Outcome and mutational landscape of patients with PIK3CA-mutated metastatic breast cancer (mBC)
Authors: M.F. Mosele, A. Lusque, A. Tran Dien, N. Droin, C. Le Tourneau, L. Lacroix, I. Bieche, C. Massard, F. Bertucci, F. André
Journal: Annals of Oncology (2019)

Background: In a recent study, α-selective PI3K inhibitor improved outcome in PIK3CA mutated HR+/Her2- mBC. Thus, to optimally position PI3K inhibitors, we have investigated the natural history of PIK3CA mutated BC. Methods: 649 patients with mBC from SAFIR02 trial (NCT02299999), with available mutational profile and clinical data were selected for outcome analysis. PIK3CA mutations were prospectively determined by NGS on metastatic sample. In addition, we looked at mutations enriched in PIK3CA mutant mBC (n = 629, whole exome sequencing). Results: 22% of patients (n = 143) harbor PIK3CA mutation in tumor sample. 29% (n = 104) of HR+/Her2- and 10% (n = 27) of TNBC tumors presented PIK3CA mutation (p < 0.001). HR+/Her2- PIK3CA mutated patients were less sensitive to chemotherapy (Odds ratio multivariate: 0.40; 95% CI [0.22-0.71]; p = 0.002). The median overall survival (OS) for patients with PIK3CA mutated HR+/Her2- mBC was 19.6 months vs. 23.5 for PIK3CA wt (p = 0.048) (HR multivariate: 1.44; 95% CI [1.02-2.03]; p = 0.039). PIK3CA mutated HR+/Her2- mBC were enriched in MAP3K1 mutation (17% vs. 5%, p = 0.0002), whereas PIK3CA wt tumors were enriched in GATA3 (25% vs. 14%, p = 0.022) or AKT1 mutations (11% vs. 3%, p = 0.008). In patients with HR+/Her2-/PIK3CA mutant mBC, the 24 months OS for MAP3K1 mutated patients was 14.7% vs. 45.5% for wt (p = 0.0059) (HR multivariate: 1.84; 95% CI [1.07-3.15]; p = 0.02). In TNBC, the median OS in patients with PIK3CA mutated tumors was 24.2 months vs. 14 for PIK3CA wt (p = 0.028). We further looked at the distribution of PIK3CA mutation in mTNBC, according to HR expression on 1ry tumor. 6% of patients with TNBC both on primary and metastasis presented a PIK3CA mutation (9/138), whereas 39% of patients with TNBC on metastasis and HR+ on 1ry tumor had PIK3CA mutation (14/36). Conclusions: Patients with PIK3CA mutated HR+/Her2- mBC are less sensitive to chemotherapy and present a poor outcome. In this population, MAP3K1 mutations are more frequent and are associated with shorter survival. Patients with PIK3CA mutated TNBC have better survival. This could be explained by an enrichment of PIK3CA mutations in luminal BC who lost HR in the metastatic setting.Table150O Efficacy resultsKaplan-Meier estimatorsP+T [%/median (95% CI)]P+T with chemo [%/median (95% CI)]2-year OS (%)*Binomial with 90% CI reported;76.2 (68.4-82.9)*Binomial with 90% CI reported;76.2 (68.4-82.9)*Binomial with 90% CI reported;ER+ and/or PgR +75.0 (64.9-83.4) *Binomial with 90% CI reported;74.2 (63.9-82.9) *Binomial with 90% CI reported;ER - and PgR -81.1 (67.4-90.8) *Binomial with 90% CI reported;79.5 (66.0-89.4) *Binomial with 90% CI reported;1st line PFS (median - mo)#8.4 (7.7-12.0)23.3 (17.6-32.6)ER+ and/or PgR +8.3 (6.3-13.5)23.7 (18.2-33.8)ER - and PgR -8.8 (7.9-14.6)22.2 (11.4-32.6)1st CNS metastasis was ignored for this endpoint.* Binomial with 90% CI reported; Open table in a new tab 1st CNS metastasis was ignored for this endpoint. Editorial acknowledgement: Bojana Stefanovska. Clinical trial identification: NCT02299999. Legal entity responsible for the study: Unicancer/Gustave Roussy. Funding: ARC, Breast Cancer res Foundation and French NCI. Disclosure: C. Massard: Consultant/advisory fees: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion. F. André: Research grants and compensation to institution: Novartis, AZ, Daiichi, Roche, Lilly, Pfizer. All other authors have declared no conflicts of interest.