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

Genome Medicine

Thomas Bachelot¹  Frédérique Berger²  Lisa Belin²  François-Clément Bidard³  Paul Cottu³  Aurélie Comte³  Walid Chemlali⁴  Rosette Lidereau⁴  Anaïs Boulai⁴  Céline Callens⁴  Keltouma Driouch⁴  Zakia Tariq⁴  Ivan Bièche⁴  Mahasti Saghatchian⁵  Sylvie Giacchetti⁶  Vincent Servois⁷  Patricia Legoix⁸  Sylvain Baulande⁸  Virginie Bernard⁸  Mario Campone⁹  Etienne Brain^1,10  Anne Vincent- Salomon^1,11  Brigitte Sigal Zafrani^1,11  Virginie Fourchotte^1,12 

[1] Centre Léon Bérard;Department of Biostatistics, Institut Curie;Department of Medical Oncology, Institut Curie, PSL Research University;Genetics Department, Institut Curie, PSL Research University;Gustave Roussy Cancer Campus;Hôpital Saint Louis, Breast diseases center;Imaging Department, Institut Curie, PSL Research University;Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, PSL Research University;Institut de Cancérologie de l’Ouest Nantes;Medical Oncology, Institut Curie;Pathology and Tumor Biology Department, Institut Curie, PSL Research University;Surgery Department, Institut Curie;

关键词: Breast cancer;    Metastasis;    Next generation sequencing;    Targetable genes;    Prognosis;    de novo metastases;   

DOI  :  10.1186/s13073-021-00862-6

来源: DOAJ

【 摘 要 】

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 ).

【 授权许可】

Unknown