Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study
-
Published:2021-03-15
Issue:1
Volume:13
Page:
-
ISSN:1756-994X
-
Container-title:Genome Medicine
-
language:en
-
Short-container-title:Genome Med
Author:
Callens Céline, Driouch Keltouma, Boulai Anaïs, Tariq Zakia, Comte Aurélie, Berger Frédérique, Belin Lisa, Bièche Ivan, Servois Vincent, Legoix Patricia, Bernard Virginie, Baulande Sylvain, Chemlali Walid, Bidard François-Clément, Fourchotte Virginie, Salomon Anne Vincent-, Brain Etienne, Lidereau Rosette, Bachelot Thomas, Saghatchian Mahasti, Campone Mario, Giacchetti Sylvie, Zafrani Brigitte Sigal, Cottu PaulORCID
Abstract
Abstract
Background
Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use.
Methods
We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months).
Results
Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology.
Conclusions
Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse.
Trial registration
The trial was registered at ClinicalTrials.gov (NCT01956552).
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
Reference52 articles.
1. Burstein HJ, Curigliano G, Loibl S, Dubsky P, Gnant M, Poortmans P, et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol. 30:1541–57. 2. Cardoso F, Paluch-Shimon S, Senkus E, Curigliano G, Aapro MS, André F, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5)†. Ann Oncol. 2020;31(12):1623–49. 3. Rugo HS, Rumble RB, Macrae E, Barton DL, Connolly HK, Dickler MN, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol. 2016;34:3069–103. 4. Van Poznak C, Somerfield MR, Bast RC, Cristofanilli M, Goetz MP, Gonzalez-Angulo AM, et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2015;33:2695–704. 5. Schrijver WAME, Suijkerbuijk KPM, van Gils CH, van der Wall E, Moelans CB, van Diest PJ. Receptor conversion in distant breast cancer metastases: a systematic review and meta-analysis. JNCI J Natl Cancer Inst. 2018;110:568–80.
Cited by
12 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|