Abstract
Cancer progression is driven in part by genomic alterations1. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations2, leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies3,4. 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 treatment5 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 (gBRCA1: HR = 0.36, 90% CI: 0.14–0.89; gBRCA2: 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.
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Acknowledgements
We thank the patients and their families, as well as the investigators (especially V. Massard, T. l’Haridon, L. Venat-Bouvet, F. Del Piano, X. Tchiknavorian, N. Dohollou and C. Alliot) and their staff involved in SAFIR02-BREAST and SAFIR-PI3K. We also thank the UNICANCER team involved in both trials and C. Honfo Ga for data management. We also thank members of the IDMC (N. Turner, S. Loibl, S. Novello, E. Felip, S, Litiere and D. Beltram). The study was funded by Fondation ARC, AstraZeneca, the IHU-B programme (PRISM) and the Breast Cancer Research Foundation. AstraZeneca also supported targeted therapy (capivasertib, AZD2014, AZD8931, AZD4547, olaparib, selumetinib, bicalutamide and vandetanib) supply and distribution to the study sites. Novartis supported the supply of targeted therapy (alpelisib).
Author information
Authors and Affiliations
Contributions
F.A., T.B., T.F. and M.J. designed the study. F.A. and T.B. were the coordinators of the SAFIR02-BREAST trial. F.A. and A.G. were the coordinators of the SAFIR-PI3K trial. M.J. and A.J. operated the trial. T.B., M.A., F.D., M.-P.S., M.C., H.B., C.L.-P., W.J., F.C., J.-M.F., C.L.-P., M.-A.M.R., J.-C.T., N.I., A. Mege, P.B., B.Y., N.H. and A.G. included patients in the trial. I.B., L.L., E.R., S.B., V.A., I.S., M.K., C.L., N.S., P.G., L.L.C. and A. Morel performed genomic analyses. A.T.-D. collected genomic data and stored them on EGA. F.A., T.B., F. Mosele, T.F., A.L., I.B., M.J., F. Montemurro and A.J. wrote the manuscript. All authors have read and agreed on the content of the manuscript.
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Competing interests
F.A. received research funding and served as a speaker/advisor (compensated by the hospital) for Pfizer, Roche, Lilly, Daiichi Sankyo, AstraZeneca and Novartis. T.B. received research funding and served as a speaker/advisor (compensated by the hospital) for Roche, Novartis, Pfizer, Seattle Genetics, Lilly and AstraZeneca. M.A. received research funding and served as a speaker/advisor (compensated by the hospital) for Novartis, AstraZeneca, Seattle Genetics, Abvie and Pfizer. M.C. received research funding and served as a speaker/advisor (compensated by the hospital) for AstraZeneca, Novartis, Abbvie, Sanofi, Lilly, Pfizer, Sandoz, ACCORD, G1 Therapeutic, Pierre Fabre Oncology, Servier, Roche, Daiichi and Gilead. F.D. received research funding and served as a speaker/advisor (compensated by the hospital) for Roche, Novartis, Lilly, Pfizer, Eisai, MSD and AstraZeneca. C.L.-P. received research funding and served as a speaker/advisor (compensated by the hospital) for AstraZeneca, Roche and Pfizer. A.G. received research funding and served as a speaker/advisor (compensated by the hospital) for AstraZeneca, Pfizer, Novartis, Roche and MSD. M.-A.M.R. received research funding and served as a speaker/advisor for Pfizer, Novartis, Lilly, Roche, MSD and Myriad. W.J. received research funding and served as a speaker/advisor for AstraZeneca, BMS, Daiichi Sankyo, Eisai, Lilly France, MSD, Novartis, Pfizer and Roche. B.Y. received research funding and served as a speaker/advisor for MSD, AstraZeneca, GSK-TESARO, BAYER, Roche-Genentech, ECS Progastrine, Novartis, LEK, Amgen, Clovis Oncology, Merck Serono, BMS, SEAGEN and Myriad. P.B. served as a speaker/advisor for Roche, BMS, IPSEN, MSD, Bayer, Amgen, Esai, Janssen Cilag, Pfizer, Novartis and Astellas and received honoraria from Seagen. N.H. received research funding from Novartis and Pfizer, and served as a consultant for AstraZeneca, Roche, Novartis and Pfizer. N.I. received research funding and served as a speaker/advisor (compensated by the hospital) for Ipsen and Transgene. J.-C.T. received research funding and served as a speaker/advisor (compensated by the hospital) for Pfizer and AstraZeneca. J.-M.F. received research funding and served as a speaker/advisor for Pfizer and Esai. T.F. consulted for Cellectis (compensated by the hospital). The following authors declared no competing interests: F. Mosele, L.L., G.E., A. Mege, F.C., M.-P.S., I.B., E.R., I.S., V.A., S.B., A. Morel, A.T.-D., A.L., H.B., M.J., A.J., L.L.C., M.K., P.G. and N.S. C.L. participated in advisory boards for MSD, BMS, Merck Serono, GSK, AstraZeneca, Nanobiotix, Roche, Rakuten, Seattle Genetics and Celgene. F. Montemurro received consultancy fees from Roche, AstraZeneca, Daiichi Sankyo, SeaGen, MSD, Eli Lilly, Pierre Fabre and Novartis, and travel grants from Roche.
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Extended data figures and tables
Extended Data Fig. 1
CONSORT diagram of the trial.
Extended Data Fig. 2 Genomic alterations identification in patients with HR+/Her2- (left panel) or TNBC (right panel).
The analysis focuses on the 50 genes that were included in the first panel and on the copy number analyses.
Extended Data Fig. 3 Subgroup analysis regarding efficacy of targeted therapy on Progression free survival, in patients presenting an ESCAT I/II alteration.
The figure reports unadjusted Hazard Ratio (diamonds) and 90% confidence intervals (error bars) estimated using a Cox proportional hazard model in each subgroup for progression or death according to clinical and biological variables. P-value for interaction between treatment arm and each variable was estimated using a Cox proportional hazard model fitted with the treatment arm, the variable and an interaction term between treatment arm and variable. All statistical tests were two sided. No adjustment was made for multiple comparisons. *: A: tyrosine kinase, B: PI3K/mTOR pathway, C: MEK pathway, D: DNA repair.
Extended Data Fig. 4 Subgroup analysis regarding efficacy of targeted therapy on progression free survival, in the intent-to-treat population.
The figure reports unadjusted Hazard Ratio (diamonds) and 95% confidence intervals (error bars) estimated using a Cox proportional hazard model in each subgroup for progression or death according to clinical and biological variables. P-value for interaction between treatment arm and each variable was estimated using a Cox proportional hazard model fitted with the treatment arm, the variable and an interaction term between treatment arm and variable. All statistical tests were two sided. No adjustment was made for multiple comparisons. *: A: tyrosine kinase, B: PI3K/mTOR pathway, C: MEK pathway, D: DNA repair.
Supplementary information
Supplementary Data 1
Statistical report for the trial and ancillary analyses.
Supplementary Data 2
Report regarding TP53, HRD and PIK3CA mutations.
Supplementary Data 3
Original protocol for SAFIR02-BREAST.
Supplementary Data 4
Final version of the SAFIR02-BREAST protocol.
Supplementary Data 5
SAFIR-PI3K protocol.
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Andre, F., Filleron, T., Kamal, M. et al. Genomics to select treatment for patients with metastatic breast cancer. Nature 610, 343–348 (2022). https://doi.org/10.1038/s41586-022-05068-3
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DOI: https://doi.org/10.1038/s41586-022-05068-3
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