Spectrum of PIK3CA/AKT mutations across molecular subtypes of triple-negative breast cancer.

Abstract

The heterogeneity of triple-negative breast cancer (TNBC) confers variable response to chemotherapy that results in poor outcome and relapse. Due to lack of targeted therapy, there is a need to provide molecular classification of TNBC and identify probable therapeutic targets. We classified TNBC into surrogate molecular subtypes by immunohistochemistry and evaluated hotspot mutations (N = 80) in PIK3CA (exon 4, 9, and 20) and AKT1 (exon 2) in TNBC subtypes by Sanger sequencing. TNBCs were classified into Basal-like 1(BL1) (n = 20, 25%), Mesenchymal (n = 19, 23.75%), Luminal Androgen (LAR) (n = 12, 15%), Basal+Mesenchymal (Mixed type) (n = 10, 12.5%), and unclassified subtype (n = 19, 23.75%). PIK3CA mutations were observed in 16.25% (13/80) TNBC cases. PIK3CA mutations were more frequent in exon 20 (8.7%) than in exon 9 (5%) and exon 4 (2.5%). PIK3CA mutations were frequent in LAR subtype (33.3%) followed by unclassified type (31.5%), Mesenchymal (10.5%), and BL1 (5%) subtypes. Two hotspot mutations were found in AKT1 (T21I, E17K) in mixed and unclassified subtype. This study highlights the heterogeneity within TNBCs. Higher frequencies of PIK3CA mutations were noted in LAR subtypes and unclassified type, comparable to their incidence reported in literature in ER-positive tumors. The mutation status can be used as potential biomarker for PI3K inhibitors in TNBC subgroups.