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

ABSTRACT: INTRODUCTION:Triple 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. METHODS:We 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. RESULTS:PIK3CA 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. CONCLUSIONS:While 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.

SUBMITTER: Lehmann BD

PROVIDER: S-EPMC4187324 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Lehmann Brian D BD Bauer Joshua A JA Schafer Johanna M JM Pendleton Christopher S CS Tang Luojia L Johnson Kimberly C KC Chen Xi X Balko Justin M JM Gómez Henry H Arteaga Carlos L CL Mills Gordon B GB Sanders Melinda E ME Pietenpol Jennifer A JA

Breast cancer research : BCR 20140808 4

<h4>Introduction</h4>Triple 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 ...[more]

PMID: 25103565

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Project description:IntroductionOverexpression of the androgen receptor (AR) characterizes a distinct molecular subset of triple negative breast carcinomas (TNBC). The role of AR as a prognostic/predictive biomarker in TNBC is controversial, but increasing evidence suggests that this subset may respond to therapeutic agents targeting AR. Evaluation of AR has not been standardized, and criteria for selection of patients for antiandrogen therapy remain controversial. In this study we determine the appropriate threshold of AR immunoreactivity to define AR positive (AR+) TNBC, describe the clinicopathologic features of AR+ TNBC, and discuss the utility of AR positivity as a prognostic and predictive marker in TNBC.Materials and methods135 invasive TNBC processed in accordance with ASCO/CAP guidelines, were immunostained for AR. Clinicopathologic features of AR+ TNBC were analyzed and compared to AR negative (AR-) TNBC. Patients' age, tumor size, tumor grade, lymph node status, proliferation rate, immunopositivity for EGFR, CK5/6, Ki-67, and disease free survival (DFS) were evaluated statistically.ResultsA 1% cutpoint was confirmed as the appropriate threshold for AR positivity. Using this cutpoint 41% of 135 TNBC were AR+. AR+ TNBC occurred in older women, were larger, had lower mean proliferation rate and increased incidence of axillary metastasis than AR- TNBC. 76% of TNBC with apocrine morphology were AR+. A subset of AR+TNBC expressed basal markers (EGFR and CK5/6). A prognostic model was created.SummaryAR identifies a heterogeneous group of TNBC. Additional evaluation of EGFR expression allowed us to stratify TNBCs into 3 risk groups with significant differences in DFS and therapeutic implications: low-risk (AR+ EGFR-) which represents the LAR molecular subtype with the best prognosis and may benefit the most from anti-androgen therapies; high-risk (AR- EGFR+) which represents the basal molecular subtype with the worst prognosis and may benefit the most from chemotherapy regimens; intermediate-risk (AR+EGFR+ and AR-EGFR-) TNBC with an intermediate prognosis. Prospective trials are required to further validate this prognostic and predictive grouping.

Project description:Increased rates of locoregional recurrence (LR) have been observed in triple negative breast cancer (TNBC) despite multimodality therapy, including radiation (RT). Recent data suggest inhibiting the androgen receptor (AR) may be an effective radiosensitizing strategy, and AR is expressed in 15-35% of TNBC tumors. The aim of this study was to determine whether seviteronel (INO-464), a novel CYP17 lyase inhibitor and AR antagonist, is able to radiosensitize AR-positive (AR+) TNBC models. In cell viability assays, seviteronel and enzalutamide exhibited limited effect as a single agent (IC50 > 10 μM). Using clonogenic survival assays, however, AR knockdown and AR inhibition with seviteronel were effective at radiosensitizing cells with radiation enhancement ratios of 1.20-1.89 in models of TNBC with high AR expression. AR-negative (AR-) models, regardless of their estrogen receptor expression, were not radiosensitized with seviteronel treatment at concentrations up to 5 μM. Radiosensitization of AR+ TNBC models was at least partially dependent on impaired dsDNA break repair with significant delays in repair at 6, 16, and 24 h as measured by immunofluorescent staining of γH2AX foci. Similar effects were observed in an in vivo AR+ TNBC xenograft model where there was a significant reduction in tumor volume and a delay to tumor doubling and tripling times in mice treated with seviteronel and radiation. Following combination treatment with seviteronel and radiation, increased binding of AR occurred at DNA damage response genes, including genes involved both in homologous recombination and non-homologous end joining. This trend was not observed with combination treatment of enzalutamide and RT, suggesting that seviteronel may have a different mechanism of radiosensitization compared to other AR inhibitors. Enzalutamide and seviteronel treatment also had different effects on AR and AR target genes as measured by immunoblot and qPCR. These results implicate AR as a mediator of radioresistance in AR+ TNBC models and support the use of seviteronel as a radiosensitizing agent in AR+ TNBC.

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

Publications

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

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