PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors

Abstract

IntroductionTriple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses the androgen receptor (AR+). TNBC cells derived from these luminal AR + tumors have high frequency phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. The purpose of this study was to determine if targeting phosphoinositide 3-kinase (PI3K) alone or in combination with an AR antagonist is effective in AR + TNBC.MethodsWe determined the frequency of activating PIK3CA mutations in AR + and AR- TNBC clinical cases. Using AR + TNBC cell line and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability.ResultsPIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects.ConclusionsWhile approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with AR + TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR + TNBC; and, we show that the growth and viability of AR + TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0406-x) contains supplementary material, which is available to authorized users.

Anti-androgen therapy in triple-negative breast cancer

“…The combination of bicalutamide and the PI3K inhibitors pictilisib and apitolisib showed additive efficacy in PI3K-mutant TNBC cells in vitro and in vivo [Lehmann et al 2014]. Enzalutamide plus everolimus appeared to be synergistic in multiple in vitro preclinical models of BC, including TNBC [Gordon et al 2014].…”

Immunoexpression of lactoferrin in triple-negative breast cancer patients: A proposal to select a less aggressive subgroup

“…TNBC shows biological aggressiveness and a higher recurrence rate, with no benefit from endocrine or HER2-targeted therapies (1)(2)(3). A number of studies have previously been performed to identify additional prognostic markers to better classify TNBC and stratify it into subgroups with different clinical courses (3)(4)(5)(6)(7)(8).…”

1976 Significance of PIK3CA mutations in patients with early breast cancer treated with adjuvant chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) study

“…PI3K-AKT signaling is an important driving pathway in breast cancer, triggered by growth factor receptor activation, such as insulin-like growth factor receptors (IGF-R), epidermal growth factor receptor (EGFR) and HER2, by steroid hormone receptors, estrogen (ER), progesterone receptors (PgR), as well as by genetic aberrations of some of its components, more frequently HER2 amplification, PIK3CA mutations and phosphatase and tensin homolog (PTEN) loss [2]. Also, evidence of cross-talk between androgen receptors (AR) and the PI3K-AKT pathway has been reported [3][4][5]. Pathway activation leads to phosphorylation of AKT at two different amino acid residues, pAKT473 and pAKT308.…”