Abstract P1-13-03: Association of PIK3CA mutation with clinical response to specific endocrine therapies in metastatic hormone receptor positive (HR+) breast cancer
Authors: Micalizzi Douglas S , Juric Dejan , Niemierko Andrzej , Reynolds Kerry L , Borger Darrell , Vora Sadhna R , Isakoff Steven J , Moy Beverly , Ellisen Leif W , Bardia Aditya 
Published: May 2015

Background: Phosphatidylinositol 3-kinase (PI3K) gene (PIK3CA) mutations are the most common somatic mutations in breast cancer. Preclinical models suggest that activating mutations in PIK3CA may mediate resistance to endocrine therapy in breast cancer, and multiple clinical trials testing combinations of endocrine therapy with PI3K inhibitors are ongoing. However, the role of PIK3CA in modulating the clinical response to endocrine therapies is less clear, with some studies suggesting that PIK3CA mutations are associated with improved prognosis in HR+ breast cancer. The primary objective of this study was to evaluate the association of PIK3CA mutation with clinical response to endocrine therapies in metastatic HR+ breast cancer.

Methods: We identified patients with metastatic HR+ /HER2 negative breast cancer, including ER+/PR+ (estrogen receptor/progesterone receptor) and ER+/PR-, to determine the time to progression (TTP) on first-line endocrine therapy for metastatic disease. PIK3CA mutations, including 8 common hotspot mutations, were assessed by a robust, high-throughput tumor genotyping assay (Snapshot), developed at our institution, using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. Actuarial analysis of TTP was performed using Cox proportional hazard method to compute Hazard Ratio (HR) and 95% Confidence Intervals (CI).

Results: Between 2009 and 2012, we identified 188 patients with HR+ metastatic breast cancer who had tumor genotyping performed. PIK3CA mutations were identified in 32.2% of tumors, including mutations in both helical (exon 9) and kinase (exon 20) domains (60% and 40%, respectively). The PIK3CA mutant and wild type patients had a similar median age at diagnosis of metastatic disease (55.8 and 56.7 years; p=0.2), ER+/PR+ tumors (75.0% vs 76.4%; p=0.8), and median TTP (8.2 versus 11.4 months; p=0.6). After adjusting for age at diagnosis and ER+/PR+ versus ER+/PR-, the TTP on first-line endocrine therapy did not vary among patients with PIK3CA mutations versus wild type (HR: 0.94; 95% CI:0.62-1.43; p=0.8), but did vary by type of endocrine therapy. Patients with PIK3CA mutations, as compared to wild type patients, had shorter TTP with fulvestrant (HR: 3.6; 95% CI:1.2-11.0; p=0.03), but not with aromatase inhibitors (AIs) (HR: 0.70; 95% CI:0.44-1.1; p=0.1), suggesting that mutant PIK3CA may specifically modulate the response to fulvestrant therapy. We did not observe any difference in TTP for exon 9 versus 20 PIK3CA mutations, though numbers were small resulting in limited statistical power.

Conclusion: Among patients with metastatic HR+ breast cancer in this study, PIK3CA mutations are associated with decreased time to progression with fulvestrant, but not with AIs, suggesting that the these mutations may mediate resistance to specific endocrine therapies. Further studies are needed to confirm these findings and provide mechanistic insights to help guide optimal selection of endocrine therapy and combination with PI3K directed therapy in metastatic HR+ breast cancer.

Citation Format: Douglas S Micalizzi, Dejan Juric, Andrzej Niemierko, Kerry L Reynolds, Darrell Borger, Sadhna R Vora, Steven J Isakoff, Beverly Moy, Leif W Ellisen, Aditya Bardia. Association of PIK3CA mutation with clinical response to specific endocrine therapies in metastatic hormone receptor positive (HR+) breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-03.