AUA 2022: Implementation of Germline Testing in Prostate Cancer

(UroToday.com) In a podium presentation at the 2022 Society of Urologic Oncology Meeting held in conjunction with the American Urologic Association Annual Meeting held in New Orleans and virtually, Dr. Giri discussed the implementation of germline testing.

She first addressed the question of the role of germline testing in prostate cancer and clinical implications. In doing so, she began with a discussion of the historical context. Genetic testing for breast and ovarian cancer began in routine clinical practice more than two decades ago. BRCA testing (and other focused gene testing) became standard of care with risk assessment. Shortly thereafter, Lynch Syndrome testing also gained rapid uptake. However, in prostate cancer, this has taken much longer. Testing has also manifested somewhat differently with multigene testing used to inform precision medicine approaches.

 One of the limitations to the adoption of genetic testing in prostate cancer has been an inability to identify common, high prevalence alterations. While pathogenic mutations are seen in 5-7% of patients with early stage disease and 10-15% of those with metastatic disease, a large number of different mutations account for this and the most common of these (eg. BRCA) are found in no more than 4% of patients.

In part for this reason and partly due to the changing landscape of genetic testing, she emphasized that there has been a migration from criteria driven genetic testing to criteria free testing. In the current, criteria free, model, affected patients with relevant tumor types may undergo genetic testing to drive precision therapy, clinical trial eligibility, cancer screening for additional tumor types, and cascade testing.

Among the many identified pathogenic mutations in prostate cancer, Dr. Giri emphasized that there are differential implications. Some of these may provide prognostic information while not being actionable, such as HOXB13. However, others including BRCA1 and 2 may have direct, clinically actionable implications. In most cases, the clinical actionability of these relates to eligibility for novel targeted treatments including PARP inhibitors (in the base of homologous recombination repair deficiency) or immune checkpoint inhibitors (in the case of microsatellite instability). Additionally, they may have implications for clinical trial eligibility.

Dr. Giri, in this context, discussed the results of the PROfound trial, a phase III randomized controlled trial of the PARP inhibitor olaparib. This trial was designed with biomarker inclusion (requiring alterations in one of 15 genes involved in homologous recombination repair) and biomarker stratification (with cohort A defined as those with alterations in BRCA1, BRCA2, or ATM and cohort B comprising the remainder). This study showed a significant benefit to olaparib compared to novel hormonal agent switch and led to FDA approval for this treatment approach in this biomarker selected population.

However, alterations such as BRCA2 may have important implications for patients earlier in the disease trajectory: work from the Johns Hopkins group has shown that for patients otherwise well suited for active surveillance, progression is much more common among those men with BRCA alterations.

 Further, it should be noted that for patients with these alterations, there may be important implications for their family members in a manner that dramatically changes their health care, even when there are not direct, clinically actionable implications for the proband, so called cascade testing. The IMPACT trial has demonstrated that BRCA2 carriers have a higher cancer incidence rate, are diagnosed at a younger age, and are more likely to have clinically significant disease than non-carriers. Thus, among patients with know BRCA2 alterations, the NCCN guidelines recommend starting prostate cancer screening at age 40.

Highlighting that prostate cancer germline testing guidance may come from many guidelines, she emphasized that this is appropriate for patients with metastatic disease, regional/nodal disease, intraductal/cribriform histology, with high and very-high risk localized disease, with Ashkenazi Jewish heritage, or with relevant family history.

Second, she considered the principles of genetic counseling and genetic testing. Traditionally, this has been driven by genetic counselors who provide pre-test counseling followed by a post-test discussion of results and implications. Increasingly, clinicians are taking on the role of pre-test counseling with referral to genetics counselors reserved for those patients with evidence of alterations on testing. Given this increasing burden on clinicians, she cited the recent Philadelphia consensus which provides an implementation framework for prostate cancer genetic evaluation and management. 

Finally, she addressed questions relating to the implementation of genetics care delivery models, highlighting many ongoing efforts and opportunities within her research program. She first noted the helix webtool (helix.guide) which provides provider education and clinical use guidance regarding prostate cancer genetic testing. This tool asks a variety of intake questions regarding patient demographic and disease characteristics to help guide clinicians. It further has education modules to help clinicians develop comfort and familiarity in this area. She then discussed the ENGAGEMENT study which, through recordings of case conferences, allows access to a multi-disciplinary approach to prostate cancer genetics care and a virtual genetics board.

Lastly, she discussed the EMPOWeR study which assessed the role of self-directed pretest video-based genetic education, rather than meeting with a genetics counselor.

Dr. Giri, therefore, concluded that genetic testing has become central to the management of prostate cancer. Understanding when and why it is indicated is critical for all physicians treating prostate cancer. Close collaboration between genetics counselors, oncology, urology, and primary care is critical to manage this rapidly evolving space.