Abstract P2-08-01: PIK3CA mutations associate with decreased Ki67 in early stage breast cancer (BC) and better outcomes in patients even among those with low Ki67 tumors.

Abstract

Abstract Background: In studies of over 450 BC patients (pts) with > 10 years follow-up, pts with PIK3CA-mutated primary tumors had improved clinical outcome (Kalinsky et al 2009, Cizkova et al 2012). PIK3CA mutations associated with favorable clinicopathologic features: lower grade, smaller size, lymph node negativity (−), ER positivity (+), HER2−. In BC, several studies have suggested that PIK3CA mutations do not associate with PI3K/mTOR pathway activation (Loi et al 2010, Stemke-Hale et al 2008). To gain additional insight into the favorable biology imparted by a PIK3CA mutation in early stage BC and to identify predictive biomarkers, we performed immunohistochemistry (IHC) on tissue microarrays (TMA) constructed from 590 primary BCs. Methods: TMAs derived from FFPE tumors previously genotyped for PIK3CA mutations (rate of 32.5%, 192/590) were stained for ER, HER2 and AR (Kalinsky et al 2009). Here, we performed additional stains for MIB1 (Ki67 proliferation index, Ki67), p53 and markers of PI3K pathway activation (pS6, PTEN). Slides were scanned with Aperio ScanScope XT and segmented using TMALab (Aperio). Images were analyzed with the Aperio algorithm based on staining pattern (nuclear, cytoplasmic, membrane) and scored for % + and intensity. Manual review was performed for tumors with less than 3 cores or discordant results. PTEN was scored manually: 0 (no tumor staining, PTEN loss), 1 (tumor < stroma), or 2 (tumor ≥ stroma). P values were based on the log-rank test for comparison of Kaplan-Meier curves for disease free survival (DFS), Chi-square test for categorical variables and t-test for continuous variables. Results: On average, 66 cases (11%) were non-informative for each IHC stain, due to missing cores or insufficient tumor cells. In a binary analysis of Ki67 using a cutoff of ≥10% + cells, PIK3CA mutated tumors demonstrated significantly lower proliferation index with only 9.4% of tumors (16/170) having high Ki67 as compared to 23.6% of wild-type PIK3CA tumors (82/347) (P = .001). Ki67 was also highly associated with PIK3CA genotype when analyzed with a cutoff of ≥13.25% + cells or as a continuous variable. Importantly, DFS was significantly different when analyzed by PIK3CA genotype and Ki67 (P = .01). Among pts with low Ki67 tumors (n = 419), PIK3CA mutation associated with longer DFS (10yr 79%, CI 69–85) as compared to wild-type PIK3CA (10yr 71%, CI 64–77). When PI3K pathway interactions were analyzed, PTEN loss associated with wild-type PIK3CA (P<.001), although PTEN loss occurred with mutated PIK3CA in 11 hormone receptor (HR)+ tumors. In analysis of pS6 with a binary cutoff of ≥20% + cells, high pS6 associated with HER2+ (P<.001), HR- (P<.001) and high tumor grade (P = 0.003), but did not associate with PIK3CA genotype (P = .13). PIK3CA mutation was associated with lower pS6 when pS6 % + cells was analyzed as a continuous variable (P = .01). Conclusions: PIK3CA mutation associates with lower Ki67 in early stage BC. Even among pts with low Ki67 tumors, PIK3CA mutation associates with improved clinical oucome. pS6 is not increased in PIK3CA-mutated tumors which likely indicates that mTORC1 signaling is not activated as a result of PIK3CA mutation in early stage ER+ BC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-08-01.