Prophylactic radical prostatectomy in BRCA2 carriers?

How to assess men with familial prostate cancer

Prof. Chris Bangma Erasmus MC Dept. of Urology Rotterdam (NL)

c.h.bangma@ erasmusmc.nl

Prof. Peter Albers Universitätsklinikum Düsseldorf (DE)

complex, and no universal method for offering this information is available. In many European countries facilities have been created for genetic counselling, however, waiting lists are long. A molecular tumour board needs to shape the molecular results into an advice that is palatable for client as well as health professional. That is why in urology often a compact assessment of familial cancer incidence is performed, and based on that, a preliminary risk assessment is made to serve further decision making.

consuming [8], while genetic tests on the many existing BRCA2 mutations are not standardised. Implementation of genetic evaluation and consultation might be made feasible through remote counselling.

References

1. Castro E, Goh C, Leongamornlert D, Saunders E, Tymrakiewicz M, Dadaev T, et al. Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer. Eur Urol. 2015;68(2):186-93.

p.albers@dkfzheidelberg.de

The increased public awareness on the genetic susceptibility of diseases is leading to an increased consumption of genetic screening tests worldwide. It has been estimated that over 30 million people actively underwent some form of germline testing, and it is expected that with decreasing consumer costs this might intensify rapidly. With the growing knowledge on the familial incidence of some cancers, our urologic patients will be stimulated to ask for genetic testing facing the development of a malignancy at older age, or to be informed on genetic risks considering their offspring. For prostate cancer it is perceived that a malignancy can run in families, but the observation is often used more as an explanation in retrospect than as a tool to modulate the diagnostic or therapeutic care path. Is it needed, and what impact does it have?

In the recent EAU23 session on familial prostate cancer, the work-up for the evaluation of men with a positive family history on prostate, ovarian, and breast cancer was discussed. The in-depth evaluation of the family is the terrain of clinical genetics. The consultation takes time, as a proper understanding of the impact of testing results is needed, as is a proper consent. The text might be

A ‘positive family history’ might lead to genetic testing, and reveal the presence of a gene mutation within the BRCA2 gene that is considered pathologic, and may lead to cancer. A malfunctioning BRCA2 gene does not sufficiently correct DNA-mistakes in the process of cell renewal. Not always will this result in a cancer in the prostate, and in case of a BRCA2 presence, it is estimated that during a life time the risk is ca 60%, leading to a worse survival compared to non-carriers [1]. Which is considerably more compared to the 11% chance on relevant PCa in the general population.

In the absence of genetic testing, there is no scientific argument to alter the normal work-up with a strong familial cancer tendency, however it might raise awareness and induce extra testing, e.g. by MRI in young patients.

However, the interpretation of MRI in young patients is not easy. Dr. Schlemmer (DE) explained on the variation in nodules seen on MRI of men participating in the PROBASE study, and emphasised that it needs special expertise to report on men aged 50 or younger [2]. A case presentation by Dr. Linares (ES) concerned a 55-year old BRCA2 carrier with a PSA of 2.12 ng/ml and a negative MRI, who by consensus of the discussion panel continued to be screened by PSA and DRE only, and MRI on indication. By illustrating the NCCN 2023 guidelines [3], Prof. Morgans (US) showed that based on the limited data available it should be considered to advise BRCA2 testing in men diagnosed with high-risk or metastatic PCa, and in men with a positive family history [4, 5]. As risk on other cancers is increased in BRCA2 carriers [6], in many countries male breast selfexamination is promoted [7]. But the genetic counselling, if available, can be tedious and time

In BRCA2 carriers with ISUP1 (Gleason 3+3) low risk tumours (case by Dr. Cogelnik from Gradec), Prof. Radtke (DE) showed the increased risk of early progression and worse outcome [9], but that there are no biomarkers other than MRI that play a role in estimating that risk. Overconsumption of diagnostics is high in this group, according to Prof. Boesen (DK), and MRI-only is not yet sufficiently mature to independently indicate biopsies in active surveillance. There is no evidence that a positive family history for PCa urges a more intense follow-up [10]. Nevertheless, Prof. Coelho (BR) made a strong plea for radical surgery in this patient group, in which the outcome is worse compared to men without germline mutations. The parallel of ‘prophylactic’ radical prostatectomy with BRCA2 positive women at risk for breast cancer is easy to suggest, and a randomised trial in BRCA2-positive men with low risk cancers for observation versus surgery has been initiated in Canada [11].

At a time in which the impact of a BRCA2 carrier status on younger men for the rest of their life is high, but the health professionals still do not have sufficient evidence to decide what to do, it might be best to focus on how to bring sufficient observations from around the world together to create fast and more relevant information. More than 30 million people have used consumer genetic tests, and they might at some time knock on our clinic door. In Germany, the German Cancer Aid has recently funded the organisation of a Prostate Cancer Prevention Clinic (ProFam-Risk*) for men with familial history. These kind of consultations are in place in other parts of Europe and the US as well. But the expert panel at EAU23 made a plea to gather data of these prevention clinics in order to get a more scientific view on the risks and also the magnitude of anxiety of men who ask for consultation. A lot is still to do in order not to overdiagnose and overtreat men with familial prostate cancer.

*abstract Anna Henrike Rabe, EAU23:Trials in progress

2. Krilaviciute A, Albers P, Lakes J, Radtke JP, Herkommer K, Gschwend J, et al. Adherence to a risk-adapted screening strategy for prostate cancer: First results of the PROBASE trial. Int J Cancer. 2023;152(5):854-64.

3. Schaeffer EM, Srinivas S, Adra N, An Y, Barocas D, Bitting R, et al. NCCN Guidelines(R) Insights: Prostate Cancer, Version 1.2023. J Natl Compr Canc Netw. 2022;20(12):1288-98.

4. Seibert TM, Garraway IP, Plym A, Mahal BA, Giri V, Jacobs MF, et al. Genetic Risk Prediction for Prostate Cancer: Implications for Early Detection and Prevention. Eur Urol. 2023;83(3):241-8.

5. Bancroft EK, Page EC, Brook MN, Thomas S, Taylor N, Pope J, et al. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. Lancet Oncol. 2021;22(11):1618-31.

6. Lee DJ, Hausler R, Le AN, Kelly G, Powers J, Ding J, et al. Association of Inherited Mutations in DNA Repair Genes with Localized Prostate Cancer. Eur Urol. 2022;81(6):55967.

7. Segal N, Ber Y, Benjaminov O, Tamir S, Yakimov M, Kedar I, et al. Imaging-based prostate cancer screening among BRCA mutation carriers-results from the first round of screening. Ann Oncol. 2020;31(11):1545-52.

8. Paller CJ, Antonarakis ES, Beer TM, Borno HT, Carlo MI, George DJ, et al. Germline Genetic Testing in Advanced Prostate Cancer; Practices and Barriers: Survey Results from the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium. Clin Genitourin Cancer. 2019;17(4):275-82 e1.

9. Carter HB, Helfand B, Mamawala M, Wu Y, Landis P, Yu H, et al. Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer. Eur Urol. 2019;75(5):743-9.

10. Telang JM, Lane BR, Cher ML, Miller DC, Dupree JM. Prostate cancer family history and eligibility for active surveillance: a systematic review of the literature. BJU Int. 2017;120(4):464-7.

11. Clark R, McAlpine K, Fleshner N. A Clinical Trial of Prophylactic Prostatectomy for BRCA2 Mutation Carriers: Is Now the Time? Eur Urol Focus. 2021;7(3):506-7.