Mutations of the catalytic domain of PI3 kinase and correlation with clinical outcome in trastuzumab-treated metastatic breast cancer (MBC).

Abstract

582 Background: Resistance to HER2 antagonism in HER2-positive breast cancer has been associated with activation of the PI3K signaling pathway. PIK3CA mutations in exon 9 and exon 20 have been shown to activate the AKT-mTOR pathway downstream of EGFR-family receptor tyrosine kinases, where most targeted drugs for breast cancer exert their effect. Methods: We measured PIK3CA mutation status in exons 9 (E545K and E542K) and 20 (H1047R) using two different methods [pyrosequencing (Monogram) and an allele-specific, real-time PCR assay (D×S)] and correlated the results with clinical outcomes in a cohort of patients (pts) with trastuzumab-treated MBC. Results: 22/85 pts (26%) with available FFPE tissue had mutations in exon 9 or exon 20. Results obtained by the two methods were 100% concordant. No statistically significant association was seen between the presence of PIK3CA mutations and the levels of HER2, HER3, or p95HER2, as measured by VeraTag™ (HERmark), although there was a trend favoring lower p95 levels in mutants (p=0.07). Including all pts, no differences were observed in either PFS (HR 1.23 for mutant vs. WT, p=0.47) or OS (HR 1.56, p=0.19). In HER2 FISH-positive pts (N=65), no differences were observed in either PFS (HR 1.72, p=0.15) or OS (HR 2.08, p=0.09). PIK3CA mutants fared better in the FISH-negative population (N=20) for PFS (HR 0.34, p=0.03) but not for OS (HR 0.74, p=0.6). Among pts that overexpressed HER2 protein (>13.8 by HERmark, N=59), those with exon 9 mutations, but not those with exon 20 mutations, experienced shorter PFS (HR 8.04, p=0.004 and HR 1.06, p=0.89, respectively) and OS (HR 4.85, p=0.03 and HR 1.48, p=0.45, respectively) when compared to PI3K WT pts. Conclusions: Exon 9 mutations appeared to exert a deleterious effect on outcomes, but exon 20 mutations did not. Pts with PIK3CA mutations, but without HER2 gene amplification, experienced better outcomes on trastuzumab treatment than PIK3CA WT pts, while no association was observed in HER2 amplified pts. These data are hypothesis-generating and require confirmation in larger controlled datasets of trastuzumab-treated MBC pts. Grant support from Komen for the Cure.