Somatic and Germline BRCA 1 and 2 Mutations in Advanced NSCLC From the SAFIR02-Lung Trial

Jordi Remon; Benjamin Besse; Alexandra Leary; Ivan Bièche; Bastien Job; Ludovic Lacroix; Aurélie Auguste; Marjorie Mauduit; Clarisse Audigier-Valette; Judith Raimbourg; Anne Madroszyk; Stefan Michels; Mohammed Amine Bayar; Marta Jimenez; Jean-Charles Soria; Etienne Rouleau; Fabrice Barlesi

doi:10.1016/j.jtocrr.2020.100068

Somatic and Germline BRCA 1 and 2 Mutations in Advanced NSCLC From the SAFIR02-Lung Trial

JTO Clin Res Rep. 2020 Jun 11;1(3):100068. doi: 10.1016/j.jtocrr.2020.100068. eCollection 2020 Sep.

Authors

Jordi Remon¹, Benjamin Besse^{1

2}, Alexandra Leary^{1

3}, Ivan Bièche⁴, Bastien Job⁵, Ludovic Lacroix⁵, Aurélie Auguste^{3

5}, Marjorie Mauduit⁶, Clarisse Audigier-Valette⁷, Judith Raimbourg⁸, Anne Madroszyk⁹, Stefan Michels¹⁰, Mohammed Amine Bayar¹⁰, Marta Jimenez⁶, Jean-Charles Soria^{1

2}, Etienne Rouleau^{3

4}, Fabrice Barlesi^{1

11}

Affiliations

¹ Cancer Medicine Department, Gustave Roussy, Villejuif, France.
² University Paris-Saclay, Orsay, France.
³ Service de Génétique des Tumeurs, Département de Biologie et Pathologie Médicale, INSERM U981, Gustave Roussy, Villejuif, France.
⁴ Service de Génétique, Institut Curie, Paris, France.
⁵ Laboratoire de Recherche Translationnelle, AMMICA, INSERM US23/CNRS UNS3655, Gustave Roussy, Villejuif, France.
⁶ Unicancer, Paris, France.
⁷ Pneumology Department, CHI Toulon, France.
⁸ Oncology Department, Institut de Cancérologie de l'Ouest, Nantes, France.
⁹ Pneumology Department, Institut Paoli Calmettes, Marseille, France.
¹⁰ Service de Biostatistics and Epidemiology, Gustave Roussy and CESP, INSERM, University Paris-Saclay, Villejuif, France.
¹¹ Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France.

Abstract

Introduction: Molecular profiling is considered a standard of care in advanced NSCLC. A comprehensive next-generation sequencing panel can discover somatic or germline BRCA1/2 mutations that are new druggable molecular alterations. However, the phenotypic and potential therapeutic relevance of BRCA1/2 mutation in NSCLC remains poorly defined.

Methods: From April 2014 to March 2017, 600 newly diagnosed, EGFR/ALK negative patients with advanced NSCLC were enrolled in the SAFIR02-Lung trial. Molecular profiling was done at study entry on archival tissue or frozen tissue collected from a new biopsy specimen before the third cycle of platinum-based chemotherapy. The prevalence of BRCA1/2 variants and its biological relevance were assessed. A homologous recombinant deficiency (HRD) score was based on the copy number variation data, and the germline status was determined by blood analysis. The BRCA Share database and the French CGG consortium were the references for the variant classification.

Results: Of 379 patients with a molecular profile discussed in a tumor molecular board, BRCA1/2 variants were identified in 20 patients (5.3%), including eight patients (2.1%) with a confirmed pathogenic BRCA mutation. Two patients (0.5%) harbored a germline BRCA2 mutation, and for six others, a somatic BRCA mutation was identified (1.6%). All were men and mainly smokers (88%). The overall response rate to chemotherapy was 13%. BRCA variants of unknown significance were detected in 12 patients (3.2%), achieving an 8.3% overall response rate with chemotherapy. One-third of tumors carrying pathogenic BRCA mutations or variants of unknown significance had biallelic inactivation and high HRD score. Overall survival of this cohort was 12.8 months.

Conclusions: Pathogenic BRCA1/2 mutations occur in 2.1% of patients with advanced NSCLC. The predictive role of BRCA mutation for making treatment decisions in NSCLC seems limited based on clinical response (low platinum sensitivity) and molecular features (discrepancy between biallelic inactivation and high HRD score).

Keywords: Advanced non–small cell lung cancer; BRCA mutation; Next-generation sequencing; PARP inhibitors; SAFIR trial.