Are Androgen Receptors Receiving Proper Respect?
Lonergan et al, Journal of Carcinogenesis 2011
The androgen receptor (AR), also known as NR3C4p, is activated by binding with androgenic hormones such as testosterone, in the cytoplasm and transposing it into the nucleus. The AR is the primary target for the endocrine therapy of prostate cancer. The AR is found on the X-chromosome and consists of 2757 nucleotides.
Though receiving little attention, it is nonetheless widely expressed in breast cancer and is found in approximately 77% of all cases. More specifically, the AR is expressed in 88% of ER+, 59% of Her2+ ad 32% of triple negative cases (TNBC). Overall, 65% of all breast cancers in men and 85% of ER+ cases express the AR.
What is apparent is that the value of the AR is not clearly defined, though it appears to be indicative of a well-differentiated tumor and may well suggest a better prognosis. Phase 2 studies suggest a lower complete response to neoadjuvant chemotherapy. Furthermore, it has been suggested that resistance to hormone therapy in ER+ tumors would drive a cancer to be more AR dependent. The work of Cochrane et al suggests that the absolute percentage of cells staining positive for the AR is less important than the AR:ER ratio. They found that ratios ≥ 2 were associated with a higher incidence of positive nodes, and are three times more likely to fail on tamoxifen or an aromatase inhibitor compared to women with low ratios. In a study of 192 patients, they also noted that tumors with high AR:ER ratios failed 11 months earlier than those with low ratios. The authors suggest that AR-directed therapy may be appropriate therapy for patients that relapse on anti-estrogen therapy.
More recently, attention has turned to the place of the AR in the treatment of TNBC. TNBCs generally lack the typical targets for endocrine therapy, with chemotherapy being the only option. PARP inhibitors have been used more recently in chemo-resistant cancers, particularly in tumors expressing BRCA mutated genes. Because more recent studies have found that a majority of TNBC cells stain positive for AR (>10%), the AR is under investigation as a target for therapy.
In a meta-analysis of 13 studies, it appears that AR+ TNBCs generally had lower grade tumors and prolonged disease-free survival. Consequently, it is assumed to be less likely to respond to chemotherapy because of its low proliferation rate. Interestingly, TNBC with low AR expression may still benefit from AR inhibition. Thus far precise AR-regulated genes which are essential to TNBC biology remain to be determined and validated as biomarkers.
Currently, trials of antiandrogens are underway, most of which utilizing enzalutamide, plus or minus chemotherapy. One issue in the metastatic setting is obtaining tissue for AR testing using IHC. Testing for circulating tumor cells in this setting seems to hold great promise.
In conclusion, many breast cancers including TNBCs are driven at least in part by the androgen receptor. Again, it seems that the ratio of AR to ER may be more important than the absolute level of AR as determined by IHC with ratios ≥2 more likely to fail anti-estrogen therapy. Though IHC is typically used for assessment, blood-based approaches may be more useful in the metastatic setting. Several novel drugs may also provide additional options for AR+, TNBCs. Furthermore, little is known about the optimal combinations of antiandrogens and chemotherapy.
Is the routine determination of ARs in all breast tumors ready for prime time? At the moment, unlikely, but we may be close.