F Mosele1, B Stefanovska2, A Lusque3, A Tran Dien4, I Garberis5, N Droin6, C Le Tourneau7, M-P Sablin8, L Lacroix9, D Enrico1, I Miran10, C Jovelet10, I Bièche11, J-C Soria12, F Bertucci13, H Bonnefoi14, M Campone15, F Dalenc3, T Bachelot16, A Jacquet17, M Jimenez17, F André18. 1. Department of Medical Oncology, Gustave Roussy, Villejuif, France. 2. INSERM, Gustave Roussy Cancer Campus, UMR981, Villejuif, France. 3. Institut Claudius Regaud, IUCT-O, Toulouse, France. 4. Bioinformatics Platform, Gustave Roussy, Villejuif, France. 5. INSERM, Gustave Roussy Cancer Campus, UMR981, Villejuif, France; Paris-Saclay University, Paris, France. 6. Genomic Core Facility UMS AMMICA Gustave Roussy, Villejuif, France. 7. Department of Drug Development and Innovation, Institut Curie, Paris, France; INSERM U900, Saint-Cloud, France; Paris-Saclay University, Paris, France. 8. Department of Medical Oncology, Institut Curie, Paris, France. 9. Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France; Genomic Platform and Biobank, CNRS UMS3655-INSERM US23, AMMICA, Gustave Roussy, F-94805, Villejuif, France. 10. Genomic Platform and Biobank, CNRS UMS3655-INSERM US23, AMMICA, Gustave Roussy, F-94805, Villejuif, France. 11. Department of Genetics, Institut Curie, Paris, France; INSERM U1016, Paris Descartes University, Paris, France. 12. University of Paris-Sud, Orsay, France. 13. CRCM, Predictive Oncology team, Aix-Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, Marseille, France. 14. Department of Medical Oncology, Institut Bergonie, Bordeaux, France. 15. Department of Medical Oncology, Institut of Cancerology Ouest, Nantes, France. 16. Department of Medical Oncology, Center Leon Berard, Lyon, France. 17. Precision Medicine Group, UNICANCER, Paris, France. 18. Department of Medical Oncology, Gustave Roussy, Villejuif, France; INSERM, Gustave Roussy Cancer Campus, UMR981, Villejuif, France; University of Paris-Sud, Orsay, France. Electronic address: FABRICE.ANDRE@gustaveroussy.fr.
Abstract
BACKGROUND: α-Selective phosphatidylinositol 3-kinase (PI3K) inhibitors improve outcome in patients with PIK3CA-mutated, hormone receptor-positive (HR+)/Her2- metastatic breast cancer (mBC). Nevertheless, it is still unclear how to integrate this new drug family in the treatment landscape. PATIENTS AND METHODS: A total of 649 patients with mBC from the SAFIR02 trial (NCT02299999), with available mutational profiles were selected for outcome analysis. PIK3CA mutations were prospectively determined by next-generation sequencing on metastatic samples. The mutational landscape of PIK3CA-mutated mBC was assessed by whole-exome sequencing (n = 617). Finally, the prognostic value of PIK3CA mutations during chemotherapy was assessed in plasma samples (n = 44) by next-generation sequencing and digital PCR. RESULTS: Some 28% (104/364) of HR+/Her2- tumors and 10% (27/255) of triple-negative breast cancer (TNBC) presented a PIK3CA mutation (P < 0.001). PIK3CA-mutated HR+/Her2- mBC was less sensitive to chemotherapy [adjusted odds ratio: 0.40; 95% confidence interval (0.22-0.71); P = 0.002], and presented a worse overall survival (OS) compared with PIK3CA wild-type [adjusted hazard ratio: 1.44; 95% confidence interval (1.02-2.03); P = 0.04]. PIK3CA-mutated HR+/Her2- mBC was enriched in MAP3K1 mutations (15% versus 5%, P = 0.0005). In metastatic TNBC (mTNBC), the median OS in patients with PIK3CA mutation was 24 versus 14 months for PIK3CA wild-type (P = 0.03). We further looked at the distribution of PIK3CA mutation in mTNBC according to HR expression on the primary tumor. Some 6% (9/138) of patients without HR expression on the primary and 36% (14/39) of patients with HR+ on the primary presented PIK3CA mutation (P < 0.001). The level of residual PIK3CA mutations in plasma after one to three cycles of chemotherapy was associated with a poor OS [continuous variable, hazard ratio: 1.03, 95% confidence interval (1.01-1.05), P = 0.007]. CONCLUSION: PIK3CA-mutated HR+/Her2- mBC patients present a poor outcome and resistance to chemotherapy. Patients with PIK3CA-mutated TNBC present a better OS. This could be explained by an enrichment of PIK3CA mutations in luminal BC which lost HR expression in the metastatic setting. TRIAL REGISTRATION: SAFIR02 trial: NCT02299999.
BACKGROUND: α-Selective phosphatidylinositol 3-kinase (PI3K) inhibitors improve outcome in patients with PIK3CA-mutated, hormone receptor-positive (HR+)/Her2- metastatic breast cancer (mBC). Nevertheless, it is still unclear how to integrate this new drug family in the treatment landscape. PATIENTS AND METHODS: A total of 649 patients with mBC from the SAFIR02 trial (NCT02299999), with available mutational profiles were selected for outcome analysis. PIK3CA mutations were prospectively determined by next-generation sequencing on metastatic samples. The mutational landscape of PIK3CA-mutated mBC was assessed by whole-exome sequencing (n = 617). Finally, the prognostic value of PIK3CA mutations during chemotherapy was assessed in plasma samples (n = 44) by next-generation sequencing and digital PCR. RESULTS: Some 28% (104/364) of HR+/Her2- tumors and 10% (27/255) of triple-negative breast cancer (TNBC) presented a PIK3CA mutation (P < 0.001). PIK3CA-mutated HR+/Her2- mBC was less sensitive to chemotherapy [adjusted odds ratio: 0.40; 95% confidence interval (0.22-0.71); P = 0.002], and presented a worse overall survival (OS) compared with PIK3CA wild-type [adjusted hazard ratio: 1.44; 95% confidence interval (1.02-2.03); P = 0.04]. PIK3CA-mutated HR+/Her2- mBC was enriched in MAP3K1 mutations (15% versus 5%, P = 0.0005). In metastatic TNBC (mTNBC), the median OS in patients with PIK3CA mutation was 24 versus 14 months for PIK3CA wild-type (P = 0.03). We further looked at the distribution of PIK3CA mutation in mTNBC according to HR expression on the primary tumor. Some 6% (9/138) of patients without HR expression on the primary and 36% (14/39) of patients with HR+ on the primary presented PIK3CA mutation (P < 0.001). The level of residual PIK3CA mutations in plasma after one to three cycles of chemotherapy was associated with a poor OS [continuous variable, hazard ratio: 1.03, 95% confidence interval (1.01-1.05), P = 0.007]. CONCLUSION:PIK3CA-mutated HR+/Her2- mBC patients present a poor outcome and resistance to chemotherapy. Patients with PIK3CA-mutated TNBC present a better OS. This could be explained by an enrichment of PIK3CA mutations in luminal BC which lost HR expression in the metastatic setting. TRIAL REGISTRATION: SAFIR02 trial: NCT02299999.
Authors: Jeffrey Chun Hin Chan; James Chung Hang Chow; Connie Hoi Man Ho; Therese Yue Man Tsui; William C Cho Journal: J Cancer Res Clin Oncol Date: 2021-03-24 Impact factor: 4.553
Authors: Rulla M Tamimi; A Heather Eliassen; Tengteng Wang; Yujing J Heng; Gabrielle M Baker; Vanessa C Bret-Mounet; Liza M Quintana; Lisa Frueh; Susan E Hankinson; Michelle D Holmes; Wendy Y Chen; Walter C Willett; Bernard Rosner Journal: Cancer Epidemiol Biomarkers Prev Date: 2022-10-04 Impact factor: 4.090
Authors: Javier Cortés; Violeta Serra; Albert Gris-Oliver; Yasir H Ibrahim; Martín A Rivas; Celina García-García; Mònica Sánchez-Guixé; Fiorella Ruiz-Pace; Cristina Viaplana; José M Pérez-García; Antonio Llombart-Cussac; Judit Grueso; Mireia Parés; Marta Guzmán; Olga Rodríguez; Pilar Anton; Patricia Cozar; Maria Teresa Calvo; Alejandra Bruna; Joaquín Arribas; Carlos Caldas; Rodrigo Dienstmann; Paolo Nuciforo; Mafalda Oliveira Journal: Br J Cancer Date: 2021-03-15 Impact factor: 7.640