Phosphatidyl-inositol-3-kinase Alpha catalytic subunit kinase domain mutations impart a favorable prognosis on estrogen receptor positive breast cancer through a mechanism that is independent of responsiveness to endocrine treatment.

Abstract

#6060 Background. Mutations in the alpha catalytic subunit of phosphoinositol-3-kinase (PIK3CA) occur in approximately 30% of ER positive breast cancers but the impact of PIK3CA mutation status on the response to endocrine therapy has not been adequately studied.
 Methods. cDNA and genomic DNA derived from baseline formalin-fixed core biopsy specimens from two neoadjuvant endocrine therapy trials (P024 and the letrozole alone arm of the RAD 2222 trial) were sequenced to detect exon 9 (helical domain - HC) and exon 20 (kinase domain - KD) mutations in PIK3CA. Interactions between mutation status and clinical, pathological and biomarker response to neoadjuvant letrozole and tamoxifen were determined.
 Results. No impact of PIK3CA KD mutation on the efficacy of letrozole or tamoxifen on either clinical, pathological or Ki67 biomarker response to neoadjuvant endocrine therapy was detected in either study. In the 2222 trial, PI3KCA mutation status (KD and HD) was associated with higher levels of pAKT (P=0.01) confirming these mutations activate the PI3 kinase pathway. Despite the lack of an interaction with short term endocrine therapy efficacy endpoints, PIK3CA KD mutation, but not HD mutation, was a favorable prognostic factor for relapse free survival in the P024 trial (RFS log rank P=0.02) and the protective effect was maintained in a Cox proportional hazards model for relapse that included post treatment (surgical), Ki67 and ER and pathological node status and tumor size (HR for no KD mutation, 14, CI:1.9-105 P=0.01). The KD mutation-associated protective effect was particularly dramatic in a tumor subset that exhibited a biomarker profile indicative of endocrine therapy resistance and poor outcome (RFS Log Rank P=0.007 within worst outcome group).
 Conclusion: In agreement with other studies, PIK3CA KD mutations but not HD mutations are associated with a favorable outcome in ER+ breast cancer but the protective effect of KD mutation is apparently independent of the degree of sensitivity to endocrine treatment. An alternative explanation for the protective effect of the presence of a KD domain mutation is that this mutation class reduces the metastatic potential of breast cancer. Pharmacological strategies that plan to specifically target tumors with PIK3CA KD mutations should take this possibility into account. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6060.