More than 12 percent of men with prostate cancer carry an inherited genetic mutation.

“Of the 1162 men in the study, 64 percent had a history of prostate cancer, while 36 percent had a history of prostate cancer and at least one additional cancer. The results showed that 12.1 percent of men with prostate cancer were positive for one or more hereditary cancer mutations in the genes tested. Additionally, the positive rate was significantly higher among men with prostate cancer plus one other cancer (14.7 percent). The inherited mutations were found in genes with a well-known prostate cancer risk (i.e., BRCA2) as well as genes historically associated with other cancer types including breast and colon. These findings suggest that hereditary cancer testing in men with prostate cancer may aid in medical management decision making to reduce overall cancer risk.”

Reid R, et al. Inherited germline mutations in men with prostate cancer. Presented at 2018 Genitourinary Cancer Symposium. J Clin Oncol 2018; 36 (suppl 6S; abstr 357).

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Up to 50% of clinically significant findings missed by single-syndrome testing.

“Multi-gene hereditary cancer testing detected >1 pathogenic variants (PVs) in 6.7% of individuals. PVs were most common in BRCA1 and BRCA2 (42.2%) and 5 additional breast cancer-risk genes (32.9%). Up to 50% of all clinically significant findings would have been missed by single-syndrome testing.”

Rosenthal ET, et al. Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories. Cancer Genetics 2017; 218-219:58-68.

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Germline cancer susceptibility gene mutations found in ~10% of CRC patients.

“Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC [colorectal cancer]. MSI/MMR [microsatellite instability/mismatch repair deficiency] testing reliably identifies LS [Lynch syndrome] probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.”

Yurgelun MB, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J of Clin Onc 2017. J of Clin Onc 2017; 35(10): 1086-95.

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Next generation sequencing (NGS) detects germline and somatic variants.

“Given the significant phenotypic overlap of many hereditary cancer syndromes, NGS panels enable the simultaneous analysis of multiple genes associated with increased cancer risks […]. This enables medical management decisions to be informed by gene-specific guidelines based on known risks associated with germline variants. However, the quantitative nature of NGS also enables the detection of somatic variants that may complicate genetic test interpretation.”

Coffee B, et al. Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel. Cancer Genetics 2017; 211:5-8.

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Prostate cancer is an indication for BRCA and Lynch syndrome testing.

“There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome.”

Giri VN, et al. Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017. JCO 2017.

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Combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients than localized PCa patients.

“…our study provides additional evidence that the mutation status of ATM and BRCA1/2 distinguishes the risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time.”

Na R, et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur Urol. 2017 May;71(5):740-747. doi: 10.1016/j.eururo.2016.11.033. Epub 2016 Dec 15. PubMed PMID: 27989354; PMCID: PMC5535082.

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33.3% of mutation positive patients did not meet testing criteria for gene in which they carried a mutation.

“Multigene panel testing should be considered for all patients with early-onset colorectal cancer.”

Pearlman R, et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol 2017; 3(4):464-71.

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Frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of men with localized prostate cancer.

“…the identification of a germline mutation in a DNA-repair gene provides information that is key to relatives, both male and female, and that can prompt “cascade” counseling to identify cancer predisposition and deploy risk-reduction strategies. Prospective studies assessing the prognostic and predictive significance of mutations in DNA-repair genes with regard to clinical outcomes are now needed to inform personalized care.”

Pritchard CC, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer NEJM 2016 Aug 4;375(5):443-53. doi: 10.1056/NEJMoa1603144. Epub 2016 Jul 6. PubMed PMID: 27433846; PubMed Central PMCID: PMC4986616.

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Testing with a gene panel increased the number of positive test results in ovarian cancer patients by 53.8% over BRCA1/2 testing alone.

“Our results demonstrate the benefits of multigene panels for patients with personal history of ovarian cancer, particularly for the identification of moderate-penetrance mutations that would not otherwise be identified by single-syndrome testing.”

Langer LR, et al. Hereditary cancer testing in patients with ovarian cancer using a 25-gene panel. JCSO 2016 July; 14:314-19.

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Myriad myRisk identified 70% more deleterious mutations than BRCA testing alone, with 42% of these in women over age 45.

“Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group.”

Tung N, et al. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 2016 May 1; 34(13):1460-8.

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Platinum compounds have moderate anti-tumour activity in molecularly unselected patients with advanced prostate cancer.

“…the identification of predictive biomarkers and the clinical evaluation of platinum compounds in molecularly selected patients with advanced prostate cancer is thus important and should be supported to improve the prognosis of these patients.”

Hager S, et al. Anti-tumour activity of platinum compounds in advanced prostate cancer-a systematic literature review. Ann Oncol. 2016 Jun;27(6):975-84. doi: 10.1093/annonc/mdw156. Epub 2016 Apr 6. Review. PubMed PMID: 27052650.

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Panel testing may replace targeted genetic testing.

“Because clinical criteria for Lynch syndrome (LS) analysis appear to identify a substantial number of probands with unexpected actionable mutations in high-penetrance non-LS cancer susceptibility genes, panel testing ultimately may replace targeted genetic testing in patients with suspected LS, except when tumor testing suggests a specific underlying mismatch repair (MMR) mutation.”

Yurgelun MB, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology 2015 Sep; 149(3):604-13.

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Using a panel test could prevent inaccurate, or even limited, family histories from restricting testing options.

“Offering hereditary panel testing as a first and final, ‘single-tier’, option was explored. A ‘two-tiered’ approach, in which panel testing is offered reflexively following stricter criteria, was then applied to the same data. Within our cohort of 105 patients, the single-tier approach was associated with a higher mutation detection rate (6.7% vs 3.8%) and variant of uncertain significance (VUS) rate (0.94 vs 0.23 average per person) compared to a two-tiered approach.”

Yorczyk A, et al. Use of panel tests in place of single gene tests in the cancer genetics clinic. Clin Genet 2015 Sep; 88(3):278-82.

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Clinical implications of the results of multiple studies on gBRCAm in men with and without PCa.

“…men with a suspected or confirmed germline BRCA mutation are a small but clinically important patient group. It is important that we identify the potential BRCA mutation carriers among the great numbers of men with PCa or increased PSA levels in our daily clinical practice, and that we manage them and their families adequately.”

Bratt O, et al. Clinical Management of Prostate Cancer in Men with BRCA Mutations. Eur Urol. 2015 Aug;68(2):194-5. doi: 10.1016/j.eururo.2014.11.005. Epub 2014 Nov 15. PubMed PMID: 25465969.

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Many syndromes present with overlapping cancers – and have no distinct, recognizable phenotypes.

“Our data demonstrate a substantial phenotypic overlap among patients for multiple common inherited cancer syndromes, which likely complicates diagnosis and test selection. This supports the value of multigene panels to identify pathogenic mutations in the absence of a clinically specific phenotype.”

Saam J, et al. Patients tested at a laboratory for hereditary cancer syndromes show an overlap for multiple syndromes in their personal and familial cancer histories. Oncology 2015; 89(5):288-93.

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Panel testing benefits appropriately selected patients.

“The frequency of mutations in genes other than BRCA1/2 was 4.3% in the NGS 25-gene panel, and most mutations (3.9%) were in genes associated with breast/ovarian cancer. Multiple-gene sequencing may benefit appropriately selected patients, especially those with a personal or family history of more than 1 possible genetic syndrome.”

Tung N, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 2015 Jan 1; 121(1):25-33.

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gBRCAm are associated with worse prostate cancer outcomes.

“Our study demonstrates that BRCA carriers treated for localized PCa have worse outcomes than noncarriers because they relapse and progress earlier to lethal metastatic disease.”

Castro E, et al. Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer. Eur Urol. 2015 Aug;68(2):186-93. doi: 10.1016/j.eururo.2014.10.022. Epub 2014 Nov 6. PubMed PMID: 25454609.

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BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis.

“…our results show that a wide spectrum of pathogenic mutations in the BRCA1 and BRCA2 genes confers a more aggressive PCa phenotype with a higher probability of locally advanced and metastatic disease and that the presence of a germline BRCA2 mutation is a prognostic marker associated with poorer survival.”

Castro E, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 May 10;31(14):1748-57. doi: 10.1200/JCO.2012.43.1882. Epub 2013 Apr 8. PubMed PMID: 23569316; PubMed Central PMCID: PMC3641696.

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