Prognostic significance of germline mutations in DNA homologous recombination repair genes in patients with primary metastatic prostate cancer

Background. Since recently, hereditary and somatic defects in DNA homologous recombination repair (HHR) genes have been considered as promising prognostic and predictive markers for prostate cancer. However, despite the growing evidence of their prognostic significance, these biomarkers are not included in the standard prognostic classifications for primary hormone-sensitive metastatic prostate cancer (mPCa).

Aim. To assess the frequency of germline HHR DNA mutations in the Belarusian population of patients with primary mPCa and to evaluate the prognostic significance of this biomarker for long-term mPCa treatment outcomes.

Materials and methods. The study included 97 patients with primary mPCa, aged between 45 and 88 years (median age 66 years) who had their HHR DNA mutation status determined from venous blood samples. Next-generation sequencing was used for genetic analysis. All patients received standard initial treatment including androgen deprivation and docetaxel chemotherapy. Cox univariate and multivariate regression analyses were conducted for major prognostic factors and genetic status and overall survival (OS) as the endpoint. The total cohort was split into three prognostic groups.

Results. Рathogenic germline HHR DNA mutations were found in 16 patients (16.5 %; 95 % CI 9–24 %). The median OS and progression-free survival in the overall group were 31 months (95 % CI 25–38 months) and 15 months (95% CI 10–19 months), respectively. In the multivariate analysis with stepwise exclusion, the final model included two independent prognostic factors: HHR DNA mutation status (p = 0.028) and alkaline phosphatase (ALP) level (p <0.001). Based on pre-treatment ALP levels and HHR DNA mutation status, patients were categorized into groups with favorable, intermediate, and unfavorable prognosis, with median OS of 46 months, 31 months, and 18 months, respectively (p <0.0001).

Conclusion. In patients with primary mPCa, the frequency of germline HHR DNA mutations was 16.5 %. In the multivariate analysis, HHR DNA mutations statistically significantly correlated with OS. We developed prognostic classification of primary mPCa based on pre-treatment ALP levels and HHR DNA mutation status.

1. Cancer in Belarus: figures and facts. Data analysis of the Belarusian Cancer Register: Eds.: S.L. Polyakov. Minsk: RNPC OMR im. N.N. Alexandrova, 2022. 280 p. (In Russ.).

2. Robinson B.D., Mosquera J.M., Ro Jar Y. et al. Precision molecular pathology of prostate cancer. Mol Pathol Libr: Springer Cham, 2018. Pp. 13–26.

3. Cheng H.H., Sokolova A.O., Schaeffer E.M. et al. Germline and somatic mutations in prostate cancer for the clinician. J Natl Compr Canc Netw 2019;17(5):515–21. DOI: 10.6004/jnccn.2019.7307

4. Al Olama A.A., Kote­Jarai Z., Berndt S.I. et al. A meta­analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 2014;46(10):1103–9. DOI: 10.1038/ng.3094

5. Eeles R., Goh C., Castro E. et al. The genetic epidemiology of prostate cancer and its clinical implications. Nat Rev Urol 2014;11(1):18–31. DOI: 10.1038/nrurol.2013.266

6. Pritchard C.C., Mateo J., Walsh M.F. et al. Inherited DNA­repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375(5):443–53. DOI: 10.1056/NEJMoa1603144

7. Lecarpentier J., Silvestri V., Kuchenbaecker K.B. et al. Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 muta­ tion carriers using polygenic risk scores. J Clin Oncol 2017;35(10):2240–50. DOI: 10.1200/JCO.2016.69.4935

8. Robinson D., Van Allen E.M., Wu Y.M. et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161(5):1215–28. DOI: 10.1016/j.cell.2015.06.053

9. Warner E.W., Yip S.M., Chi K.N. et al. DNA repair defects in prostate cancer: impact for screening, prognostication and treatment. BJU Int 2018;123(5):769–76. DOI: 10.1111/bju.14576

10. Castro E., Goh C., Olmos D. et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 2013;31(14):1748–57. DOI: 10.1200/JCO.2012.43.1882

11. Leongamornlert D., Saunders E., Dadaev T. et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer 2014;110(6):1663–72. DOI: 10.1038/bjc.2014.30

12. Na R., Zheng S.L., Han M. et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur Urol 2017;71(5):740–7. DOI: 10.1016/j.eururo.2016.11.033

13. Abida W., Armenia J., Gopalan A. et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol 2017;2017:PO.17.00029. DOI: 10.1200/PO.17.00029

14. Castro E., Romero­Laorden N., Del Pozo A. et al. PROREPAIR­B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration­ resistant prostate cancer. J Clin Oncol 2019;37(6):490–503. DOI: 10.1200/JCO.18.00358

15. Cui M., Gao X.S., Gu X. et al. BRCA2 mutations should be screened early and routinely as markers of poor prognosis: evidence from 8,988 patients with prostate cancer. Oncotarget 2017;8(25):40222–32. DOI: 10.18632/oncotarget.16712

16. Mok O.H., Alkhushaym N., Fallatah S. et al. The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta­analysis. Prostate 2019;79(8):880–95. DOI: 10.1002/pros.23795

17. Kyriakopoulos C.E., Chen Y.H., Carducci M.A. et al. Chemohormonal therapy in metastatic hormone­sensitive prostate cancer: long­term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol 2018;36(11):1080–7. DOI: 10.1200/JCO.2017.75.3657