Efficacy and Safety of Targeting Androgen Receptor in Advanced Breast Cancer: A Systematic Review

Author(s): Loay Kassem, Kyrillus S. Shohdy*, Nafie F. Makady, Dalal S. Salem, Nadia Ebrahim, Mostafa Eldaly

Journal Name: Current Cancer Therapy Reviews

Volume 15 , Issue 3 , 2019

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Graphical Abstract:


Abstract:

Background: Androgen receptor (AR) upstreams complex signaling pathways that regulate cell proliferation and contribute to breast tumorignensis. Several clinical trials were initiated to investigate the clinical relevance of targeting AR especially in hormone-receptor-negative breast cancer.

Methods: The search was performed in PubMed and the meeting libraries of ASCO, ESMO, SABCS, ImpakT congresses from January 2005 to July 2017. The following key words were used: Breast cancer, Androgen receptor, androgen agonist/antagonist, Flutamide, Abiraterone, Bicalutamide, Enzalutamide, Enobosarm, selective androgen receptor modulator.

Results: Screening of title/abstracts yielded a total of 20 relevant results. Of those, twelve studies were found eligible: eleven clinical trials along with one case report. Response rates ranged from 0 to 12% while clinical benefit rates reached up to 35% in 2 studies (with enzalutamide and enobosarm). Progression-free survival ranged from 2.8 to 4.5 months. The most widely used cutoff for AR expression was 10%. High expression of AR was associated with more clinical benefit. Regarding safety, anti-androgens were generally well tolerated with hot flushes, elevated transaminases and fatigue being the most commonly reported across all agents.

Conclusion: Androgen receptor pathway targeting in advanced breast cancer remains a valid option with reasonable clinical benefit in non-selected patients. Future studies are needed to define an AR addicted cohort with better responses and outcome.

Keywords: Breast cancer, androgen receptor, efficacy, safety, antiandrogens, signaling pathways.

[1]
Wang X, Yarid N, McMahon L, Yang Q, Hicks DG. Expression of androgen receptor and its association with estrogen receptor and androgen receptor downstream proteins in normal/benign breast luminal epithelium. Appl Immunohistochem Mol Morphol AIMM 2014; 22(7): 498-504.
[2]
Wang X. Androgen Receptor (AR) and breast cancer: Reference to the AR status in normal/benign breast luminal cells. Receptors Clin Investig 2015; 2(2): 4-7.
[3]
Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000; 406(6797): 747-52.
[4]
Wang C, Pan B, Zhu H, Zhou Y, Mao F, Lin Y. Prognostic value of androgen receptor in triple negative breast cancer : A meta-analysis. Oncotarget 2016; 7(29): 46482.
[5]
Vera-Badillo FE, Templeton AJ, De Gouveia P, et al. Androgen receptor expression and outcomes in early breast cancer: A systematic review and meta-analysis. J Natl Cancer Inst 2014; 106(1): 1-11.
[6]
Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: Expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol 2010; 23(2): 205-12.
[7]
Safarpour D, Tavassoli FA. A targetable androgen receptor- Positive breast cancer subtype hidden among the triple-negative cancers. Arch Pathol Lab Med 2015; 139(5): 612-7.
[8]
Narayanan R, Dalton J. Androgen receptor: A complex therapeutic target for breast cancer. Cancers (Basel) 2016; 8(12): 108.
[9]
Herrmann JB, Adair FE. The effect of testosterone propionate on carcinoma of the female breast with soft tissue metastases. J Clin Endocrinol Metab 1946; 6(12): 769-75.
[10]
Kennedy BJ. Fluoxymesterone therapy in advanced breast cancer. N Engl J Med 1958; 259(14): 673-5.
[11]
Perrault DJ, Logan DM, Stewart DJ, Bramwell VH, Paterson AH, Eisenhauer EA. Phase II study of flutamide in patients with metastatic breast cancer. A National Cancer Institute of Canada Clinical Trials Group study. Invest New Drugs 1988; 6(3): 207-10.
[12]
Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II Trial of Bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 2013; 19(19): 5505-12.
[13]
Arce-Salinas C, Riesco-Martinez MC, Hanna W, Bedard P, Warner E. Complete response of metastatic androgen receptor-positive breast cancer to bicalutamide: Case report and review of the literature. J Clin Oncol 2016; 34(4): e21-4.
[14]
Castan CJ, Schmid P, Awada A, et al. 13P * Stage 1 results from MDV3100-11: A 2-stage study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). Ann Oncol 2015; 26(Suppl. 3): iii6.
[15]
Krop I, Cortes J, Miller K, et al. Abstract P4-22-08: A single-arm phase 2 study to assess clinical activity, efficacy and safety of enzalutamide with trastuzumab in HER2+ AR+ metastatic or locally advanced breast cancer. Cancer Res 2017; 77(4 suppl) P4- 22-08
[16]
Schwartzberg LS, Yardley D, Elias A, et al. A phase I/Ib study of enzalutamide alone and in combination with endocrine therapies in women with advanced breast cancer. Clin Cancer Res 2017; 23(15): 4046-54.
[17]
Traina T, Yardley D, O’Shaughnessy J, et al. Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). J Clin Oncol 2015; 33(15)(Suppl.): 1003.
[18]
Traina TA, Yardley DA, Schwartzberg LS, et al. overall survival (OS) in patients (Pts) with diagnostic positive (Dx+) breast cancer: Subgroup analysis from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in AR+ triple-negative breast cancer (TNBC) treated with 0-1 prior li. J Clin Oncol 2017; 35: 1089.
[19]
Bonnefoi H, Grellety T, Tredan O, et al. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann Oncol 2016; 27(5): 812-8.
[20]
O’Shaughnessy J, Campone M, Brain E, et al. Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptorpositive metastatic breast cancer. Ann Oncol 2016; 27(1): 106-13.
[21]
Yardley D, Peacock N, Young R, et al. Abstract P5-14-04: A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer: Interim analysis. Cancer Res 2016; 76(4 Supplement) P5-14-4-P5-14-04
[22]
Rampurwala M, Wisinski KB, Burkard ME, et al. Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Invest New Drugs 2016; 35(1): 87-94.
[23]
Gucalp A, Danso MA, Elias AD, Bardia A, Ali HY, Potter D. Phase (Ph) 2 stage 1 clinical activity of seviteronel, a selective CYP17-lyase and androgen receptor (AR) inhibitor, in women with advanced AR+ triple-negative breast cancer (TNBC) or estrogen receptor (ER)+ BC: CLARITY-01. J Clin Oncol 2017; 35(15): 1102.
[24]
Overmoyer B, Sanz-Altimira P, Partridge AH, et al. Abstract P1- 13-04: Enobosarm for the treatment of metastatic, estrogen and androgen receptor positive, breast cancer. Final results of the primary endpoint and current progression free survival. Cancer Res 2015; 75(9 Suppl) P1-13-4-P1-13-04
[25]
Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): A randomised, double-blind, phase 2 study. Lancet Oncol 2016; 17(2): 153-63.
[26]
Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol 2017; 465: 134-42.
[27]
Bird IM, Abbott DH. The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature. J Steroid Biochem Mol Biol 2015; 163(2015): 136-46.
[28]
Dobs AS, Boccia RV, Croot CC, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol 2013; 14(4): 335-45.
[29]
Martín M, Ruiz A, Muñoz M, et al. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol 2007; 8(3): 219-25.
[30]
Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 2007; 25(23): 3407-14.
[31]
Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomised study. Lancet 2011; 377(9769): 914-23.
[32]
Perez EA, Hillman DW, Mailliard JA, et al. Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 2004; 22(14): 2849-55.
[33]
Awada A, Garcia AA, Chan S, et al. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: A randomised phase 2 study. Lancet Oncol 2013; 14(12): 1216-25.
[34]
Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003; 348(24): 2431-42.
[35]
Gan L, Chen S, Wang Y, et al. Inhibition of the androgen receptor as a novel mechanism of taxol chemotherapy in prostate cancer. Cancer Res 2009; 69(21): 8386-94.
[36]
von Wahlde M-K, Hülsewig C, Ruckert C, Götte M, Kiesel L, Bernemann C. The anti-androgen drug dutasteride renders triple negative breast cancer cells more sensitive to chemotherapy via inhibition of HIF-1α-/VEGF-signaling. Gynecol Endocrinol 2015; 31(2): 160-4.
[37]
Miller K, Krop I, Schwartzberg L, et al. Abstract P3-07-25: Improved clinical outcomes on enzalutamide observed in patients with PREDICT AR+ triple-negative breast cancer: Prognosis or prediction? Cancer Res 2016; 76(4 Suppl) P3-7-25-P3-07–25
[38]
Loibl S, Müller BM, von Minckwitz G, et al. Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 2011; 130(2): 477-87.
[39]
Masuda H, Baggerly KA, Wang Y, et al. Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res 2013; 19(19): 5533-40.
[40]
Lehmann BD, Bauer JA, Schafer JM, et al. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res 2014; 16(4): 406.
[41]
Ramos C, Hoke NN, Wilks T, et al. Androgen receptor (AR) activation in breast cancer (BC) liver metastases. J Clin Oncol 2017; 35: 11619.
[42]
Ni M, Chen Y, Lim E, et al. Targeting androgen receptor in estrogen receptor-negative breast cancer. Cancer Cell 2012; 20(1): 119-31.
[43]
Shohdy KS, Kassem L, Mangalik A. Is the clinical benefit rate at sixteen weeks a reliable end point? J Clin Oncol 2018; 36(23): 2457-8.


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Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [197 - 206]
Pages: 10
DOI: 10.2174/1573394714666180821145032
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