PCA 2020: Prostate Cancer Genetics: Heritable Causes that Impact Treatment

Atlanta, Georgia (UroToday.com) Dr. Edward Schaeffer of Northwestern University in Chicago, Illinois, presented on "Prostate Cancer Genetics: Heritable Causes that Impact Treatment" at the 2020 Prostate Cancer Academy.

Dr. Schaeffer started his talk by differentiating somatic and germline mutations. Somatic mutations occur in non-germline tissues and they are not inherited, accounting for sporadic cancers which are 90 to 95% of cancers. On the other hand, germline mutations occur initially in eggs and sperm and are heritable, with mutation being present in all body cells, and they account for 5-10% of cancers in the population. He then summarized the features of hereditary cancer syndromes, which includes early age of diagnosis, multiple generations affected with cancer, multiple primary cancers in a single individual, same or related cancers in two-plus close relatives, rare cancers or tumors, and lastly, known cultural or ancestry groups at higher risk. Dr. Schaeffer then explained how BRCA2 germline mutations lead to prostate cancer development, with the second hit occurring in prostatic epithelial cells. He then mentioned that for somatic testing, a biopsy of the tissue is needed, and identifying these mutations could have utility at various stages of treatment. 

Dr. Schaeffer then talked about the role of germline screening in affected individuals as it could reduce the risk of other cancers with augmented screening, may affect treatment options, or alter surgical management. In unaffected individuals, Germline screening could improve screening requirements, manage anxiety, or alter risk reduction strategies. Urologists are already identifying at-risk patients with family history and are well suited to offer the tests available within their institution.

Dr. Schaeffer then discussed the mutations in patients with an early onset of prostate cancer. HOXB13 mutation is one such mutation present with strong family history and manifests at a younger age, but there is no difference in pathologic grade or stage. The other mutations which affect prostate cancer are alterations in DNA repair pathways such as BRCA1 and 2 and MSH2. He then described the association of BRCA1 and 2 mutations with increased risk of prostate cancer and pointed out that these mutations are associated with poor clinical outcomes and are associated with increased nodal status, relapse, and death, especially with BRCA2. He then highlighted a multi-center study that showed 12% of men with metastatic prostate cancer have germline mutations in DNA repair genes regardless of age or family history of prostate cancer, and approximately 5% of men with high risk localized cancer have these mutations. Genetic testing in men with high-risk localized or metastatic prostate cancer may allow them to act as sentinels for their family members. 

Dr. Schaeffer then summarized the PROfound trial, which compared olaparib for metastatic castration-resistant prostate cancer (mCRPC) to enzalutamide or abiraterone. All men included in the study had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination. Cohort A had ≥1 alteration in BRCA1, BRCA2, or ATM, while Cohort B had alterations in any of 12 other prespecified genes. Improved progression-free survival and overall survival for patients were noted on olaparib, especially in cohort A.

He then talked about the open-label Phase II TRITON2 trial, which looked at rucaparib in men with mCRPC associated with DNA damage response (DDR) deficiency. One hundred and ninety patients had received rucaparib with a median follow-up of 13.1 months. Of these 190 patients, 98 patients had BRCA1 or 2 alterations, and among these patients overall, 52% prostate-specific antigen (PSA) response rate was noted. Fourty-three point nine percent of patients had a confirmed overall response rate and durable responses, with the majority lasting more than 24 weeks. The overall response rate was poor for other patients. He also mentioned that these drugs come with significant side effects, particularly hematologic and nausea, decreased appetite, and fatigue. Based on these remarkable trials, olaparib and rucaparib were granted FDA approval.

Dr. Schaeffer then highlighted a study by Dr. Carter that looked at 1,200 patients in two active surveillance cohorts and found that BRCA1, 2, ATM carriers are rare. Only 26 patients were carriers for these mutations, but these mutation carriers are likely to be upgraded in surveillance to Gleason grade 2 or higher. Continuing surveillance in these mutation carriers is debatable. He also highlighted that Lynch syndrome patients are associated with an increased risk of prostate and urothelial cancer. Lynch syndrome is a mutation in mismatch repair typically associated with increased colorectal, urothelial, gastric cancer. The National Comprehensive Cancer Network (NCCN) guidelines now recommend considering genetic testing for all men with high risk localized to metastatic prostate cancer. The NCCN also recommends consideration of testing for any prostate cancer if there is a strong family history.    

Dr. Schaeffer then concluded his summary of genetic testing in prostate cancer with the slide, as shown below.

genetic screening in prostate cancer

Presented by: Edward M. Schaeffer, MD, PhD, Chair, Department of Urology, Edmund Andrews Professor of Urology, Professor of Urology, Northwestern School of Medicine, Chicago, Illinois

Written by: Abhishek Srivastava, MD, Urologic Oncologist, Atlantic Urology Clinics and Carolina Urology Research Center, Myrtle Beach, South Carolina, Twitter: @shekabhishek at the 2020 Prostate Cancer Academy, October 1st - 3rd, 2020 in Atlanta, Georgia