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AUA 2019

AUA 2019: Men With BRCA1 and BRCA2 Mutations and Low/Intermediate Grade Prostate Cancer May Harbor Additional Genomic Alterations of More Aggressive Disease: Implications for Active Surveillance

Chicago, IL (UroToday.com) Active surveillance is recommended as a treatment option for men presenting with low risk (Gleason 3+3) and some intermediate risk (Gleason 3+4) prostate cancer. However, BRCA1 or 2 germline mutations have been implicated in prostate cancer and affected men are at higher risk for developing prostate cancer and for failure after localized therapy1. Among 148 men with prostate cancer from families with a strong history of breast and ovarian cancer, 40 men had BRCA2 germline mutations and presented with higher risk disease – 66% were greater than or equal to Gleason 82. For these patients, a BRCA2 mutation was associated with an increased risk of prostate cancer death (HR 4.5, 95%CI 2.12-9.52). There is ongoing controversy as to whether men with BRA1 or BRCA2 mutations should be offered active surveillance. It is unknown if germline BRCA1 or 2 mutations in active surveillance candidacy are associated with more aggressive histologic grade, higher stage or other worse genetic alterations, such as RB1 and p53 deletions. Dr. Marc Dall’Era from UC-Davis presented his group’s work assessing these hypothesis at the 2019 AUA Annual meeting prostate cancer active surveillance session.

Dr. Dall’Era’s team analyzed sequencing data from 498 men who underwent radical prostatectomy from The Cancer Genome Atlas (TCGA) data set. The primary outcome was the difference in the proportions of active surveillance candidates among subjects with BRCA homodeletions and non-homodeletions. Tests for differences in the proportions were conducted using Fisher’s Exact Test. Equivalence tests for proportions of active surveillance candidates were conducted using the two one-sided tests (TOST) method. As a secondary outcome, they studied the associated coincident mutations in the men with BRCA1 and BRCA2 homodeletions.

There were 41 men (8%) of the cohort had homodeletion of BRCA1 or BRCA2. Ten men (2%) had complete loss of BRCA1 while 31 (6%) had loss of BRCA2. Overall, BRCA 1 or 2 was altered in 11% of the cohort, primarily manifesting as deep deletions. Rates of candidacy for active surveillance based on histology and stage (defined as stage T2, Gleason 6) were not different between subjects with and without BRCA 1 or 2 homodeletions. Interestingly, these findings were similar when the active surveillance criteria are modified to add Gleason 3+4 subjects.

AUA 2019 BRCA Status

Fifty percent of men with organ confined (<=pT2), 3+3 and 3+4 prostate cancer with BRCA1 or BRCA2 homodeletions had concomitant RB1 deletions compared with 16.5% of the entire cohort (p=0.002). This was primarily driven by BRCA2 deletions co-occurrent with RB1 deletions (log OR 2.4, p < 0.001), both of which are in close proximity on the long arm of chromosome 13. Twenty-nine percent of men from this group had concomitant p53 deletions compared to 7.5% of the entire cohort (p=0.004).

Limitations of the study included (i) this not being a prospective series of men with confirmed germline mutations in BRCA1 or 2, (ii) histology and stage radical prostatectomy were used as a surrogate for active surveillance candidates, (iii) this study did not include biopsy information or PSA and (iv) there were no long-term survival outcomes.

Dr. Dall’Era concluded with several key take-home messages:

  • Men with prostate cancer and BRCA 1 or BRCA 2 homodeletions present with similar stage and grade tumors than men without these deletions
  • Despite having low or low intermediate-grade histology, however, BRCA1 and BRCA2 deleted tumors are enriched with deletions in RB1 and TP53, both of which are associated with more aggressive phenotypes and treatment resistance.
Dr. Dall’Era notes that he would consider enrolling patients with BRCA 1 or 2 homodeletions on active surveillance, but with very close follow-up.


Presented by: Marc Dall’Era, MD, Vice Chair of Urology, Associate Professor, University of California-Davis Health, Sacramento, CA
Co-authored by: Christopher Evans, Primo Lara, John Mcpherson, Sacramento, CA

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University, Medical College of Georgia, Twitter: @zklaassen_md at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois


References: 
1. 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):1748-1757.
2. Thorne H, Willems AJ, Niedermayr E, et al. Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families. Cancer Prev Res 2011 Jul;4(7):1002-1010.