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

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.