42. PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality

Abstract

Breast cancer is a common malignancy with current therapies tailored to steroid hormone (ER, PR) and HER2 receptor status. Understanding the biological basis of resistance to current targeted therapies and the identification of new potential therapeutic targets is an ongoing challenge. The PI3K pathway is altered in a high proportion of breast cancers and may contribute to endocrine resistance. We undertook the first integrative study of mutational and expression analysis of key regulators of the PI3K pathway in a cohort of invasive breast cancer patients with known treatment outcomes. The alterations identified in our cohort of breast cancer patients included <i>PIK3CA</i> mutations 7%, i.e., 12 of 168 cancers, <i>PIK3CA</i> amplification 14%, i.e., 28 of 209 cancers, PTEN loss 28%, i.e., 73 of 258 tumours and pAKT activation 24%, i.e., 62 of 258 tumours. Overall 72%, i.e., 139 of 193 primary breast cancers, where at least one parameter was altered, had an activated PI3K pathway. PI3K pathway activation was significantly associated with negative ER (<i>p</i>=0.0008) and PR (<i>p</i>=0.006) status, high tumour grade (<i>p</i>=0.032) and a ‘basal-like' phenotype (<i>p</i>=0.030), where 92%, i.e., 25 of 27 tumours had an active pathway. In univariate analysis an activated PI3K pathway was associated with death from breast cancer; however, in multivariate analysis it was not an independent predictor of breast cancer-related death. No association was identified between an activated pathway and tamoxifen or chemotherapy-treated patients. We conclude that >70% of breast cancers have an altered PI3K pathway and this might be exploited to therapeutic advantage especially in ‘basal-like' cancers.