Androgen receptor signaling mechanism in prostate cancer: resistance to antiandrogen therapy and association with DNA repair genes

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Abstract

Background. Metastatic castration-resistant prostate cancer remains a complex problem due to patients' previous treatments and limited selection of subsequent therapies. While 2nd generation antiandrogens are initially effective, resistance to them is not an exceptional event. Mechanisms depending on androgen receptor and independent of it have been described. A special focus is on mutations in DNA repair genes, particularly genes involved in homologous recombination repair (HRR) as a possible cause of somatic genetic abnormalities specifically in progressive metastatic disease. However, data on the effect of the HRR defect on the effectiveness of antiandrogen therapy for prostate cancer are very limited, which requires additional clinical studies.

Aim. To evaluate the effect of clinical, morphological, molecular and genetic factors on the effectiveness of enzalutamide antiandrogen therapy in patients with prostate cancer and known mutations in DNA repair genes involved in HRR and mismatch repair.

Materials and methods. The study was performed at the Clinical Oncological Dispensary No. 1 (Krasnodar). Retrospective analysis of clinical and morphological parameters of 54 patients with prostate cancer who received enzalutamide antiandrogen therapy and with known status of germ line and somatic mutations of HRR DNA repair genes (BRCA1, BRCA2, ATM, BARD, BRIP1, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD54L, FANCL) and microsatellite instability in immunohistochemical determination of mismatch repair deficit was performed. Statistical analysis was performed using IBM SPSS Statistics v.22 software.

Results and conclusion. In 17 of 54 patients, pathogenic germline and somatic mutations of HRR genes were detected: 7 mutations in BRCA2 gene, 4 - in CHEK2, 2 - in BRCA1, 2 - in CDK12, 1 - in BRIP1 and 1 - in ATM. It was shown that in the group of patients with metastatic castration-resistant prostate cancer, histological grade per the International Society of Urological Pathology (ISUP) G2 (total Gleason score 7 (3 + 4)) is significantly associated with the absence of HRR mutation, and grade G3 (total Gleason score 7 (4 + 3)) was associated with HRR mutations (р <0.05). Increase in prostate-specific antigen (PSA) level/biochemical progression 12-16 weeks after enzalutamide therapy start was significantly associated with metastatic castration-resistant prostate cancer without HRR mutations (р <0.05). In case of tumor response to enzalutamide therapy, decrease in PSA level did not depend on the age of disease onset, differentiation grade, primary advancement, previous docetaxel treatment, and presence of HRR mutation. Cox multivariate regression test showed that prescription of docetaxel before enzalutamide increased the risk of PSA-progression (hazard ratio (HR) 5.160; 95 % confidence interval (CI) 1.549-17.189; р = 0.008) and radiographic progression (HR 5.161; 95 % CI 1.550-17.187; р = 0.008). Progression risk decreased with increased level of PSA decrease 12-16 weeks after enzalutamide therapy start: for PSA decrease >30 % HR 0.150; 95 % CI 0.040-0.570; р = 0.005; for PSA decrease >50 % HR 0.039; 95 % CI 0.006-0.280; р = 0.001; for PSA decrease >90 % HR 0.116; 95 % CI 0.036-0.375; р = 0.000. Presence of HRR mutation, age <58 years, primary metastatic disease and poorly differentiated morphology did not affect duration without PSA-progression (p >0.05). Kaplan-Meier curves showed a trend towards increased time to development of castration resistance in the group of primary early cancer (Breslow р = 0.06; Tarone-Ware р = 0.062). Subgroup analysis showed that in the cohort of patients with castration-resistant prostate cancer (n = 48), absence of HRR mutation in patients who previously received docetaxel therapy increases time to PSA-progression compared to patients with mutations (log-rank р <0.05).

About the authors

A. I. Stukan

Clinical Oncological Dispensary No. 1, Ministry of Health of Krasnodar region; Kuban State Medical University, Ministry of Health of Russia

Author for correspondence.
Email: jolie86@bk.ru
ORCID iD: 0000-0002-0698-7710

Anastasiya I. Stukan.

146 Dimitrova St., Krasnodar 350040; 4 Mitrofana Sedina St., Krasnodar 350063

Russian Federation

A. Yu. Goryainova

Clinical Oncological Dispensary No. 1, Ministry of Health of Krasnodar region; Kuban State Medical University, Ministry of Health of Russia

ORCID iD: 0000-0001-7127-7945

146 Dimitrova St., Krasnodar 350040; 4 Mitrofana Sedina St., Krasnodar 350063

Russian Federation

M. M. Grigoryan

Clinical Oncological Dispensary No. 1, Ministry of Health of Krasnodar region

146 Dimitrova St., Krasnodar 350040

Russian Federation

V. F. Kutyan

Clinical Oncological Dispensary No. 1, Ministry of Health of Krasnodar region

ORCID iD: 0009-0005-2183-7920

146 Dimitrova St., Krasnodar 350040

Russian Federation

V. S. Zhdanov

Clinical Oncological Dispensary No. 1, Ministry of Health of Krasnodar region

146 Dimitrova St., Krasnodar 350040

Russian Federation

T. Yu. Semiglazova

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia; I.I. Mechnikov North-West State Medical University, Ministry of Health of Russia

ORCID iD: 0000-0002-4305-6691

68 Leningradskaya St., Pesochnyy, Saint Petersburg 197758; 41 Kirochnaya St., Saint Petersburg 191015

Russian Federation

E. N. Imyanitov

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia; I.I. Mechnikov North-West State Medical University, Ministry of Health of Russia; Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia

ORCID iD: 0000-0003-4529-7891

68 Leningradskaya St., Pesochnyy, Saint Petersburg 197758; 41 Kirochnaya St., Saint Petersburg 191015; 2 Litovskaya St., Saint Petersburg 194100

Russian Federation

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СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
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