Abstract
We aim to elucidate the prognostic value of PIK3CA mutations and copy number (CN) gain (PIK3CA-mut/gain) in hormone receptor-positive and HER2-negative (HR + /HER2−) breast cancer (BC). We analyzed primary HR + /HER2− BC from three publicly available datasets comprising over 2000 samples and assessed the associations with tumoral and clinical characteristics and outcome. Clinical benefit (CB) in alpelisib-treated patients from two studies including 46 patients was analyzed. About 8–10% of HR + /HER2− primary BC had PIK3CA-mut/gain. In two of the datasets analyzed, among patients with PIK3CA mutant tumors, those with mut/gain had significantly worse outcome compared to those with CN neutral (PIK3CA-mut/neut) and PIK3CA-mut/gain remained an independent prognostic factor. CB of alpelisib-treated patients with PIK3CA-mut/gain and PIK3CA-mut/neut tumors was comparable. PIK3CA CN might help clarifying the prognostic and predictive role of PIK3CA mutations. Further studies are warranted.
Highlights
The phosphoinositide 3-kinases (PI3K) pathway plays a critical role in breast cancer (BC) and is frequently altered in hormone receptor positive and HER2 negative (HR + /HER2−) disease[1]
In MSK-2018, significantly higher levels of PIK3CA copy number (CN) were observed in metastatic HR + /HER2− compared to primary BC samples, both in tumors unselected for PIK3CA mutations (p = 5.3e −24), and in PIK3CA mutant and wt tumors (Fig. 1g and Supplementary Fig. 2)
In this study we primarily aimed to perform a comprehensive analysis on the prognostic role of PIK3CA CN gain with cooccurring PIK3CA mutations in well characterized and publicly available datasets of patients with HR + /HER2− BC
Summary
The phosphoinositide 3-kinases (PI3K) pathway plays a critical role in breast cancer (BC) and is frequently altered in hormone receptor positive and HER2 negative (HR + /HER2−) disease[1]. Somatic mutations of the PIK3CA gene, encoding for the class IA PI3K p110α subunit, are the most common activating mutations, occurring in 30–50% of ER + /HER2− early BC2,3 and in 28% of metastatic disease[4]. Many studies evaluated the prognostic relevance of PIK3CA mutations in primary BC with conflicting results[2,5,6]. Gain in PIK3CA copy number (CN) has been described in BC8–18. It was shown that tumors with high PIK3CA CN have more aggressive prognostic features, including large tumor size, high tumor grade, and negative HR status and are more likely to occur in patients with HR and HER2 negative disease[9]. In about half of the tumors, gain in PIK3CA CN co-occurs with PIK3CA mutations[8,10]
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