Individuals with MSH6 and PMS2 mutations may present with HBOC phenotype.

“These results provide a new perspective on Lynch syndrome and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer (HBOC) phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with mismatch repair (MMR) mutations.”

Espenschied CR, et al. Multigene panel testing provides a new perspective on Lynch syndrome. J Clin Oncol 2017, 35.

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Aggressive prostate cancer at early age associated with BRCA1, BRCA2 and ATM.

“Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.”

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. European Urology 2017 May; 71(5): 740-7. doi: 10.1016/j.eururo.2016.11.033.

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Aggressive prostate cancer at early age associated with BRCA1, BRCA2 and ATM.

“Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.”

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. European Urology 2017 May; 71(5): 740-7. doi: 10.1016/j.eururo.2016.11.033.

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Multigene panels should be used for the assessment of cancer risk beyond the classic predisposition syndromes.

“The use of multigene testing in the clinical setting will better define both the optimal care of patients with cancer (management of the primary cancer; definition of risk of second malignancies; and assignment of specific treatments like PARP inhibitors) and the management of unaffected individuals (earlier surveillance, chemoprevention and/or prophylactic surgery).”

Graffeo R, et al. Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care. Breast Cancer Res Treat 2016 Dec; 160(3):393-410. Epub 2016 Oct 12.

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“Canonical” genetic workup fails to detect patients with other mutations.

“The findings of this large population-based study [Pearlman R, et al.] demonstrate that the incorporation of multigene panel genetic testing in the evaluation of patients with CRC [colorectal cancer] will increase the diagnosis of individuals with genetic predisposition to cancer and will expand current knowledge regarding the associated phenotypes, further supporting the cost-effectiveness of testing that can guide management for patients with cancer and their at-risk relatives.”

Vilar E and Stoffel EM, et al. Universal genetic testing for younger patients with colorectal cancer. JAMA Oncol 2016 Dec 15. doi:10.1001/jamaoncol.2016.5193.

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Clinical utility of panel testing in BRCA negative patients.

“This study demonstrates the clinical utility of multigene panels in a group of high risk individuals who previously tested negative for a BRCA1/2 mutation. This retesting approach revealed a pathogenic mutation in 11% of cases. Retesting led to significant change in clinical management in a majority of patients with actionable mutations (7 out of 11), as well as in those with mutations in genes which do not have specific management guidelines.”

Yadav S, et al. Outcomes of retesting BRCA negative patients using multigene panels. Fam Cancer 2016 Nov 22; 16(3): 319-28. doi:10.1007/s10689-016-9956-7.

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Up to 79% of women from BRCA negative families desire multiplex genetic testing.

“Female first-degree relatives of breast cancer patients who tested negative for BRCA1/2 mutations (N = 149) completed a survey assessing multiplex genetic testing interest and risk communication preferences. Interest in testing was high (70%) and even higher if results could guide risk-reducing behavior changes such as taking medications (79%).”

Flores KG, et al. Factors associated with interest in gene-panel testing and risk communication preferences in women from BRCA1/2 negative families. J Genet Counsel 2016 Aug; 26(3): 480-90. doi:10.1007/s10897-016-0001-7.

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70% of physicians changed management based on panel results.

“Multi-gene panel testing increases the yield of mutations detected and adds to the capability of providing individualized cancer risk assessment.”

Ricker C, et al. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Genetics 2016 April; 209(4):130-7.

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RAD51C and RAD51D genes play a role in invasive EOC.

“[…] results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of epithelial ovarian cancer (EOC) that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.”

Song H, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol 2015 Sept; 33(26):2901-14.

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Several genes beyond BRCA1 and 2 have robust evidence associating them with breast cancer risk.

“We have […] reviewed the genes for which the evidence of association with breast cancer is sufficiently robust to be incorporated into personalized risk prediction.”

Easton DF, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015 Jun; 372:2243-225.

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Appropriate surgical intervention improves overall survival.

“We conclude that contralateral risk-reducing mastectomy is associated with improved overall survival in BRCA1/2 mutation carriers with a history of primary breast cancer.”

Heemskerk-Gerritsen, et al. Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer 2015 Feb; 136(3):668-77.

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PALB2 mutation carriers have a significant increased risk of breast cancer.

“Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.”

Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014 Oct;
371(6):497-506.

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Testing beyond a negative BRCA 1/2 result using multi-gene sequencing leads to greater detection of pathogenic mutations.

“Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp.”

Kurian AW, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014 Jul 1; 32(19):2001-9.

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Greater sensitivity prevents more cancer, saving healthcare dollars.

“Compared with alternative tests, using BRACAnalysis® would save $624,000 and prevent 9 [breast cancer] and/or [ovarian cancer] cases per year for a 1-million member health system.”

Stenehjem D, et al. Economic analysis of alternative genetic tests for BRCA1 and BRCA2 mutations. Scientific poster presented at the 31st Annual Breast Cancer Conference in Miami, FL, March 2014.

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Appropriate prophylactic surgery improves survival rates.

“This study suggests that women who are positive for BRCA mutations and who are treated for stage I or II breast cancer with bilateral mastectomy are less likely to die from breast cancer than women who are treated with unilateral mastectomy.”

Metcalfe K, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. BMJ 2014 Feb; 348:g226.

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Oophorectomy reduces risk of ovarian, fallopian tube, or peritoneal cancer in women with a BRCA1 or BRCA2 mutation.

“Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.”

Finch APM, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014 May; 32(15): 1547-53.

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Panel testing for multiple genes saves thousands of healthcare dollars – and identifies more genes contributing to ovarian cancers.

“More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.”

Walsh T, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011 Nov 1; 108(44):18032-7.

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Risk-reducing surgery improves mortality rates.

“Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.”

Domcheck S, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010; 304(9):967-75.

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