Association between PIK3CA mutation status and development of brain metastases in HR+/HER2- metastatic breast cancer

Abstract Background CNS metastases is a devastating complication of breast cancer, occurring in approximately 10%–15% of patients with metastatic breast cancer (MBC) and resulting in median survival of less than one year in historic cohorts. Biological factors that govern metastases to the brain, including the role of activating PIK3CA mutations, the most common actionable alterations in HR+/HER2- MBC, are poorly understood. Methods In this retrospective cohort study, we determined the cumulative incidence of brain metastasis in PIK3CA mutant and PIK3CA non-mutant HR+/HER2- MBC patients treated at the Massachusetts General Hospital and genotyped during their routine clinical care with a highly sensitive multiplexed assay for real time mutation profiling of clinical samples. Results In the overall cohort of 307 patients, 120 patients (39.1%) had PIK3CA mutant disease and 187 patients (60.9%) had PIK3CA non-mutant disease, comparable to previously published results. Median OS from the time of diagnosis of metastatic disease was 3.96 yrs (95% CI 3.40-4.87 yrs) for PIK3CA mutant patients and 4.43 yrs (95% CI 3.82-5.32 yrs) for PIK3CA non-mutant patients, p = 0.6. 22.44% of patients with HR+/HER2- disease developed brain metastases; 30.83% of PIK3CA mutant patients and 17.11% of PIK3CA non-mutant patients developed CNS metastases, p = 0.0049. Median time to the development of CNS disease was 8.61 yrs for PIK3CA mutant subset and not reached (NR) for PIK3CA non-mutant subset, p = 0.0086. Among patients with CNS metastases, median OS for PIK3CA mutant patients was 0.48 yrs (95% CI 0.27-0.74) and for PIK3CA non-mutant it was 1.09 yrs (95% CI 0.39-2.27), p = 0.019). Conclusions Brain metastases are common in HR+/HER2- MBC. This incidence of brain metastases is particularly high among patients with HR+/HER2- tumors harboring a PIK3CA mutation, where it approaches the incidence historically seen in HER2+ MBC. Early recognition of symptoms potentially related to brain metastases is important even in HR+/HER2- subtype of breast cancer. High incidence of brain metastases in PIK3CA mutant HR+/HER2- MBC warrants development of blood-brain barrier penetrant agents targeting the PI3K/AKT/mTOR pathway. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure S. Isakoff: Advisory / Consultancy, Research grant / Funding (institution): Myriad; Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Research grant / Funding (institution): Immunomedics; Advisory / Consultancy, Research grant / Funding (institution): Mylan; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Pharmamar; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy, Research grant / Funding (institution): OncoPep; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. A. Bardia: Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Immunomedics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Radius Health; Advisory / Consultancy, Research grant / Funding (institution): Specturm; Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Innocrin; Research grant / Funding (self): Biothernostics. P.K. Brastianos: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Bristol-Myer Squibb; Advisory / Consultancy: Genentech-Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Lily; Advisory / Consultancy: TESARO; Advisory / Consultancy: AngioChem. D. Juric: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Syros; Advisory / Consultancy: Ipsen; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Placon Therapeutics. All other authors have declared no conflicts of interest.