PIK3CAcopy-number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer

Abstract

As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations ofPIK3CArepresent the second most common alteration in TNBC after theTP53mutation, with a prevalence of ∼10%–15%. Considering the well-established predictive role ofPIK3CAmutations for response to agents targeting the PI3K/AKT/mTOR pathway, several clinical trials are currently evaluating these drugs in patients with advanced TNBC. However, much less is known regarding the actionability ofPIK3CAcopy-number gains, which represent a thoroughly common molecular alteration in TNBC, with a prevalence estimated at 6%–20%, and are listed as “likely gain-of-function” alterations in the OncoKB database. In the present paper, we describe two clinical cases in which patients harboringPIK3CA-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value ofPIK3CAamplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based onPIK3CAcopy-number status, we urge for the introduction ofPIK3CAamplification as a criterion for patient selection in future clinical trials in this setting.