|
1
|
Meillan N, Rivera S, Ederhy S, Gueiderikh A, Lamrani-Ghaouti A, De Vathaire F, Allodji RS. Early Breast Cancer Treatment and Cardiac Events: A Systematic Review. Clin Breast Cancer 2025:S1526-8209(25)00085-0. [PMID: 40288934 DOI: 10.1016/j.clbc.2025.03.018] [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: 10/29/2024] [Revised: 03/07/2025] [Accepted: 03/23/2025] [Indexed: 04/29/2025]
Abstract
Cancer-treatment induced cardiovascular diseases are a concern in early breast cancer, especially when radiation is involved and systemic treatments may contribute. Our primary objective was to estimate the frequency of cardiac adverse events after early breast cancer treatment. We performed a systematic review on cardiac events after early breast cancer treatment, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, by searching PubMed, Scopus and Web of Science and cross-checking references from international guidelines on breast cancer treatment and cardio-oncology. Eighty-one studies were selected. Reporting of cardiac events and dose parameters was heterogeneous among studies due to the variability of the events being considered, follow-up duration and patient's age (most reported less than 5% with some as high as 34% at a maximum follow-up of 28 years). The most frequent are ischemic and valvular heart disease. Radiation modalities (hypofractionation, boost, partial or nodal irradiation) do not seem to change the risk of cardiac events. Anthracycline and aromatase inhibitors increase long-term cardiac risk, whereas anti-HER2-related effects are mostly transient. Myocardites with immunotherapy are rare (<1%) but follow-up is short. Other chemotherapy agents and poly(adenosine-diphosphate-ribose)-polymerase inhibitors have not been shown to increase cardiac risks which is reduced with more recent treatments, and increased by young age at diagnosis and previous cardiac risk factors. Advances in treatment seem to lower cardiac events. Prospective studies with exhaustive reporting of toxicity and radiotherapy features are warranted as well as the help of a cardio-oncologist to manage risk factors.
Collapse
Affiliation(s)
- Nicolas Meillan
- Oncology-radiation therapy department, Victor Dupouy Hospital, Argenteuil, France; Gustave Roussy, Comprehensive Cancer Research Center, Villejuif, France; Centre for Research in Epidemiology and Population Health, U1018 Institut National de la Santé et de la Recherche Médicale (INSERM), Villejuif, France; Paris-Saclay University, Unité Mixte de Recherche (UMR), 1018, Villejuif, France.
| | - Sofia Rivera
- Gustave Roussy, Comprehensive Cancer Research Center, Villejuif, France; Gustave Roussy, Radiation Therapy Department, Villejuif, France; Paris-Saclay University, Gustave Roussy, Institut National de la Santé et de la Recherche Médicale (INSERM) 1030, Villejuif, France
| | - Stéphane Ederhy
- Department of Cardiology, UNICO Cardio-Oncology Program, Saint-Antoine Hospital, AP-HP, Paris, France; Inserm U 856, 75013 Paris, France
| | - Anna Gueiderikh
- Gustave Roussy, Radiation Therapy Department, Villejuif, France
| | | | - Florent De Vathaire
- Gustave Roussy, Comprehensive Cancer Research Center, Villejuif, France; Centre for Research in Epidemiology and Population Health, U1018 Institut National de la Santé et de la Recherche Médicale (INSERM), Villejuif, France; Paris-Saclay University, Unité Mixte de Recherche (UMR), 1018, Villejuif, France
| | - Rodrigue Setcheou Allodji
- Gustave Roussy, Comprehensive Cancer Research Center, Villejuif, France; Centre for Research in Epidemiology and Population Health, U1018 Institut National de la Santé et de la Recherche Médicale (INSERM), Villejuif, France; Paris-Saclay University, Unité Mixte de Recherche (UMR), 1018, Villejuif, France
| |
Collapse
|
|
2
|
Rahadi A, Mahardya RTK, Listiani P, Herlinawaty E, Nugraha RR, Budiman DR, Suharlim C. Calibration of transition probabilities to model survival of adjuvant trastuzumab for early breast cancer in Indonesia. Int J Technol Assess Health Care 2025; 41:e18. [PMID: 40135279 PMCID: PMC11955306 DOI: 10.1017/s0266462325000157] [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] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/27/2025]
Abstract
OBJECTIVES Cost-effectiveness models fully informed by real-world epidemiological parameters yield the best results, but they are costly to obtain. Model calibration using real-world data/evidence (RWD/E) on routine health indicators can provide an alternative to improve the validity and acceptability of the results. We calibrated the transition probabilities of the reference chemotherapy treatment using RWE on patient overall survival (OS) to model the survival benefit of adjuvant trastuzumab in Indonesia. METHODS A Markov model comprising four health states was initially parameterized using the reference-treatment transition probabilities, obtained from published international evidence. We then calibrated these probabilities, targeting a 2-year OS of 86.11 percent from the RWE sourced from hospital registries. We compared projected OS duration and life-years gained (LYG) before and after calibration for the Nelder-Mead, Bound Optimization BY Quadratic Approximation, and generalized reduced gradient (GRG) nonlinear optimization methods. RESULTS The pre-calibrated transition probabilities overestimated the 2-year OS (92.25 percent). GRG nonlinear performed best and had the smallest difference with the RWD/E OS. After calibration, the projected OS duration was significantly lower than their pre-calibrated estimates across all optimization methods for both standard chemotherapy (~7.50 vs. 11.00 years) and adjuvant trastuzumab (~9.50 vs. 12.94 years). LYG measures were, however, similar (~2 years) for the pre-calibrated and calibrated models. CONCLUSIONS RWD/E calibration resulted in realistically lower survival estimates. Despite the little difference in LYG, calibration is useful to adapt external evidence commonly used to derive transition probabilities to the policy context, thereby enhancing the validity and acceptability of the modeling results.
Collapse
Affiliation(s)
- Arie Rahadi
- Management Sciences for Health, Arlington, VA, USA
| | | | - Putri Listiani
- Center for Health Financing Policy and Insurance Management, Gadjah Mada University, Sleman, Yogyakarta, Indonesia
| | - Eva Herlinawaty
- Center for Health Financing and Decentralization Policy, Ministry of Health Republic of Indonesia, Central Jakarta, Jakarta, Indonesia
| | | | - Dani Ramdhani Budiman
- Center for Health Financing and Decentralization Policy, Ministry of Health Republic of Indonesia, Central Jakarta, Jakarta, Indonesia
| | | |
Collapse
|
|
3
|
Schlam I, Loi S, Salgado R, Swain SM. Tumor-infiltrating lymphocytes in HER2-positive breast cancer: potential impact and challenges. ESMO Open 2025; 10:104120. [PMID: 39826475 PMCID: PMC11786075 DOI: 10.1016/j.esmoop.2024.104120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/22/2025] Open
Abstract
INTRODUCTION In this review, we evaluate the role of stromal tumor-infiltrating lymphocytes (sTILs) as a biomarker in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, exploring the prognostic and predictive potential in various treatment settings. METHODS Data from multiple clinical trials in the early and metastatic settings, focusing on TILs' correlation with pathologic complete response (pCR), progression-free survival (PFS), and overall survival across early and metastatic HER2-positive breast cancer were summarized. This review also discusses TILs' assessment methods, interobserver variability, and emerging technologies to assess TILs. RESULTS TILs have been identified as a highly reproducible biomarker that predicts pCR in patients receiving neoadjuvant therapy and serves as a prognostic indicator for long-term outcomes in several breast cancer subtypes, including HER2-positive. Studies indicate that higher TIL levels correlate with better recurrence-free survival rates. Despite these findings, there is no consensus on the optimal TIL threshold for clinical decision making, and further research is required on how to incorporate TILs into routine clinical practice. CONCLUSIONS TILs represent a promising biomarker in HER2-positive breast cancer, particularly in early disease settings. This assessment could guide treatment de-escalation or intensification, tailoring therapies to individual patient profiles. Due to their prognostic importance, TILs can be added to pathology reports. However, further validation in clinical trials is essential for the widespread adoption of TILs in clinical practice.
Collapse
Affiliation(s)
- I Schlam
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA. https://twitter.com/ilanaschlam
| | - S Loi
- Peter Mac Callum Cancer Centre, Melbourne, Victoria, Australia. https://twitter.com/LoiSher
| | - R Salgado
- Peter Mac Callum Cancer Centre, Melbourne, Victoria, Australia; ZAS-Hospitals, Antwerp, Belgium. https://twitter.com/TILsWorkGroup
| | - S M Swain
- Georgetown Lombardi Comprehensive Cancer Center, Washington, USA; MedStar Health, Columbia, Maryland, USA.
| |
Collapse
|
|
4
|
Zhao H, Shen C, Laureano JJ, Lei X, Niu J, Giordano SH, Chavez-MacGregor M. Real-world neoadjuvant and adjuvant Trastuzumab-containing regimen patterns and their association with survival among patients with operable HER2-positive breast cancer from 2007 to 2021. Breast Cancer Res Treat 2025; 210:191-203. [PMID: 39576449 PMCID: PMC11787242 DOI: 10.1007/s10549-024-07552-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 11/05/2024] [Indexed: 02/02/2025]
Abstract
PURPOSE Chemotherapy in combination with trastuzumab is the standard neoadjuvant and adjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Assessing the regimens administered to patients with HER2-positive BC in the real world is lacking. We evaluated neoadjuvant and adjuvant regimen patterns among HER2-positive BC patients (2007 to 2021) identified in a health insurance claims database. METHODS Female BC patients ≥ 18 years who received chemotherapy, surgery, and trastuzumab were chosen from Optum's de-identified Clinformatics® Data Mart database. Summary statistics, Joinpoint models, Kaplan-Meier survival curves, and Cox regression models were used to analyze the data. RESULTS We identified 6474 patients (median age 60 years), 71.7% were White, 10.9% were Black, 8.6% were Hispanic, 4.1% were Asian, and 4.7% had unknown race/ethnicity. About 33.8% received neoadjuvant therapy and neoadjuvant therapy use increased with an annual percent change of 10.24% (P < .001). The three most common regimens were adjuvant docetaxel, carboplatin, and trastuzumab (TCH; 29.0%); adjuvant paclitaxel and trastuzumab (17.7%); and neoadjuvant TCH with pertuzumab followed by adjuvant trastuzumab (17.7%). The 5-year overall survival (OS) was 96% (95% CI, 95-96%). Patients had an increased risk of death if they were ≥ 59 years at diagnosis, had a health maintenance organization or other insurance plan, had dual Medicare/Medicaid eligibility, had a mastectomy, did not receive 18 cycles of trastuzumab, or received regimens not recommended by the National Comprehensive Cancer Network. CONCLUSION Treatment regimen patterns for HER2-positive BC evolved in correspondence with the U.S. Food and Drug Administration's approval of new drugs for this cancer and National Comprehensive Cancer Network treatment guidelines.
Collapse
Affiliation(s)
- Hui Zhao
- Department of Health Services Research Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
- Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
- Penn State Cancer Institute, Hershey, PA, USA
| | - Chan Shen
- Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
- Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
- Penn State Cancer Institute, Hershey, PA, USA
| | - Jaime J Laureano
- Department of Health Services Research Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
- Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
- Penn State Cancer Institute, Hershey, PA, USA
| | - Xiudong Lei
- Department of Health Services Research Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
- Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
- Penn State Cancer Institute, Hershey, PA, USA
| | - Jiangong Niu
- Department of Health Services Research Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
- Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
- Penn State Cancer Institute, Hershey, PA, USA
| | - Sharon H Giordano
- Department of Health Services Research Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
- Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
- Penn State Cancer Institute, Hershey, PA, USA
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mariana Chavez-MacGregor
- Department of Health Services Research Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
- Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA, USA.
- Penn State Cancer Institute, Hershey, PA, USA.
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| |
Collapse
|
|
5
|
Elsayed L, Reed E, Modi S, Tandra PK, Copur MS, Samson K, Krishnamurthy J. Investigating the Efficacy and Safety of a Dose-Dense Paclitaxel, Cyclophosphamide With Trastuzumab in Stage I-II Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer. Clin Breast Cancer 2024; 24:676-682.e1. [PMID: 39261255 DOI: 10.1016/j.clbc.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/07/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUND The evolution of systemic therapies has improved outcomes for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Nonetheless, the tolerability and safety profile of systemic therapies represent an area for further improvement. Here we report the results of a phase 2 trial evaluating a nonanthracycline, nonplatinum adjuvant treatment regimen for patients following initial surgical resection. METHODS We enrolled patients with stage I or II HER2+ breast cancer who underwent upfront surgery to receive adjuvant treatment with 6 cycles of dose-dense Paclitaxel, cyclophosphamide and Trastuzumab (PC-H) every 2 weeks, followed by 13 cycles of maintenance trastuzumab every 3 weeks to complete 52 weeks of treatment (compromising 19 cycles). The primary objective was to determine the safety and feasibility of adjuvant PC-H, measured by the completion rate frequency and the grade of adverse events, using National Cancer Institute Common Terminology Criteria. The secondary objective was to estimate relapse-free survival and overall survival. RESULTS Between 2010 and 2019, a total of 39 patients were enrolled. Of those, 34 patients (87.18%) completed the planned treatment. Severe adverse events of grade 3 or 4 occurred in 27 patients (69.23%), including 3 patients (7.69%) with grade 3-4 decrease in ejection fraction. At median follow up of 5.6 years, all 39 patients were alive. The 5-year relapse-free survival was 94.30% (95% CI: 75.3-100). CONCLUSIONS PC-H demonstrated overall safety and efficacy, yielding high rates of relapse-free survival among patients with early stage (HER2+) breast cancer.
Collapse
Affiliation(s)
- Lina Elsayed
- Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE
| | - Elizabeth Reed
- Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE
| | - Shivani Modi
- Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE
| | - Pavan K Tandra
- Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE
| | - Mehmet S Copur
- Mary Lanning Healthcare, Morrison Cancer Center, Department of Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Kaeli Samson
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE
| | - Jairam Krishnamurthy
- Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE.
| |
Collapse
|
|
6
|
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.
Collapse
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
| |
Collapse
|
|
7
|
Chen YA, Lai HW, Su HC, Loh EW, Huang TW, Tam KW. Efficacy and safety of adjuvant therapies in older patients with breast cancer: a systematic review and meta-analysis of real-world data. Breast Cancer 2024; 31:739-753. [PMID: 39085679 DOI: 10.1007/s12282-024-01622-1] [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: 03/27/2024] [Accepted: 07/29/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Insufficient data available for older patients with breast cancer complicates decision-making regarding optimal treatment. A systematic review that uses real-world data is required for assessing the effectiveness and potential adverse effects of various therapies for this age group of patients. METHODS Databases of PubMed, Embase, and Cochrane Library were searched. We included clinical studies that evaluated various treatments for geriatric breast cancer, including adjuvant radiation therapy, hypofractionated radiation therapy (hypo-RT) and accelerated and partial breast irradiation (APBI), endocrine therapy, chemotherapy, and targeted therapy. RESULTS A total of 71 studies were retrieved. Adjuvant radiation therapy significantly improved overall survival (OS) compared with no radiation [hazard ratio (HR) = 0.60, 95% confidence interval (CI) 0.54-0.67]. The pooled estimates of OS for hypo-RT and APBI demonstrated no inferiority compared with conventional radiation. Both endocrine treatment (HR = 0.63, 95% CI 0.43-0.92) and chemotherapy (HR = 0.76, 95% CI 0.65-0.88) significantly increased OS compared with no treatment. Trastuzumab monotherapy significantly enhanced OS compared with no trastuzumab use (HR = 0.23, 95% CI 0.07-0.73). CONCLUSION Despite concerns about potential complications during treatment in older patients, proactive therapies significantly increase their survival rates. For patients who are frailer, hypo-RT and APBI offer survival rates comparable to traditional modalities. Additionally, targeted therapy as a monotherapy holds promise as a viable option for patients with HER2-positive breast cancer who cannot undergo chemotherapy. Therefore, by conducting thorough general assessments and clinical evaluations, the side effects of postoperative treatments can be effectively managed.
Collapse
Affiliation(s)
- Yu-An Chen
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsuan-Wen Lai
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hui-Chen Su
- Department of Pharmacy, Chi Mei Medical Center, Tainan City, Taiwan
| | - El-Wui Loh
- Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Medical Imaging, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Tsai-Wei Huang
- Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan
- School of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan
| | - Ka-Wai Tam
- Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan.
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, 291, Zhongzheng Road, Zhonghe District, New Taipei City, 23561, Taiwan.
| |
Collapse
|
|
8
|
Zahedi F, Jafari A, Nasiri Motlagh B, Hamedi SH, Salek R, Khandoozi S, Farshchian N, Shahidsales S, Mafi AR, Hosseini S, Amouheidari A, Varshoee Tabrizi F, Khanjani N, Ahmadloo N, Dayyani M, Khodabakhshi R, Mojahed MM, Keshvari M, Fazl Ersi M, Mirsadraee M, Izadpanahi P, Saadipoor A, Nasrollahi H, Anbiaee R, Emadi Torghabeh A, Keramati A, Amiran SA, Bayat Mokhtari N, Taghizadeh Kermani A, Anvari K, Sadeghi Ivari M, Dayani M, Amirabadi A, Saeidi Saedi H, Sabzvari A, Kafi H, Homaei Shandiz F. Safety evaluation of the trastuzumab biosimilar in Iranian women with HER2-positive breast cancer undergoing adjuvant chemotherapy: a post-marketing surveillance. Expert Opin Drug Saf 2024:1-6. [PMID: 39076099 DOI: 10.1080/14740338.2024.2385483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 06/12/2024] [Accepted: 06/27/2024] [Indexed: 07/31/2024]
Abstract
BACKGROUND Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). This post-marketing surveillance evaluates the safety of a trastuzumab biosimilar (AryoTrust), produced by AryoGen Co. Iran in Iranian women with HER2-positive non-metastatic breast cancer (BC). RESEARCH DESIGN AND METHODS The patients who had undergone adjuvant chemotherapy regimens received trastuzumab every 3 weeks for nine cycles. The study started in February 2017 and finished in August 2022. Data regarding safety were collected using booklets and then analyzed. RESULTS A total of 597 women with a mean ±SD age of 48.13 ± 10.18 years underwent 5,313 injection cycles. They received pre-study chemotherapies consisting of anthracyclines, taxanes, both, or other medications in 6.70, 7.20, 82.41, and 2.01% of the cases, respectively. One hundred and thirty-nine patients experienced at least one adverse event (AE). The most common AEs were decreased ejection fraction (EF, 5.7%), peripheral neuropathy (5.36%), and nausea (5.19%). Meningioma was the only life-threatening serious AE. Furthermore, bone pain and infusion-related reactions were the two most common grade three AEs. Nevertheless, the mean EF of patients did not change notably during the study. CONCLUSIONS The results demonstrate that this trastuzumab biosimilar is a generally well tolerated and safe treatment for HER2-positive BC. CLINICAL TRIAL REGISTRATION www.clinicaltrials.gov identifier is NCT06021379.
Collapse
Affiliation(s)
- Fatemeh Zahedi
- Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Anya Jafari
- Department of Radiation Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Seyed Hassan Hamedi
- Radiation Oncology Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Roham Salek
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedreza Khandoozi
- Cancer Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Negin Farshchian
- Imam Reza Hospital, Kermanshah University of Medicine Sciences, Kermanshah, Iran
| | | | - Ahmad R Mafi
- Department of Radiation Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sare Hosseini
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Nezhat Khanjani
- Department of Radiation Oncology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Niloofar Ahmadloo
- Department of Radiation Oncology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdieh Dayyani
- Radiotherapy and Oncology Department, Reza Radiotherapy and Oncology Center, Mashhad, Iran
| | | | | | - Masoumeh Keshvari
- Department of Radiation Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mitra Fazl Ersi
- Radiotherapy and Oncology Department, Reza Radiotherapy and Oncology Center, Mashhad, Iran
| | - Marjaneh Mirsadraee
- Radiotherapy and Oncology Department, Reza Radiotherapy and Oncology Center, Mashhad, Iran
| | - Payam Izadpanahi
- Radiotherapy and Oncology Department, Reza Radiotherapy and Oncology Center, Mashhad, Iran
| | - Afshin Saadipoor
- Department of Radiation Oncology, Erfanniyayesh Hospital, Tehran, Iran
| | - Hamid Nasrollahi
- Department of Radiation Oncology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Robab Anbiaee
- Department of Radiation Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Emadi Torghabeh
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Keramati
- Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Seyed Ahmadreza Amiran
- Department of Internal Medicine, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Narges Bayat Mokhtari
- Radiotherapy and Oncology Department, Reza Radiotherapy and Oncology Center, Mashhad, Iran
| | | | - Kazem Anvari
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Malihe Dayani
- Department of Radiation Oncology, Imam Reza Hospital of Kermanshah, Kermanshah, Iran
| | - Amir Amirabadi
- Innovative Medical Research Center, Faculty of Medicine, Islamic Azad University Mashhad Branch, Mashhad, Iran
| | - Hamid Saeidi Saedi
- Associated Professor of Radiation Oncology, Guilan University of Medical Sciences, Guilan, Iran
| | - Araz Sabzvari
- CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Hamidreza Kafi
- Medical Department, Orchid Pharmed Company, Tehran, Iran
| | - Fatemeh Homaei Shandiz
- Department of Radiation Oncology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
9
|
Braun M, Piasecka D, Sadej R, Romanska HM. FGFR4-driven plasticity in breast cancer progression and resistance to therapy. Br J Cancer 2024; 131:11-22. [PMID: 38627607 PMCID: PMC11231301 DOI: 10.1038/s41416-024-02658-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 03/10/2024] [Accepted: 03/12/2024] [Indexed: 07/10/2024] Open
Abstract
Breast cancer (BCa) is a complex and heterogeneous disease, with different intrinsic molecular subtypes that have distinct clinical outcomes and responses to therapy. Although intrinsic subtyping provides guidance for treatment decisions, it is now widely recognised that, in some cases, the switch of the BCa intrinsic subtype (which embodies cellular plasticity), may be responsible for therapy failure and disease progression. Aberrant FGFR4 signalling has been implicated in various cancers, including BCa, where it had been shown to be associated with aggressive subtypes, such as HER2-enriched BCa, and poor prognosis. More importantly, FGFR4 is also emerging as a potential driver of BCa intrinsic subtype switching, and an essential promoter of brain metastases, particularly in the HER2-positive BCa. Although the available data are still limited, the findings may have far-reaching clinical implications. Here, we provide an updated summary of the existing both pre- and clinical studies of the role of FGFR4 in BCa, with a special focus on its contribution to subtype switching during metastatic spread and/or induced by therapy. We also discuss a potential clinical benefit of targeting FGFR4 in the development of new treatment strategies.
Collapse
Affiliation(s)
- Marcin Braun
- Department of Pathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland
| | - Dominika Piasecka
- Laboratory of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, Gdansk, Poland
| | - Rafal Sadej
- Laboratory of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, Gdansk, Poland.
| | - Hanna M Romanska
- Department of Pathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland.
| |
Collapse
|
|
10
|
Johnson KCC, Ni A, Quiroga D, Pariser AC, Sudheendra PK, Williams NO, Sardesai SD, Cherian M, Stover DG, Gatti-Mays M, Ramaswamy B, Lustberg M, Jhawar S, Skoracki R, Wesolowski R. The survival benefit of adjuvant trastuzumab with or without chemotherapy in the management of small (T1mic, T1a, T1b, T1c), node negative HER2+ breast cancer. NPJ Breast Cancer 2024; 10:49. [PMID: 38898072 PMCID: PMC11187074 DOI: 10.1038/s41523-024-00652-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 06/01/2024] [Indexed: 06/21/2024] Open
Abstract
There is limited data regarding the added benefit of adjuvant systemic therapy in the management of small, node-negative, HER2+ breast cancer. In a multi-institutional retrospective analysis using the American Society of Clinical Oncology CancerLinQ database, we compared survival outcomes among T1a-c N0 HER2+ patients diagnosed between 2010 to 2021 who received locoregional therapy alone or in combination with adjuvant trastuzumab (+/- chemotherapy). Primary outcomes were invasive disease-free survival (iDFS) and overall survival (OS). Of the 1,184 patients, 436 received locoregional therapy alone. We found a statistically significant improvement in iDFS (HR 0.73, P = 0.003) and OS (HR 0.63, P = 0.023) on univariate analysis with adjuvant trastuzumab with or without chemotherapy which remained statistically significant on multivariate analysis. Three-arm univariate analysis found that iDFS was significantly improved with trastuzumab monotherapy (P = 0.003) and combination therapy (P = 0.027) compared to observation. Subgroup data suggests that T1b/c tumors derive the greatest benefit.
Collapse
Affiliation(s)
- Kai C C Johnson
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Ai Ni
- Division of Biostatistics, The Ohio State University College of Public Health, Columbus, OH, USA
| | - Dionisia Quiroga
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Ashley C Pariser
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | | | - Nicole O Williams
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Sagar D Sardesai
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Mathew Cherian
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Daniel G Stover
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | | | | | - Maryam Lustberg
- Smilow Cancer Hospital, Yale Cancer Center, New Haven, CT, USA
| | - Sachin Jhawar
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Roman Skoracki
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Robert Wesolowski
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
| |
Collapse
|
|
11
|
Zagami P, Trapani D, Nicolò E, Corti C, Valenza C, Criscitiello C, Curigliano G, Carey LA. Cardiotoxicity of Agents Used in Patients With Breast Cancer. JCO Oncol Pract 2024; 20:38-46. [PMID: 37983586 PMCID: PMC10827297 DOI: 10.1200/op.23.00494] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 11/22/2023] Open
Abstract
Cancer and cardiovascular diseases are the two major causes of mortality, morbidity, and disability worldwide. The improvement in effective therapeutic options for the management of breast cancer (BC) has led to an increased number of BC survivors, who can experience long-term toxicities from cancer treatments. Adverse events including cardiovascular toxicities must be considered in light of effectiveness of recently approved drugs for BC treatment, including elacestrant, tucatinib, neratinib, olaparib, the immune checkpoint inhibitors, trastuzumab deruxtecan, or sacituzumab govitecan. Many cancer drugs affect the cardiovascular system with a range of clinical manifestations. Prompt diagnosis and treatment as well as a multidisciplinary approach involving a cardio-oncologist is optimal for management of these cardiovascular events.
Collapse
Affiliation(s)
- Paola Zagami
- Department of Oncology and Hematology, University of Milano, Milan, Italy
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - Dario Trapani
- Department of Oncology and Hematology, University of Milano, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - Eleonora Nicolò
- Department of Oncology and Hematology, University of Milano, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - Chiara Corti
- Department of Oncology and Hematology, University of Milano, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - Carmine Valenza
- Department of Oncology and Hematology, University of Milano, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - Carmen Criscitiello
- Department of Oncology and Hematology, University of Milano, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - Giuseppe Curigliano
- Department of Oncology and Hematology, University of Milano, Milan, Italy
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - Lisa Anne Carey
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| |
Collapse
|
|
12
|
Wilbers A, Quinn KR, Okut H, Helmer SD, Tenofsky PL. Systemic Therapy in Elderly Patients With Her2/Neu-Positive Breast Cancer: A SEER Database Study. Am Surg 2023; 89:5690-5696. [PMID: 37132385 DOI: 10.1177/00031348231173993] [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] [Indexed: 05/04/2023]
Abstract
BACKGROUND The use of systemic therapy in elderly patients with Her2/neu-positive breast cancers has been questioned given the potential for cardiac side effects with several of the agents frequently used. This study aimed to evaluate trends in use of systemic therapy in patients 70 years and older. METHODS The 2010-2016 SEER database was used to collect data on female patients with non-metastatic Her2/neu-positive breast cancer. Data was stratified to compare systemic therapy use in patients <70 vs ≥70. RESULTS A total of 62,014 patients were included in the study. Of those, 79.0% (38,760) of patients <70 years old received systemic therapy while only 45.2% (5844) of patients ≥70 received systemic therapy (P < .001). Of patients ≥70 with ER positive tumors, 42.1% received systemic therapy and those with ER negative tumors, 52.1% received systemic therapy. The mortality rate in patients ≥70 was 8.5% in those who received systemic therapy and 12.1% in those who did not (P < .001). CONCLUSIONS There remains a significant difference in rates of systemic therapy administration in the elderly population with an associated increase in mortality due to their cancer. Continuing educational efforts could be of benefit.
Collapse
Affiliation(s)
- Ashley Wilbers
- Department of Surgery, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
| | - Karson R Quinn
- Department of Surgery, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
| | - Hayrettin Okut
- Office of Research, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
| | - Stephen D Helmer
- Department of Surgery, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
| | - Patty L Tenofsky
- Department of Surgery, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
- Department of Surgery, Ascension via Christi Clinic, Wichita, KS, USA
| |
Collapse
|
|
13
|
Garutti M, Cucciniello L, Arpino G, Fabi A, Livi L, Munzone E, Staropoli N, Zamagni C, Zambelli A, Puglisi F. Risk-Based Therapeutic Strategies for HER2-Positive Early Breast Cancer: A Consensus Paper. Clin Breast Cancer 2023; 23:e458-e469. [PMID: 37543499 DOI: 10.1016/j.clbc.2023.07.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/11/2023] [Accepted: 07/24/2023] [Indexed: 08/07/2023]
Abstract
Breast cancer represents the most commonly diagnosed neoplasm worldwide and the HER2-positive subtype accounts for nearly 1 in 5 breast cancers. The majority of patients with breast cancer present with an early-stage disease upon diagnosis, which is thus susceptible to virtually curative treatment strategies. For a stage, I T1a/b N0 HER2-positive disease, upfront surgery followed by adjuvant therapy is the preferred approach. However, there is some uncertainty regarding the appropriate management of stage cT1c cN0, as both the neoadjuvant approach and upfront surgery have been proven to be feasible therapeutic options. The aim of this Delphi consensus was to define the best strategies for the treatment of early HER2-positive breast cancer. This work may help clinicians in the management of early HER2-positive breast cancer.
Collapse
Affiliation(s)
- Mattia Garutti
- CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy.
| | - Linda Cucciniello
- CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| | - Grazia Arpino
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Alessandra Fabi
- Precision Medicine in Breast Cancer Unit, Department of Woman and Child Health and Public Health, IRCCS, Scientific Directorate, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
| | - Lorenzo Livi
- Radiation Oncology Unit, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | - Elisabetta Munzone
- Division of Medical Senology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Nicoletta Staropoli
- Medical Oncology and Translational Medical Oncology Units, Department of Experimental and Clinical Medicine, Magna Graecia University, AOU Materdomini Catanzaro, Campus Salvatore Venuta, Catanzaro, Italy
| | - Claudio Zamagni
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Alberto Zambelli
- Department of Biomedical Sciences Humanitas University and IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
| | - Fabio Puglisi
- CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| |
Collapse
|
|
14
|
Sposito M, Belluomini L, Pontolillo L, Tregnago D, Trestini I, Insolda J, Avancini A, Milella M, Bria E, Carbognin L, Pilotto S. Adjuvant Targeted Therapy in Solid Cancers: Pioneers and New Glories. J Pers Med 2023; 13:1427. [PMID: 37888038 PMCID: PMC10608226 DOI: 10.3390/jpm13101427] [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: 08/24/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/28/2023] Open
Abstract
Targeted therapy (TT) has revolutionized cancer treatment, successfully applied in various settings. Adjuvant TT in resected early-stage gastrointestinal stromal tumors (GIST), melanoma, non-small cell lung cancer (NSCLC), and breast cancer has led to practice-changing achievements. In particular, standard treatments include BRAF inhibitors for melanoma, osimertinib for NSCLC, hormone therapy or HER2 TT for breast cancer, and imatinib for GIST. Despite the undeniable benefit derived from adjuvant TT, the optimal duration of TT and the appropriate managing of the relapse remain open questions. Furthermore, neoadjuvant TT is emerging as valuable, particularly in breast cancer, and ongoing studies evaluate TT in the perioperative setting for early-stage NSCLC. In this review, we aim to collect and describe the large amount of data available in the literature about adjuvant TT across different histologies, focusing on epidemiology, major advances, and future directions.
Collapse
Affiliation(s)
- Marco Sposito
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Lorenzo Belluomini
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Letizia Pontolillo
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy; (L.P.); (E.B.)
- Medical Oncology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Daniela Tregnago
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Ilaria Trestini
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Jessica Insolda
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Alice Avancini
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Michele Milella
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Emilio Bria
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy; (L.P.); (E.B.)
- Medical Oncology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Luisa Carbognin
- Gynecology Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, 00168 Roma, Italy;
| | - Sara Pilotto
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| |
Collapse
|
|
15
|
Ivanovic N, Bjelica D, Loboda B, Bogdanovski M, Colakovic N, Petricevic S, Gojgic M, Zecic O, Zecic K, Zdravkovic D. Changing the role of pCR in breast cancer treatment - an unjustifiable interpretation of a good prognostic factor as a "factor for a good prognosis". Front Oncol 2023; 13:1207948. [PMID: 37534241 PMCID: PMC10391828 DOI: 10.3389/fonc.2023.1207948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 07/03/2023] [Indexed: 08/04/2023] Open
Abstract
Pathologic complete response (pCR) after neoadjuvant systemic therapy (NAST) of early breast cancer (EBC) has been recognized as a good prognostic factor in the treatment of breast cancer because of its significant correlation with long-term disease outcome. Based on this correlation, pCR has been accepted by health authorities (FDA, EMA) as a surrogate endpoint in clinical trials for accelerated drug approval. Moreover, in recent years, we have observed a tendency to treat pCR in routine clinical practice as a primary therapeutic target rather than just one of the pieces of information obtained from clinical trials. These trends in routine clinical practice are the result of recommendations in treatment guidelines, such as the ESMO recommendation "…to deliver all planned (neoadjuvant) treatment without unnecessary breaks, i.e. without dividing it into preoperative and postoperative periods, irrespective of the magnitude of tumor response", because "…this will increase the probability of achieving pCR, which is a proven factor for a good prognosis…". We hypothesize that the above recommendations and trends in routine clinical practice are the consequences of misunderstanding regarding the concept of pCR, which has led to a shift in its importance from a prognostic factor to a desired treatment outcome. The origin of this misunderstanding could be a strong subconscious incentive to achieve pCR, as patients who achieved pCR after NAST had a better long-term outcome compared with those who did not. In this paper, we attempt to prove our hypothesis. We performed a comprehensive analysis of the therapeutic effects of NAST and adjuvant systemic therapy (AST) in EBC to determine whether pCR, as a phenomenon that can only be achieved at NAST, improves prognosis per se. We used published papers as a source of data, which had a decisive influence on the formation of the modern attitude towards EBC therapy. We were unable to find any evidence supporting the use of pCR as a desired therapeutic goal because NAST (reinforced by pCR) was never demonstrated to be superior to AST in any context.
Collapse
Affiliation(s)
- Nebojsa Ivanovic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
- Department of Surgery, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dragana Bjelica
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Barbara Loboda
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Masan Bogdanovski
- Faculty of Philosophy, Department of Philosophy, University of Belgrade, Belgrade, Serbia
| | - Natasa Colakovic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
- Department of Surgery, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Simona Petricevic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Milan Gojgic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Ognjen Zecic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
| | - Katarina Zecic
- Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Darko Zdravkovic
- Department of Surgical Oncology, University Hospital Medical Center (UHMC) “Bezanijska kosa”, Belgrade, Serbia
- Department of Surgery, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| |
Collapse
|
|
16
|
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.
Collapse
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.
| | | | | |
Collapse
|
|
17
|
Lu Y, Pan W, Deng S, Dou Q, Wang X, An Q, Wang X, Ji H, Hei Y, Chen Y, Yang J, Zhang HM. Redefining the Incidence and Profile of Fluoropyrimidine-Associated Cardiotoxicity in Cancer Patients: A Systematic Review and Meta-Analysis. Pharmaceuticals (Basel) 2023; 16:ph16040510. [PMID: 37111268 PMCID: PMC10146083 DOI: 10.3390/ph16040510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/14/2023] [Accepted: 03/21/2023] [Indexed: 04/01/2023] Open
Abstract
Aim: The cardiac toxicity that occurs during administration of anti-tumor agents has attracted increasing concern. Fluoropyrimidines have been used for more than half a century, but their cardiotoxicity has not been well clarified. In this study, we aimed to assess the incidence and profile of fluoropyrimidine-associated cardiotoxicity (FAC) comprehensively based on literature data. Methods: A systematic literature search was performed using PubMed, Embase, Medline, Web of Science, and Cochrane library databases and clinical trials on studies investigating FAC. The main outcome was a pooled incidence of FAC, and the secondary outcome was specific treatment-related cardiac AEs. Random or fixed effects modeling was used for pooled meta-analyses according to the heterogeneity assessment. PROSPERO registration number: (CRD42021282155). Results: A total of 211 studies involving 63,186 patients were included, covering 31 countries or regions in the world. The pooled incidence of FAC, by meta-analytic, was 5.04% for all grades and 1.5% for grade 3 or higher. A total of 0.29% of patients died due to severe cardiotoxicities. More than 38 cardiac AEs were identified, with cardiac ischemia (2.24%) and arrhythmia (1.85%) being the most frequent. We further performed the subgroup analyses and meta-regression to explore the source of heterogeneity, and compare the cardiotoxicity among different study-level characteristics, finding that the incidence of FAC varied significantly among different publication decades, country/regions, and genders. Patients with esophagus cancer had the highest risk of FAC (10.53%), while breast cancer patients had the lowest (3.66%). The treatment attribute, regimen, and dosage were significantly related to FAC. When compared with chemotherapeutic drugs or targeted agents, such a risk was remarkably increased (χ2 = 10.15, p < 0.01; χ2 = 10.77, p < 0.01). The continuous 5-FU infusion for 3–5 consecutive days with a high dosage produced the highest FAC incidence (7.3%) compared with other low-dose administration patterns. Conclusions: Our study provides comprehensive global data on the incidence and profile of FAC. Different cancer types and treatment appear to have varying cardiotoxicities. Combination therapy, high cumulative dose, addition of anthracyclines, and pre-existing heart disease potentially increase the risk of FAC.
Collapse
Affiliation(s)
- Yajie Lu
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
- The State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Air Force Medical University, Xi’an 710032, China
- Correspondence: (Y.L.); (H.-M.Z.)
| | - Wei Pan
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
| | - Shizhou Deng
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
| | - Qiongyi Dou
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
| | - Xiangxu Wang
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
| | - Qiang An
- The Department of Biomedical Engineering, Air Force Medical University, Xi’an 710032, China
| | - Xiaowen Wang
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
| | - Hongchen Ji
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
| | - Yue Hei
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
| | - Yan Chen
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
| | - Jingyue Yang
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
| | - Hong-Mei Zhang
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an 710032, China
- Correspondence: (Y.L.); (H.-M.Z.)
| |
Collapse
|
|
18
|
Satishkumar M, Ramesh M, Sanjive JG. A Prospective Multi-Institutional Observational Study on ER, PR, HER2/NEU, and Ki-67 Expression and Discordance Pattern in Primary and Metastatic and Recurrent Carcinoma Breast and Its Therapeutic Implications and Prognostic Outcome. Indian J Surg Oncol 2023; 14:72-80. [PMID: 36891419 PMCID: PMC9986365 DOI: 10.1007/s13193-022-01622-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 08/10/2022] [Indexed: 11/29/2022] Open
Abstract
Only few studies reported in literature that has elucidated in detail the implications of molecular typing in metastatic and recurrent breast cancer. In this prospective study, we have analysed in depth the pattern of expression, discordances of molecular markers in various metastatic sites, and recurrent cases and their response to chemotherapy/targeted agents and the prognostic outcome. The primary aim of the study was to determine ER, PR, HER2/NEU, and Ki-67 from recurrent and metastatic carcinoma breast to study the expression pattern and discordance and also to study the degree of discordance in relation to the site of metastasis and pattern of metastasis (synchronous vs metachronous) and discordance pattern with the response to chemotherapy and median overall survival rates in months in available subset of patients. Prospective open-label study done at the Government Rajaji Hospital, Madurai Medical College, and Government Royapettah Hospital, Kilpauk Medical College, India, from November 2014 to August 2021. All breast carcinoma patients with recurrence or oligo metastasis (defined as one organ with less than 5 metastases in our study) with known receptor status were eligible and 110 patients were enrolled in the study. ER (ER + to ER -) discordance was seen in 19 (26.38%) cases. PR (PR + to PR -Ve) discordance was seen in 14 (19.17%) cases. HER2/NEU (HER2/NEU + Ve to -Ve) discordance was seen in 3 (16.6%) cases. Ki-67 discordance was seen in 54 (49.09%) cases. High Ki-67 as a proliferative marker has increased response to chemotherapy but earlier relapse and disease progression especially in Luminal B type. In further subset analysis, ER, PR, and HER2/NEU discordance is higher for lung metastasis (ER, PR 61.1%, p value .001, HER2/NEU 5.5%), followed by liver metastasis (ER, PR 50%, p value .0023, 1 case turning ER -ve to + ve, HER2/NEU 1 (10%)). In lung, discordance is more for metachronous metastasis. In liver, discordance is 100% for synchronous metastasis. Synchronous metastasis with discordance in ER and PR is associated with rapid disease progression. High Ki-67 subset of Luminal B-like tumors progressed rapidly than triple negative and HER2/NEU positive subset. Complete clinical response rate in contralateral axillary node metastasis group was 87.8%, followed by local only recurrence with high Ki-67 where chemotherapy had response rate of 81% and 2 years DFS of 93.12% after excision. Certain subsets like contralateral axillary nodes and supraclavicular nodes which present as oligo metastatic disease with discordance and high Ki-67 respond well to chemotherapeutics and targeted agents improving the OS in this subset of patients. Molecular markers and their expression and discordance pattern determine the therapeutic outcome and prognosis of the disease. Early identification and targeting the discordance would go a long way in improving the outcome and DFS and OS of breast cancer patients.
Collapse
Affiliation(s)
- Maheswaran Satishkumar
- Department of Surgical Oncology, Madurai Medical College, Madurai, 625020 Tamil Nadu India
- Department of Surgical Oncology, Government Royapettah Hospital, Chennai, 600014 Tamil Nadu India
| | - Muthuvel Ramesh
- Department of Surgical Oncology, Madurai Medical College, Madurai, 625020 Tamil Nadu India
| | - Jeevan G. Sanjive
- Department of Surgical Oncology, Madurai Medical College, Madurai, 625020 Tamil Nadu India
| |
Collapse
|
|
19
|
Effects of trastuzumab and trastuzumab emtansine on corrected QT interval and left ventricular ejection fraction in patients with metastatic (HER2+) breast cancer. Egypt Heart J 2023; 75:11. [PMID: 36781707 PMCID: PMC9925620 DOI: 10.1186/s43044-023-00331-y] [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: 08/23/2021] [Accepted: 01/12/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Trastuzumab and trastuzumab emtansine are specific antibody and antibody-drug conjugates used in the treatment of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer. The aim of this study was to test their effect on the QTc interval duration and left ventricular ejection fraction (LVEF) in our patients, two parameters used in evaluation of cardiotoxicity. From May 2015 to October 2017, 26 patients with preserved LVEF were included in the study. All of them were previously treated with standard paclitaxel and cisplatin-based chemotherapy regimens. Electrocardiogram (ECG) was recorded just before each trastuzumab dose application and six months after the last dose. Echocardiography with LVEF measurement was performed several days before the application of the initial dose, and six months after the last cycle. Later, 24 patients with metastatic disease received additional treatment with trastuzumab emtansine after six months and the same ECG and echocardiography protocol was performed again. Due to reduction in LVEF, two patients were discontinued from additional treatment. RESULTS A statistically significant QTc prolongation was found after each drug dose application, with an increase in mean QTc duration with every successive application, reaching the peak QTc values just before the fifth cycle of treatment. The QTc interval returned to its initial value six months after the last cycle (p < 0.001). These results were similar for both drugs. Mean LVEF before both treatment protocols was significantly higher compared to LVEF value after the treatment. LVEF before trastuzumab emtansine treatment was non-significantly higher than LVEF after trastuzumab treatment. CONCLUSION Trastuzumab and trastuzumab emtansine cardiotoxicity manifested as a significant and progressive QTc prolongation after successive drug applications, reaching the peak value just before the fifth cycle of both drugs. Both medications also caused statistically significant but asymptomatic LVEF reduction. Complete reversibility of cardiotoxic effects of both drugs was confirmed by QTc interval and LVEF normalisation after the treatment discontinuation.
Collapse
|
|
20
|
Shima H, Kutomi G, Kuga Y, Wada A, Satomi F, Sato K, Kyuno D, Nishikawa N, Uno S, Kameshima H, Ohmura T, Hasegawa T, Takemasa I. Additional effect of anthracycline in preoperative chemotherapy with a sequential anthracycline‑containing regimen preceded by pertuzumab, trastuzumab and docetaxel combination therapy. Exp Ther Med 2022; 25:68. [PMID: 36605524 PMCID: PMC9798155 DOI: 10.3892/etm.2022.11767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/28/2022] [Indexed: 12/14/2022] Open
Abstract
The proper use of anthracycline-containing regimens in combination with anti-HER2-targeted therapy in a neoadjuvant setting for patients with HER2-positive breast cancer has not been resolved. Regimens preceded by anthracyclines have become the standard of care, and although the order has no significant impact on HER2-negative breast cancer, it is inconclusive as to whether a taxane-first sequence would have a similar effect on HER2-positive breast cancer. The present study aimed to investigate the benefit of a taxane-first sequence and of adriamycin and cyclophosphamide (AC) in patients with non-clinical complete response (non-cCR) to pertuzumab, trastuzumab and docetaxel (PTD). The present single-center prospective observational study was performed to investigate PTD followed by AC, and aimed to clarify the cCR rate after PTD alone and the pathological clinical response (pCR) rate after subsequent AC in patients without cCR after PTD alone. A total 24 patients were analyzed; of these, 14 achieved pCR (pCR rate, 58.3%). While four of 14 patients (28.6%) in the intention-to-treat population achieved pCR, nine of 14 patients (64.3%) achieved pCR with AC but not cCR after PTD. The median tumor reduction rate after four cycles of PTD was 58.9% (range, 20.8-100%) in all 24 patients, whereas the reduction rate after PTD-AC was 76.9% (range, 31.1-100%). Cardiac serious adverse events occurred in three patients (12.5%). In conclusion, a high pCR rate was observed for the taxane-first sequence. Patients were highly responsive to PTD, but some cases achieved additional antitumor effects after AC, which resulted in pCR without cCR after PTD alone. Since cardiotoxicity remains a significant problem, a higher risk-benefit treatment strategy is required to aim for AC omission. Trial registration number: UMIN000046338, name of registry: UMIN-CTR, date of registration: December 10, 2021.
Collapse
Affiliation(s)
- Hiroaki Shima
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan,Correspondence to: Dr Hiroaki Shima, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Goro Kutomi
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan
| | - Yoko Kuga
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan
| | - Asaka Wada
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan
| | - Fukino Satomi
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan
| | - Kiminori Sato
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan,Department of Surgery, Takikawa Municipal Hospital, Takikawa, Hokkaido 073-0022, Japan
| | - Daisuke Kyuno
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan
| | | | - Satoko Uno
- Department of Surgery, Muroran City General Hospital, Muroran, Hokkaido 051-8512, Japan
| | | | - Tosei Ohmura
- Department of Surgery, Higashi Sapporo Hospital, Sapporo, Hokkaido 003-8585, Japan
| | - Tadashi Hasegawa
- Department of Surgical Pathology, Sapporo Medical University Sapporo, Hokkaido 060-8543, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan
| |
Collapse
|
|
21
|
Tumor-Infiltrating Lymphocytes and Immune Response in HER2-Positive Breast Cancer. Cancers (Basel) 2022; 14:cancers14246034. [PMID: 36551522 PMCID: PMC9776701 DOI: 10.3390/cancers14246034] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/24/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022] Open
Abstract
Human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer accounts for 15 to 25% of breast cancer cases. Although therapies based on the use of monoclonal anti-HER2 antibodies present clinical benefit for a subtype of patients with HER2-positive breast cancer, more than 50% of them are unresponsive to targeted therapies or they eventually relapse. In recent years, reactivation of the adaptive immune system in patients with solid tumors has emerged as a therapeutic option with great potential for clinical benefit. Since the approval of the first treatment directed against HER2 as a therapeutic target, the range of clinical options has expanded greatly, and, in this sense, cellular immunotherapy with T cells relies on the cytotoxicity generated by these cells, which ultimately leads to antitumor activity. Lymphocytic infiltration of tumors encompasses a heterogeneous population of immune cells within the tumor microenvironment that exhibits distinct patterns of immune activation and exhaustion. The prevalence and prognostic value of tumor-infiltrating lymphocyte (TIL) counts are associated with a favorable prognosis in HER2-positive breast cancers. This review discusses emerging findings that contribute to a better understanding of the role of immune infiltrates in HER2-positive breast cancer. In addition, it summarizes the most recent results in HER2-positive breast cancer immunotherapy and anticipates which therapeutic strategies could be applied in the immediate future.
Collapse
|
|
22
|
Williams AD, Solis O, Sterbling HM, Murray A, Sogunro O, De La Cruz LM. Are We Overtreating Patients With T1a HER2+ Breast Cancer? An Analysis of the National Cancer Database. Clin Breast Cancer 2022; 22:828-839. [PMID: 36151019 DOI: 10.1016/j.clbc.2022.07.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/19/2022] [Accepted: 07/24/2022] [Indexed: 01/25/2023]
Abstract
INTRODUCTION The potential benefit of systemic therapy in patients with T1a HER2+ cancers is not well understood, and no consensus guidelines exist. We sought to investigate practice patterns of chemotherapy use in this population. METHODS From the National Cancer Database (2013-2018), we identified female patients with HER2+ cancers staged as cT1aN0 or pT1aN0 and stratified by receipt of chemotherapy. Using univariate and multivariable analyses we assessed the clinicopathologic features associated with the receipt of chemotherapy. We also compared rates of overall survival (OS). RESULTS Of 5176 women with cT1aN0 HER2+ cancers, 88 (2%) received neoadjuvant chemotherapy. Younger age and hormone-receptor (HR) negative tumors were factors independently associated with receipt of neoadjuvant chemotherapy (all P < .001). Of 11,688 women with pT1aN0 HER2+ cancers, 5,588 (48%) received adjuvant chemotherapy. Rates of use increased over the analysis period from 39% in 2013 to 53% in 2018 (P < .001). Factors independently associated with receipt of adjuvant chemotherapy included younger age, having a poorly differentiated tumor, exhibiting lymphovascular invasion, undergoing adjuvant radiation (all P < .001). There were no differences in OS when comparing those who did and did not receive chemotherapy in either group. CONCLUSIONS The use of chemotherapy in patients with HER2+ T1a cancers is increasing over time and is, as expected, more common among patients with unfavorable clinicopathologic features. Since no prognostic algorithm currently exists, more prospective data is needed to understand which of these patients may derive benefit from systemic therapy and which may safely avoid the morbidity of chemotherapy.
Collapse
Affiliation(s)
- Austin D Williams
- Breast Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | | | | | | |
Collapse
|
|
23
|
Dabi Y, Bendifallah S, Suisse S, Haury J, Touboul C, Puchar A, Favier A, Daraï E. Overview of non-coding RNAs in breast cancers. Transl Oncol 2022; 25:101512. [PMID: 35961269 PMCID: PMC9382556 DOI: 10.1016/j.tranon.2022.101512] [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: 06/20/2022] [Revised: 07/18/2022] [Accepted: 08/02/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer in women is the second most common cancer and the fifth leading cause of cancer death worldwide. Although earlier diagnosis and detection of breast cancer has resulted in lower mortality rates, further advances in prevention, detection, and treatment are needed to improve outcomes and survival for women with breast cancer as well as to offer a personalized therapeutic approach. It is now well-established that non-coding RNAs (ncRNAs) represent 98% of the transcriptome but in-depth knowledge about their involvement in the regulation of gene expression is lacking. A growing body of research indicates that ncRNAs are essential for tumorigenesis by regulating the expression of tumour-related genes. In this review, we focus on their implication in breast cancer genesis but also report the latest knowledge of their theragnostic and therapeutic role. We highlight the need for accurate quantification of circulating ncRNAs which is determinant to develop reliable biomarkers. Further studies are mandatory to finally enter the era of personalized medicine for women with breast cancer.
Collapse
Affiliation(s)
- Yohann Dabi
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris; Clinical Research Group (GRC) Paris 6: Centre Expert Endométriose (C3E), Sorbonne University (GRC6 C3E SU); INSERM UMR_S_938, Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Sorbonne University, Paris 75020, France.
| | - Sofiane Bendifallah
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris; Clinical Research Group (GRC) Paris 6: Centre Expert Endométriose (C3E), Sorbonne University (GRC6 C3E SU); INSERM UMR_S_938, Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Sorbonne University, Paris 75020, France
| | | | - Julie Haury
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris
| | - Cyril Touboul
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris; Clinical Research Group (GRC) Paris 6: Centre Expert Endométriose (C3E), Sorbonne University (GRC6 C3E SU); INSERM UMR_S_938, Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Sorbonne University, Paris 75020, France
| | - Anne Puchar
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris
| | - Amélia Favier
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris
| | - Emile Daraï
- Sorbonne University - Department of Obstetrics and Reproductive Medicine, Hôpital Tenon, 4 rue de la Chine, 75020 Paris; Clinical Research Group (GRC) Paris 6: Centre Expert Endométriose (C3E), Sorbonne University (GRC6 C3E SU); INSERM UMR_S_938, Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Sorbonne University, Paris 75020, France
| |
Collapse
|
|
24
|
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.
Collapse
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
| |
Collapse
|
|
25
|
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]
|
|
26
|
Agostinetto E, Ameye L, Martel S, Aftimos P, Pondé N, Maurer C, El-Abed S, Wang Y, Vicente M, Chumsri S, Bliss J, Kroep J, Colleoni M, Petrelli F, Del Mastro L, Moreno-Aspitia A, Piccart M, Paesmans M, de Azambuja E, Lambertini M. PREDICT underestimates survival of patients with HER2-positive early-stage breast cancer. NPJ Breast Cancer 2022; 8:87. [PMID: 35859079 PMCID: PMC9300724 DOI: 10.1038/s41523-022-00452-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 07/01/2022] [Indexed: 11/09/2022] Open
Abstract
The prognostic performance of PREDICT in patients with HER2-positive early breast cancer (EBC) treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies is unclear. Therefore, we investigated its prognostic performance using data extracted from ALTTO, a phase III trial evaluating adjuvant lapatinib ± trastuzumab vs. trastuzumab alone in patients with HER2-positive EBC. Our analysis included 2794 patients. After a median follow-up of 6.0 years (IQR, 5.8-6.7), 182 deaths were observed. Overall, PREDICT underestimated 5-year OS by 6.7% (95% CI, 5.8-7.6): observed 5-year OS was 94.7% vs. predicted 88.0%. The underestimation was consistent across all subgroups, including those according to the type of anti HER2-therapy. The highest absolute differences were observed for patients with hormone receptor negative-disease, nodal involvement, and large tumor size (13.0%, 15.8%, and 15.3%, respectively). AUC under the ROC curve was 73.7% (95% CI 69.7-77.8) in the overall population, ranging between 61.7% and 77.7% across the analyzed subgroups. In conclusion, our analysis showed that PREDICT highly underestimated OS in HER2-positive EBC. Hence, it should be used with caution to give prognostic estimation to HER2-positive EBC patients treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies.
Collapse
Affiliation(s)
- Elisa Agostinetto
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), Brussels, Belgium
- Humanitas University, Department of Biomedical Sciences, via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
| | - Lieveke Ameye
- Data Center, Institut Jules Bordet, Brussels, Belgium
| | - Samuel Martel
- Department of Hemato-Oncology, CISSS Montérégie-Centre/Hôpital Charles-Le Moyne, Université de Sherbrooke, Greenfield Park, QC, Canada
| | - Philippe Aftimos
- Clinical Trials Conduct Unit, Institut Jules Bordet - Université Libre de Bruxelles, Brussels, Belgium
| | - Noam Pondé
- Clinical Oncology Department, AC Camargo Cancer Center, São Paulo, Brazil
| | - Christian Maurer
- University of Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
| | | | | | - Malou Vicente
- Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Saranya Chumsri
- Robert and Monica Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, FL, USA
| | - Judith Bliss
- The Institute of Cancer Research, Clinical Trials & Statistics Unit, London, UK
| | - Judith Kroep
- Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300, RC, Leiden, The Netherlands
| | | | | | - Lucia Del Mastro
- Department of Medical Oncology, U.O. Clinica di Oncologia medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy
| | - Alvaro Moreno-Aspitia
- Robert and Monica Jacoby Center for Breast Health, Mayo Clinic, Jacksonville, FL, USA
| | - Martine Piccart
- Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | | | - Evandro de Azambuja
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), Brussels, Belgium
| | - Matteo Lambertini
- Department of Medical Oncology, U.O. Clinica di Oncologia medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy.
| |
Collapse
|
|
27
|
Deo SVS, Sharma J, Kumar S. GLOBOCAN 2020 Report on Global Cancer Burden: Challenges and Opportunities for Surgical Oncologists. Ann Surg Oncol 2022; 29:6497-6500. [PMID: 35838905 DOI: 10.1245/s10434-022-12151-6] [Citation(s) in RCA: 202] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 06/25/2022] [Indexed: 01/07/2023]
Abstract
Cancer is emerging as a major public health challenge globally. Recently, IARC (International Association of Research on Cancer) published global cancer burden using GLOBOCAN 2020 estimates for 36 cancers in 185 countries of the world. As per the estimates of the World Health Organization (WHO) in 2019, cancer is the first or second leading cause of death in 112 of 183 countries. The major takeaways of the GLOBOCAN 2020 report relevant to the surgical oncology community include the rising global burden of cancer, global disparity in cancer incidence and mortality in different geographic regions, and the impact of the human development index (HDI) on cancer incidence and projected global cancer burden by 2040. In this article, we discuss the implications of the GLOBOCAN report on future global cancer control strategies and the role of surgical oncologists in the fight against cancer.
Collapse
Affiliation(s)
- S V S Deo
- Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India.
| | - Jyoti Sharma
- Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Sunil Kumar
- Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
28
|
Cai YW, Shao ZM, Yu KD. Determining the Optimal (Neo)Adjuvant Regimen for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Regarding Survival Outcome: A Network Meta-Analysis. Front Immunol 2022; 13:919369. [PMID: 35844533 PMCID: PMC9279606 DOI: 10.3389/fimmu.2022.919369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 05/26/2022] [Indexed: 11/13/2022] Open
Abstract
Background The optimal (neo)adjuvant regimen for human epidermal growth factor receptor-2 (HER2)-positive breast cancer regarding survival outcomes remains unclear. Methods We searched Web of Science, PubMed, and the Cochrane Central Register of Controlled Trials systematically to find out randomized controlled studies, up to January 2022, that compared different anti-HER2 regimens in the (neo)adjuvant setting. The primary endpoint was disease-free survival (DFS). We used a Bayesian statistical model to combine direct and indirect comparisons and used odds ratios (ORs) to pool effect sizes and performed the surface under the cumulative ranking area (SUCRA) curves to estimate the ranking probabilities of various regimens. For survival outcomes, we performed two parallel analyses, one based on data from both neoadjuvant and adjuvant studies and the other specific to adjuvant studies. All statistics were two-sided. Results Fifteen studies were finally enrolled. Regarding DFS, the overall analysis indicated that the top two regimens for HER2-positive breast cancer were chemotherapy plus trastuzumab with lapatinib, and chemotherapy plus trastuzumab with pertuzumab (SUCAR of 81% and 79%, respectively), with the OR of 0.99 [95% confidence interval (CI), 0.59 to 1.54]; the parallel analysis specific to adjuvant trials indicated that the top two regimens were chemotherapy plus trastuzumab with sequential neratinib, and chemotherapy plus trastuzumab with pertuzumab (SUCRA of 80% and 76%, respectively), with the OR of 1.04 (95% CI, 0.63 to 1.73). The dual-target therapy that combines trastuzumab and pertuzumab showed the highest risk of inducing cardiac events, with an SUCRA of 92%. Conclusions Chemotherapy plus trastuzumab and pertuzumab might be the optimal regimen for HER2-positive breast cancer in improving the survival rate. However, the cardiotoxicity of this dual-target therapy should be taken care of.
Collapse
Affiliation(s)
- Yu-Wen Cai
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhi-Ming Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Key Laboratory of Breast Cancer, Shanghai, China
| | - Ke-Da Yu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Ke-Da Yu, ; orcid.org/0000-0002-2883-1282
| |
Collapse
|
|
29
|
Närvä E, Taskinen ME, Lilla S, Isomursu A, Pietilä M, Weltner J, Isola J, Sihto H, Joensuu H, Zanivan S, Norman J, Ivaska J. MASTL is enriched in cancerous and pluripotent stem cells and influences OCT1/OCT4 levels. iScience 2022; 25:104459. [PMID: 35677646 PMCID: PMC9167974 DOI: 10.1016/j.isci.2022.104459] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 03/04/2022] [Accepted: 05/13/2022] [Indexed: 11/01/2022] Open
Abstract
MASTL is a mitotic accelerator with an emerging role in breast cancer progression. However, the mechanisms behind its oncogenicity remain largely unknown. Here, we identify a previously unknown role and eminent expression of MASTL in stem cells. MASTL staining from a large breast cancer patient cohort indicated a significant association with β3 integrin, an established mediator of breast cancer stemness. MASTL silencing reduced OCT4 levels in human pluripotent stem cells and OCT1 in breast cancer cells. Analysis of the cell-surface proteome indicated a strong link between MASTL and the regulation of TGF-β receptor II (TGFBR2), a key modulator of TGF-β signaling. Overexpression of wild-type and kinase-dead MASTL in normal mammary epithelial cells elevated TGFBR2 levels. Conversely, MASTL depletion in breast cancer cells attenuated TGFBR2 levels and downstream signaling through SMAD3 and AKT pathways. Taken together, these results indicate that MASTL supports stemness regulators in pluripotent and cancerous stem cells.
Collapse
Affiliation(s)
- Elisa Närvä
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
| | - Maria E. Taskinen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
| | | | - Aleksi Isomursu
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
| | - Mika Pietilä
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
| | - Jere Weltner
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
| | - Jorma Isola
- Laboratory of Cancer Biology, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland
| | - Harri Sihto
- Department of Pathology, University of Helsinki, 00290 Helsinki, Finland
| | - Heikki Joensuu
- University of Helsinki and Comprehensive Cancer Center, Helsinki University Hospital, 00290 Helsinki, Finland
| | - Sara Zanivan
- CRUK Beatson Institute, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Jim Norman
- CRUK Beatson Institute, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Johanna Ivaska
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
- Department of Life Technologies, University of Turku, 20520 Turku, Finland
- Western Finnish Cancer Center (FICAN West), University of Turku, 20520 Turku, Finland
- Foundation for the Finnish Cancer Institute, Tukholmankatu 8, Helsinki, Finland
| |
Collapse
|
|
30
|
Lu Y, Deng S, Dou Q, Pan W, Liu Q, Ji H, Wang X, Zhang HM. Treatment-Related Coronary Disorders of Fluoropyrimidine Administration: A Systematic Review and Meta-Analysis. Front Pharmacol 2022; 13:885699. [PMID: 35645806 PMCID: PMC9140752 DOI: 10.3389/fphar.2022.885699] [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: 02/28/2022] [Accepted: 04/07/2022] [Indexed: 12/02/2022] Open
Abstract
Background: Coronary disorders are recognized as the most common manifestation of fluoropyrimidine-related cardiotoxicity in clinical practice. However, there are limited and conflicting data on the incidence and profiles of fluoropyrimidine-related coronary disorders. In this meta-analysis, we aimed to systematically assess the incidence of all-grade and grade 3 or higher fluoropyrimidine-related coronary disorders, and further explore the factors that influence its occurrence. Methods: Studies reporting the fluoropyrimidine-related coronary disorders were retrieved from a systematic search of English literature in the PubMed, Web of Science, Medline, and Cochrane database from 1 Jan 2001, to 1 Jan 2022. The NIH assessment tool was used to evaluate the quality of each study. The data of basic study characteristics, treatment details, and results of coronary toxicities were extracted. According to the results of the heterogeneity test (I2 and p-value statistic), a random-effect model or fixed-effect model was selected for the pooled analysis of the incidence of adverse coronary events. Subgroup analysis was conducted to further explore the risks influencing the occurrence of fluoropyrimidine-related coronary disorders. The stability and publication bias of our results were evaluated by sensitivity analysis and Egger test, respectively. Results: A total of 63 studies were finally included in our pooled analysis, involving 25,577 patients. The pooled cumulative incidence of all-grade and grade 3 or higher coronary disorders was 2.75% (95% CI 1.89%–3.76%) and 1.00% (95% CI 0.62%–1.47%), respectively. The coronary disorders were most reported as myocardial ischemia (1.28%, 95% CI 0.42%–2.49%) and angina/chest pain (1.1%, 95% CI 0.54%–1.81%). Subgroup analysis revealed that studies in the female-only population seemed to have a lower incidence of fluoropyrimidine-related coronary disorders. The occurrence of adverse coronary events varied among different tumor types. Patients with esophageal cancer have the highest coronary toxicity (6.32%), while those with breast cancer have a relatively lower incidence (0.5%). Coronary disorders induced by 5-FU monotherapy are more frequent than that induced by capecitabine (3.31% vs. 1.21%, p < 0.01). Fluoropyrimidine combination therapy, whether combined with other chemotherapy drugs, targeted therapy drugs, or radiotherapy, significantly increased the incidence of coronary complications (p < 0.01). Conclusion: This meta-analysis has defined the incidence of fluoropyrimidine-related coronary disorders and depicted its epidemiological profiles for the first time, which may provide a reference for clinical practice in cancer management.
Collapse
|
|
31
|
Zou Y, Zheng S, Xie X, Ye F, Hu X, Tian Z, Yan SM, Yang L, Kong Y, Tang Y, Tian W, Xie J, Deng X, Zeng Y, Chen ZS, Tang H, Xie X. N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nat Commun 2022; 13:2672. [PMID: 35562334 PMCID: PMC9106694 DOI: 10.1038/s41467-022-30217-7] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 04/21/2022] [Indexed: 12/26/2022] Open
Abstract
Intrinsic and acquired anti-HER2 resistance remains a major hurdle for treating HER2-positive breast cancer. Using genome-wide CRISPR/Cas9 screening in vitro and in vivo, we identify FGFR4 as an essential gene following anti-HER2 treatment. FGFR4 inhibition enhances susceptibility to anti-HER2 therapy in resistant breast cancer. Mechanistically, m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance. Notably, suppression of FGFR4 dramatically diminishes glutathione synthesis and Fe2+ efflux efficiency via the β-catenin/TCF4-SLC7A11/FPN1 axis, resulting in excessive ROS production and labile iron pool accumulation. Ferroptosis, a unique iron-dependent form of oxidative cell death, is triggered after FGFR4 inhibition. Experiments involving patient-derived xenografts and organoids reveals a synergistic effect of anti-FGFR4 with anti-HER2 therapy in breast cancer with either intrinsic or acquired resistance. Together, these results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Collapse
Affiliation(s)
- Yutian Zou
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shaoquan Zheng
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xinhua Xie
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Feng Ye
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiaoqian Hu
- School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhi Tian
- College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Shu-Mei Yan
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lu Yang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yanan Kong
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yuhui Tang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wenwen Tian
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jindong Xie
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xinpei Deng
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yan Zeng
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhe-Sheng Chen
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
| | - Hailin Tang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| | - Xiaoming Xie
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| |
Collapse
|
|
32
|
Morganti S, Bianchini G, Giordano A, Giuliano M, Curigliano G, Criscitiello C. How I treat HER2-positive early breast cancer: how long adjuvant trastuzumab is needed? ESMO Open 2022; 7:100428. [PMID: 35272131 PMCID: PMC8908056 DOI: 10.1016/j.esmoop.2022.100428] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/03/2023] Open
Abstract
Since its first approval in 2006, 1 year of adjuvant trastuzumab has been the standard of care for early-stage HER2-positive breast cancer. Nevertheless, the optimal duration of adjuvant trastuzumab was uncertain, and the standard 12-month duration has been questioned by a number of different trials. Although most of these studies were formally negative, a patient-level meta-analysis presented at the 2021 European Society for Medical Oncology (ESMO) meeting first showed the non-inferiority of 6-month trastuzumab. Through this review, we sought to take a closer look at the meta-analysis and the included trials to explain why we believe that non-inferiority should be interpreted with caution. Indeed, here we underline how the meta-analysis’ results were mainly driven by the PERSEPHONE study, an old trial that tested non-standard chemo-trastuzumab regimens in a relatively low-risk population with doubtful endpoints. In summary, considering all the limitations of this analysis and the increasing use of effective anthracycline-free de-escalation strategies, we are convinced that 1-year trastuzumab should remain the standard of care.
The standard 1-year duration of adjuvant trastuzumab has been questioned by a number of trials. At ESMO 2021, the meta-analysis by Earl et al. showed that 6-month adjuvant trastuzumab is not inferior to 12-month. The PERSEPHONE trial was the main driver of the meta-analysis’ results, but it has several limitations. Alternative anthracycline-free de-escalation strategies proved to be effective for HER2+ early breast cancer patients. 12-month adjuvant trastuzumab should remain the standard of care.
Collapse
Affiliation(s)
- S Morganti
- Division of Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hematology, University of Milan, Milan, Italy; Dana-Farber Cancer Institute, Boston, USA
| | - G Bianchini
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy. https://twitter.com/BianchiniGP
| | - A Giordano
- Dana-Farber Cancer Institute, Boston, USA. https://twitter.com/antgiorda
| | - M Giuliano
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - G Curigliano
- Division of Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hematology, University of Milan, Milan, Italy. https://twitter.com/curijoey
| | - C Criscitiello
- Division of Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and Hematology, University of Milan, Milan, Italy.
| |
Collapse
|
|
33
|
Bychkov D, Joensuu H, Nordling S, Tiulpin A, Kücükel H, Lundin M, Sihto H, Isola J, Lehtimäki T, Kellokumpu-Lehtinen PL, von Smitten K, Lundin J, Linder N. Outcome and Biomarker Supervised Deep Learning for Survival Prediction in Two Multicenter Breast Cancer Series. J Pathol Inform 2022; 13:9. [PMID: 35136676 PMCID: PMC8794033 DOI: 10.4103/jpi.jpi_29_21] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/10/2021] [Accepted: 06/20/2021] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Prediction of clinical outcomes for individual cancer patients is an important step in the disease diagnosis and subsequently guides the treatment and patient counseling. In this work, we develop and evaluate a joint outcome and biomarker supervised (estrogen receptor expression and ERBB2 expression and gene amplification) multitask deep learning model for prediction of outcome in breast cancer patients in two nation-wide multicenter studies in Finland (the FinProg and FinHer studies). Our approach combines deep learning with expert knowledge to provide more accurate, robust, and integrated prediction of breast cancer outcomes. MATERIALS AND METHODS Using deep learning, we trained convolutional neural networks (CNNs) with digitized tissue microarray (TMA) samples of primary hematoxylin-eosin-stained breast cancer specimens from 693 patients in the FinProg series as input and breast cancer-specific survival as the endpoint. The trained algorithms were tested on 354 TMA patient samples in the same series. An independent set of whole-slide (WS) tumor samples from 674 patients in another multicenter study (FinHer) was used to validate and verify the generalization of the outcome prediction based on CNN models by Cox survival regression and concordance index (c-index). Visual cancer tissue characterization, i.e., number of mitoses, tubules, nuclear pleomorphism, tumor-infiltrating lymphocytes, and necrosis was performed on TMA samples in the FinProg test set by a pathologist and combined with deep learning-based outcome prediction in a multitask algorithm. RESULTS The multitask algorithm achieved a hazard ratio (HR) of 2.0 (95% confidence interval [CI] 1.30-3.00), P < 0.001, c-index of 0.59 on the 354 test set of FinProg patients, and an HR of 1.7 (95% CI 1.2-2.6), P = 0.003, c-index 0.57 on the WS tumor samples from 674 patients in the independent FinHer series. The multitask CNN remained a statistically independent predictor of survival in both test sets when adjusted for histological grade, tumor size, and axillary lymph node status in a multivariate Cox analyses. An improved accuracy (c-index 0.66) was achieved when deep learning was combined with the tissue characteristics assessed visually by a pathologist. CONCLUSIONS A multitask deep learning algorithm supervised by both patient outcome and biomarker status learned features in basic tissue morphology predictive of survival in a nationwide, multicenter series of patients with breast cancer. The algorithms generalized to another independent multicenter patient series and whole-slide breast cancer samples and provide prognostic information complementary to that of a comprehensive series of established prognostic factors.
Collapse
Affiliation(s)
- Dmitrii Bychkov
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Program, Finland
| | - Heikki Joensuu
- iCAN Digital Precision Cancer Medicine Program, Finland
- Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Stig Nordling
- Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland
| | - Aleksei Tiulpin
- Research Unit of Medical Imaging, Physics and Technology, University of Oulu, Oulu, Finland
- Department of Diagnostic Radiology, Oulu University Hospital, Oulu, Finland
- Ailean Technologies Oy, Oulu, Finland
| | - Hakan Kücükel
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Program, Finland
| | - Mikael Lundin
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Harri Sihto
- Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland
| | - Jorma Isola
- Department of Cancer Biology, BioMediTech, University of Tampere, Tampere, Finland
| | | | | | | | - Johan Lundin
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Program, Finland
- Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
| | - Nina Linder
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Program, Finland
- Department of Women's and Children's Health, International Maternal and Child Health, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
34
|
T M A, Joseph P R, Abraham AA, Mathew M, Kumar BS. Cardiac toxicity of patients on short course trastuzumab in combination with chemotherapy (FinHer Protocol) in breast cancer. Breast J 2021; 27:811-816. [PMID: 34510637 DOI: 10.1111/tbj.14289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/31/2021] [Indexed: 12/01/2022]
Abstract
FinHer regimen is considered a relatively cardiac safe regimen for Her 2 positive breast cancer in resource-limited settings. There is limited data on cardiotoxicity of this regimen. Out of 1200 patients diagnosed with carcinoma breast during the study period, three hundred Her2-positive early-breast cancer patients received FinHer protocol were included. Among the 300 patients, a total of 71 patients (24%) experienced cardiac toxicity including asymptomatic EF loss in 62 patients (21%) and symptomatic LVEF loss in nine patients (3%). Among patients with symptomatic LVEF loss, six patients had symptomatic cardiac toxicity, one patient (0.3%) had symptoms with fall in EF after completion of treatment, one patient (0.3%) had Congestive cardiac failure (CHF); one patient (0.3%) had non-ST elevation myocardial infarction (NSTEMI). Later, trastuzumab was rechallenged in all 62 patients (24%) with asymptomatic LVEF loss and six patients (2%) with symptomatic LVEF loss. One patient with CHF and NSTEMI was not rechallenged. Hypertension and diabetic mellitus which were the two factors found to have risk on univariate logistic regression analysis although it was not statistically significant. None of these patients further experienced cardiac toxicity at 24 months follow-up except one patient. Although FinHer protocol is considered a cardiac safe protocol, cardiotoxicity associated with trastuzumab which can manifest as an asymptomatic decline in LVEF is more than usually expected in a real-world scenario.
Collapse
Affiliation(s)
- Anoop T M
- Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Rona Joseph P
- Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Anju Anna Abraham
- Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Mintu Mathew
- Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| | - Bhavya S Kumar
- Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
| |
Collapse
|
|
35
|
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: 193] [Impact Index Per Article: 48.3] [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.
Collapse
|
|
36
|
Schmidt M, Edlund K, Hengstler JG, Heimes AS, Almstedt K, Lebrecht A, Krajnak S, Battista MJ, Brenner W, Hasenburg A, Rahnenführer J, Gehrmann M, Kellokumpu-Lehtinen PL, Wirtz RM, Joensuu H. Prognostic Impact of Immunoglobulin Kappa C ( IGKC) in Early Breast Cancer. Cancers (Basel) 2021; 13:3626. [PMID: 34298839 PMCID: PMC8304855 DOI: 10.3390/cancers13143626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/09/2021] [Accepted: 07/16/2021] [Indexed: 01/12/2023] Open
Abstract
We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1010 patients with early breast cancer were randomly allocated to either docetaxel-containing or vinorelbine-containing adjuvant chemotherapy. HER2-positive patients were additionally allocated to either trastuzumab or no trastuzumab. Hormone receptor-positive patients received tamoxifen. IGKC was evaluated in 909 tumors using quantitative real-time polymerase chain reaction, and the influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates. Interactions were analyzed using Cox regression. IGKC expression, included as continuous variable, was independently associated with DDFS in a multivariable analysis also including age, molecular subtype, grade, and pT and pN stage (HR 0.930, 95% CI 0.870-0.995, p = 0.034). An independent association with DDFS was also found in a subset analysis of triple-negative breast cancers (TNBC) (HR 0.843, 95% CI 0.724-0.983, p = 0.029), but not in luminal (HR 0.957, 95% CI 0.867-1.056, p = 0.383) or HER2-positive (HR 0.933, 95% CI 0.826-1.055, p = 0.271) cancers. No significant interaction between IGKC and chemotherapy or trastuzumab administration was detected (Pinteraction = 0.855 and 0.684, respectively). These results show that humoral immunity beneficially influences the DDFS of patients with early TNBC.
Collapse
Affiliation(s)
- Marcus Schmidt
- Department of Obstetrics and Gynecology, University Medical Center Mainz, 55131 Mainz, Germany; (A.-S.H.); (K.A.); (A.L.); (S.K.); (M.J.B.); (W.B.); (A.H.)
| | - Karolina Edlund
- Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, 44139 Dortmund, Germany; (K.E.); (J.G.H.)
| | - Jan G. Hengstler
- Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, 44139 Dortmund, Germany; (K.E.); (J.G.H.)
| | - Anne-Sophie Heimes
- Department of Obstetrics and Gynecology, University Medical Center Mainz, 55131 Mainz, Germany; (A.-S.H.); (K.A.); (A.L.); (S.K.); (M.J.B.); (W.B.); (A.H.)
| | - Katrin Almstedt
- Department of Obstetrics and Gynecology, University Medical Center Mainz, 55131 Mainz, Germany; (A.-S.H.); (K.A.); (A.L.); (S.K.); (M.J.B.); (W.B.); (A.H.)
| | - Antje Lebrecht
- Department of Obstetrics and Gynecology, University Medical Center Mainz, 55131 Mainz, Germany; (A.-S.H.); (K.A.); (A.L.); (S.K.); (M.J.B.); (W.B.); (A.H.)
| | - Slavomir Krajnak
- Department of Obstetrics and Gynecology, University Medical Center Mainz, 55131 Mainz, Germany; (A.-S.H.); (K.A.); (A.L.); (S.K.); (M.J.B.); (W.B.); (A.H.)
| | - Marco J. Battista
- Department of Obstetrics and Gynecology, University Medical Center Mainz, 55131 Mainz, Germany; (A.-S.H.); (K.A.); (A.L.); (S.K.); (M.J.B.); (W.B.); (A.H.)
| | - Walburgis Brenner
- Department of Obstetrics and Gynecology, University Medical Center Mainz, 55131 Mainz, Germany; (A.-S.H.); (K.A.); (A.L.); (S.K.); (M.J.B.); (W.B.); (A.H.)
| | - Annette Hasenburg
- Department of Obstetrics and Gynecology, University Medical Center Mainz, 55131 Mainz, Germany; (A.-S.H.); (K.A.); (A.L.); (S.K.); (M.J.B.); (W.B.); (A.H.)
| | - Jörg Rahnenführer
- Department of Statistics, TU Dortmund University, 44221 Dortmund, Germany;
| | | | | | | | - Heikki Joensuu
- Department of Oncology, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland;
| |
Collapse
|
|
37
|
Goyal P, Doval DC, Agarwal C, Jain P, Chaudhari K, Domadia K, Redhu P, Koyyala VPB, Goel V, Batra U, Talwar V, Bothra S. Current Treatment Approaches for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in Adjuvant and Neoadjuvant Settings. Indian J Med Paediatr Oncol 2021. [DOI: 10.1055/s-0041-1729726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AbstractBreast cancer (BC) is the second most common cancer and the second leading cause of mortality among women globally. Approximately 20 to 25% of BC patients have amplification of the human epidermal growth factor receptor 2 (HER2) genes, a marker of poor prognosis. However, the introduction of anti-HER2-therapies (trastuzumab, followed closely by lapatinib, pertuzumab, trastuzumab emtansine, and neratinib) has changed the natural history of HER2-positive BC and improved the outcome in HER2-positive BC patients. The preeminence of anti-HER2 combination therapy in achieving complete inhibition of the various HER receptor dimers has been demonstrated in clinical studies. However, despite these therapeutic advances, tumors expressing estrogen receptor have poorer responses to targeted therapy and are more likely to relapse. A better understanding of resistance to existing anti-HER2 agents, along with the role played by the microenvironment and of interconnected signaling pathways, can permit tailor-made therapeutic options for each patient. This review aimed to evaluate treatment approaches for BC patients with HER2-positive disease in the adjuvant and neoadjuvant settings, also exploring the possibilities of extended duration of anti-HER2 maintenance therapy.
Collapse
Affiliation(s)
- Pankaj Goyal
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Dinesh Chandra Doval
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Chaturbhuj Agarwal
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Parveen Jain
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Krushna Chaudhari
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Kshitij Domadia
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Pallavi Redhu
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | | | - Varun Goel
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Ullas Batra
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Vineet Talwar
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Sneha Bothra
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| |
Collapse
|
|
38
|
Alanko J, Tanner M, Vanninen R, Auvinen A, Isola J. Triple-negative and HER2-positive breast cancers found by mammography screening show excellent prognosis. Breast Cancer Res Treat 2021; 187:267-274. [PMID: 33420595 PMCID: PMC8062374 DOI: 10.1007/s10549-020-06060-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/15/2020] [Indexed: 01/20/2023]
Abstract
PURPOSE Our purpose was to explore the prognosis of aggressive breast cancers of the HER2 oncogene amplification (HER2 +) and triple-negative (TN) subtypes detected by screening, as well as the prognosis of interval cancers (clinically due to symptoms between screening rounds) and cancers in screening nonparticipants. METHODS The study population comprised of 823 breast cancers in women aged 50-69 years from 2006-2014. Of these, 572 were found by screening mammography (69%), 170 were diagnosed between the screening rounds (21%), and 81 were diagnosed in women who did not participate in the screening program (10%). RESULTS The majority of all HER2 + (59%) and TN cancers (57%) in this age group were detected by screening. Screen-detected HER2 + tumors were small (median 12 mm), and node-negative (84%). During a median follow-up of eight years, the distant disease-free survival of screen-detected HER2 + and TN cancers was better than that of interval and nonparticipant cancers (age-adjusted HR = 0.16, 95% CI 0.03-0.81 and HR = 0.09, 95% CI 0.01-0.79, respectively). In nonparticipants, the distant disease-free survival of these cancers was worse than in participants (age-adjusted HR = 2.52, 95% CI 0.63-10.11 and HR = 5.30, 95% 1.16-24.29, respectively). CONCLUSION In the 50-69 age group, the majority of HER2 + and TN cancers can be found by a quality assured population-based mammography screening. Despite their generally aggressive behavior, after a median follow-up of 8 years, distant disease-free survival was over 90% of these cancers detected by screening. The worst prognosis of these cancers was in women who did not participate in screening.
Collapse
Affiliation(s)
- Johanna Alanko
- Laboratory of Cancer Biology, Faculty of Medicine and Health Technology, Screening Clinic of Terveystalo, Tampere University, Tampere, Finland.
| | - Minna Tanner
- Department of Oncology, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland
| | - Ritva Vanninen
- Department of Clinical Radiology, School of Medicine, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland
| | - Anssi Auvinen
- Faculty of Social Sciences (Health Sciences), Tampere University, Tampere, Finland
| | - Jorma Isola
- Laboratory of Cancer Biology, Faculty of Medicine and Health Technology, Jilab Inc., Tampere University, Tampere, Finland
| |
Collapse
|
|
39
|
Tarantino P, Morganti S, Curigliano G. Targeting HER2 in breast cancer: new drugs and paradigms on the horizon. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:139-155. [PMID: 36046143 PMCID: PMC9400740 DOI: 10.37349/etat.2021.00037] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/09/2021] [Indexed: 12/23/2022] Open
Abstract
About 15-20% of all breast cancers (BCs) are defined human epidermal growth factor receptor 2 (HER2)-positive, based on the overexpression of HER2 protein and/or amplification of ERBB2 gene. Such alterations lead to a more aggressive behavior of the disease, but also predict response to treatments targeting HER2. Indeed, several anti-HER2 compounds have been developed and approved in the last two decades, significantly improving our ability to cure patients in the early setting, and greatly extending their survival in the advanced setting. However, recent evolutions in this field promise to improve outcomes even further, through advancements in established HER2-targeting strategies, as well as the exploration of novel strategies. In particular, the engineering of new antibody-drug conjugates, with higher drug-to-antibody ratios (DARs) and cleavable linkers, has already led to the development of a highly effective drug, namely trastuzumab deruxtecan, recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of advanced HER2-positive (HER2+) BC, and currently in study in the early setting. Moreover, the novel tyrosine kinase inhibitor tucatinib was recently approved by FDA and EMA, showing to improve survival of HER2+ advanced BC patients, particularly in those with brain metastasis. Immunotherapy is also being investigated in the HER2+ subtype, through immune-checkpoint inhibition, cancer vaccines and adoptive-cell therapies. Overall, the enlarging arsenal of promising anti-HER2 compounds is expected to deliver significant improvements in the prognosis of both early and advanced HER2+ BC in the years to come. Moreover, some of such agents are showing encouraging activity in the much wider population of HER2-low advanced BC patients, challenging current BC classifications. If confirmed, this new paradigm would potentially expand the population deriving benefit from HER2-targeted treatments to up to 70% of all advanced BC patients, leading to a revolution in current treatment algorithms, and possibly to a redefinition of HER2 classification.
Collapse
Affiliation(s)
- Paolo Tarantino
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Hematology, University of Milan, 20122 Milan, Italy
| | - Stefania Morganti
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Hematology, University of Milan, 20122 Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Department of Oncology and Hematology, University of Milan, 20122 Milan, Italy
| |
Collapse
|
|
40
|
Ma J, Tang X, Hu Q, Wang Q, Chen Y, Li X, Luo T, Cao D. Optimum adjuvant trastuzumab duration for human epidermal growth factor receptor-2 positive breast cancer: a network meta-analysis of randomized trials. Transl Cancer Res 2021; 10:1628-1643. [PMID: 35116489 PMCID: PMC8799215 DOI: 10.21037/tcr-20-2378] [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: 06/21/2020] [Accepted: 03/05/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND Adjuvant trastuzumab treatment for 12 months is the standard-of-care for early HER2-positive breast cancer; however, the optimal duration is unclear. We performed a network meta-analysis (NMA) to determine the optimal treatment duration. METHODS We identified 16 randomized controlled trials involving 29,837 patients that assessed trastuzumab treatment in HER2-positive early breast cancer. Our NMA compared six trastuzumab durations: observation, T-9 weeks, T-12 weeks, T-6 months, T-12 months, and T-24 months. We assessed overall survival (OS), disease-free survival (DFS), acceptability, and cardiotoxicities and grade 3-4 nonhematologic toxicities, and ranked the durations in terms of efficacy and safety by surface under the cumulative ranking (SUCRA). RESULTS Pairwise meta-analysis showed that while T-6 months was associated with a significant reduction in DFS compared to T-12 months. In our NMA, increasing or decreasing durations showed a significant benefit in DFS compared to observation; however, decreasing durations was not associated with a significant reduction in DFS compared with T-12 months, regardless of the lymph node and hormone receptor statuses. SUCRA ordered the optimum durations of trastuzumab treatment based on PFS as T-12 months (95.6%), T-24 months (69.6%), T-6 months (53.2%), T-9 weeks (41.2%), T-12 weeks (34.3%) and observation (6.1%). CONCLUSIONS Escalating trastuzumab treatment beyond T-12 months confers no additional survival benefit but increased risk of cardiotoxicities. Furthermore, de-escalating treatment confers no improvement on OS compared to T-12 months. These data suggest that T-12 months is the most appropriate treatment schedule for HER2-positive early breast cancer.
Collapse
Affiliation(s)
- Ji Ma
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaofang Tang
- Department of Emergency, Disaster Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiancheng Hu
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qingfeng Wang
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Chen
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaofen Li
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Luo
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Molecular Diagnosis of Cancer, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, China
| | - Dan Cao
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
41
|
Joel A, Georgy JT, Thumaty DB, John AO, Chacko RT, Rebekah G, Sigamani E, Chandramohan J, Manipadam MT, Cherian AJ, Abraham DT, Jacob PM, Sebastian P, Backianathan S, Singh A. Neoadjuvant chemotherapy with biosimilar trastuzumab in human epidermal growth factor receptor 2 overexpressed non-metastatic breast cancer: patterns of use and clinical outcomes in India. Ecancermedicalscience 2021; 15:1207. [PMID: 33912232 PMCID: PMC8057782 DOI: 10.3332/ecancer.2021.1207] [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: 10/23/2020] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is associated with poor prognosis and access to anti-HER2 treatment is still a challenge in lower-middle income countries. The availability of the biosimilar trastuzumab has improved access by lowering the costs. We report the pattern of use of neoadjuvant ± adjuvant trastuzumab and outcomes in patients with HER2-positive non-metastatic breast cancer treated with regimens incorporating shorter durations of therapy and the use of the biosimilar trastuzumab compared to the innovator. METHODS We conducted a retrospective analysis of patients with non-metastatic HER2-positive breast cancer treated with neoadjuvant ± adjuvant trastuzumab (innovator (n = 34 (33%)) and biosimilar (n = 70 (67%)) manufactured by Biocon Biologics) with chemotherapy. Information regarding chemotherapy regimens, duration of trastuzumab use (≤12 weeks and >12 weeks), pathological response (Miller Payne grade), disease free survival (DFS), overall survival (OS) and safety data were collected from electronic medical records. RESULTS A total of 135 patients were analysed with a median age of 51 years (range: 23-82); of these, 57% were postmenopausal, 31.8% were hormone receptor positive and 62.9% had stage III disease. The overall pathological complete response (p-CR) in both breast and axilla increased to 37.6% in patients treated with trastuzumab preoperatively as compared to 22.2% in patients who did not receive any trastuzumab. Patients receiving innovator trastuzumab and biosimilar trastuzumab showed a p-CR of 28.5% and 41.7%, respectively. At a median follow-up of 42 months (range: 3-114), there were 18 relapses and 11 deaths. The 3-year DFS was 87.1% and OS was 92.2%. Cardiac dysfunction developed in 4 of 78 (5.1%) evaluable patients. CONCLUSION Access to anti-HER2 therapy in the treatment of non-metastatic HER2-positive breast cancer in resource-constrained settings has improved significantly with the availability of the biosimilar trastuzumab. Imbalances in patient profiles at baseline in routine clinical practice led to inconclusive outcomes of ≤12 weeks versus >12 weeks trastuzumab treatment. However, on the basis of historical data, patients could be offered shorter duration of trastuzumab when a standard 1-year treatment of adjuvant trastuzumab is not feasible in resource-constrained settings. The p-CR using the biosimilar trastuzumab in neoadjuvant treatment has been observed to be comparable to the innovator trastuzumab.
Collapse
Affiliation(s)
- Anjana Joel
- Department of Medical Oncology, Christian Medical College, Vellore 632004, India
| | - Josh Thomas Georgy
- Department of Medical Oncology, Christian Medical College, Vellore 632004, India
| | - Divya Bala Thumaty
- Department of Medical Oncology, Christian Medical College, Vellore 632004, India
| | - Ajoy Oommen John
- Department of Medical Oncology, Christian Medical College, Vellore 632004, India
| | - Raju Titus Chacko
- Department of Medical Oncology, Christian Medical College, Vellore 632004, India
| | - Grace Rebekah
- Department of Biostatistics, Christian Medical College, Vellore 632004, India
| | | | - Jagan Chandramohan
- Department of Pathology, Christian Medical College, Vellore 632004, India
| | | | - Anish Jacob Cherian
- Department of Endocrine Surgery, Christian Medical College, Vellore 632004, India
| | | | | | - Patricia Sebastian
- Department of Radiation Therapy, Christian Medical College, Vellore 632004, India
| | | | - Ashish Singh
- Department of Medical Oncology, Christian Medical College, Vellore 632004, India
| |
Collapse
|
|
42
|
Fourati N, Trigui R, Charfeddine S, Dhouib F, Kridis WB, Abid L, Khanfir A, Mnejja W, Daoud J. [Concomitant radiotherapy and trastuzumab: Rational and clinical implications]. Bull Cancer 2021; 108:501-512. [PMID: 33745737 DOI: 10.1016/j.bulcan.2020.12.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 12/01/2020] [Accepted: 12/18/2020] [Indexed: 11/25/2022]
Abstract
The HER2 receptor (Human Epidermal Growth Receptor 2) is a transmembrane receptor with tyrosine kinase activity that is over-expressed in 25-30 % of breast carcinomas. Its activation is associated with an exaggeration of cell proliferation with an increase in repair capacity resulting in increased radioresistance. On cardiac tissues, HER2 receptor activation plays a cardio-protective role. Trastuzumab, the first anti-HER2 drug used to treat patients with breast cancer overexpressing HER2 receptor , inhibits the cascade of reactions resulting in the proliferation of tumor cells, thus restoring cellular radiosensitivity. However, the combination of Trastuzumab with radiation therapy also removes HER2 receptor cardio-protective role on myocardial cells which increases the risk of cardiotoxicity. Thus, the concomitant association of these two modalities has long been a subject of controversy. Recent advances in radiation therapy technology and early detection of cardiac injury may limit the cardiotoxicity of this combination. Through this review, we developed the biological basis and the benefit-risk of concomitant combination of radiotherapy and Trastuzumab in adjuvant treatment of breast cancers overexpressing HER2 and we discuss the modalities of its optimization.
Collapse
Affiliation(s)
- Nejla Fourati
- Université de Sfax, CHU d'Habib-Bourguiba, faculté de médecine, service de radiothérapie carcinologique, Sfax, Tunisie.
| | - Rim Trigui
- Université de Sfax, CHU d'Habib-Bourguiba, faculté de médecine, service de radiothérapie carcinologique, Sfax, Tunisie
| | - Selma Charfeddine
- Université de Sfax, CHU d'Hedi-Chaker, faculté de médecine, service de cardiologie, Sfax, Tunisie
| | - Fatma Dhouib
- Université de Sfax, CHU d'Habib-Bourguiba, faculté de médecine, service de radiothérapie carcinologique, Sfax, Tunisie
| | - Wala Ben Kridis
- Université de Sfax, CHU d'Habib-Bourguiba, faculté de médecine, service d'oncologie médicale, Sfax, Tunisie
| | - Leila Abid
- Université de Sfax, CHU d'Hedi-Chaker, faculté de médecine, service de cardiologie, Sfax, Tunisie
| | - Afef Khanfir
- Université de Sfax, CHU d'Habib-Bourguiba, faculté de médecine, service d'oncologie médicale, Sfax, Tunisie
| | - Wafa Mnejja
- Université de Sfax, CHU d'Habib-Bourguiba, faculté de médecine, service de radiothérapie carcinologique, Sfax, Tunisie
| | - Jamel Daoud
- Université de Sfax, CHU d'Habib-Bourguiba, faculté de médecine, service de radiothérapie carcinologique, Sfax, Tunisie
| |
Collapse
|
|
43
|
Jackisch C, Barcenas CH, Bartsch R, Palma JD, Glück S, Harbeck N, Macedo G, O'Shaughnessy J, Pistilli B, Ruiz-Borrego M, Rugo HS. Optimal Strategies for Successful Initiation of Neratinib in Patients with HER2-Positive Breast Cancer. Clin Breast Cancer 2021; 21:e575-e583. [PMID: 33678567 DOI: 10.1016/j.clbc.2021.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/25/2021] [Accepted: 02/01/2021] [Indexed: 10/22/2022]
Abstract
Neratinib is an irreversible, pan-human epidermal growth factor inhibitor that has shown efficacy across human epidermal growth factor receptor 2 (HER2)-positive breast cancer settings. Neratinib is indicated for use as extended adjuvant therapy for HER2-positive early-stage breast cancer or, in combination with capecitabine, in the treatment of HER2-positive metastatic breast cancer. The primary tolerability concern with neratinib is diarrhea, and severe diarrhea early in treatment can lead to a substantial proportion of patients discontinuing neratinib, which may lead to reduced or nonexistent efficacy. In order to establish a set of treatment recommendations for use of neratinib, on May 12, 2020, an expert panel of oncologists and gastroenterologists met virtually to discuss the role of neratinib in the treatment of patients with HER2-positive breast cancer. The panel reviewed the current data on neratinib, including efficacy across settings and diarrhea management strategies. Based on these data and their clinical experience, the panelists developed a set of recommendations to guide selection of patients for neratinib, implement weekly dose escalation at initiation of therapy, and prophylactically manage diarrhea.
Collapse
Affiliation(s)
- Christian Jackisch
- Department of Gynecology and Obstetrics, Klinikum Offenbach, Offenbach, Germany.
| | - Carlos H Barcenas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Rupert Bartsch
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria
| | - Jack Di Palma
- Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, AL
| | - Stefan Glück
- Medical Affairs, Oncology, Regeneron Pharmaceuticals, Tarrytown, NY
| | - Nadia Harbeck
- Breast Center, Department of Gynecology and Obstetrics, LMU University Hospital, Munich, Germany
| | - Guilherme Macedo
- Department of Gastroenterology and Hepatology, Sao Joao Hospital, Porto, Portugal
| | - Joyce O'Shaughnessy
- Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX; Baylor University Medical Center, Dallas, TX; The US Oncology Network, Dallas, TX
| | - Barbara Pistilli
- Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | - Manuel Ruiz-Borrego
- Department of Medical Oncology, Hospital Universitario Virgen del Rocio, Seville, Spain
| | - Hope S Rugo
- Department of Medicine, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA
| |
Collapse
|
|
44
|
Kolarova I, Melichar B, Vanasek J, Ryska A, Horackova K, Petera J, Vosmik M, Sirak I, Dolezel M. Controversies of radiotherapy in human epidermal growth factor receptor (HER)-2 positive breast cancer patients. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2021; 165:19-25. [PMID: 33542544 DOI: 10.5507/bp.2021.007] [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: 10/08/2020] [Accepted: 01/15/2021] [Indexed: 11/23/2022] Open
Abstract
Tumor biology plays a crucial role in the systemic treatment, specifically in HER2-positive tumors. Distinct biological behavior of breast cancer subtypes is associated with different rates of locoregional recurrence (LRR). HER2- positive breast cancer patients treated with surgery in combination with radiation, without trastuzumab have poor outcome, including high LRR. The efficacy of radiotherapy in HER-2-positive breast cancer appears to be associated with the expression of estrogen receptors. In patients with HER-2-positive breast cancer, studies conducted before the introduction of trastuzumab indicated higher benefit of adjuvant radiation in patients with hormone receptor-positive tumors compared to patients with tumors not expressing hormone receptors. The introduction of agents targeting HER-2 has transformed the management of these patients, resulting in improved outcomes. The data of clinical studies show that the administration of trastuzumab as part of a multimodality approach (with radiation based on standard guidelines) results in improved outcomes, including lower locoregional recurrence. The risk of cardiac toxicity associated with radiation to the heart and administration of potential cardiotoxic trastuzumab is not clear. In patients treated concomitantly with regional lymph node irradiation and anti-HER-2 agents after prior anthracycline-based chemotherapy minimizing the dose to the myocardium, e.g. respiratory gating or proton beam radiotherapy, have been suggested.
Collapse
Affiliation(s)
- Iveta Kolarova
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic
- Faculty of Health Studies, Pardubice University, Pardubice, Czech Republic
| | - Bohuslav Melichar
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic
- Department of Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Czech Republic
- Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove, Charles University, Czech Republic
| | - Jaroslav Vanasek
- Faculty of Health Studies, Pardubice University, Pardubice, Czech Republic
- Oncology Centre, Multiscan, Pardubice, Czech Republic
| | - Ales Ryska
- The Fingerland Department of Pathology, Charles University Medical Faculty and University Hospital Hradec Kralove, Czech Republic
| | - Katerina Horackova
- Faculty of Health Studies, Pardubice University, Pardubice, Czech Republic
| | - Jiri Petera
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic
- Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove, Charles University, Czech Republic
| | - Milan Vosmik
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic
- Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove, Charles University, Czech Republic
| | - Igor Sirak
- Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Czech Republic
- Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove, Charles University, Czech Republic
| | - Martin Dolezel
- Department of Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Czech Republic
- Department of Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| |
Collapse
|
|
45
|
Erickson AW, Habbous S, Hoey C, Jerzak KJ, Das S. Dual- versus single-agent HER2 inhibition and incidence of intracranial metastatic disease: a systematic review and meta-analysis. NPJ Breast Cancer 2021; 7:17. [PMID: 33602948 PMCID: PMC7892568 DOI: 10.1038/s41523-021-00220-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 01/07/2021] [Indexed: 12/19/2022] Open
Abstract
Observational studies have suggested that HER2 inhibition with trastuzumab may be associated with an increased incidence of intracranial metastatic disease (IMD) due to its ability to prolong survival. We hypothesized that prolonged survival associated with dual-agent HER2 inhibition may be associated with an even higher incidence of IMD. This study pooled estimates of IMD incidence and survival among patients with HER2-positive breast cancer receiving dual- versus single-agent HER2 targeted therapy, as well as trastuzumab versus chemotherapy, observation, or another HER2-targeted agent. We searched PubMed, EMBASE, and CENTRAL from inception to 25 March 2020. We included randomized controlled trials that reported IMD incidence for patients with HER2-positive breast cancer receiving trastuzumab as the experimental or control arm irrespective of disease stage. Among 465 records identified, 19 randomized controlled trials (32,572 patients) were included. Meta-analysis of four studies showed that dual HER2-targeted therapy was associated with improved overall survival (HR 0.76; 95% CI, 0.66–0.87) and progression-free survival (HR 0.77; 95% CI, 0.68–0.87) compared to single HER2-targeted therapy, but the risk of IMD was similar (RR 1.03; 95% CI, 0.83–1.27). Our study challenges the hypothesis that prolonged survival afforded by improved extracranial disease control is associated with increased IMD incidence.
Collapse
Affiliation(s)
| | - Steven Habbous
- Ontario Health (Cancer Care Ontario), Toronto, ON, Canada
| | - Christianne Hoey
- Evaluative Clinical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Katarzyna J Jerzak
- Department of Medicine, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada
| | - Sunit Das
- Institute of Medical Science, University of Toronto, Toronto, Canada. .,Division of Neurosurgery, University of Toronto, Toronto, Canada. .,Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada.
| |
Collapse
|
|
46
|
Bychkov D, Linder N, Tiulpin A, Kücükel H, Lundin M, Nordling S, Sihto H, Isola J, Lehtimäki T, Kellokumpu-Lehtinen PL, von Smitten K, Joensuu H, Lundin J. Deep learning identifies morphological features in breast cancer predictive of cancer ERBB2 status and trastuzumab treatment efficacy. Sci Rep 2021; 11:4037. [PMID: 33597560 PMCID: PMC7890057 DOI: 10.1038/s41598-021-83102-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 01/29/2021] [Indexed: 02/08/2023] Open
Abstract
The treatment of patients with ERBB2 (HER2)-positive breast cancer with anti-ERBB2 therapy is based on the detection of ERBB2 gene amplification or protein overexpression. Machine learning (ML) algorithms can predict the amplification of ERBB2 based on tumor morphological features, but it is not known whether ML-derived features can predict survival and efficacy of anti-ERBB2 treatment. In this study, we trained a deep learning model with digital images of hematoxylin–eosin (H&E)-stained formalin-fixed primary breast tumor tissue sections, weakly supervised by ERBB2 gene amplification status. The gene amplification was determined by chromogenic in situ hybridization (CISH). The training data comprised digitized tissue microarray (TMA) samples from 1,047 patients. The correlation between the deep learning–predicted ERBB2 status, which we call H&E-ERBB2 score, and distant disease-free survival (DDFS) was investigated on a fully independent test set, which included whole-slide tumor images from 712 patients with trastuzumab treatment status available. The area under the receiver operating characteristic curve (AUC) in predicting gene amplification in the test sets was 0.70 (95% CI, 0.63–0.77) on 354 TMA samples and 0.67 (95% CI, 0.62–0.71) on 712 whole-slide images. Among patients with ERBB2-positive cancer treated with trastuzumab, those with a higher than the median morphology–based H&E-ERBB2 score derived from machine learning had more favorable DDFS than those with a lower score (hazard ratio [HR] 0.37; 95% CI, 0.15–0.93; P = 0.034). A high H&E-ERBB2 score was associated with unfavorable survival in patients with ERBB2-negative cancer as determined by CISH. ERBB2-associated morphology correlated with the efficacy of adjuvant anti-ERBB2 treatment and can contribute to treatment-predictive information in breast cancer.
Collapse
Affiliation(s)
- Dmitrii Bychkov
- Institute for Molecular Medicine Finland (FIMM), Nordic EMBL Partnership for Molecular Medicine, University of Helsinki, Helsinki, Finland. .,iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.
| | - Nina Linder
- Institute for Molecular Medicine Finland (FIMM), Nordic EMBL Partnership for Molecular Medicine, University of Helsinki, Helsinki, Finland.,iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.,Department of Women's and Children's Health, International Maternal and Child Health, Uppsala University, Uppsala, Sweden
| | - Aleksei Tiulpin
- Physics and Technology, Research Unit of Medical Imaging, University of Oulu, Oulu, Finland.,Department of Diagnostic Radiology, Oulu University Hospital, Oulu, Finland.,Ailean Technologies Oy, Oulu, Finland
| | - Hakan Kücükel
- Institute for Molecular Medicine Finland (FIMM), Nordic EMBL Partnership for Molecular Medicine, University of Helsinki, Helsinki, Finland.,iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
| | - Mikael Lundin
- Institute for Molecular Medicine Finland (FIMM), Nordic EMBL Partnership for Molecular Medicine, University of Helsinki, Helsinki, Finland
| | - Stig Nordling
- Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland
| | - Harri Sihto
- Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland
| | - Jorma Isola
- Department of Cancer Biology, BioMediTech, University of Tampere, Tampere, Finland
| | | | | | | | - Heikki Joensuu
- iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.,Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Johan Lundin
- Institute for Molecular Medicine Finland (FIMM), Nordic EMBL Partnership for Molecular Medicine, University of Helsinki, Helsinki, Finland.,iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.,Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
47
|
Zeidman M, Schmidt H, Alberty-Oller JJ, Pisapati KV, Ahn S, Mazumdar M, Ru M, Moshier E, Port E. Trends in neoadjuvant chemotherapy versus surgery-first in stage I HER2-positive breast cancer patients in the National Cancer DataBase (NCDB). Breast Cancer Res Treat 2021; 187:177-185. [PMID: 33392839 DOI: 10.1007/s10549-020-06041-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 11/28/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced HER2 + breast cancer (BC). Optimal sequencing of treatment (NAC vs. surgery first) is less clear cut in stage I (T1N0) HER2 + BC, where information from surgical pathology could impact adjuvant treatment decisions. Utilizing the NCDB, we evaluated the trend of NAC use compared to upfront surgery in patients with small HER2 + BC. METHODS We identified NCDB female patients diagnosed with T1 N0 HER2 + BC from 2010 through 2015. Prevalence ratios (PR) using multivariable robust Poisson regression models were calculated to measure the association between baseline characteristics and the receipt of NAC. Analysis of trends over time was denoted by annual percent change (APC) of NAC versus surgery upfront. RESULTS Of the 14,949 that received chemotherapy and anti-HER2 therapy during the study period, overall 1281 (8.6%) received NAC and 13,668 (91.4%) received adjuvant treatment. Patients receiving NAC increased annually from 4.2% in 2010 to 17.3% in 2015, with the most rapid increase occurring between years 2013 (8.5%) and 2014 (14.2%). The greatest increase was seen in patients with cT1c tumors with an APC of 37.8% over the study period (95% CI 29.0, 47.3%, p < 0.01), although a significant trend was likewise seen in patients with cT1a (APC = 26.1%,95% CI 1.59, 56.6%), and cT1b (APC = 27.4%, 95% CI 18.0, 37.7%) tumors. Predictors of neoadjuvant therapy receipt were age younger than 50 (PR = 1.69, 95% CI 1.52, 1.89), Mountain/Pacific area (PR = 1.24, 95% CI 1.05, 1.46), and estrogen receptor negativity (ER- PR + : PR = 2.01, 95% CI 1.51, 2.68; ER- PR- : PR = 1.49, 95% CI 1.32, 1.69). CONCLUSIONS Neoadjuvant therapy for T1 N0 HER2 + BC increased over the study period and was mostly due increased use in clinical T1c tumors. This may be consistent with secular change in Pertuzumab treatment following FDA approval in 2013.
Collapse
Affiliation(s)
- Michael Zeidman
- Dubin Breast Center of the Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA. .,Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Hank Schmidt
- Dubin Breast Center of the Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA.,Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - J Jaime Alberty-Oller
- Dubin Breast Center of the Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA.,Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kereeti V Pisapati
- Dubin Breast Center of the Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA.,Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Soojin Ahn
- Dubin Breast Center of the Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA.,Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Madhu Mazumdar
- Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Institute for Healthcare Delivery Science at the Mount Sinai Health System, New York, NY, USA
| | - Meng Ru
- Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Institute for Healthcare Delivery Science at the Mount Sinai Health System, New York, NY, USA
| | - Erin Moshier
- Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Institute for Healthcare Delivery Science at the Mount Sinai Health System, New York, NY, USA
| | - Elisa Port
- Dubin Breast Center of the Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA.,Icahn School of Medicine at Mount Sinai, New York, NY, USA
| |
Collapse
|
|
48
|
Elsamany S, Elsisi GH, Hassanin F, Jafal M. Budget impact analysis of subcutaneous trastuzumab compared to intravenous trastuzumab in Saudi HER2-positive breast cancer patients. Expert Rev Pharmacoecon Outcomes Res 2020; 21:511-518. [PMID: 33275459 DOI: 10.1080/14737167.2021.1860024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Background: This study was aimed to assess the budget impact of SC trastuzumab compared to IV trastuzumab in patients with HER2-positive breast cancer (BC) from the perspective of the governmental health sector in Saudi Arabia, over a 3-year time horizon.Methods: A model was developed to calculate the direct medical and indirect costs for 394 incidents HER2-positive BC patients per year who would receive SC trastuzumab compared to IV formulation. We calculated drug acquisition costs for fixed, loading, and subsequent doses of trastuzumab. One-way sensitivity analysis was conducted.Results: Two scenarios were modeled: the first scenario evaluated the impact of gradual replacement of IV formulation by SC, the second scenario, evaluated impact of totally replacing IV formulation. The total annual costs in the first scenario were estimated to be SAR 177 million (USD 98 million) for IV trastuzumab compared to SAR 143 million (USD 79 million) for SC formulation, leading to a total budget saving of SAR 34,527,346 (USD 19,181,858). In the second scenario, the total annual costs were estimated to be SAR 108 million (USD 60 million) for SC trastuzumab compared to SAR 177 million (USD 98 million) for IV formulation, leading to budget savings of SAR 69,054,692 (USD 36,363,717).Conclusion: Benefits of the SC formulation over IV infusions are being converted to realistic monetary benefits for all providers and payers.
Collapse
Affiliation(s)
- Shereef Elsamany
- Oncology Center, King Abdullah Medical City, Makkah, Saudi Arabia.,Oncology Center, Mansoura University, Mansoura, Egypt
| | - Gihan Hamdy Elsisi
- HEOR Department, Cairo University, HTA Office, LLC, Cairo, Egypt.,Faculty of Economics and Political Science, Cairo University, Giza, Egypt
| | - Fayza Hassanin
- Oncology Nursing, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Mohamed Jafal
- Clinical Pharmacy, King Abdullah Medical City, Makkah, Saudi Arabia
| |
Collapse
|
|
49
|
Ban M, Petrić Miše B, Vrdoljak E. Early HER2-Positive Breast Cancer: Current Treatment and Novel Approaches. Breast Care (Basel) 2020; 15:560-569. [PMID: 33447229 PMCID: PMC7768133 DOI: 10.1159/000511883] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 09/25/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Trastuzumab significantly improves outcomes in early HER2-positive breast cancer, irrespectively of any prognostic or predictive factors. Unfortunately, about a quarter of patients receiving neoadjuvant trastuzumab experience disease recurrence, revealing the unquestionable need for further improvement of treatment outcomes. SUMMARY Adding HER2 blockade to adjuvant trastuzumab with pertuzumab and neratinib improves invasive disease-free survival (IDFS), particularly for those at highest risk of recurrence. A shift toward a neoadjuvant strategy for patients with a higher risk of recurrence could result in further treatment optimization. For patients without a pathological complete response (pCR) after the neoadjuvant part of the therapy, a switch to adjuvant trastuzumab emtansine significantly improves IDFS and distant recurrence-free survival and shows a trend towards improved overall survival (OS). On the other hand, for low-risk patients, chemotherapy deescalation should be strongly considered with the use of trastuzumab monotherapy as an anti-HER2 backbone. KEY MESSAGES Neoadjuvant therapy should be offered for a significant proportion of HER2-positive early breast cancer patients with a higher risk of recurrence. Postneoadjuvant treatment should be tailored according to the initial stage of disease and the response to neoadjuvant treatment.
Collapse
Affiliation(s)
- Marija Ban
- Department of Oncology, Clinical Hospital Centre Split, School of Medicine, University of Split, Split, Croatia
| | | | | |
Collapse
|
|
50
|
Hu Q, Wang X, Chen Y, Li X, Luo T, Cao D. Optimum duration of adjuvant trastuzumab in treatment of human epidermal growth factor receptor-2 positive early breast cancer: protocol for a network meta-analysis of randomised controlled trials. BMJ Open 2020; 10:e035802. [PMID: 33444169 PMCID: PMC7682472 DOI: 10.1136/bmjopen-2019-035802] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 11/05/2020] [Accepted: 11/10/2020] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Controversy regarding optimum duration of trastuzumab treatment remains in patients with human epidermal growth factor receptor-2 (HER2) positive early breast cancer. The objective of applying network meta-analysis (NMA) is to integrate existing evidence based on direct and indirect comparisons of efficacy and safety, and then to determine the duration of trastuzumab treatments with the greatest impact on therapeutic outcomes in HER2-positive early breast cancers. METHODS AND ANALYSIS Electronic searching of trastuzumab treatments for early breast cancer by titles and abstracts will be conducted for the period from inception to 16 June 2019 in PubMed, Cochrane Library, Embase and ClinicalTrils.gov, as well as the annual meetings of San Antonio Breast Cancer Symposium (SABCS), European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) online archives. The outcomes of interest are overall survival, disease-free survival, acceptability, cardiotoxicities and grade 3 to 4 non-haematological toxicities. Two independent reviewers will screen and extract eligible data based on the inclusion and exclusion criteria, and then assess the risk of bias and evidence quality of individual studies using Cochrane Collaboration's tool and Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The heterogeneity, transitivity and inconsistency of NMA will be evaluated. In addition, we will perform subgroup and sensitivity analyses to assess the robustness and reliability of findings in our NMA. ETHICS AND DISSEMINATION Ethics approval is not required for our NMA. Findings from our NMA will be submitted as peer-reviewed journal manuscripts and international conference reports. TRIAL REGISTRATION NUMBER CRD42019139109.
Collapse
Affiliation(s)
- Qiancheng Hu
- Department of Abdominal Oncology, Cancer Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Xin Wang
- Department of Abdominal Oncology, Cancer Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Ye Chen
- Department of Abdominal Oncology, Cancer Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Xiaofen Li
- Department of Abdominal Oncology, Cancer Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Ting Luo
- Breast Medical Oncology, Clinical Research Center for Breast, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Dan Cao
- Department of Abdominal Oncology, Cancer Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
| |
Collapse
|