Jewish American Heritage Month

Posted By admin on August 29, 2020

Germline genetic testing is a key component of prostate cancer treatment, and broader testing criteria combined with reduced barriers to these tests could result in better informed care, including preventive surveillance, according to data from a recent study.1

Results from the retrospective study done in a total of 986 patients with prostate cancer who participated in a sponsored testing program showed that 16% (n = 153) of patients who underwent genetic testing had positive germline result; of these patients, 14% (n = 138) had pathogenic (P)/likely pathogenic (LP) variants and 1.5% (n = 15) had increased risk alleles (IRAs). Moreover, these patients were found to have 167 P/LP variants in 31 genes, as well as 19 IRAs in APC and HOXB13.

A total of 129 patients with P/LP variants had staging data available. This information indicated that 70 patients had very high-risk disease (stage III/IV), 23 had high-risk disease (stage III), and 36 had intermediate- to low-risk disease (stage IIa, IIb, and IIc). Among patients who had P/LP variants or risk alleles, only 36% reported having a family history of prostate, breast, ovarian, or pancreatic cancer.

Our initial findings from this study of [patients with] prostate cancer found an overall positive rate of 16% with 75% of positive patients being eligible for implementation of gene-specific management guidelines, precision therapies and/or clinical treatment trials, the study authors wrote. Of patients with P/LP variants, 64% did not have a close family history of prostate, breast, ovarian, or pancreatic cancer, and therefore would not have been eligible for testing based on National Comprehensive Cancer Network (NCCN) criteria.

Current criteria for germline testing in patients who have been diagnosed with prostate cancer may present a barrier to some individuals, especially those who dont have specific features regarding personal or family history, according to the investigators. Previous data have suggested that these testing criteria can exclude patients who actually harbor germline variants, which could potentially lead to suboptimal care.2

To address this, investigators launched a sponsored testing program aimed at increasing access to germline genetic testing for patients with prostate cancer through the utilization of broader criteria and eliminating cost barriers.

The program launched in July 2019 and continued throughout October 2019. Each patient enrolled on the program underwent testing that included an 84-gene, multicancer germline panel. Positive results included P and LP variants as well as IRAs. Of the 986 patients enrolled, the majority, or 70% (n = 692), were Caucasian, 13% were African American (n = 127), 3% were Hispanic (n = 33), 1.7% were Ashkenazi Jewish (n = 17), 1.0% were Asian (n = 10), and the remaining 11% (n = 107) were of unreported, mixed, or other ethnicity.

Additional results showed that when investigators evaluated diagnostic yield by disease stage, the very high-risk subgroup had a positive rate of 16%, the high-risk subgroup had a positive rate of 17%, and the intermediate- to low-risk subgroup had a positive rate of 14%.

Overall, no association of statistical significance was observed between disease stage and germline positive rate. The intermediate-/low-risk patients, who would not be indicated for germline testing based on current guidelines, had a positive rate of 14% (including P/LP variants and IRAs), the study authors wrote. Of the 36 intermediate-/low-risk patients with positive variants, 27(75%) had variants in clinically actionable genes.

Notably, 71% of patients who tested positive had P/LP variants that confers eligibility for gene-specific targeted agents or clinical trials based on variants in homologous repair or mismatch repair genes, the authors added.

These data imply that broader testing criteria could help to better inform care for many patients who might otherwise be overlooked for testing, according to the authors. By reducing barriers to testing, the authors conclude that more patients with prostate cancer would have access to crucial actionable genetic information that could lead to more targeted treatment approaches that could potentially improve outcomes.

New Recommendations Call for Increased Access to Germline Testing

The 2019 Philadelphia Prostate Cancer Consensus Conference, which brought together healthcare experts, stakeholders, and leaders from national organizations, was held to address challenges with germline testing in clinical practice and to map out a framework to increase accessibility to testing in the precision medicine era.

To do this, the panel set 3 goals: to define optimal germline testing approaches that comprise expanded panel testing options and evolving genetic data, to determine consistent germline testing indications and management, and to establish alternative genetic evaluation models in order to compensate for the shortage of genetic counseling services.3

A total of 97 participants attended the conference; these included experts in urology, medical oncology, radiation oncology, clinical genetics, and genetic counseling spaces, among others. In total, 76 participants were included on the final voting panel.

Panel members conducted a literature review with thematic topics that focused on prostate cancer risk, germline mutations by clinical and molecular characteristics of the disease, clinical multigene testing data, germline mutations in diverse populations, genetic testing capabilities and considerations, genetic counseling implementation, NCCN genetic testing guidelines, genetic testing for precision medicine in the metastatic setting, germline implications for active surveillance of early-stage disease, and germline implications for early disease detection.

Large germline panels and somatic testing were recommended for metastatic prostate cancer. Reflex testing to examine priority genes followed by expanded testing was recommended for several scenarios. Investigators determined these priority genes to be BRCA1/2 and mismatch repair genes with regard to metastatic disease treatment, and ATM in broader testing to help determine clinical trial eligibility. Additionally, BRCA2 was suggested for active surveillance discussions.

Upon completion of their review, the panel established criteria for germline prostate cancer genetic testing. Men with metastatic disease, including those with castration-resistant or castration-sensitive prostate cancer, meet the criteria for testing. In order for patients with nonmetastatic disease to be considered for genetic testing, they must either be of Ashkenazi Jewish ancestry, have advanced disease, have intraductal or ductal pathology, or be grade group 4 (Gleason sum 8) or above. Patients who have a brother or father, or 2 or more male relatives, who received a prostate cancer diagnosis and were under 60 years of age, who died from prostate cancer, or who had metastatic disease should also be considered for testing.

For those with metastatic disease, priority germline testing was recommended for those with BRCA1/2, DNA MMR genes, and further gene testing based on family history. Somatic next-generation sequencing was recommended for all men with metastatic disease. Additionally, confirmatory germline testing for somatic mutations was recommended for those with BRCA2 genes.

Reflex testing may be optimal for patients with nonmetastatic disease, according to the panel. with a recommendation to test for BRCA2 variants. For patients without a prostate cancer diagnosis but with an applicable family history, priority genes for risk assessment include BRCA2 and HOXB13.

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Increased Access to Germline Testing Needed in Prostate Cancer - OncLive

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