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      Consensus Guidelines on Genetic` Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons


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          The purpose of this consensus guideline is to outline recommendations for genetic testing that medical professionals can use to assess hereditary risk for breast cancer.


          Literature review included large datasets, basic and clinical science publications, and recent updated national guidelines. Genetic testing to assess hereditary risk of cancer is a complex, broad, and dynamic area of medical research. The dominant focus of this guideline is limited in scope to breast cancer.


          There is a lack of consensus among experts regarding which genes among many should be tested in different clinical scenarios. There is also variation in the degree of consensus regarding the understanding of risk and appropriate clinical management of mutations in many genes.


          Genetic testing should be made available to all patients with a personal history of breast cancer. Recent data are reviewed that support genetic testing being offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment recommendations. Patients who had genetic testing previously may benefit from updated testing. Genetic testing should be made available to patients without a history of breast cancer who meet National Comprehensive Cancer Network guidelines. Finally, variants of uncertain significance are not clinically actionable and these patients should be managed based on their individual risk factors.

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          Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations.

          Data concerning the efficacy of bilateral prophylactic oophorectomy for reducing the risk of gynecologic cancer in women with BRCA1 or BRCA2 mutations are limited. We investigated whether this procedure reduces the risk of cancers of the coelomic epithelium and breast in women who carry such mutations. A total of 551 women with disease-associated germ-line BRCA1 or BRCA2 mutations were identified from registries and studied for the occurrence of ovarian and breast cancer. We determined the incidence of ovarian cancer in 259 women who had undergone bilateral prophylactic oophorectomy and in 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. The length of postoperative follow-up for both groups was at least eight years. Six women who underwent prophylactic oophorectomy (2.3 percent) received a diagnosis of stage I ovarian cancer at the time of the procedure; two women (0.8 percent) received a diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9 percent) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. With the exclusion of the six women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial cancer (hazard ratio, 0.04; 95 percent confidence interval, 0.01 to 0.16). Of 99 women who underwent bilateral prophylactic oophorectomy and who were studied to determine the risk of breast cancer, breast cancer developed in 21 (21.2 percent), as compared with 60 (42.3 percent) in the control group (hazard ratio, 0.47; 95 percent confidence interval, 0.29 to 0.77). Bilateral prophylactic oophorectomy reduces the risk of coelomic epithelial cancer and breast cancer in women with BRCA1 or BRCA2 mutations.
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            Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.

            Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample. Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants. In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes. 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. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients. © 2014 by American Society of Clinical Oncology.
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              Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing.

              Inherited loss-of-function mutations in the tumor suppressor genes BRCA1, BRCA2, and multiple other genes predispose to high risks of breast and/or ovarian cancer. Cancer-associated inherited mutations in these genes are collectively quite common, but individually rare or even private. Genetic testing for BRCA1 and BRCA2 mutations has become an integral part of clinical practice, but testing is generally limited to these two genes and to women with severe family histories of breast or ovarian cancer. To determine whether massively parallel, "next-generation" sequencing would enable accurate, thorough, and cost-effective identification of inherited mutations for breast and ovarian cancer, we developed a genomic assay to capture, sequence, and detect all mutations in 21 genes, including BRCA1 and BRCA2, with inherited mutations that predispose to breast or ovarian cancer. Constitutional genomic DNA from subjects with known inherited mutations, ranging in size from 1 to >100,000 bp, was hybridized to custom oligonucleotides and then sequenced using a genome analyzer. Analysis was carried out blind to the mutation in each sample. Average coverage was >1200 reads per base pair. After filtering sequences for quality and number of reads, all single-nucleotide substitutions, small insertion and deletion mutations, and large genomic duplications and deletions were detected. There were zero false-positive calls of nonsense mutations, frameshift mutations, or genomic rearrangements for any gene in any of the test samples. This approach enables widespread genetic testing and personalized risk assessment for breast and ovarian cancer.

                Author and article information

                Ann Surg Oncol
                Ann. Surg. Oncol
                Annals of Surgical Oncology
                Springer International Publishing (Cham )
                24 July 2019
                24 July 2019
                : 26
                : 10
                : 3025-3031
                [1 ]ISNI 0000 0004 0448 5156, GRID grid.414134.7, Department of Surgery, , Hamilton Medical Center, ; Dalton, GA USA
                [2 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department Breast Surgical Oncology, , MD Anderson Cancer Center, ; Houston, TX USA
                [3 ]GRID grid.431068.8, Reinsch Pierce Family Center for Breast Health, , Virginia Hospital Center, ; Arlington, VA USA
                [4 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Surgical Oncology, , Massachusetts General Hospital, ; Boston, MA USA
                [5 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Surgery, , Mayo Clinic, ; Rochester, MN USA
                [6 ]ISNI 0000 0001 2192 2723, GRID grid.411935.b, Department of Surgery, , Johns Hopkins Hospital, ; Baltimore, MD USA
                [7 ]ISNI 0000 0004 1937 0423, GRID grid.471368.f, Department of Surgery, , Mount Sinai Beth Israel, ; New York, NY USA
                [8 ]Texas Health Physicians Group, Dallas, TX USA
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                : 18 April 2019
                Breast Oncology
                Custom metadata
                © Society of Surgical Oncology 2019

                Oncology & Radiotherapy
                Oncology & Radiotherapy


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