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Androgen Receptor mRNA levels determine the prognosis in triple-negative breast cancer patients.

ABSTRACT: BACKGROUND:Anti-Androgen Receptor (AR) therapy holds promise for a subset of AR expressing triple-negative breast cancer (TNBC) patients. However, current AR assays are suboptimal in detecting the dynamic range of AR expression, contributing to its controversial role in TNBC disease prognosis. This study is aimed at evaluating the feasibility of qRT-PCR to sensitively and robustly detect AR mRNA levels for prognostication. METHODS:mRNA expression profiling was performed on FFPE blocks from a retrospective cohort of 101 TNBC patients using qRT-PCR and compared with AR protein expression by immunohistochemistry . Statistical analyses included Spearman's rank correlation, Chi-square and Kaplan-Meier analyses. Distant Metastasis Free Survival was used as the end point in survival analysis. RESULTS:AR mRNA expression was observed in 34/101 patients (34%) whereas 12/80 cases (15%) were positive by IHC. qRT-PCR could thus detect more AR positive patients as compared to IHC, with 75% (9/12) concordance between the two methods. Co-expression of GATA3 and FOXA1 mRNA was observed in 85 and 88% of AR mRNA positive tumors, respectively. AR mRNA positivity was significantly correlated with age at disease onset (p?=?0.02), high FOXA1/GATA3 (p?

SUBMITTER: Govindan S

PROVIDER: S-EPMC7419184 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Androgen Receptor mRNA levels determine the prognosis in triple-negative breast cancer patients.

Govindan Sindhu S Siraganahalli Eswaraiah Mallikarjuna M Basavaraj Chetana C Adinarayan Manjula M Sankaran Satish S Bakre Manjiri M

BMC cancer 20200810 1

<h4>Background</h4>Anti-Androgen Receptor (AR) therapy holds promise for a subset of AR expressing triple-negative breast cancer (TNBC) patients. However, current AR assays are suboptimal in detecting the dynamic range of AR expression, contributing to its controversial role in TNBC disease prognosis. This study is aimed at evaluating the feasibility of qRT-PCR to sensitively and robustly detect AR mRNA levels for prognostication.<h4>Methods</h4>mRNA expression profiling was performed on FFPE bl ...[more]

PMID: 32778063

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Project description:ObjectiveDifferent molecular subtypes of triple-negative breast cancer (TNBC) have previously been identified through analysis of gene expression profiles. The luminal androgen receptor (LAR) subtype has been shown to have a lower rate of pathologic complete response to neoadjuvant chemotherapy than other TNBC subtypes. The purpose of this study was to determine if the imaging features of TNBCs differ by AR (androgen receptor) status, which is a surrogate immunohistochemical (IHC) marker for the chemoresistant LAR subtype of TNBC.Materials and methodsThis sub-study was part of a clinical trial in patients with stage I-III TNBC who were prospectively monitored for response while receiving neoadjuvant systemic therapy (NAST) at a single comprehensive cancer center. This interim imaging analysis included 144 patients with known AR status measured by IHC. AR-positive (AR+) tumors were defined as those in which at least 10% of tumor cells had positive nuclear AR staining. Two experienced, fellowship-trained breast radiologists who were blinded to the IHC results retrospectively reviewed and reached consensus on all imaging studies for the index lesion (i.e., mammogram, ultrasound, and breast magnetic resonance imaging). The index lesion for each patient was reviewed and described according to the fifth edition of the Breast Imaging Reporting and Data System lexicon. Logistic regression modeling was used to identify imaging features predictive of AR status. p ≤ 0.05 was considered statistically significant.ResultsUnivariate logistic regression models for AR status showed that AR+ TNBC was significantly associated with heterogeneously dense breast composition on mammography (p = 0.02), mass with calcifications (p = 0.05), irregular mass shape on mammography (p = 0.03), and irregular mass shape on sonography (p = 0.003). Multivariate logistic regression models for AR status showed that AR+ TNBC was significantly associated with heterogeneously dense breast composition on mammography (p = 0.01), high mass density on mammography (p = 0.003), and irregular mass shape on sonography (p = 0.0004).ConclusionThe imaging features of TNBCs differ by AR status. Multimodality breast imaging may help identify the LAR subtype of TNBC, which has been shown to be a subtype that is relatively resistant to neoadjuvant chemotherapy.

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.

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Androgen Receptor mRNA levels determine the prognosis in triple-negative breast cancer patients.

Publications

Androgen Receptor mRNA levels determine the prognosis in triple-negative breast cancer patients.

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