EAU 2017: Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death

London, England (UroToday.com) Increased prostate cancer risk is associated with BRCA1/2 and ATM germline mutations. This study aimed to directly assess whether these specific germline mutations distinguish lethal from indolent prostate cancer and whether they confer any effect on age at death.

This was a retrospective case study including 313 patients who died of prostate cancer and 486 patients with localized prostate cancer of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. Mutation carrier rates and their effect on lethal prostate cancer were analyzed using univariate and multivariate regression analysis.

The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal prostate cancer patients (6.07%) than localized prostate cancer patients (1.23%), P=0.0002. There was also a significant difference among lethal prostate cancer patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97%) in patients who died ≤60, 61-65, 66-70, 71-75, and over 75 years, respectively, (P-trend=0.046) and time to death after diagnosis ,12.26%, 4.76%, and 0.98% in patients who died ≤5, 6-10, and >10 years after a prostate cancer diagnosis, respectively, (P-trend=0.0006).

Survival analysis revealed a significant worse prognosis with median survival time of 5 years, (95% Confidence Interval: 2.1-7.9 years) in mutation carriers, and 16 years (95% Confidence Interval: 1.8-15.2 years), in non-mutation carriers, Kaplan-Meier log-rank P=3.7×10-10. Mutation status remained an independent predictor of lethal prostate cancer after adjusting for race, age, PSA, and Gleason score at time of diagnosis with a hazard ratio=2.13, (95% Confidence Interval 1.24-3.66, P=0.004). Results did not vary among different racial populations.

In conclusion, patients harbouring BRCA1/2 and ATM germline mutations have a more aggressive and lethal prostate cancer and tend to die earlier.

Speaker: Na R., Zheng S.L., Han M., Yu H., Jiang D., Shah S. Ewing C., Zhang L.3 Novakovic K.4, Petkewicz J., Gulukota K., Helseth D., Quinn M., Humphries E., Wiley K., Isaacs S, Wu Y.1, Liu X.2 Zhang N., Wang C-H., Khandekar J., Hulick P., Shevrin D., Cooney K., Shen Z.1, Partin A., Carter H.B., Carducci M., Eisenberger M., Denmeade S., McGuire M., Walsh P., Helfand B., Brendler C., Ding Q.1, Xu J., Isaacs W.

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto

at the #EAU17 - March 24-28, 2017- London, England