derived biomarkers in monitoring vasculitis disease activity during follow-up. Breast 2022; 61:35-42. [PMID: 34894465 PMCID: PMC8669110 DOI: 10.1016/j.breast.2021.11.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 11/15/2021] [Accepted: 11/23/2021] [Indexed: 01/03/2023] Open
Abstract
Targeted therapies against human epidermal growth factor receptor 2 (HER2) are associated with increased interstitial lung disease (ILD). Trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine have markedly extended HER2 breast cancer survival but current knowledge on how these HER2-targeted agents induce interstitial lung disease is still poorly defined due to limited cases in the literature. Physicians mostly managed this complication by dose interruption, dose de-escalation, or discontinuation with success. In 2019, the FDA had granted accelerated approval on trastuzumab deruxtecan (T-Dxd) in HER2 breast cancer in the late line setting. Severe ILD incidence rate was over ten percent and led to fatal outcomes in 2.2% of patients in the T-Dxd trial. Searching for biomarkers to detect ILD incidence before it becomes clinically fulminant or for treatment response monitoring is of high clinical value. A Case of life-threatening trastuzumab-induced ILD was encountered in our facility. The ILD was confirmed to be antineutrophil cytoplasmic antibody (ANCA) pulmonary capillaritis. The biomarker of neutrophil extracellular traps (NETs), serum MPO-DNA complex, showed a good correlation with the clinical severity. Soon after B cell depleting agent rituximab usage, the serum MPO-DNA outperformed ANCA autoantibody and maintained its correlation with clinical severity. In addition to the trastuzumab-induced ILD case, a prospective cohort in our facility also confirmed the usefulness of MPO-DNA in monitoring vasculitis activity. We postulated that upfront testing with biomarkers of vasculitis during HER2 targeted treatment with high ILD incidence may be beneficial in the future.
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Affiliation(s)
- Chen-Han Chang
- Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan.
| | - Chiau-Jing Jung
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Ming Huang
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Lo Chiao
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Yih-Leong Chang
- Graduate Institute of Pathology, College of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Pathology, National Taiwan University Cancer Center and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Song-Chou Hsieh
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ching-Hung Lin
- Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yu-Min Kuo
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Efficacy of adjuvant trastuzumab in women with HER2-positive T1a or bN0M0 breast cancer: a population-based cohort study. Sci Rep 2022; 12:1068. [PMID: 35058536 PMCID: PMC8776836 DOI: 10.1038/s41598-022-05209-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 01/03/2022] [Indexed: 01/03/2023] Open
Abstract
Adjuvant trastuzumab has been associated with superior survival in women with ≥ T1c or node-positive HER2-positive early-stage breast cancer; however, there is a lack of phase III trials in women with T1a/bN0 disease. Our study aimed to assess the outcomes of women with HER2-positive T1a/bN0 breast cancer who received adjuvant trastuzumab in Saskatchewan, Canada. We evaluated all women diagnosed with HER2-positive T1a/bN0 breast cancer in Saskatchewan between 2008 and 2017. We performed Cox proportional multivariable analysis to determine factors correlated with survival. In addition, inverse probability treatment weighting (IPTW) using propensity score was performed to assess benefit of adjuvant trastuzumab. Ninety-one eligible women with a median age of 61 years (range 30–89) were identified. Thirty-nine (43%) women received adjuvant trastuzumab. Women who received trastuzumab were younger and had a higher rate of T1b disease. Overall, 3% of women who received trastuzumab compared to 12% of women who did not receive trastuzumab developed breast cancer recurrence (p = 0.23). Five-year disease-free survival (DFS) of women who received adjuvant trastuzumab was 94.8% compared to 82.7% of women who did not receive trastuzumab (p = 0.22). Five-year overall survival was 100% of women who received trastuzumab compared to 90.4% of women who did not receive adjuvant trastuzumab (p = 0.038). In the multivariable analysis, grade III tumors were correlated with inferior DFS (hazard ratio [HR] 5.5, 95% CI [1.7–17.7]). The propensity score using the inverse probability of treatment weighting showed that lack of adjuvant trastuzumab was correlated inferior DFS, with an HR of 4 (95% CI 1.05–15.5). Women with HER2-positive T1a/bN0 breast cancer had overall low recurrence of breast cancer. However, the results of this exploratory analysis indicate that women who received adjuvant trastuzumab had better survival.
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Sengoz T, Karakaya YA, Gultekin A, Yaylali O, Senol H, Yuksel D. Relationships of 18F-FDG uptake by primary tumors with prognostic factors and molecular subtype in ductal breast cancer. Rev Esp Med Nucl Imagen Mol 2022; 41:32-38. [PMID: 34991834 DOI: 10.1016/j.remnie.2021.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVES In this study, we aimed to investigate the correlation between SUVmax of primary tumor and prognostic factors/molecular subtype in ductal breast cancer patients. MATERIALS AND METHODS We retrospectively reviewed 150 female patients with pathologically proven invasive ductal breast cancer from January 2015 to October 2019 who underwent 18F-FDG PET/CT for initial staging. Histopathological prognostic features of the primary tumor (histological grade, hormone receptor status, Ki-67 index, vb.) were obtained from the tru-cut biopsy report. In 18F-FDG PET/CT studies, the maximum standardized uptake value (SUVmax) of the primary breast tumor was calculated and compared with the presence of axillary lymphadenopathy and/or distant metastases, histopathological prognostic factors and molecular subtype. RESULTS The high SUVmax of primary breast tumors is significantly correlated with the clinicopathological factors: high tumor size, high histologic grade, high Ki-67 index, axillary lymph node positivity and distant metastasis. SUVmax value was significantly higher in patients with basal subtype than patients with Luminal A subtype (8,14 ± 3,71 and 4,64 ± 2,45, p = 0,002). Correlation analysis revealed a low correlation between Ki-67 index and SUVmax (r = 0,276, p = 0,001) and moderate correlation between tumor size and SUVmax (r = 0,470, p = 0,001). In multivariate linear regression analysis, Ki-67 index and tumor size had a statistically significant effect on SUVmax values. As these parameters increase, it is seen that it increases SUVmax values (p = 0,004, Std Beta: 0,228, 95% CI:0,010-0,055 and p = 0,001, Std Beta:0,374, 95% CI:0,55-0,136, respectively). CONCLUSION High SUVmax value is associated with factors suggesting poor prognosis. Pretreatment 18F-FDG PET/CT can be used as a tool to predict prognosis in breast cancer.
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Affiliation(s)
- Tarik Sengoz
- Pamukkale University, Medical Faculty, Department of Nuclear Medicine, Denizli, Turkey.
| | - Yeliz Arman Karakaya
- Pamukkale University, Medical Faculty, Department of Pathology, Denizli, Turkey.
| | - Aziz Gultekin
- Pamukkale University, Medical Faculty, Department of Nuclear Medicine, Denizli, Turkey.
| | - Olga Yaylali
- Pamukkale University, Medical Faculty, Department of Nuclear Medicine, Denizli, Turkey.
| | - Hande Senol
- Pamukkale University, Medical Faculty, Department of Biostatistics, Denizli, Turkey.
| | - Dogangun Yuksel
- Pamukkale University, Medical Faculty, Department of Nuclear Medicine, Denizli, Turkey.
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Yi YW, You KS, Park JS, Lee SG, Seong YS. Ribosomal Protein S6: A Potential Therapeutic Target against Cancer? Int J Mol Sci 2021; 23:ijms23010048. [PMID: 35008473 PMCID: PMC8744729 DOI: 10.3390/ijms23010048] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/19/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022] Open
Abstract
Ribosomal protein S6 (RPS6) is a component of the 40S small ribosomal subunit and participates in the control of mRNA translation. Additionally, phospho (p)-RPS6 has been recognized as a surrogate marker for the activated PI3K/AKT/mTORC1 pathway, which occurs in many cancer types. However, downstream mechanisms regulated by RPS6 or p-RPS remains elusive, and the therapeutic implication of RPS6 is underappreciated despite an approximately half a century history of research on this protein. In addition, substantial evidence from RPS6 knockdown experiments suggests the potential role of RPS6 in maintaining cancer cell proliferation. This motivates us to investigate the current knowledge of RPS6 functions in cancer. In this review article, we reviewed the current information about the transcriptional regulation, upstream regulators, and extra-ribosomal roles of RPS6, with a focus on its involvement in cancer. We also discussed the therapeutic potential of RPS6 in cancer.
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Affiliation(s)
- Yong Weon Yi
- Department of Biochemistry, College of Medicine, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea; (Y.W.Y.); (K.S.Y.); (J.-S.P.)
- Department of Nanobiomedical Science, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea
| | - Kyu Sic You
- Department of Biochemistry, College of Medicine, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea; (Y.W.Y.); (K.S.Y.); (J.-S.P.)
- Graduate School of Convergence Medical Science, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea
| | - Jeong-Soo Park
- Department of Biochemistry, College of Medicine, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea; (Y.W.Y.); (K.S.Y.); (J.-S.P.)
| | - Seok-Geun Lee
- Graduate School, Kyung Hee University, Seoul 02447, Korea
- Correspondence: (S.-G.L.); (Y.-S.S.); Tel.: +82-2-961-2355 (S.-G.L.); +82-41-550-3875 (Y.-S.S.); Fax: +82-2-961-9623 (S.-G.L.)
| | - Yeon-Sun Seong
- Department of Biochemistry, College of Medicine, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea; (Y.W.Y.); (K.S.Y.); (J.-S.P.)
- Graduate School of Convergence Medical Science, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea
- Correspondence: (S.-G.L.); (Y.-S.S.); Tel.: +82-2-961-2355 (S.-G.L.); +82-41-550-3875 (Y.-S.S.); Fax: +82-2-961-9623 (S.-G.L.)
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Klauser AL, Hirschfeld M, Ritter A, Rücker G, Jäger M, Gundarova J, Weiss D, Juhasz-Böss I, Berner K, Erbes T, Asberger J. Anticarcinogenic Effects of Odorant Substances Citral, Citrathal R and Cyclovertal on Breast Cancer in vitro. BREAST CANCER: TARGETS AND THERAPY 2021; 13:659-673. [PMID: 34916844 PMCID: PMC8668161 DOI: 10.2147/bctt.s322619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 09/17/2021] [Indexed: 12/09/2022]
Abstract
Purpose In 2020, breast cancer still represents the most common type of cancer in women worldwide. Depending on the specific molecular subtype, clinical breast cancer management comprises surgery, radiotherapy, chemotherapy and targeted therapy. Furthermore, there are some therapeutic approaches from the field of complementary and alternative medicine. Current research focuses on the elucidation of new therapeutic targets for treatment development. Odorant substances affect apoptosis, proliferation and cell cycle in healthy and cancerous cells. Exact signalling pathways involved are not entirely clear. The present study aims to analyse their therapeutic potential in breast cancer. Methods This study focuses on the effect of commonly used odorant substances (citral, citrathal R, cyclovertal, para-cymol, hexylacetat, herbavert, dihydromyrcerol and limonen) on the breast cancer cell lines MDA-MB-231, T47-D and BT474. Methodologically, this study applied cell culturing, MTT assay for detection of IC50 of the odorant substance, RNA purification followed by qRT-PCR, protein isolation and Western Blot, as well as immunocytochemistry. Further, this study investigates the role of transient receptor potential channel V1 (TRPV1), involved in the mechanisms of action for some odorant substances. Therefore, capsazepine, a TRPV1 antagonist, was used. Results The odorant substances citral, citrathal R and cyclovertal have significant pro-apoptotic (p < 0.001), anti-proliferative (p < 0.001) and cell cycle-arresting effects measurable in RNA expression as well as in protein levels and immunocytochemical staining. The combination of citral and capsazepine no longer showed significant pro-apoptotic, antiproliferative, and cell cycle inhibitory effects compared to the compounds alone. This indicates that TRPV1 is necessary for the signal transduction of citral. Conclusion This present study reveals three odorant substances with effects on cell viability, indicating their potential use in breast cancer therapy. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/-gpMvmx9sCU
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Affiliation(s)
| | - Marc Hirschfeld
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany
- Institute of Veterinary Medicine, University of Göttingen, Göttingen, Germany
| | - Andrea Ritter
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Gerta Rücker
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Institute of Medical Biometry and Statistics, Medical Center – University of Freiburg, Freiburg, Germany
| | - Markus Jäger
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Julia Gundarova
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Daniela Weiss
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Ingolf Juhasz-Böss
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Kai Berner
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Thalia Erbes
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Jasmin Asberger
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Obstetrics and Gynecology, Medical Center – University of Freiburg, Freiburg, Germany
- Correspondence: Jasmin Asberger Department of Obstetrics and Gynecology, Faculty of Medicine and Medical Center – University of Freiburg, Hugstetterstr. 55, Freiburg, 79106, GermanyTel +49 761 270 30020Fax +49 761 270 30370 Email
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Gordon JL, Hinsen KJ, Reynolds MM, Brown MA. Anticancer Impact of Nitric Oxide (NO) and NO Combination with SMYD-3 Inhibitor on Breast Carcinomas. Diseases 2021; 9:82. [PMID: 34842655 PMCID: PMC8628812 DOI: 10.3390/diseases9040082] [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: 10/07/2021] [Revised: 11/04/2021] [Accepted: 11/09/2021] [Indexed: 11/16/2022] Open
Abstract
Despite enormous advances in the detection and treatment of breast cancer, it still remains the leading cancer diagnosis and has the second highest mortality rate. Thus, breast cancer research is a high priority for academics and clinicians alike. Based on previous research indicating the potential of nitric oxide (NO) and SMYD-3 inhibition, this work sought to expand upon these concepts and combine the two approaches. Both NO (from S-Nitrosoglutathione (GSNO)), termed Group 1, and a combination therapeutic, inhibitor-4 (SMYD-3 inhibitor) plus NO (from GSNO), termed Group 2, were evaluated for their efficacy on breast carcinoma cell lines MCF7 and MDA-MB-231, and the normal MCF10A breast cell line, using cellular viability, colony formation capacity, cytotoxicity, and cellular apoptosis analysis. These results indicated that, in Group 1, breast carcinoma lines MCF7 and MDA-MB-231, cells experienced a moderate reduction in cellular viability (~20-25%), a large reduction in colony formation capacity (~80-90%), a moderate increase in the relative number of dead cells, and a moderate increase in cellular apoptosis. Group 2 was significantly more impactful, with a ~50% knockdown in cellular viability, a 100% reduction in colony formation capacity, a large increase in the relative number of dead cells, and a large increase in cellular apoptosis. Additionally, Group 2 induced a very small impact on the normal MCF10A cell line. Cumulatively, this work revealed the exciting impact of this combination therapeutic, indicating its potential for clinical application and further research.
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Affiliation(s)
- Jenna L. Gordon
- Department of Chemistry, Colorado State University, Fort Collins, CO 80521, USA;
| | - Kristin J. Hinsen
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80521, USA;
| | - Melissa M. Reynolds
- Department of Chemistry, Department of Chemical and Biological Engineering, School of Biomedical Chemistry, Colorado State University, Fort Collins, CO 80523, USA
| | - Mark A. Brown
- Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80521, USA;
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Chen HL, Chen Q, Deng YC. Pathologic complete response to neoadjuvant anti-HER2 therapy is associated with HER2 immunohistochemistry score in HER2-positive early breast cancer. Medicine (Baltimore) 2021; 100:e27632. [PMID: 34871229 PMCID: PMC8568472 DOI: 10.1097/md.0000000000027632] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 10/13/2021] [Indexed: 01/05/2023] Open
Abstract
To evaluate whether pathologic complete response (pCR) to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) therapy is dependent on the HER2 immunohistochemistry (IHC) score.A total of 181 HER2-positive early breast cancer patients who had received neoadjuvant anti-HER2 therapy were included in this study. Associations were examined between IHC score and tumor pCR status (commonly defined by ypT0+ypN0, ypT0/is+ypN0, or ypT0/is).In trastuzumab-based neoadjuvant-treated patients, ypT0+ypN0 was achieved in 46.0% of patients with HER2 IHC 3+ tumors but only 25.0% of patients with HER2 IHC 2+/fluorescence in situ hybridization (FISH)-positive tumors (P = .016). When pCR was defined as ypT0/is+ypN0 or ypT0/is, 54.7% and 61.3% of patients with HER2 IHC 3+ tumors had a pCR, whereas only 29.5% and 38.6% with HER2 IHC 2+/FISH-positive tumors achieved pCR (P = .004 and P = .008, respectively). The association between dual HER2 blockade and pCR was almost exclusively confined to HER2 IHC 3+ tumors (ypT0+ypN0: 61.9% vs 38.9%, P = .013; ypT0/is+ypN0: 71.4% vs 47.4%, P = .009; and ypT0/is: 81.0% vs 52.6%, P = .002) and was absent in HER2 IHC 2+/FISH-positive tumors. Multivariate logistic regression revealed that HER2 IHC 3+ tumors had a significantly higher probability of achieving ypT0+ypN0 (odds ratio [OR], 0.265; 95% confidence interval [CI], 0.109-0.645; P = .003), ypT0/is+ypN0 (OR, 0.221; 95% CI, 0.094-0.521; P = .001), and ypT0/is (OR, 0.254; 95% CI, 0.111-0.583; P = .001) than HER2 IHC 2+/FISH-positive tumors. A significantly better pCR rate was also found in patients with T1 tumors and patients with dual HER2 blockade.The pCR rate was highly correlated with the HER2 IHC score in neoadjuvant anti-HER2 treatment. The addition of pertuzumab to a neoadjuvant trastuzumab-based regimen improved pCR rates, but there was no significant difference in pCR rates in the IHC 2+/FISH-positive group. This suggests that HER2 IHC scores can predict the effectiveness of treatment.
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Erol M, Önner H, Eren Karanis Mİ. Evaluation of the Histopathological Features of Early-stage Invasive Ductal Breast Carcinoma by 18Fluoride-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. Mol Imaging Radionucl Ther 2021; 30:129-136. [PMID: 34658227 PMCID: PMC8522516 DOI: 10.4274/mirt.galenos.2021.25582] [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] [Indexed: 12/02/2022] Open
Abstract
Objectives: This study investigates the relationship between 18fluoride-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) parameters and histopathological features in patients with early-stage invasive ductal breast carcinoma (IDBC). Methods: Patients with early-stage IDBC who underwent 18F-FDG PET/CT scan for staging were included in this retrospective study. The status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2, Ki-67 proliferative index, and grades of tumors were recorded. The conventional metabolic parameters [maximum standard uptake value (SUVmax) and average standard uptake value] and volume-based parameters [metabolic tumor volume (MTV) and total lesion glycolysis] of the primary tumor were obtained from the 18F-FDG PET/CT images. The associations and correlations between the 18F-FDG PET/CT parameters and histopathological features were assessed. Results: One hundred forty-three patients were included. 18F-FDG PET/CT parameters, other than MTV, were significantly associated with the ER and PR status and Ki-67 index, while T-staging was significantly associated with all 18F-FDG PET/CT parameters. In the axillary lymph node (ALN) involvement, no significant difference was found in the 18F-FDG PET/CT parameters. In terms of the pathological stage, a significant difference was found in all 18F-FDG PET/CT parameters. 18F-FDG PET/CT parameters, other than MTV, were significantly higher in non-luminal breast tumors than luminal tumors and in high-grade tumors than low-grade ones. Triple-negative tumors had the highest 18F-FDG PET/CT parameter, but the difference was insignificant for MTV. The SUVmax had the strongest correlation with Ki-67 proliferative index. Conclusion: Tumors with aggressive histopathological features had higher 18F-FDG PET/CT parameter values. This study suggests that 18F-FDG PET/CT may provide prognostic information in patients with early-stage IDBC.
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Affiliation(s)
- Mustafa Erol
- University of Health Sciences Turkey, Konya City Hospital, Clinic of Nuclear Medicine, Konya, Turkey
| | - Hasan Önner
- University of Health Sciences Turkey, Konya City Hospital, Clinic of Nuclear Medicine, Konya, Turkey
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Grimm EV, Allison KH, Hicks DG, Swenson KK, Krueger J, Yaziji H, Downs-Kelly E, Rendi MH, Susnik B, Tsai ML, Lillemoe TJ. HER2 Testing: Insights From Pathologists' Perspective on Technically Challenging HER2 FISH Cases. Appl Immunohistochem Mol Morphol 2021; 29:635-642. [PMID: 34282066 DOI: 10.1097/pai.0000000000000946] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 04/01/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE College of American Pathologists and the American Society of Clinical Oncology guidelines provide straightforward criteria for HER2 interpretation in breast carcinomas; however, a subset of cases present unusual diagnostic dilemmas. MATERIALS AND METHODS Ten challenging HER2 fluorescence in situ hybridization (FISH) cases were selected for analysis. The study included a variety of problematic cases such as those with discordant immunohistochemistry (IHC) and FISH results, cases with high intratumoral variability in HER2 copy number, a case with a highly amplified clone in 5% to 10% of the tumor sample, and a case with tumor cells containing tightly clumped HER2 signals. Six high volume HER2 FISH laboratories performed and interpreted HER2 FISH (adding HER2 IHC if necessary). Interpretation strategies were discussed. RESULTS There was 100% concordance between laboratories in 4/10 cases. Tumors with increased intratumoral variability (tumors with high variability in HER2 copy number per cell but which otherwise do not fulfill College of American Pathologists and the American Society of Clinical Oncology criteria for heterogeneity) exhibited 100% concordance in 3/4 cases, but 1 case had only 50% agreement. Low positive HER2 cases (group 1 cases with <6 average HER2 copies/cell) had 1 laboratory disagreeing with the majority in 4/4 cases, and this was the only category with discordance between IHC and FISH methodologies. All laboratories identified the case with heterogeneity and interpreted it as positive. Five of the 6 laboratories interpreted the case with tightly clustered HER2 signals as positive. CONCLUSIONS This study offers specific observations and interpretation strategies that laboratories can use when confronted with difficult HER 2 cases. It then highlights communication strategies a laboratory may use to discuss these unusual HER2 results with the clinical team.
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Affiliation(s)
- Erin V Grimm
- Allina Health Laboratories/Hospital Pathology Associates
| | | | - David G Hicks
- University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY
| | - Karen K Swenson
- Allina Health System, Virginia Piper Cancer Institute, Minneapolis, MN
| | - Janet Krueger
- Allina Health System, Virginia Piper Cancer Institute, Minneapolis, MN
| | | | | | - Mara H Rendi
- Allina Health Laboratories/Hospital Pathology Associates
| | - Barbara Susnik
- Allina Health Laboratories/Hospital Pathology Associates
| | - Michaela L Tsai
- Allina Health System, Virginia Piper Cancer Institute, Minneapolis, MN
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Zhang Y, Liu M, Yang H, Wang S. Physicians’ Perception of the Evidence in Relation to Primary Endpoints of Clinical Trials on Breast Cancer. Breast Care (Basel) 2021; 17:180-187. [DOI: 10.1159/000518260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 06/21/2021] [Indexed: 11/19/2022] Open
Abstract
<b><i>Objective:</i></b> To investigate physicians’ perception of the evidence of clinical trials on breast cancer. <b><i>Methods:</i></b> A survey was conducted by the Chinese Society of Breast Surgeons. We investigated the physicians’ perception of meaningful endpoints, appropriate follow-up duration, and clinically acceptable benefit through online questionnaires. <b><i>Results:</i></b> Among 278 validated questionnaires, the majority of the questions had no consistent answer. For local treatment, 30.6, 28.8, and 28.4% of participants regarded locoregional recurrence (LRR), disease-free survival (DFS), and overall survival (OS) as the most meaningful endpoint, respectively, 47.5% believed that 5-year follow-up can alter clinical practice, and 34.5% thought it should be >10 years. In the adjuvant setting, 45.7, 38.5, and 12.9% regarded DFS, OS, and LRR as the most meaningful endpoint, respectively, 52.5% thought that 10-year follow-up was solid, while 37.4% thought that 5-year follow-up was enough. In the advanced setting, 49.6, 24.1, and 23.7% considered progression-free survival, quality of life, and OS the most meaningful endpoint, respectively, and 39.6 and 28.8% considered that a follow-up of 1 year and 3 years, respectively, was meaningful. Similarly, the clinically acceptable absolute difference was inconsistent. <b><i>Conclusion:</i></b> Most Chinese oncologists advocated that surrogate endpoints could be used in certain circumstances, though OS was the most reliable one in breast cancer studies. Doctors’ perceptions of follow-up time and magnitude of benefit vary widely, reflecting the fact that there are many unanswered questions about supporting the use of new cancer treatments; a common understanding needs to be reached, such as a very consensual surrogate endpoint and a meaningful sufficiently large therapeutic benefit.
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Burguin A, Diorio C, Durocher F. Breast Cancer Treatments: Updates and New Challenges. J Pers Med 2021; 11:808. [PMID: 34442452 PMCID: PMC8399130 DOI: 10.3390/jpm11080808] [Citation(s) in RCA: 186] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 12/31/2022] Open
Abstract
Breast cancer (BC) is the most frequent cancer diagnosed in women worldwide. This heterogeneous disease can be classified into four molecular subtypes (luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC)) according to the expression of the estrogen receptor (ER) and the progesterone receptor (PR), and the overexpression of the human epidermal growth factor receptor 2 (HER2). Current BC treatments target these receptors (endocrine and anti-HER2 therapies) as a personalized treatment. Along with chemotherapy and radiotherapy, these therapies can have severe adverse effects and patients can develop resistance to these agents. Moreover, TNBC do not have standardized treatments. Hence, a deeper understanding of the development of new treatments that are more specific and effective in treating each BC subgroup is key. New approaches have recently emerged such as immunotherapy, conjugated antibodies, and targeting other metabolic pathways. This review summarizes current BC treatments and explores the new treatment strategies from a personalized therapy perspective and the resulting challenges.
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Affiliation(s)
- Anna Burguin
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1T 1C2, Canada;
- Cancer Research Center, CHU de Québec-Université Laval, Quebec City, QC G1V 4G2, Canada;
| | - Caroline Diorio
- Cancer Research Center, CHU de Québec-Université Laval, Quebec City, QC G1V 4G2, Canada;
- Department of Preventive and Social Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1T 1C2, Canada
| | - Francine Durocher
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1T 1C2, Canada;
- Cancer Research Center, CHU de Québec-Université Laval, Quebec City, QC G1V 4G2, Canada;
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Bradley R, Braybrooke J, Gray R, Hills R, Liu Z, Peto R, Davies L, Dodwell D, McGale P, Pan H, Taylor C, Anderson S, Gelber R, Gianni L, Jacot W, Joensuu H, Moreno-Aspitia A, Piccart M, Press M, Romond E, Slamon D, Suman V, Berry R, Boddington C, Clarke M, Davies C, Duane F, Evans V, Gay J, Gettins L, Godwin J, James S, Liu H, MacKinnon E, Mannu G, McHugh T, Morris P, Read S, Straiton E, Wang Y, Crown J, de Azambuja E, Delaloge S, Fung H, Geyer C, Spielmann M, Valagussa P, Albain K, Anderson S, Arriagada R, Bartlett J, Bergsten-Nordström E, Bliss J, Brain E, Carey L, Coleman R, Cuzick J, Davidson N, Del Mastro L, Di Leo A, Dignam J, Dowsett M, Ejlertsen B, Francis P, Gnant M, Goetz M, Goodwin P, Halpin-Murphy P, Hayes D, Hill C, Jagsi R, Janni W, Loibl S, Mamounas EP, Martín M, Mukai H, Nekljudova V, Norton L, Ohashi Y, Pierce L, Poortmans P, Raina V, Rea D, Regan M, Robertson J, Rutgers E, Spanic T, Sparano J, Steger G, Tang G, Toi M, Tutt A, Viale G, Wang X, Whelan T, Wilcken N, Wolmark N, Cameron D, Bergh J, Pritchard KI, et alBradley R, Braybrooke J, Gray R, Hills R, Liu Z, Peto R, Davies L, Dodwell D, McGale P, Pan H, Taylor C, Anderson S, Gelber R, Gianni L, Jacot W, Joensuu H, Moreno-Aspitia A, Piccart M, Press M, Romond E, Slamon D, Suman V, Berry R, Boddington C, Clarke M, Davies C, Duane F, Evans V, Gay J, Gettins L, Godwin J, James S, Liu H, MacKinnon E, Mannu G, McHugh T, Morris P, Read S, Straiton E, Wang Y, Crown J, de Azambuja E, Delaloge S, Fung H, Geyer C, Spielmann M, Valagussa P, Albain K, Anderson S, Arriagada R, Bartlett J, Bergsten-Nordström E, Bliss J, Brain E, Carey L, Coleman R, Cuzick J, Davidson N, Del Mastro L, Di Leo A, Dignam J, Dowsett M, Ejlertsen B, Francis P, Gnant M, Goetz M, Goodwin P, Halpin-Murphy P, Hayes D, Hill C, Jagsi R, Janni W, Loibl S, Mamounas EP, Martín M, Mukai H, Nekljudova V, Norton L, Ohashi Y, Pierce L, Poortmans P, Raina V, Rea D, Regan M, Robertson J, Rutgers E, Spanic T, Sparano J, Steger G, Tang G, Toi M, Tutt A, Viale G, Wang X, Whelan T, Wilcken N, Wolmark N, Cameron D, Bergh J, Pritchard KI, Swain SM. Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol 2021; 22:1139-1150. [PMID: 34339645 PMCID: PMC8324484 DOI: 10.1016/s1470-2045(21)00288-6] [Show More Authors] [Citation(s) in RCA: 190] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality. METHODS We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs). FINDINGS Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14·4 months and median follow-up was 10·7 years (IQR 9·5 to 11·9). The risks of breast cancer recurrence (RR 0·66, 95% CI 0·62 to 0·71; p<0·0001) and death from breast cancer (0·67, 0·61 to 0·73; p<0·0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Absolute 10-year recurrence risk was reduced by 9·0% (95% CI 7·4 to 10·7; p<0·0001) and 10-year breast cancer mortality was reduced by 6·4% (4·9 to 7·8; p<0·0001), with a 6·5% reduction (5·0 to 8·0; p<0·0001) in all-cause mortality, and no increase in death without recurrence (0·4%, -0·3 to 1·1; p=0·35). The proportional reduction in recurrence was largest in years 0-1 after randomisation (0·53, 99% CI 0·46 to 0·61), with benefits persisting through years 2-4 (0·73, 0·62 to 0·85) and 5-9 (0·80, 0·64 to 1·01), and little follow-up beyond year 10. Proportional recurrence reductions were similar irrespective of recorded patient and tumour characteristics, including ER status. The more high risk the tumour, the larger the absolute reductions in 5-year recurrence (eg, 5·7% [95% CI 3·1 to 8·3], 6·8% [4·7 to 9·0], and 10·7% [7·7 to 13·6] in N0, N1-3, and N4+ disease). INTERPRETATION Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics. FUNDING Cancer Research UK, UK Medical Research Council.
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Davey S, Grover S, Bilker WB, Setlhako DI, Ralefala TB, Manshimba P, Gross R, DeMichele A, Shulman LN, Martei YM. Retrospective cohort analysis of prescription patterns of cancer medications during periods of drug stockouts in Botswana. BMJ Open 2021; 11:e049574. [PMID: 34253674 PMCID: PMC8276292 DOI: 10.1136/bmjopen-2021-049574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE Cancer drug stockouts occur at high frequencies globally, however, their effects on treatment are understudied in sub-Saharan Africa (SSA). We aimed to determine whether causes of suboptimal cancer treatment prescriptions differed between periods of stockout and full treatment supply. DESIGN A retrospective cohort study of systemic therapy prescriptions for patients diagnosed with the twelve most common solid tumour cancers treated in 2016. SETTING Princess Marina Hospital in Gaborone, Botswana. PARTICIPANTS Patients in the retrospective cohort who experienced any suboptimal treatment events, defined as ≥7 days delay or switch from guideline-concordant initiated therapy. PRIMARY AND SECONDARY OUTCOME MEASURES Frequency of delays and patterns of prescription changes for specific regimens and cancer types. RESULTS 167/378 patients contributed to 320 suboptimal events (115 therapy switches, 167 delays and 38 events with both), over 1452 total chemotherapy cycles received. Events during stockout were 43% delays, 43% switches and 14% both during stockout periods and 67.2% delays, 24.4% switches and 8.4% both during non-stockout periods (p<0.001). Majority of switches involved de-escalation of initially prescribed guideline-recommended regimens in patients with breast cancer, Kaposi sarcoma and patients with colorectal cancer, which occurred more frequently during periods of drug stockouts. Among patients with breast cancer, substitution of docetaxel for paclitaxel event occurred exclusively during paclitaxel drug stockout. Delays of ≥7 days events were most frequent in breast cancer patients receiving paclitaxel during stockout, and combination doxorubicin and cyclophosphamide even during periods of non-stockout. CONCLUSIONS The aetiology of suboptimal events differed during stockout and non-stockout periods. Prescription patterns that involved de-escalation of initiated therapy and substitution of paclitaxel with docetaxel occurred frequently during periods of drug stockout. Further research needs to be conducted to understand the impact of stockout on survival and barriers to maintaining essential cancer medicines supplies in SSA, and the factors driving frequent delays in therapy delivery.
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Affiliation(s)
- Sonya Davey
- Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Surbhi Grover
- Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Warren B Bilker
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dipho I Setlhako
- Oncology Department, Princess Marina Hospital, Gaborone, Botswana
| | | | | | - Robert Gross
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Medicine (Infectious Diseases), University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Angela DeMichele
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Medicine (Hematology-Oncology), University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lawrence N Shulman
- Department of Medicine (Hematology-Oncology), University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Yehoda M Martei
- Department of Medicine (Hematology-Oncology), University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Wang L, Zhang Y, He Y, Li J, Wang T, Xie Y, Fan Z, Ouyang T. Impact of dose-dense neoadjuvant chemotherapy on pathologic response and survival for HER2-positive breast cancer patients who receive trastuzumab. NPJ Breast Cancer 2021; 7:75. [PMID: 34117262 PMCID: PMC8196206 DOI: 10.1038/s41523-021-00284-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 05/27/2021] [Indexed: 12/14/2022] Open
Abstract
To compare outcomes in patients with human epidermal growth factor receptor-2 (HER2)-positive breast cancer who received either dose-dense neoadjuvant chemotherapy (NAC) with trastuzumab or standard-interval chemotherapy with trastuzumab. Patients with HER2-positive breast cancer who received NAC, including epirubicin and cyclophosphamide followed by paclitaxel with trastuzumab were included. Patients were divided into either the dose-dense or standard-interval group. We compared pathologic complete remission (pCR), distant disease-free survival (DDFS), event-free survival (EFS), and breast cancer-specific survival (BCSS) between the two groups. Two hundred (49.6%) patients received dose-dense NAC, and 203 (50.4%) received standard-interval NAC. The pCR rate was 38.4% in the dose-dense group and 29.2% in the standard-interval group (P = 0.052). In patients with lymph node (LN) metastases, the LN pCR rate was 70.9% in the dose-dense group and 56.5% in the standard-interval group (P = 0.037). After a median follow-up of 54.6 months, dose-dense chemotherapy presented an improvement on DDFS (hazard ratio [HR] = 0.49, 95% confidence interval [CI]: 0.19–1.28, EFS (HR = 0.54, 95% CI: 0.24–1.21), and BCSS (HR = 0.41, 95% CI: 0.11–1.51), but the difference was not significant. Compared with standard-interval chemotherapy, dose-dense chemotherapy resulted in a superior 5-year DDFS (100% vs. 75.3%, P = 0.017) and 5-year EFS (96.9% vs. 78.3%, P = 0.022) in patients younger than 40 years. HER2-positive patients can achieve a higher LN pCR rate with dose-dense NAC than with standard-interval NAC with trastuzumab. Better survival may also be achieved with dose-dense chemotherapy with trastuzumab than with standard-interval chemotherapy with trastuzumab among young patients (age ≤ 40 years).
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Affiliation(s)
- Lize Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yang Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yingjian He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jinfeng Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Tianfeng Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yuntao Xie
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhaoqing Fan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Tao Ouyang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.
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Sengoz T, Karakaya YA, Gültekin A, Yaylali O, Senol H, Yuksel D. Relationships of 18F-FDG uptake by primary tumors with prognostic factors and molecular subtype in ductal breast cancer. Rev Esp Med Nucl Imagen Mol 2021; 41:S2253-654X(20)30211-0. [PMID: 34090841 DOI: 10.1016/j.remn.2020.11.006] [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: 08/20/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 11/30/2022]
Abstract
OBJECTIVES In this study, we aimed to investigate the correlation between SUVmax of primary tumor and prognostic factors/molecular subtype in ductal breast cancer patients. MATERIALS AND METHODS We retrospectively reviewed 150 female patients with pathologically proven invasive ductal breast cancer from January 2015 to October 2019 who underwent 18F-FDG PET/CT for initial staging. Histopathological prognostic features of the primary tumor (histological grade, hormone receptor status, Ki-67 index, vb.) were obtained from the tru-cut biopsy report. In 18F-FDG PET/CT studies, the maximum standardized uptake value (SUVmax) of the primary breast tumor was calculated and compared with the presence of axillary lymphadenopathy and/or distant metastases, histopathological prognostic factors and molecular subtype. RESULTS The high SUVmax of primary breast tumors is significantly correlated with the clinicopathological factors: high tumor size, high histologic grade, high Ki-67 index, axillary lymph node positivity and distant metastasis. SUVmax value was significantly higher in patients with basal subtype than patients with Luminal A subtype (8.14±3.71 and 4.64±2.45, p=0.002). Correlation analysis revealed a low correlation between Ki-67 index and SUVmax (r=0.276, p=0.001) and moderate correlation between tumor size and SUVmax (r=0.470, p=0.001). In multivariate linear regression analysis, Ki-67 index and tumor size had a statistically significant effect on SUVmax values. As these parameters increase, it is seen that it increases SUVmax values (p=0.004, Std Beta: 0.228, 95% CI: 0.010-0.055 and p=0.001, Std Beta: 0.374, 95% CI: 0.55-0.136, respectively). CONCLUSION High SUVmax value is associated with prognotic factors suggesting poor prognosis. Pretreatment 18F-FDG PET/CT can be used as a tool to predict prognosis in breast cancer.
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Affiliation(s)
- T Sengoz
- Pamukkale University, Medical Faculty, Department of Nuclear Medicine, Denizli, Turkey.
| | - Y A Karakaya
- Pamukkale University, Medical Faculty, Department of Pathology, Denizli, Turkey
| | - A Gültekin
- Pamukkale University, Medical Faculty, Department of Nuclear Medicine, Denizli, Turkey
| | - O Yaylali
- Pamukkale University, Medical Faculty, Department of Nuclear Medicine, Denizli, Turkey
| | - H Senol
- Pamukkale University, Medical Faculty, Department of Biostatistics, Denizli, Turkey
| | - D Yuksel
- Pamukkale University, Medical Faculty, Department of Nuclear Medicine, Denizli, Turkey
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