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 < 0.05) and distant recurrence. AR mRNA positive patients had poorer DMFS (43%; p = 0.002). DMFS dropped further to 26% (p = 0.006) in AR (+)/high FOXA1/GATA3 patients. AR mRNA expression together with node positivity had the worst DMFS (23%; p < 0.0001) compared to patients who were either positive for any one of these, or negative for both AR and node status. Low Ki67 mRNA with AR mRNA positivity also had poorer DMFS (39%; p = 0.001) compared to patients expressing low Ki67 with no AR mRNA expression. Conclusion: qRT-PCR was more sensitive and reliable in detecting the dynamic expression levels of AR compared to IHC and this variation could be explained by the higher sensitivity of the former method. High AR mRNA expression was strongly associated with expression of AR protein, high FOXA1/GATA3 mRNA, and with poor prognosis. qRT-PCR was more efficient in detecting the AR positive cases compared to IHC. A distinct signature involving high GATA3/FOXA1, low Ki67, and node positivity in AR mRNA positive tumors correlated with poor prognosis. Thus, AR mRNA screening can serve as an effective prognostic marker along with offering potential targeted therapy options for TNBC.

Obesity and Androgen Receptor Signaling: Associations and Potential Crosstalk in Breast Cancer Cells

“…In luminal BC cells, the observation of a similar effect on AR gene expression, has led to the hypothesis that high LEP levels might potentiates the oncogenic effects of the ER by reducing AR levels and its inhibitory action on the ER. In contrast, opposite effects on AR expression could be observed in ER− or low ER expression cells, which would be consistent with the confirmed pro-tumorigenic role of both, LEP and the AR, in basal-like BC subtypes [ 74 , 103 ] ( Figure 6 ).…”

“…In contrast, 80–90% of ER+ tumors are also AR-positive (AR+) and associated with favorable prognoses (e.g., longer relapse-free survival, lower tumor grade, and smaller tumor size) [ 97 , 98 ], which has been confirmed in several meta-analyses [ 99 , 100 , 101 ]. Regarding ER− BC, up to 31% of them are reported to be AR+ [ 102 ] and although some experimental studies and meta-analyses show that AR positivity is associated with improved outcomes [ 101 , 103 , 104 ], other studies have reported contradictory results [ 7 , 105 , 106 ]. Despite the above, recent evidence have shown that AR pathway activity is increased in all BC subtypes compared with normal breast tissue [ 107 ], making this signaling pathway an interesting target in the study of mammary tumor development and progression.…”

Intrinsic Subtypes and Androgen Receptor Gene Expression in Primary Breast Cancer. A Meta-Analysis

“…Nevertheless, AR significance in BC is still unclear, since AR positivity has been associated with different clinical outcomes in BC patients, according to the ER status. In ER+ BC, AR positivity is considered an independent prognostic factor of a good outcome, but in the subset of ER- BCs, there have been contradictory reports [ 5 , 9 , 10 , 41 ]. Here, the analyses performed in more than seven thousand BC patients showed that AR mRNA levels were significantly higher in women with ER+ tumors.…”

“…However, the significance of its expression is not fully defined, since AR positivity (AR+) has been associated with different clinical outcomes and, contrary biological actions, all of them are apparently dependent on the ER status [ 5 ]. Thus, in ER positive (ER+) tumors, AR positivity is associated with reduced cell proliferation [ 6 ] and favorable clinicopathological features and prognoses [ 7 ], while in ER negative (ER-)/AR+ BC cases, it is generally accepted that AR promotes cell proliferation [ 8 ], although clinical studies have also reported contradictory results [ 9 , 10 ]. In this regard, clinical trials using enobosarm (selective AR modulator—SARM) or antiandrogens (i.e., bicalutamide and enzalutamide), when administered to ER+ BC patients, did not show clinical benefit rates (NCT02463032) [ 11 , 12 ].…”

Androgen Receptor: A New Marker to Predict Pathological Complete Response in HER2-Positive Breast Cancer Patients Treated with Trastuzumab Plus Pertuzumab Neoadjuvant Therapy

“…The androgen receptor (AR) can be detected in most breast cancers, but both its expression level and prognostic effect vary. In triple-negative breast cancers (TNBCs), the luminal AR subtype expresses high levels of AR and shows decreased relapse-free survival [7][8][9][10]. In hormone receptor (HR)-positive breast cancers, AR expression is associated with better outcomes [10][11][12][13].…”