Journal Article

Genomics to select treatment for patients with metastatic breast cancer

Mege, Alice, Gestraud, Pierre, Bachelot, Thomas, Le Tourneau, Christophe, Jimenez, Marta, Lefeuvre-Plesse, Claudia, Ferrero, Jean-Marc, Rouleau, Etienne, Morel, Alain, Tran-Dien, Alicia, Sablin, Marie-Paule, Mosele, Fernanda, Thery, Jean-Christophe, Lacroix, Ludovic, Filleron, Thomas, Isambert, Nicolas, Montemurro, Filippo, Barthelemy, Philippe, Jacot, William, Hajjaji, Nawale, Bieche, Ivan, Emile, George, Cherif, Linda Larbi, Jacquet, Alexandra, Servant, Nicolas, Andre, Fabrice, Soubeyran, Isabelle, Gonçalves, Anthony, Arnedos, Monica, Coussy, Florence, Dalenc, Florence, Campone, Mario, Bonnefoi, Hervé, Boyault, Sandrine, Lusque, Amelie, Attignon, Valery, You, Benoit, Mouret-Reynier, Marie-Ange, Kamal, Maud

2022

Overview

Cancer progression is driven in part by genomic alterations 1 . The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations 2 , leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies 3 , 4 . Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment 5 with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) 6 (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27–0.61, P  < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56–1.06, P  = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76–1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations ( n  = 49) derived high benefit from olaparib (g BRCA1 : HR = 0.36, 90% CI: 0.14–0.89; g BRCA2 : HR = 0.37, 90% CI: 0.17–0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer. Targeted therapies matched to genomics improved progression-free survival when genomic alterations were classified as level I/II (according to ESCAT), and genomics should thus be driven by target actionability in patients with metastatic breast cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45 / 45/23 / 631/67/1347 / 692/53/2423 / BRCA1 protein / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer therapies / Chemotherapy / Clinical Decision-Making - methods / Clinical trials / Disease Progression / DNA Mutational Analysis / DNA sequencing / ErbB-2 protein / Female / Genes, BRCA1 / Genes, BRCA2 / Genome, Human - genetics / Genomics / Heterogeneity / Humanities and Social Sciences / Humans / Life Sciences / Metastases / Metastasis / multidisciplinary / Mutation / Neoplasm Metastasis - drug therapy / Neoplasm Metastasis - genetics / Neoplasm Metastasis - pathology / Patients / Phthalazines - therapeutic use / Piperazines - therapeutic use / Science / Science (multidisciplinary) / Survival