Androgen Receptor Function and Targeted Therapeutics Across Breast Cancer Subtypes

Emily A. Kolyvas; Carlos Caldas; Kathleen Kelly; Saif S. Ahmad


Breast Cancer Res. 2022;24(79) 

In This Article

Radiation Therapy and AR

RT along with pharmacotherapy and surgery continues to play an important role in the treatment of BC. RT following breast-conserving surgery halves the rate at which the disease recurs and reduces the BC death rate by approximately a sixth.[108] While this multimodal treatment approach has proven to be effective for many women, some will still go on to develop recurrent disease, including many women diagnosed with TNBC. Speers et al. showed that patients with TNBC who have AR expression above the median were more likely to have locoregional recurrence following RT; however, there was no difference in locoregional recurrence in the TNBC patients who were not treated with RT. Importantly, this was shown in retrospective data sets and therefore it cannot be assumed that the clinicopathological status of the patients in the RT-treated and non-RT-treated groups are comparable.[109] A retrospective study of BC found that following RT, relapsed tumours were more likely to express AR than non-relapsed tumours.[110] Additionally, Yard et al. found that within a subgroup of 28 BC cell lines from an RT resistance screen AR mRNA levels were correlated to relative RT resistance. They went on to show that AR+ BC cells that were treated with DHT before RT had less DNA damage than cells treated with enzalutamide before RT. They attributed this to increased activation of DNA-PKcs.[111]

As previously discussed, TNBC is generally associated with poor survival despite RT and chemotherapy and these patients also suffer increased rates of locoregional recurrence.[112–114] Consequently, strategies that can improve responses to RT in these patients would be of significant clinical value. A subgroup of TNBC is known to express AR, and this group has been shown to be susceptible to targeting of the AR.[48] Clinical trials are currently underway to assess this blockade in patients with metastatic BC expressing AR (NCT00468715, NCT03055312, NCT00755885, NCT01889238, NCT02580448— Further studies have demonstrated that targeting AR may be useful not only as a monotherapy, but as a means of radiosensitizing TNBC.[100,104,109,115] It is suggested that inhibiting AR with enzalutamide in AR+ TNBC (as well as in PCa) can decrease the potential for DNA repair, leading to amplified damage from RT and ultimately cell death. This has been hypothesized to occur, in part, due to an abrogation of the expression of DNA-PKcs.[100,104,109] This radiosensitization has also been observed using seviteronel in AR+ TNBC, where radiosensitization was induced due to delayed DSB repair.[116] The potential for AR-targeting- therapies as a means of radiosensitizing TNBC is under active investigation and remains a promising therapeutic strategy for this subtype.