Comprehensive Analysis Identifies Variability in PI3K Pathway Alterations in Triple-Negative Breast Cancer Subtypes

PURPOSE The PI3K pathway is frequently altered in triple-negative breast cancer (TNBC). Limited cell line and human data suggest that TNBC tumors characterized as mesenchymal (M) and luminal androgen receptor (LAR) subtypes have increased incidence of alterations in the PI3K pathway. The impact of PI3K pathway alterations across TNBC subtypes is poorly understood. METHODS Pretreatment tumor was evaluated from operable TNBC patients enrolled on a clinical trial of neoadjuvant therapy (NAT; A Robust TNBC Evaluation fraMework to Improve Survival ClinicalTrials.gov identifier: NCT02276443 ). Tumors were characterized into seven TNBC subtypes per Pietenpol criteria (basal-like 1, basal-like 2, immunomodulatory, M, mesenchymal stem-like, LAR, and unstable). Using whole-exome sequencing, RNA sequencing, and immunohistochemistry for PTEN, alterations were identified in 32 genes known to activate the PI3K pathway. Alterations in each subtype were associated with pathologic response to NAT. RESULTS In evaluated patients (N = 177), there was a significant difference in the incidence of PI3K pathway alterations across TNBC subtypes ( P < .01). The highest incidence of alterations was seen in LAR (81%), BL2 (79%), and M (62%) subtypes. The odds ratio for pathologic complete response (pCR) in the presence of PIK3CA mutation, PTEN mutation, and/or PTEN loss was highest in the LAR subtype and lowest in the M subtype, but these findings did not reach statistical significance. Presence of PIK3CA mutation was associated with pCR in the LAR subtype ( P = .02). CONCLUSION PI3K pathway alteration can affect response to NAT in TNBC, and targeted agents may improve outcomes, particularly in patients with M and LAR TNBC.