Abstract P1-14-01: Phosphatidylinositol 3-Kinase (PI3K) Pathway Activation in Breast Cancer Brain Metastases

Abstract

Abstract Background: Brain metastases (BM) are a devastating consequence of advanced breast cancer (BC) for which novel, targeted therapies are urgently needed. The PI3K pathway plays a critical role in the initiation and progression of BC. Alterations in this pathway are implicated in approximately 50% of BC. The role of PI3K activation in BCBM has yet to be explored. Material and Methods: Under IRB approval (UNC and Duke), we established a clinically-annotated tumor bank including 54 BCBM and 15 matched primary BC. Activation of the PI3K pathway including pAKT, pS6K, and PTEN was assessed via immunohistochemistry (IHC, score 0-3+). BC subtype was assigned by IHC: HR+ (hormone receptor, ER+ and/or PR+)/HER2-, triple-negative (TN; ER-/PR-/HER2-), and HR +or-/HER2+. Overall survival (OS), recurrence patterns and survival following BM was evaluated by the Kaplan-Meier method and compared by the log-rank test. Results: Median age was 48 years (range 26-72). Sixty-eight percent of patients (pts) were Caucasian, 30% African-American, and 2% other ethnicities. At median follow-up of 5.9 years (yrs), 70% (38/54) of pts had died. BC subtype was confirmed among 47 pts: 30% (14/47) HR+/HER2-, 45% (21/47) TN and 25% (12/47) HR +or-/HER2+. Subtype concordance between primary BC and BM was 89% (8/9). High expression (IHC score 2-3+) of pAKT and pS6K was observed in 50% (27/54) and 72% (38/54) of the BCBM, respectively. Low expression of PTEN (IHC score 0-1) was observed in 31% (17/54) of BCBM. Concordance of PI3K biomarkers between primary BC and matched BCBM was 47% (7/15), 40% (6/15) and 80% (12/15) for pAKT, pS6K and PTEN, respectively. Both gain and loss of protein expression between primary BC and BCBM was observed in each biomarker evaluated. No significant correlation between BC subtypes and activation status of the PI3K pathway (IHC score 0-1 vs. 2-3+) was observed for pAKT, pS6K or PTEN. Median OS was 7.09 yrs (3.52, 9.21), 4.27 yrs (95% CI 1.84, 5.18), and not reached (NR) for HR+/HER2-, TN and HR +or-/HER2+, respectively (p=0.009). Median OS after BCBM diagnosis was 1.54 yrs (0.27, 2.45), 0.91 yrs (0.51, 1.49) and NR for HR+/HER2-, TN and HR +or-/HER2+, respectively (p=0.0003). Expression (0-1+ vs. 2-3+) of pAKT and pS6K in BCBM was not predictive of OS, time to BCBM recurrence or survival after BCBM (all P>0.1). Although not predictive of inferior survival following BCBM (1.2 vs. 1.5 yrs, p=0.7), low expression (0-1+ vs. 2-3+) of PTEN in BCBM predicted for inferior OS from primary BC diagnosis (5.1 vs. 6.3 yrs, p=0.03) and shorter time to BCBM (2.5 vs. 3.4 yrs, p=0.008). Conclusions: The PI3K pathway is active in most BCBM regardless of subtype. Considerable discordance exists between PI3K pathway biomarkers in the primary BC and BCBM from the same patient. Low expression of PTEN in BCBM may be prognostic. Given that small molecule inhibitors of the PI3K pathway in clinical development cross the blood brain barrier, inhibition of the PI3K pathway represents a promising therapeutic strategy for a group of patients whose prognosis is poor and for whom systemic therapies are limited. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-14-01.