Incidence of PI3K pathway alteration and response to neoadjuvant therapy (NAT) in triple negative breast cancer (TNBC) subtypes.

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561 Background: Limited cell line and human data suggest that TNBCs characterized as mesenchymal and luminal androgen receptor (LAR) commonly have alterations in the PI3K pathway. More data is needed to better characterize the role of the PI3K pathway across TNBC subtypes. Methods: Pre-treatment tumor biopsies were collected from operable TNBC patients (pts) enrolled on a clinical trial of genomically tailored NAT (ARTEMIS; NCT02276443). Tumors were categorized into 5 groups using the Pietenpol criteria: basal-like (BL) comprised of BL-1 and BL-2, mesenchymal and mesenchymal stem-like (M), immunomodulatory (IM), LAR, or unspecified (UNS). Using whole exome sequencing data, variants (single nucleotide polymorphisms and insertions/deletions) and copy number variations (CNVs) were identified in 32 genes known to activate the PI3K pathway. Results: Tumor subtyping and pathologic response to NAT was available in 127 pts (clinical stage I: 9; II: 84; III: 34). PI3K pathway alteration defined as a variant in one of the evaluated genes and/or deletion of PTEN was seen in 76 (60%) tumors. The most frequent alterations were: PTEN deletion (21%), PIK3CA variant (11%), and PIK3R1 variant (8%). PI3K alteration and residual cancer burden (RCB) rates across TNBC subtypes are shown in the table. There was a significant difference in pathologic complete response (pCR)/RCB 0 rate after NAT across TNBC subtypes (chi2 test; P = 0.02). There was a significant difference in the incidence of PI3K pathway alteration across TNBC subtypes (chi2 test; P < 0.01). Overall, the presence of PI3K alteration was not associated with pCR (Fisher exact test; P = 0.85). Pts with M tumors had a higher rate of substantial residual disease (RCB II-III) after NAT. Presence of PI3K pathway alteration was common in the M subtype and associated with RCB II-III (82% in PI3K-altered vs 33% in wild-type tumors; Fisher exact test; P = 0.02). Presence of PI3K pathway alteration was common but not associated with response in the LAR subtype. Conclusions: The incidence of PI3K pathway alteration varied by TNBC subtype but was not associated with pathologic response to NAT with the exception of increased substantial residual disease (RCB II-III) in the M subtype. [Table: see text]