Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer.

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.
Competing Interests: Disclosures CLT reports participation in advisory boards from Amgen, GSK, Astra Zeneca, Nanobiotix, MSD, BMS, Merck Serono, Roche. MPS reports courses for laboratory Servier. JCS reports that he has been a full-time employee of AstraZeneca since September 2017. Over the past 5 years he has received consultancy fees from AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda. Also he is a shareholder of AstraZeneca and Gritstone. MC reports honoraria from Novartis. FD reports honoraria from Novartis. TB reports grants from Novartis, Astrazeneca, Pfizer; personal fees from Roche, Novartis, Astrazeneca, Pfizer, SeattleGenetics; and non-financial support from Roche, Novartis, Astrazeneca, Pfizer. FA reports research grants from Novartis, speaker, and advisory boards compensated to the hospital. Outside the submitted work grants from Pfizer, Lilly, Sanofi, Roche, Astrazeneca, Daiichi. All remaining authors have declared no conflicts of interest.
(Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)