PIK3CA mutation in ER-negative and HER2-positive breast cancer with apocrine differentiation.

Targeted therapies for PIK3CA-mutated breast cancer are currently limited to the hormone receptor (HR)-positive and HER2-negative subtype. Carcinoma with apocrine differentiation (apocrine ca.) is typically characterized as ER-negative and HER2-positive/negative. Consequently, patients with apocrine ca. are generally excluded from PIK3CA genotyping and targeted therapies, even when mutations are present. Here, we investigated the prevalence and functional significance of PIK3CA mutations in apocrine ca., particularly in ER-negative (HER2-subtypes and triple-negative) subtypes. We analyzed hotspot PIK3CA mutations in apocrine ca. and invasive breast carcinoma of no special type (IBC-NST) (20 and 70 samples, respectively). PIK3CA knockdown was performed to compare the proliferation of breast cancer cell lines representing two types of apocrine ca. with PIK3CA mutations (MDA-MB-453: ER-/HER2+/AR + and MFM223: ER-/HER2-/AR+) and one without PIK3CA mutations (HCC1428: ER+/HER2-/AR-). PIK3CA mutations occurred in apocrine ca. (3/20, 15.0%) and IBC-NST (2/70, 2.9%) cases (P = 0.071). Within the ER-negative and HER2-positive subtypes, PIK3CA mutations were present in 25% of apocrine ca. (2/8) cases, whereas no mutations were observed in positive IBC-NST (0/18) (P = 0.086). siRNA-mediated PIK3CA knockdown reduced the proliferation of MDA-MB-453 (P < 0.01) and MFM223 (P = 0.01) cells, whereas no effect was observed in HCC1428 cells (P = 0.674), relative to the non-targeting siRNA control. PIK3CA mutations are present in ER-negative and HER2-positive apocrine ca., and these mutations drive PIK3CA-dependent proliferation in vitro. These results suggest that patients with apocrine ca. may benefit from PIK3CA mutation testing and subsequent targeted therapy.