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)

AR and DNA Damage Repair

Steroid hormone receptors such as ER in BC are known to be involved in regulating the DNA damage response (DDR), and suppression of ER signalling with tamoxifen has been shown to augment RT response.^[97–99] Goodwin et al. presented a mechanism by which this association between steroid hormones and DNA repair extends to AR activity in a PCa model.^[100] In men with localized PCa, the standard of care is a combination of ADT with radiation, as the combination has been shown to be more effective than either treatment on its own.^[101–103] AR activity allows for DNA DSB resolution, independent of cell cycling effects, by regulating some of the accessory factors necessary for DDR. AR acts as a transcriptional regulator of DDR factors, including DNA-PKcs, a kinase important in non-homologous end joining (NHEJ), to increase DNA repair and cell survival following DNA damage induction. Furthermore, DNA-PKcs then create a positive feedback circuit wherein AR is further activated to increase its transcription-activating potential.^[100] Polkinghorn et al. confirmed this role of AR as a transcriptional regulator of DNA repair genes, and they showed that treatment with ADT decreases the expression of these genes.^[104] Additional studies have also implicated a role for an AR-PARP1 signalling axis in breast cancer and have shown that combined inhibition of AR and PARP leads to enhanced antitumour activity by modulating the DDR.^[105,106] The implications for a role of AR in DDR make it an interesting target for combination therapeutics with RT, as AR inhibition should potentiate radiation-induced damage in a tumour-selective manner. It should also be noted, however, that while AR signalling allows for damage repair, supraphysiological androgens are associated with the induction of DSBs.^[107] For this reason, supraphysiological androgens are also under evaluation as a method of augmenting radiation response. This is actively being studied in PCa, and while it may be useful in BC, its use may be limited by side effects seen in previous studies with androgen agonists in BC.

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Breast Cancer Res. 2022;24(79) © 2022 BioMed Central, Ltd.
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Table 1. Defining AR positivity across breast cancer samples
References	ER status	HER2 status	Primary/metastatic	Antibody	AR+ definition	AR+ samples (%)	Total
Agrawal et al. [62]	ER+/ER−	±	Primary Only	AR411 DAKO	Not Reported	212 (43)	488
Gonzalez et al. [63]	ER+/ER−	Not reported	Primary & Lymph Node Metastases	AR411 DAKO	≥ 1%	83 (75)	111
Micello et al. [41]	ER− and PgR−	±	Primary Only	AR27 Novocastra	≥ 1% Nuclear	128 (57)	226
Luo et al. [64]	ER− and PgR−	-	Not Explicitly Reported	Not Reported	≥ 1% Nuclear	38 (28)	137
Niemeier et al. [15]	ER+/ER−	±	Not Explicitly Reported	AR441 DAKO	H score > 10	151(80)	189
Castellano et al. [65]	ER+	±	Primary Only	AR411 DAKO	≥ 1%	609 (71)	859
Hu et al. [28]	ER+/ER−	±	Primary Only	AR411 DAKO	≥ 10% Nuclear	1155 (79)	1467
Loibl et al. [66]	ER+/ER−	±	Primary Only	F39.4.1 BioGenex	≥ 1%	358 (53)	673
Park et al. [27]	ER+/ER−	±	Not Explicitly Reported	AR441 Thermo Scientific	≥ 10% Nuclear	541 (58)	931
Yu et al. [67]	ER+/ER−	±	Not Explicitly Reported	AR441 Lab Vision	≥ 10% Cytoplasmic	237 (72)	327
Gucalp et al. [49]	ER− and PgR−	±	Primary and Metastases	AR411 DAKO	≥ 10% Nuclear	51 (12)	424
Honma et al. [68]	ER+/ER−	±	Not Explicitly Reported	AR27 Novocastra	≥ 10% Nuclear	212 (53)	403
Tokunaga et al. [69]	ER+/ER−	±	Primary Only	AR411 DAKO	≥ 75% Nuclear	155 (62)	250
Thike et al. [60]	ER− and PgR−	-	Not Explicitly Reported	AR27 NCL-AR-318	≥ 1% Nuclear	267 (38)	699
Tsang et al. [70]	ER+/ER−	±	Primary Only	AR441 DAKO	≥ 1% Nuclear	549 (48)	1144
Aleskandarany et al. [71]	ER+/ER−	±	Not Explicitly Reported	Sc-816 Santa Cruz Biotech	H score ≥ 190	613 (54)	1141
Bronte et al. [72]	ER+/ER−	±	Primary and Metastases	SP107 Cell Marque Ventana Medical Systems	≥ 1% and ≥ 10%	136 (83) and 131 (80)	164
Candelaria et al. [73]	ER− and PgR−	-	Not Explicitly Reported	AR441 DAKO	≥ 10%	45 (31)	144
Kensler et al. [13]	ER+	±	Not Explicitly Reported	AR441 DAKO	≥ 1% Nuclear	2475(82)	3021
Xiang et al. [74]	ER+/ER−	±	Primary Only	ZA-0554 ZSGB	≥ 10% Nuclear	201 (67)	298
Zhao et al. [75]	ER− and PgR−	–	Not Explicitly Reported	Abcam ab113273	Not Reported	60 (29)	210

Table 2. Completed and ongoing trials assessing the safety and efficacy and targeting androgen receptor in breast cancer
NCT number	Title	BC subtype	AR agent drug class	Therapeutic agent	AR eligibility criteria	Menopausal status	Phase
NCT02463032	Efficacy and safety of GTx024 in patients with ER+/AR+ breast cancer	ER+/AR+	SARM	Enobosarm	Not Defined	Postmenopausal	Phase II
NCT02955394	Preoperative Fulvestrant with or without Enzalutamide in ER+/HER2− breast cancer	ER+/HER2−/AR+	Antiandrogen	Enzalutamide + Fulvestrant	Not Defined	Postmenopausal	Phase II
NCT02910050	Bicalutamide plus aromatase inhibitors in ER+/AR+/HER2− metastatic breast cancer (BETTER)	ER+/HER2−/AR+	Antiandrogen + AI	Bicalutamide + AI	Not Defined	Postmenopausal	Phase II
NCT01616758	Phase II study of GTx024 in women with metastatic breast cancer	ER+ (any AR status)	SARM	Enobosarm	Not Defined	Postmenopausal	Phase II
NCT00755885	Abiraterone acetate in treating postmenopausal women with advanced or metastatic breast cancer	AR+/ER− or ER+ (any AR status)	CYP17-lyase inhibitor	Abiraterone acetate	Not Defined	Postmenopausal	Phase I/II
NCT03207529	Alpelisib and Enzalutamide in treating patients with AR and PTEN+ metastatic breast cancer	HER2−/PTEN+/AR+	Antiandrogen	Enzalutamide + Alpelisib	≥ 1% nuclear staining	All	Phase I*
NCT02580448	CYP17-Lyase and AR inhibitor treatment with Seviteronel trial (CLARITY-01)	TNBC/AR+ or ER+/AR+	CYP17-lyase inhibitor	Seviteronel	Not Defined	Postmenopausal (if ER+)	Phase I/II
NCT02676986	Short-term preoperative treatment with Enzalutamide, alone or in combination with Exemestane in primary breast cancer (ARB)	ER+ and TNBC/AR+	Antiandrogen	Enzalutamide + Exemestane	> 0% nuclear staining	Postmenopausal (if ER+)	Phase II
NCT01990209	Orteronel as monotherapy in patients with metastatic breast cancer (MBC) that expresses AR	ER/PgR+/AR+ or TNBC/AR+	CYP17-lyase inhibitor	Orteronel	> 10% IHC staining	Postmenopausal or Pre with Ovarian Suppression (if ER+)	Phase II
NCT02067741	CR1447 in endocrine responsive-HER2- and TN-AR+ breast cancer	ER/PgR+ (HER2−) or TNBC/AR+	Antiandrogen	CR1447 (4-OH-testosterone)	> 0% IHC staining	Postmenopausal	Phase II
NCT02091960	A study to assess the efficacy and safety of enzalutamide with trastuzumab in patients with HER2+, AR+ metastatic or locally advanced BC	HER2+/AR+	Antiandrogen	Enzalutamide + Trastuzumab	Not Defined	All	Phase II
NCT00468715	Bicalutamide in treating patients with metastatic breast cancer	ER−/PgR−/AR+	Antiandrogen	Bicalutamide	> 10% nuclear staining	All	Phase II
NCT03055312	Bicalutamide in treatment of AR+ metastatic triple-negative breast cancer	TNBC/AR+	Antiandrogen	Bicalutamide	IHC ≥ 10%	All	Phase III
NCT01889238	Safety and efficacy study of enzalutamide in patients with advanced, AR+, triple-negative breast cancer	TNBC/AR+	Antiandrogen	Enzalutamide	Not Defined	All	Phase II
NCT02457910	Taselisib and Enzalutamide in treating patients with AR+ triple-negative metastatic breast cancer	TNBC/AR+	Antiandrogen	Enzalutamide + Taselisib	≥ 10% nuclear staining	All	Phase Ib/II
NCT02605486	Palbociclib in combination with Bicalutamide for the treatment of AR+ metastatic breast cancer	TNBC/AR+	Antiandrogen	Bicalutamide + Palbociclib	≥ 1% nuclear staining	All	Phase I/II
NCT02971761	Pembrolizumab and Enobosarm in treating patients with AR+ metastatic TNBC	TNBC/AR+	SARM	Enobosarm + Pembrolizumab	≥ 50% nuclear staining	All	Phase II
NCT03090165	Ribociclib and Bicalutamide in AR+ TNBC	TNBC/AR+	Antiandrogen	Bicalutamide + Ribociclib	> 0% IHC staining	All	Phase I/II
NCT02353988	AR-inhibitor Bicalutamide in treating patients with TNBC (Arbre)	TNBC/AR+	Antiandrogen	Bicalutamide	> 10% nuclear staining	All	Phase II
NCT02750358	Feasibility study of adjuvant Enzalutamide for the treatment of early-stage AR+ triple-negative breast cancer	TNBC/AR+	Antiandrogen	Enzalutamide	≥ 1% nuclear staining	All	Phase II
NCT03383679	Study on AR- and triple-negative breast cancer (START)	TNBC/AR+	Antiandrogen	Darolutamide + Capecitabine	≥ 10% IHC staining	All	Phase II
NCT02689427	Enzalutamide and paclitaxel before surgery in treating patients with stage I–III AR+ triple-negative breast cancer	TNBC/AR+	Antiandrogen	Enzalutamide + Paclitaxel	≥ 10% nuclear staining	All	Phase II*
NCT05095207	Abemaciclib in combination with Bicalutamide for androgen receptor-positive, HER2-negative metastatic breast cancer	HER2−/AR+	Antiandrogen	Abemaciclib + Bicalutamide	≥ 1% IHC staining	All	Phase Ib/II*
NCT04869943	Efficacy evaluation of Enobosarm monotherapy in treatment of AR+/ER+/HER2− metastatic breast cancer (ARTEST)	ER+/HER2−/AR+	SARM	Enobosarm	≥ 40% nuclear staining	Postmenopausal or Pre with Ovarian Suppression	Phase III*
NCT05065411	Efficacy and safety evaluation of Enobosarm in combo with Abemaciclib in treatment of ER+/HER2− metastatic breast cancer	ER+/HER2−/AR+	SARM	Enobosarm + Abemaciclib	≥ 40% nuclear staining	All	Phase III*
NCT03650894	Nivolumab, Ipilimumab, and Bicalutamide in HER2− breast cancer patients	HER2−/AR+	Antiandrogen	Nivolumab + Ipilimumab + Bicalutamide	Not Defined	All	Phase II*