Key Points Question What is the clinical utility of genomic profiling for patients with advanced solid tumors? Findings In this cohort study of 1015 patients who underwent integrative genomic profiling, a high rate of pathogenic germline variants and a subset of patients who derive substantial clinical benefit from sequencing information were identified. Meaning These findings support (1) directed germline testing for inherited cancer predisposition in all patients with advanced cancer and (2) use of integrative genomic profiling as a component of standard of care for patients with cancer of unknown origin and other rare malignant neoplasms.

Purpose: Until recently the role of germline genetics in prostate cancer care was not well defined. While important questions remain, we reviewed the current understanding of germline genetic alterations related to prostate cancer. We discuss the clinical implications for genetic counseling, genetic testing, early detection and treatment in men with these mutations. Materials and Methods: We searched PubMedÒ for English language articles published since 2001 with the key words "germline mutations," "BRCA," "family history" or "prostate cancer genetics." We also used relevant data from websites, including the Centers for Medicare and Medicaid Services, National Comprehensive Cancer NetworkÒ, Bureau of Labor Statistics and National Society of Genetic Counselors websites. Results: A number of germline mutations in DNA damage repair genes (BRCA1, BRCA2, CHEK2, ATM and PALB2) and in DNA mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) can drive the development of prostate cancer. Careful genetic counseling coupled with multipanel gene testing can help identify men with these mutations and provide enhanced understanding of the disease risk. Cascade testing of family members can then have an impact extending well beyond the index patient. In men with a pathogenic germline mutation the optimal early detection paradigm is not well defined. Data from the IMPACT study (ClinicalTrials.gov NCT00261456) that the cancer detection rate is substantially elevated in BRCA1 and BRCA2 carriers at prostate specific antigen greater than 3 ng/ml has helped establish the importance of close prostate specific antigen screening in these men. Additionally, BRCA2 and likely other DNA damage repair mutations are associated with aggressive disease, although it is not yet clear how this impacts localized disease management. However, there is strong evidence that patients with metastatic, castration resistant prostate cancer who have DNA damage repair defects respond positively to targeting PARP enzymes. In many cancers there is also evidence that patients with an increased tumor mutational burden, such as in Lynch syndrome, are particularly sensitive to immune checkpoint inhibitors. Conclusions: Emerging evidence supports the implementation of germline genetic counseling and testing as a key component of prostate cancer management. Further research is needed to elucidate the clinical significance of lesser known germline mutations and develop optimal screening, early detection and treatment paradigms in this patient population.

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Purpose: Minimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with Hereditary Paraganglioma-Pheochromocytoma Syndrome. This study aimed to evaluate the SDHx -related tumor detection rate in individuals undergoing clinical screening protocols. Methods: A multi-center retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing. Results: 263 individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n=188/263, 72%), followed by SDHD ( n=35/263, 13%) and SDHC (n=28/263, 11%). SDHx -related tumors were found in 17% (n=45/263) of the cohort. Most SDHx -related tumors were identified on baseline imaging screen (n=39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n=14/35, 40%). Of imaging screens identifying SDHx -related paraganglioma/pheochromocytoma, 29% (n=12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n=75/491) of imaging screens. Conclusion: Current SDHx screening protocols are effective at identifying SDHx -related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.

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