Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer.

OBJECTIVES: To retrospectively evaluate the response to treatment with PC-SPES, an herbal supplement, because patients with androgen-independent prostate cancer have limited treatment options. METHODS: A retrospective analysis was performed of patients with prostate cancer progression despite androgen ablation therapy who were treated with PC-SPES (3 capsules twice daily). We explored potential predictors of response. RESULTS: Twenty-three patients with androgen-independent prostate cancer were treated. The median age was 70 years. Eighteen patients had received prior secondary hormonal treatment and 10 prior chemotherapy. With a median follow-up of 8 months, 20 (87%; 95% confidence interval 66% to 97%) of 23 patients experienced a post-therapy decline in prostate-specific antigen (PSA). The median decline in PSA among these patients was 40% (range 1% to 88%). Of 23 patients, 12 (52%; 95% confidence interval 31% to 73%) had a greater than 50% decline in PSA. The median duration of the PSA response was 2.5 months (range 1 to 9+); the median time from the start of therapy to PSA progression was 6 months (range 2 to 12). Seven patients died of progressive prostate cancer. Toxicity was mild and included nipple tenderness, nausea, and diarrhea. One patient with a known history of coronary artery disease developed angina. In univariate analyses, older patients and those with a longer duration of initial androgen ablation therapy were more likely to respond to PC-SPES. CONCLUSIONS: PC-SPES is a well-tolerated and active treatment for androgen-independent prostate cancer. Additional testing is necessary to identify the active components of PC-SPES and its role in the treatment of patients with androgen-independent prostate cancer.