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Hereditary Cancer Syndromes—A Primer on Diagnosis and Management

Part 1: Breast-Ovarian Cancer Syndromes

      Abstract

      Cancer is the second leading cause of death in both men and women in the United States, with colorectal cancer and breast cancer being two of the most frequent cancer types. Hereditary causes occurring due to pathogenic sequence variants and defects in certain genes makes up roughly 5% of all colorectal cancers and breast-ovarian cancers. High-risk hereditary predisposition syndromes have been associated with a substantially increased lifetime risk for the development of colorectal cancers and breast-ovarian cancers depending on the genetic syndrome, and many people also carry an increased risk of several other cancers compared with the general population. The aim of this review was to provide comprehensive literature on the most commonly encountered hereditary predisposition syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, hamartomatous polyposis, and breast-ovarian cancer conditions. This will be presented as a 2-part series: the first part will cover the breast-ovarian cancer syndromes, and the second will focus on the inherited colorectal cancer and polyposis conditions.

      Abbreviations and Acronyms:

      ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles), ER (estrogen receptor), FDA (Food and Drug Administration), HBOC (hereditary breast-ovarian cancer), HER2 (human epidermal growth factor receptor 2), LFS (Li-Fraumeni syndrome), LS (Lynch syndrome), MMR (mismatch repair), MRI (magnetic resonance imaging), NCCN (National Comprehensive Cancer Network), PARP (poly(ADP-ribose) polymerase), VUS (variant of uncertain significance)
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      Learning Objectives: On completion of this article, you should be able to (1) differentiate between the most common clinically encountered hereditary colorectal cancer and polyposis syndromes, (2) recognize the genetic cause and associated cancer risk with these syndromes, and (3) apply cancer screening/surveillance recommendations in this high-risk population.
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      In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Jenna M. Pederson, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Samadder is a consultant for Cook Medical, Cancer Prevention Pharmaceuticals, and Janssen Research and Development. The other authors report no competing interests.
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      In the absence of any known genetic alterations, 25% to 30% of patients with colorectal and breast-ovarian cancers have a family member with the same cancer diagnosis. High-risk hereditary predisposition syndromes have been associated with a 60% to 100% lifetime risk of development of colorectal cancers and breast-ovarian cancers.
      • Kanth P.
      • Grimmett J.
      • Champine M.
      • Burt R.
      • Samadder N.J.
      Hereditary colorectal polyposis and cancer syndromes: a primer on diagnosis and management.
      Many people also carry an increased risk of several other cancers. Given the markedly increased risk of cancer, patients with a genetic predisposition are advised to follow a rigorous surveillance protocol managed by genetic counselors.
      • Kanth P.
      • Grimmett J.
      • Champine M.
      • Burt R.
      • Samadder N.J.
      Hereditary colorectal polyposis and cancer syndromes: a primer on diagnosis and management.
      The aim of this review was to provide comprehensive literature on the most commonly encountered hereditary breast-ovarian cancer (HOBC) syndromes including BRCA (for expansion of gene symbols, use search tool at www.genenames.org). We highlight the use of imaging, risk-reducing surgery, and potential chemoprevention strategies for the reduction of cancer in these conditions. Readers are also provided with best practice recommendations including optimal collaboration with genetic counseling services to manage this population with high-risk cancer. Many of the recommendations in this article are based on the National Comprehensive Cancer Network (NCCN) guidelines.
      • Zhang S.
      • Folsom A.R.
      • Sellers T.A.
      • Kushi L.H.
      • Potter J.D.
      Better breast cancer survival for postmenopausal women who are less overweight and eat less fat: the Iowa Women’s Health Study.
      Table 1 provides an overview of the cancer syndromes discussed in this review, along with their genetic cause, cancer risks, and screening/surveillance recommendations. The management of patients with hereditary cancer syndromes is best performed with a multidisciplinary approach involving medical, surgical, and genetic specialties.
      Table 1Cancer Risks, Genes Associated, and Recommendations for the Management of Hereditary Breast-Ovarian Cancer Syndromes
      SyndromeGene(s)Lifetime cancer risks (%)Screening/surveillancePreventive surgery
      HBOC syndromeBRCA1
      • Easton D.F.
      • Pharoah P.D.
      • Antoniou A.C.
      • et al.
      Gene-panel sequencing and the prediction of breast-cancer risk.
      • Couch F.J.
      • Shimelis H.
      • Hu C.
      • et al.
      Associations between cancer predisposition testing panel genes and breast cancer.
      Breast

      Ovarian

      Prostate
      • Levy-Lahad E.
      • Friedman E.
      Cancer risks among BRCA1 and BRCA2 mutation carriers.
      67-72

      4-45

      5-7
      Self breast examination beginning at age 18 y in women (at age 35 y in men)

      Clinical breast examination every 6 mo beginning at age 25 y in women (annual examination beginning at age 35 y in men)

      Breast MRI annually in women at ages 25-29 y

      Breast MRI and mammography annually at ages 30-75 y

      Consider transvaginal ultrasound and serum CA-125 annually, beginning at ages 30-35 y

      Consider prostate cancer screening in men beginning at age 45 y
      Risk-reducing bilateral mastectomy

      Risk-reducing salpingo-oophorectomy between ages 35 and 40 y (and after the completion of childbearing)
      BRCA2
      • Easton D.F.
      • Pharoah P.D.
      • Antoniou A.C.
      • et al.
      Gene-panel sequencing and the prediction of breast-cancer risk.
      • Couch F.J.
      • Shimelis H.
      • Hu C.
      • et al.
      Associations between cancer predisposition testing panel genes and breast cancer.
      Breast

      Ovarian

      Prostate

      Melanoma

      Pancreatic
      • Couch F.J.
      • Johnson M.R.
      • Rabe K.G.
      • et al.
      The prevalence of BRCA2 mutations in familial pancreatic cancer.


      Gall bladder
      66-69

      12-17
      Self breast examination beginning at age 18 y

      Clinical breast examination every 6 mo beginning at age 25 y

      Breast MRI annually at ages 25-29 y

      Breast MRI and mammography annually at ages 30-75 y

      Prostate cancer screening in men beginning at age 45 y

      Consider skin and eye examination for melanoma

      Consider transvaginal ultrasound and serum CA-125 annually, beginning at ages 30-35 y
      Risk-reducing bilateral mastectomy

      Risk-reducing salpingo-oophorectomy between ages 35 and 45 y (and after the completion of childbearing)
      HDGC syndromeCDH1Gastric

      Lobular breast
      80

      39-52
      Endoscopic screening not effective

      Mammography and MRI every 12 mo, beginning at 30 or 10 y before the earliest diagnosis in the family
      Prophylactic total gastrectomy

      Consider risk-reducing mastectomy
      LFS
      • Mai P.L.
      • Best A.F.
      • Peters J.A.
      • et al.
      Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort.
      TP53Breast

      Soft tissue sarcoma

      Brain

      Osteosarcoma
      54

      15

      6

      5
      Self breast examination beginning at age 18 y

      Clinical breast examination every 6 mo beginning at ages 20-25 y, annual physical examination including skin assessment

      Breast MRI annually at ages 20-29 y

      Breast MRI and mammography annually at ages 30-75 y

      Colonoscopy every 2-5 y beginning at age 25 y (or 5 y before the earliest onset of colon cancer in a family member)
      Consider risk-reducing mastectomy
      CA-125 = cancer antigen 125; HBOC = hereditary breast and ovarian cancer; HDGC = hereditary diffuse gastric cancer; LFS = Li-Fraumeni syndrome; MRI = magnetic resonance imaging.

      Clinical Approach to Genetic Referral and Evaluation

      Genetic testing has become a mainstream approach for identifying syndromes predisposing people to gastrointestinal and breast-ovarian cancers. Up to 10% of all gastrointestinal and breast and ovarian cancers are attributed to well-defined inherited syndromes, including Lynch syndrome (LS), familial adenomatous polyposis, MUTYH-associated polyposis, several hamartomatous polyposis conditions, and HBOC syndromes. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate screening, surveillance, and interventions to help prevent the development of malignant tumors.
      Identifying good candidates for molecular genetic testing depends in part on the hereditary syndrome and its specific phenotype. Individuals with no personal history of cancer but with a known family history of early-onset (<60 years of age) breast, ovarian, endometrial, or colorectal cancer should be referred for genetic testing. Patients with established cancers with high-risk qualities such as triple-negative status in breast cancer and synchronous or metachronous lesions should be further assessed for the presence of hereditary syndromes. The clustering of multiple cancers in 2 or 3 successive generations can also be a clue to clinicians about the possibility of an underlying hereditary syndrome. Finally, the presence of certain rare tumor types—ureteral cancers, sebaceous carcinoma, or diffuse gastric cancer—should prompt referral for genetic evaluation.

      Understanding Genetic Testing

      Genetic testing methods are continuously improving to establish diagnosis and identify at-risk relatives before the onset of cancer. Genetic testing is most often performed on a blood sample, but also can occur via saliva/buccal swab or skin biopsy. A skin biopsy is preferred in patients who have undergone an allogeneic stem cell transplant.
      If no disease-causing sequence variant is found in the index case, genetic testing is not indicated for this patient or his or her family. In this case, management must be based solely on clinical grounds. If a disease-causing pathogenic mutation is present in the index case, other family members can be tested for that specific mutation with virtually 100% accuracy. This “mutation or site-specific testing” can determine which other members require more aggressive surveillance.
      • Zhang S.
      • Folsom A.R.
      • Sellers T.A.
      • Kushi L.H.
      • Potter J.D.
      Better breast cancer survival for postmenopausal women who are less overweight and eat less fat: the Iowa Women’s Health Study.
      Finally, testing reports may identify “variants of uncertain significance” (VUS), whose clinical implications are not yet understood. In this case, the patient must be managed on clinical grounds.

      Hereditary Breast and Ovarian Cancer Syndromes

      Overview

      Most breast and ovarian cancers are sporadic (nonfamilial), with inherited predisposition syndromes accounting for 10% to 15% of breast cancers.
      Collaborative Group on Hormonal Factors in Breast Cancer
      Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101,986 women without the disease.
      • Pruthi S.
      • Gostout B.S.
      • Lindor N.M.
      Identification and management of women with BRCA mutations or hereditary predisposition for breast and ovarian cancer.
      Of the hereditary breast and ovarian cancer syndromes, a specific pathogenic mutation is identified approximately 30% of the time, most commonly in BRCA1 or BRCA2.
      • Couch F.J.
      • Nathanson K.L.
      • Offit K.
      Two decades after BRCA: setting paradigms in personalized cancer care and prevention.
      Germline pathogenic mutations in BRCA1 or BRCA2 (collectively referred to as BRCA), are autosomal dominant, highly penetrant, and the focus of this section. Furthermore, several syndromes, including Li-Fraumeni, Peutz-Jeghers, Cowden, and Lynch syndromes, are discussed because of their association with increased breast cancer risk.

      Genetics and Diagnosis

      BRCA1 and BRCA2 encode tumor suppressor proteins.
      • Farmer H.
      • McCabe N.
      • Lord C.J.
      • et al.
      Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
      As most patients with breast or ovarian cancer do not have an HBOC susceptibility syndrome, appropriate selection of patients for genetic testing is prudent (see NCCN guidelines in Table 2).
      • Daly M.B.
      • Pilarski R.
      • Berry M.
      • et al.
      NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast And Ovarian, Version 2.2017.
      • Hampel H.
      • Bennett R.L.
      • Buchanan A.
      • Pearlman R.
      • Wiesner G.L.
      Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee
      A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
      Table 2Indications to Consider Testing for Hereditary Predisposition Breast and Ovarian Cancer Syndromes
      • Daly M.B.
      • Pilarski R.
      • Berry M.
      • et al.
      NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast And Ovarian, Version 2.2017.
      • Hampel H.
      • Bennett R.L.
      • Buchanan A.
      • Pearlman R.
      • Wiesner G.L.
      Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee
      A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
      In individuals with a personal history of cancer
      • Breast cancer diagnosed at ≤50 y
      • Triple-negative breast cancer diagnosed at ≤60 y
      • Male breast cancer
      • Two primary breast cancers in the same individual
      • Breast cancer and pancreatic or gastric cancer in the same individual
      • High-risk family history, defined as any of the following: ◦ ≥1 close relative
        Close relative = first-, second-, and third-degree blood relatives on both maternal and paternal sides.
        with breast cancer at ≤50 y
        • ≥1 close relative
          Close relative = first-, second-, and third-degree blood relatives on both maternal and paternal sides.
          with invasive ovarian cancer
        • ≥2 close relatives
          Close relative = first-, second-, and third-degree blood relatives on both maternal and paternal sides.
          with breast and/or pancreatic cancer
      • Ashkenazi Jewish ancestry
      In individuals with no personal history of cancer
      • A close relative with any of the following: ◦ Known mutation in a cancer susceptibility gene
        • ≥2 Breast cancer primaries in the same individual
        • Ovarian cancer
        • Male breast cancer
        • ≥2 Close relatives with breast and/or pancreatic cancer
      a Close relative = first-, second-, and third-degree blood relatives on both maternal and paternal sides.
      A personalized genetic risk assessment incorporating pedigree analysis, personal and family histories, and statistical models can further estimate the risk of developing cancer and harboring a heritable genetic pathogenic mutation. The Claus model predicts the risk of cancer in unaffected female relatives.
      • Claus E.B.
      • Risch N.
      • Thompson W.D.
      Autosomal dominant inheritance of early-onset breast cancer: implications for risk prediction.
      The BRCAPRO model uses a Bayesian approach to estimate the probability of identifying BRCA1 or BRCA2 pathogenic mutations.
      • Berry D.A.
      • Parmigiani G.
      • Sanchez J.
      • Schildkraut J.
      • Winer E.
      Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history.
      • Chen S.
      • Parmigiani G.
      Meta-analysis of BRCA1 and BRCA2 penetrance.
      The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm risk prediction model estimates both the probability of identifying a BRCA pathogenic sequence variant and age-specific risks of developing breast and ovarian cancer.
      • Lee A.J.
      • Cunningham A.P.
      • Kuchenbaecker K.B.
      • Mavaddat N.
      • Easton D.F.
      • Antoniou A.C.
      Consortium of Investigators of Modifiers of BRCA1/2Breast Cancer Association Consortium
      BOADICEA breast cancer risk prediction model: updates to cancer incidences, tumour pathology and web interface.
      Although each model has particular strengths and weaknesses, these risk prediction tools are comparable in terms of performance.
      • Amir E.
      • Freedman O.C.
      • Seruga B.
      • Evans D.G.
      Assessing women at high risk of breast cancer: a review of risk assessment models.
      More than 1800 distinct variants have been reported for BRCA1 and 2000 variants for BRCA2.
      • Couch F.J.
      • Nathanson K.L.
      • Offit K.
      Two decades after BRCA: setting paradigms in personalized cancer care and prevention.
      The magnitude of risk (penetrance) of developing breast or ovarian cancer depends on the location and type of a particular mutation, co-occurring single-nucleotide polymorphisms, ethnicity, and environmental factors.
      Testing for hereditary susceptibility syndromes has evolved considerably since 1995, when clinically available BRCA mutation testing detected 85% of point mutations, small insertions and deletions in the BRCA1/2 genes. Since 2006, testing for large-scale deletions or rearrangements has also been possible.
      • Judkins T.
      • Rosenthal E.
      • Arnell C.
      • et al.
      Clinical significance of large rearrangements in BRCA1 and BRCA2.
      The single-gene testing strategy is still useful in select circumstances, but the advent of multigene testing panels and next generation sequencing now allow for the simultaneous assessment of multiple cancer predisposition genes for only marginally more money. After the 2013 US Supreme Court decision invalidating patents on specific genes, the number of commercially available laboratory tests blossomed.
      • Cook-Deegan R.
      • Niehaus A.
      After Myriad: genetic testing in the wake of recent supreme court decisions about gene patents.
      In the United States, there are 93 clinically available Clinical Laboratory Improvement Amendments–certified tests for diagnosing hereditary breast and ovarian cancer syndromes. Important factors in the use of these tests include institutional availability, the number of genes included in the test, depth and coverage of genes of interest, detection rates, inclusion of large rearrangements, and finally the test costs and insurance coverage. A positive test result indicates that a pathogenic mutation was identified in BRCA1, BRCA2, or other hereditary predisposition genes. Many moderate-penetrance genes are often included, but the optimal strategy for managing carriers of moderate-penetrance mutations is often unclear. Table 3 provides estimated risks of breast and ovarian cancer associated with pathogenic mutations in various hereditary cancer genes.
      Table 3Estimated Risks of Breast and Ovarian Cancer Associated With Mutations in Hereditary Cancer Panel Genes
      From JAMA Oncol.,
      • Couch F.J.
      • Shimelis H.
      • Hu C.
      • et al.
      Associations between cancer predisposition testing panel genes and breast cancer.
      with permission.
      GeneAmbry Genetics Inc casesExAC
      ExAC = Exome Aggregation Consortium; OR = odds ratio.
      controls
      Cancer risk
      No. of mutated allelesNo. of casesMutation frequency (%)No. of mutated allelesNo. of casesMutation frequency (%)OR (95% CI)P value
      ATM27429,2290.949026,6440.342.78 (2.22-3.62)2.42×10−19
      BARD15228,5360.182226,0780.082.16 (1.31-3.63)2.26×10−3
      BRIP17128,5360.254126,8400.151.63 (1.11-2.41).01
      CDKN2A684570.07724,3120.032.47 (0.83-8.16).11
      CHEK242429,0901.4616325,2150.652.26 (1.89-2.72)1.75×10−20
      CHEK2 1100delC33829,0901.1612725,2150.502.31 (1.88-2.85)3.04×10−17
      CHEK2*
      CHEK2*: Inclusion of common missense variants p.Il3157Thr and p.Ser428Phe.
      72129,0902.4842425,2151.681.48 (1.31-1.67)1.11×10−10
      MLH1415,4750.03626,6390.021.15 (0.30-4.19)>.99
      MRE11A2128,5360.072326,7670.090.86 (0.46-1.57).65
      MSH2915,4750.06625,3290.022.46 (0.81-6.93).11
      MSH63215,4750.212826,1510.111.93 (1.16-3.27).01
      NBN4828,5360.173926,2640.151.13 (0.73-1.75).59
      NF12725,9500.102926,1300.110.94 (0.55-1.62).89
      PALB224130,0250.802926,8690.117.46 (5.12-11.19)4.31×10−38
      PMS21715,4750.113324,6740.130.82 (0.44-1.47).56
      RAD504528,5360.165426,4740.200.77 (0.52-1.61).23
      RAD51C2628,5360.093126,6470.120.78 (0.47-1.37).43
      RAD51D1825,9500.07626,5550.023.07 (1.21-7.88).01
      a ExAC = Exome Aggregation Consortium; OR = odds ratio.
      b CHEK2*: Inclusion of common missense variants p.Il3157Thr and p.Ser428Phe.

      Epidemiology and Clinical Presentation

      Because of different methodologies and populations, there is a high variability in the estimated prevalence of BRCA1 and BRCA2 pathogenic mutations. In the United States, the carrier rate of BRCA mutations is approximately 1 in 400.
      • McClain M.R.
      • Palomaki G.E.
      • Nathanson K.L.
      • Haddow J.E.
      Adjusting the estimated proportion of breast cancer cases associated with BRCA1 and BRCA2 mutations: public health implications.
      The prevalence is 10 times higher in the Ashkenazi Jewish population.
      • Roa B.B.
      • Boyd A.A.
      • Volcik K.
      • Richards C.S.
      Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2.
      Among BRCA mutation carriers, the mean cumulative risk of developing breast cancer by the age of 80 is 67% to 72% in BRCA1 carriers and 66% to 69% in BRCA2 carriers.
      • Hartmann L.C.
      • Lindor N.M.
      The role of risk-reducing surgery in hereditary breast and ovarian cancer.
      • Kuchenbaecker K.B.
      • Hopper J.L.
      • Barnes D.R.
      • et al.
      Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
      The peak incidence of breast cancer occurs slightly earlier for BRCA1 mutations (ages 41-50 years compared with ages 51-60 years in BRCA2 carriers).
      • Kuchenbaecker K.B.
      • Hopper J.L.
      • Barnes D.R.
      • et al.
      Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
      The histologic subtypes of breast cancers vary considerably by BRCA gene mutation. Nearly 70% of tumors that develop in BRCA1 carriers are estrogen receptor (ER) negative, progesterone receptor negative, and human epidermal growth factor receptor 2 (HER2) negative (“triple negative”).
      • Mavaddat N.
      • Barrowdale D.
      • Andrulis I.L.
      • et al.
      Consortium of Investigators of Modifiers of BRCA1/2
      Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
      A basal-like gene expression profile, a higher mitotic rate, and higher grade tumors are also observed in BRCA1-associated breast cancers.
      • Mavaddat N.
      • Barrowdale D.
      • Andrulis I.L.
      • et al.
      Consortium of Investigators of Modifiers of BRCA1/2
      Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
      • Honrado E.
      • Osorio A.
      • Palacios J.
      • Benitez J.
      Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations.
      • Lakhani S.R.
      • Reis-Filho J.S.
      • Fulford L.
      • et al.
      Breast Cancer Linkage Consortium
      Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype.
      In BRCA2 carriers, 16% of tumors are triple negative and most (77%) express the ER.
      • Mavaddat N.
      • Barrowdale D.
      • Andrulis I.L.
      • et al.
      Consortium of Investigators of Modifiers of BRCA1/2
      Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
      Compared with the lifetime risk of breast cancer in men in the general population (0.1%), the risks in men with BRCA2 mutations (7%-14%) or BRCA1 mutations (1%) are substantially higher.
      • Lakhani S.R.
      • Reis-Filho J.S.
      • Fulford L.
      • et al.
      Breast Cancer Linkage Consortium
      Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype.
      • Evans D.G.
      • Susnerwala I.
      • Dawson J.
      • Woodward E.
      • Maher E.R.
      • Lalloo F.
      Risk of breast cancer in male BRCA2 carriers.
      • Couch F.J.
      • Farid L.M.
      • DeShano M.L.
      • et al.
      BRCA2 germline mutations in male breast cancer cases and breast cancer families.
      In general, BRCA2 carriers have a lower penetrance for ovarian cancer than do BRCA1 carriers. The cumulative risk of developing ovarian cancer by the age of 80 is 44% to 45% in BRCA1 carriers and 12% to 17% in BRCA2 carriers.
      • Hartmann L.C.
      • Lindor N.M.
      The role of risk-reducing surgery in hereditary breast and ovarian cancer.
      • Kuchenbaecker K.B.
      • Hopper J.L.
      • Barnes D.R.
      • et al.
      Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
      Serous ovarian cancers are the most common histologic subtype for both BRCA mutation carriers.
      • Mavaddat N.
      • Barrowdale D.
      • Andrulis I.L.
      • et al.
      Consortium of Investigators of Modifiers of BRCA1/2
      Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

      Breast Surveillance and Management

      Carriers of pathogenic BRCA mutations are at increased risk of developing cancer of the breasts, ovaries, fallopian tubes, peritoneal cavity, prostate, gall bladder, or pancreas. Both men and women should be offered genetic counseling and additional screening. Management options for HBOC syndromes are best described for BRCA1/2 mutation carriers, in which options include enhanced screening, preventive medications, or prophylactic risk-reducing mastectomy and salpingo-oophorectomy. The management of patients with hereditary cancer syndromes is best performed with a multidisciplinary approach involving medical, surgical, and genetic specialties.

      Screening

      For patients with HBOC syndromes who delay or opt not to pursue risk-reducing surgery, enhanced surveillance is an integral aspect of early detection of cancer. Recommendations for breast cancer screening are best defined in BRCA carriers, and these recommendations are often extrapolated to other hereditary actionable mutations. Earlier breast screening is recommended, with breast awareness training beginning at age 18 years and monthly self-breast examination; clinical breast examination every 6 months is recommended beginning at age 25 years. Between ages 25 and 29 years, annual radiographic screening with either contrast-enhanced breast magnetic resonance imaging (MRI) or annual mammography (when MRI is not available or feasible) is suggested. From ages 30 to 75 years, annual mammography and contrast-enhanced breast MRI are recommended.
      • Daly M.B.
      • Pilarski R.
      • Berry M.
      • et al.
      NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast And Ovarian, Version 2.2017.
      Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology
      Practice Bulletin No 182: hereditary breast and ovarian cancer syndrome.
      Combining mammography and breast MRI more than doubles the ability to detect tumors as compared with mammography alone and may detect tumors at earlier stages of development.
      • Phi X.A.
      • Houssami N.
      • Obdeijn I.M.
      • et al.
      Magnetic resonance imaging improves breast screening sensitivity in BRCA mutation carriers age ≥ 50 years: evidence from an individual patient data meta-analysis.
      • Warner E.
      • Hill K.
      • Causer P.
      • et al.
      Prospective study of breast cancer incidence in women with a BRCA1 or BRCA2 mutation under surveillance with and without magnetic resonance imaging.
      Although balanced by an increased cost and decreased specificity, breast MRI is an integral tool for effective surveillance and is prospectively validated to decrease the risk of distant metastases and death.
      • Kriege M.
      • Brekelmans C.T.
      • Boetes C.
      • et al.
      Magnetic Resonance Imaging Screening Study Group
      Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition.
      These recommendations may be further individualized if a family member was diagnosed with cancer before the age of 30.
      Screening for ovarian cancer is more challenging, as currently available tests perform poorly. In BRCA carriers, annual screening with transvaginal ultrasound or cancer antigen 125 is a limited approach, evidenced by the poor sensitivity (<50%) and low positive predictive value.
      • Stirling D.
      • Evans D.G.
      • Pichert G.
      • et al.
      Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to the International Federation of Gynecology and Obstetrics system.
      • Woodward E.R.
      • Sleightholme H.V.
      • Considine A.M.
      • Williamson S.
      • McHugo J.M.
      • Cruger D.G.
      Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both high-risk and population risk women is ineffective.
      Nevertheless, screening with transvaginal ultrasound or cancer antigen 125 may be considered in women who forego or delay risk-reducing salpingo-oophorectomy beginning at ages 30 to 35 years or 5 to 10 years before the earliest diagnosis of ovarian cancer in a family member.
      • Daly M.B.
      • Pilarski R.
      • Berry M.
      • et al.
      NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast And Ovarian, Version 2.2017.
      Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology
      Practice Bulletin No 182: hereditary breast and ovarian cancer syndrome.

      Risk-Reducing Surgery

      For BRCA mutation carriers without a personal history of cancer, bilateral risk-reducing (preventive) mastectomy decreases the risk of developing breast cancer by more than 90%.
      • Hartmann L.C.
      • Schaid D.J.
      • Woods J.E.
      • et al.
      Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer.
      • Rebbeck T.R.
      • Friebel T.
      • Lynch H.T.
      • et al.
      Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.
      • Hartmann L.C.
      • Sellers T.A.
      • Schaid D.J.
      • et al.
      Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers.
      • Domchek S.M.
      • Friebel T.M.
      • Singer C.F.
      • et al.
      Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
      In the United States, most women prefer surveillance for breast cancer and only 36% of women undergo bilateral risk-reducing mastectomy.
      • Metcalfe K.A.
      • Birenbaum-Carmeli D.
      • Lubinski J.
      • et al.
      Hereditary Breast Cancer Clinical Study Group
      International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers.
      In a prospective study comparing women at high risk of developing breast cancer, the group who chose risk-reducing mastectomy had a marked reduction in psychological distress and cancer-related anxiety.
      • Hatcher M.B.
      • Fallowfield L.
      • A’Hern R.
      The psychosocial impact of bilateral prophylactic mastectomy: prospective study using questionnaires and semistructured interviews.
      In an individualized approach to HBOC predisposition syndromes, risks and benefits of risk-reducing surgery will depend on many factors, including patient priorities, age, cancer history, and comorbidities. An essential component of counseling is that no surgery is 100% effective in preventing cancer, and the short-term morbidity and long-term sequelae of each procedure need to be diligently explained.
      In BRCA mutation carriers, risk-reducing (preventive) salpingo-oophorectomy is the only evidenced-based strategy to prevent cancer of the ovaries or fallopian tubes. Risk-reducing bilateral salpingo-oophorectomy reduces the risk of ovarian cancer by 80% and reduces the risk of breast cancer in premenopausal women by approximately 50%.
      • Rebbeck T.R.
      • Kauff N.D.
      • Domchek S.M.
      Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.
      • Kauff N.D.
      • Satagopan J.M.
      • Robson M.E.
      • et al.
      Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation.
      • Rebbeck T.R.
      • Lynch H.T.
      • Neuhausen S.L.
      • et al.
      Prevention and Observation of Surgical End Points Study Group
      Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations.
      • Kauff N.D.
      • Domchek S.M.
      • Friebel T.M.
      • et al.
      Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.
      The NCCN and a joint position statement from the Society of Gynecologic Oncology and the American College of Obstetricians and Gynecologists recommend offering risk-reducing salpingo-oophorectomy to carriers of BRCA1, BRCA2, or other actionable deleterious mutations between ages 35 and 40 years who have completed childbearing.
      • Daly M.B.
      • Pilarski R.
      • Berry M.
      • et al.
      NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast And Ovarian, Version 2.2017.
      Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology
      Practice Bulletin No 182: hereditary breast and ovarian cancer syndrome.
      In BRCA2 carriers, this procedure may reasonably be delayed until age 45 as the development of ovarian cancer is only 1% by age 50.
      • Hartmann L.C.
      • Lindor N.M.
      The role of risk-reducing surgery in hereditary breast and ovarian cancer.
      Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology
      Practice Bulletin No 182: hereditary breast and ovarian cancer syndrome.
      Common immediate adverse effects of surgical menopause include hot flashes, decreased libido, vaginal dryness, and dyspareunia. Short-term hormone replacement to ameliorate such symptoms does not appear to diminish the risk reduction in BRCA mutation carriers who have undergone risk-reducing salpingo-oophorectomy.
      • Rebbeck T.R.
      • Friebel T.
      • Wagner T.
      • et al.
      PROSE Study Group
      Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.
      In the general population, surgical menopause before the age of 45 has an increased risk of osteoporosis, cardiovascular disease, and death.
      • Rocca W.A.
      • Grossardt B.R.
      • de Andrade M.
      • Malkasian G.D.
      • Melton III, L.J.
      Survival patterns after oophorectomy in premenopausal women: a population-based cohort study.
      In most BRCA carriers, preventive salpingo-oophorectomy substantially decreases cancer-related anxiety and does not worsen physical or mental health–related quality of life.
      • Finch A.
      • Metcalfe K.A.
      • Chiang J.
      • et al.
      The impact of prophylactic salpingo-oophorectomy on quality of life and psychological distress in women with a BRCA mutation.

      Risk-Reducing Medications

      Many randomized placebo-controlled studies have found a reduced risk of ER-positive breast cancer in women with selective ER modulators (such as tamoxifen) or aromatase inhibitors. However, these studies involved few women harboring BRCA mutations. In 1 such study, even though only 6.6% of women were BRCA carriers, the risk reduction in breast cancer by tamoxifen was limited only to BRCA2 carriers.
      • King M.C.
      • Wieand S.
      • Hale K.
      • et al.
      National Surgical Adjuvant Breast and Bowel Project
      Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.
      Tamoxifen for primary prevention may be a reasonable strategy for BRCA2 carriers, in which more than 75% of breast cancers are ER positive. This primary prevention benefit for BRCA1 carriers is less well defined, particularly as most invasive breast cancers are hormone receptor negative.
      Oral contraceptives reduce the risk of ovarian cancer by nearly 30% in the general population, prompting interest in oral contraceptives as a preventive approach for women with HBOC syndromes.
      • Havrilesky L.J.
      • Gierisch J.M.
      • Moorman P.G.
      • et al.
      Oral contraceptive use for the primary prevention of ovarian cancer.
      In an observational study of BRCA carriers, the use of oral contraceptives reduces the risk of ovarian cancer by just more than 40%.
      • Havrilesky L.J.
      • Gierisch J.M.
      • Moorman P.G.
      • et al.
      Oral contraceptive use for the primary prevention of ovarian cancer.
      In addition, a theoretical concern about an increased risk of breast cancer for women using oral contraceptives was not observed in this study.
      • Havrilesky L.J.
      • Gierisch J.M.
      • Moorman P.G.
      • et al.
      Oral contraceptive use for the primary prevention of ovarian cancer.
      Thus, oral contraceptive use may be considered to prevent ovarian cancer in high-risk women who have not completed childbearing or as a risk-reducing strategy in women who are not undergoing risk-reducing salpingo-oophorectomy.

      Therapeutic Advances in the Management of BRCA-Associated Cancers

      Inhibitors of poly(ADP-ribose) polymerase (PARP) have emerged as effective agents for the treatment of BRCA-mutated tumors. They function by inhibiting DNA repair, leading to irreparable DNA damage and cell death (a concept known as synthetic lethality).
      • Lee J.M.
      • Ledermann J.A.
      • Kohn E.C.
      PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies.
      • Ellisen L.W.
      PARP inhibitors in cancer therapy: promise, progress, and puzzles.
      Olaparib, a PARP inhibitor, has exhibited efficacy in treating BRCA-mutated breast, pancreatic, prostate, and other advanced cancers in clinical trials,
      • Kaufman B.
      • Shapira-Frommer R.
      • Schmutzler R.K.
      • et al.
      Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
      with additional studies underway. In discussing BRCA-mutated cancers, germline (hereditary) or somatic (acquired) mutations are distinguished as this may affect response to treatment, eligibility for specific Food and Drug Administration (FDA)–approved agents, and ability to participate in clinical trials.
      In 2014, olaparib became the first FDA-approved PARP inhibitor, indicated as fourth-line (or later) treatment of BRCA-mutated advanced ovarian cancers.
      • García-Rodríguez L.A.
      • Huerta-Alvarez C.
      Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs.
      Subsequent studies evaluated an earlier use of PARP inhibitors as maintenance therapy after first-line treatment. Rucaparib received accelerated FDA-approved use for individuals with germline or somatic BRCA-mutated advanced ovarian cancer after 2 previous lines of therapy. In those who respond to first-line platinum chemotherapy, both olaparib and niraparib are options for maintenance therapy, independent of germline BRCA status. However, with both these agents, germline or somatic BRCA mutations enriched responses to PARP inhibition. Common adverse effects of PARP inhibitors include nausea, anemia, fatigue, anorexia, diarrhea, stomatitis, and thrombocytopenia.
      • Meehan R.S.
      • Chen A.P.
      New treatment option for ovarian cancer: PARP inhibitors.
      In the phase III OlympiAD study in patients with germline-BRCA mutated, HER2-negative metastatic breast cancer, the response rates were doubled with olaparib and the risk of death or disease progression was 42% lower than that with standard chemotherapy.
      • Robson M.
      • Im S.A.
      • Senkus E.
      • et al.
      Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.
      Furthermore, in a phase II study of olaparib in patients with metastatic castrate-resistant prostate cancer, all 7 patients with BRCA2 mutations (3 germline and 4 somatic) responded to treatment with olaparib.
      • Mateo J.
      • Carreira S.
      • Sandhu S.
      • et al.
      DNA-repair defects and olaparib in metastatic prostate cancer.
      Phase III studies of various PARP inhibitors in BRCA-mutated breast, pancreatic, prostate, and ovarian cancers are ongoing.
      Surgical and chemotherapy decisions are influenced by the presence of a BRCA mutation. For example, in women presenting with primary breast cancer, bilateral mastectomy is often selected for BRCA carriers because the risk of ipsilateral or contralateral breast cancer remains high.
      • Chiba A.
      • Hoskin T.L.
      • Hallberg E.J.
      • et al.
      Impact that timing of genetic mutation diagnosis has on surgical decision making and outcome for BRCA1/BRCA2 mutation carriers with breast cancer.
      Although in vitro studies found that BRCA-mutated cell lines were exquisitely sensitive to platinum agents, clinical studies preferentially selecting platinum agents in BRCA-mutated breast cancers are inconclusive.
      • Robson M.E.
      Should the presence of germline BRCA1/2 mutations influence treatment selection in breast cancer?.

      Additional Cancer Risk and Surveillance

      Germline pathogenic mutations in the BRCA genes are also associated with an increased risk of prostate cancer, uveal melanoma, pancreaticobiliary cancer (Table 1).
      • Mersch J.
      • Jackson M.A.
      • Park M.
      • et al.
      Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian.
      Men with BRCA2 germline mutations have a 5- to 8.6-fold increased risk of developing prostate cancer.
      • Mersch J.
      • Jackson M.A.
      • Park M.
      • et al.
      Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian.
      • Kote-Jarai Z.
      • Leongamornlert D.
      • Saunders E.
      • et al.
      BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients.
      Unlike in breast and ovarian cancer, the presence of a BRCA2 mutation is an independent adverse prognostic indicator, and men develop more aggressive prostate cancer with shorter survival.
      • Castro E.
      • Goh C.
      • Olmos D.
      • et al.
      Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer.
      • Taylor R.A.
      • Fraser M.
      • Livingstone J.
      • et al.
      Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.
      Men with BRCA2 mutations are recommended to begin prostate cancer screening at age 45.
      • Daly M.B.
      • Pilarski R.
      • Berry M.
      • et al.
      NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast And Ovarian, Version 2.2017.
      BRCA2 mutations account for approximately 10% of familial pancreatic cancers and 3% of patients without a family history of pancreatic cancer and confer a relative risk of approximately 3.5.
      • Couch F.J.
      • Johnson M.R.
      • Rabe K.G.
      • et al.
      The prevalence of BRCA2 mutations in familial pancreatic cancer.
      Breast Cancer Linkage Consortium
      Cancer risks in BRCA2 mutation carriers.
      In individuals with BRCA2 mutations and a family history of pancreatic cancer, an individualized approach and consideration of investigational screening protocols is recommended by the NCCN. A full body and eye examination for melanoma is also recommended because of increased risks of uveal melanoma.
      • Daly M.B.
      • Pilarski R.
      • Berry M.
      • et al.
      NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast And Ovarian, Version 2.2017.

      Additional Genes Associated With Increased Susceptibility to Breast and Ovarian Cancer

      Rare gene mutations associated with cancer predisposition syndromes include germline mutations in TP53 (Li-Fraumeni syndrome [LFS]) and CDH1 (hereditary diffuse gastric cancer syndrome). As discussed elsewhere in more detail, those with Cowden syndrome (PTEN mutation) and Peutz-Jegher syndrome (STK11 mutation) are also susceptible to developing breast cancer whereas those with LS are at increased risk of developing ovarian cancer and may have moderately increased risks of breast cancer.
      Li-Fraumeni syndrome is a rare autosomal dominant disorder characterized by a germline mutation in the tumor suppressor TP53 gene. Although only accounting for 1% of hereditary breast cancers, those with LFS have a 54% risk of developing breast cancer by age 70.
      • Mai P.L.
      • Best A.F.
      • Peters J.A.
      • et al.
      Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort.
      • Sidransky D.
      • Tokino T.
      • Helzlsouer K.
      • et al.
      Inherited p53 gene mutations in breast cancer.
      Nearly all individuals with LFS develop cancer and many develop multiple primaries. Beginning in childhood, those with LFS are vulnerable to a vast spectrum of additional cancers, including soft tissue sarcomas, osteosarcomas, brain cancer, colon cancer, and adrenocortical cancers, requiring diligent screening and counseling (Table 1).
      • Mai P.L.
      • Best A.F.
      • Peters J.A.
      • et al.
      Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort.
      Inactivating germline mutations in CDH1, a gene encoding E-cadherin, are associated with hereditary diffuse gastric cancer syndrome and confer a 39% cumulative risk of developing lobular breast cancer.
      • Pharoah P.D.
      • Guilford P.
      • Caldas C.
      International Gastric Cancer Linkage Consortium
      Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families.
      Germline pathogenic mutations in additional genes have also been explored for associations with an inherited predisposition for breast or ovarian cancer.
      • Easton D.F.
      • Pharoah P.D.
      • Antoniou A.C.
      • et al.
      Gene-panel sequencing and the prediction of breast-cancer risk.
      • Nielsen F.C.
      • van Overeem Hansen T.
      • Sørensen C.S.
      Hereditary breast and ovarian cancer: new genes in confined pathways.
      Many of these genes are included in multigene hereditary cancer testing panels that are now broadly used to identify women and men at increased risk of these cancers. The frequency of mutations in each gene is becoming more clearly defined with time because of the large number of individuals receiving clinical testing. In retrospective evaluation of patients who underwent indicated genetic testing for breast cancer using multigene panel testing (ranging from 5 to 43 genes), 7.4% of individuals had non-BRCA mutations, most commonly in PALB2, CHEK2, and ATM.
      • Kapoor N.S.
      • Curcio L.D.
      • Blakemore C.A.
      • et al.
      Multigene panel testing detects equal rates of pathogenic BRCA1/2 mutations and has a higher diagnostic yield compared to limited BRCA1/2 analysis alone in patients at risk for hereditary breast cancer.
      Similarly, in a cohort study of triple-negative breast cancers (unselected for a family history of breast or ovarian cancer), a testing panel of 17 breast cancer predisposition genes uncovered deleterious mutations in nearly 15% of patients, including 10% in BRCA1/2 and 5% in the non-BRCA genes.
      • Couch F.J.
      • Hart S.N.
      • Sharma P.
      • et al.
      Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.
      Mutation frequency in patients with ER-positive and HER2 breast cancer has been estimated at 6% and 4%, respectively. However, the relevance of several genes on these panels to breast and ovarian cancer risk has been unclear.
      A recent evaluation of more than 65,000 patients with breast cancer tested with multigene panels confirmed that pathogenic mutations in ATM, BARD1, CHEK2, PALB2, and RAD51D are associated with moderately or highly increased risks of breast cancer, which is consistent with lifetime risks of more than 20%.
      • Couch F.J.
      • Shimelis H.
      • Hu C.
      • et al.
      Associations between cancer predisposition testing panel genes and breast cancer.
      Family-based segregation studies have also found that breast cancer risk in female PALB2 mutation carriers by 70 years of age ranges from 33% in those with no family history of breast cancer to 58% in those with 2 or more first-degree relatives with breast cancer at 50 years of age.
      • Antoniou A.C.
      • Casadei S.
      • Heikkinen T.
      • et al.
      Breast-cancer risk in families with mutations in PALB2.
      • Antoniou A.C.
      • Foulkes W.D.
      • Tischkowitz M.
      Breast-cancer risk in families with mutations in PALB2.
      Women with mutations in high- and moderate-risk genes qualify by NCCN guidelines for enhanced screening for breast cancer with mammography and MRI. No guidelines for risk-reducing surgery for pathogenic mutations in moderate-risk genes have been proposed.
      Mutations in ATM, BRIP1, MSH2, MSH6, PALB2, RAD51C, and RAD51D have been associated with moderate or high risks of ovarian cancer.
      • Lilyquist J.
      • LaDuca H.
      • Polley E.
      • et al.
      Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls.
      Risk-reducing prophylactic surgery may be an important management option for women with mutations, especially those with high-risk mutations in the BRCA1, BRCA2, BRIP1, RAD51C, and RAD51D genes. Overall, commercially available tests offer comprehensive screening tests for HBOC syndromes, but managing and ascribing risk to mutations in genes with moderate penetrance and varying risk remains a challenge.
      The LS tumor spectrum has been well established to include colorectal, uterine, ureteric, pancreaticobiliary, brain, and skin (sebaceous) neoplasms. The risks of other cancers including breast and prostate cancers are less well defined. There is equipoise in the literature regarding breast cancer risk in women with LS. Some studies have found an up to 4-fold increased risk, whereas others have found no increased risk.
      • Win A.K.
      • Young J.P.
      • Lindor N.M.
      • et al.
      Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.
      • Pande M.
      • Wei C.
      • Chen J.
      • et al.
      Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry.
      In an analysis of 50,000 women who underwent multigene panel testing at a commercial laboratory, 423 women were identified with a molecular diagnosis of LS and found to have a 2- to 3-fold increased risk of age-standardized breast cancer when mutations were in the MSH6 (standard incidence ratio [SIR], 2.11; 95% CI, 1.56-2.86) and PMS2 (SIR, 2.92; 95% CI, 2.17-3.92) genes.
      • Roberts M.E.
      • Jackson S.A.
      • Susswein L.R.
      • et al.
      MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer.
      The authors of this study suggest that women with MSH6- or PMS2-associated LS may benefit from increased breast cancer screening. Further studies in less biased populations are necessary to replicate this finding before definitive recommendations can be made for increased or advanced breast screening in LS.

      Approach to VUS in Hereditary Cancer Panel Genes

      Clinical genetic testing identified many unique VUS, especially in the BRCA1, BRCA2, and mismatch repair (MMR) (MLH1, MSH2, MSH6, and PMS2) high-risk colorectal and ovarian cancer genes. These VUS include single amino acid missense changes, small in-frame insertions and deletions, and intronic alterations that may influence gene splicing. The inability to assess the clinical relevance of BRCA1/2 VUS deprives women and men with VUS of cancer risk management benefits associated with pathogenic mutations, including enhanced cancer surveillance and screening, preventive prophylactic mastectomy/oophorectomy, and eligibility for therapy with PARP inhibitors that target DNA repair defects in the associated tumors. Similarly, VUS in MMR genes cannot drive screening and surveillance for early detection beginning at a young age, preventive surgery, and the benefit of immunotherapy with checkpoint inhibitors in those affected by cancer.
      The most commonly used method for the classification of the clinical relevance of VUS in BRCA1 and BRCA2 is the ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) Consortium (https://enigmaconsortium.org/), a quantitative multifactorial probability-based model.
      • Plon S.E.
      • Eccles D.M.
      • Easton D.
      • et al.
      IARC Unclassified Genetic Variants Working Group
      Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.
      • Lindor N.M.
      • Guidugli L.
      • Wang X.
      • et al.
      A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS).
      This model incorporates sequence alignment, personal and family history of cancer, segregation of variants with cancer in families, co-occurrence of the variant with a known pathogenic mutation, population-based case-control analysis, and breast tumor pathological features.
      • Goldgar D.E.
      • Easton D.F.
      • Deffenbaugh A.M.
      • Monteiro A.N.
      • Tavtigian S.V.
      • Couch F.J.
      Breast Cancer Information Core (BIC) Steering Committee
      Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2.
      The method yields probabilities of pathogenicity in a 5-tier clinical classification scheme. The ENIGMA Consortium serves as an expert panel for the classification of BRCA1/2 VUS for the National Institutes of Health–supported ClinVar database of variants identified by genetic testing (https://www.ncbi.nlm.nih.gov/clinvar/) and the Global Alliance for Genomics and Health BRCA Exchange database (http://brcaexchange.org/) of BRCA1 and BRCA2 variants. Individual clinical testing entities also classify VUS using similar methodologies. However, high-volume genetic testing for those at risk has outpaced clinical annotation of VUS by any method because of the limited availability of family-based data for each VUS. To overcome these limitations, several laboratories have attempted to develop quantitative functional assays and validate the performance of these methods for the classification of VUS.
      • Woods N.T.
      • Baskin R.
      • Golubeva V.
      • et al.
      Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance.
      • Guidugli L.
      • Pankratz V.S.
      • Singh N.
      • et al.
      A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.
      Other efforts involving functional assessment of VUS in mouse embryonic stem cells
      • Hendriks G.
      • Morolli B.
      • Calléja F.M.
      • et al.
      An efficient pipeline for the generation and functional analysis of human BRCA2 variants of uncertain significance.
      • Biswas K.
      • Das R.
      • Eggington J.M.
      • et al.
      Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay.
      and cell-based assays measuring homology-directed repair activity, E3 ligase activity, and BARD1-binding activity of VUS in the N-terminal BARD1-binding domain of BRCA1
      • Anantha R.W.
      • Simhadri S.
      • Foo T.K.
      • et al.
      Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance.
      • Starita L.M.
      • Young D.L.
      • Islam M.
      • et al.
      Massively parallel functional analysis of BRCA1 RING domain variants.
      are under development. Although these functional assays are conducted in non–Clinical Laboratory Improvement Amendments laboratories, the results can be informative when considering the management of patients with BRCA1/2 VUS.
      In a similar fashion, classification of VUS in MMR genes is coordinated by the International Society for Gastrointestinal Hereditary Tumours (https://www.insight-group.org/variants/databases/). The International Society for Gastrointestinal Hereditary Tumours uses a standardized rule-based classification scheme with multiple lines of evidence including sequence alignment, personal and family history of cancer, segregation of variants with cancer in families, co-occurrence of the variant with a known pathogenic mutation, population-based case-control analysis, tumor-based microsatellite instability, and immunohistochemical features as well as evidence of functional consequences.
      • Thompson B.A.
      • Spurdle A.B.
      • Plazzer J.P.
      • et al.
      Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.
      Several laboratories have attempted to develop quantitative functional assays for MMR VUS. These assays include dominant-negative effects in yeast reporter assays,
      • Shcherbakova P.V.
      • Kunkel T.A.
      Mutator phenotypes conferred by MLH1 overexpression and by heterozygosity for mlh1 mutations.
      • Takahashi M.
      • Shimodaira H.
      • Andreutti-Zaugg C.
      • Iggo R.
      • Kolodner R.D.
      • Ishioka C.
      Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.
      MMR in vitro activity assays,
      • Takahashi M.
      • Shimodaira H.
      • Andreutti-Zaugg C.
      • Iggo R.
      • Kolodner R.D.
      • Ishioka C.
      Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.
      • Trojan J.
      • Zeuzem S.
      • Randolph A.
      • et al.
      Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system.
      mutation rate in the HPRT gene.
      • Blasi M.F.
      • Ventura I.
      • Aquilina G.
      • et al.
      A human cell-based assay to evaluate the effects of alterations in the MLH1 mismatch repair gene.
      As with BRCA1/2, MMR VUS are assigned to a 5-tier clinical classification scheme.
      Many VUS in BRCA1/2 and MMR genes are located in intronic regions and cannot be evaluated by functional assays. These VUS have the potential to affect normal splicing of genes leading to disrupted proteins. Spliceogenicity-based previous probabilities of pathogenicity for gene variants have recently been developed and integrated into the ENIGMA multifactorial model for BRCA1/2.
      • Vallée M.P.
      • Di Sera T.L.
      • Nix D.A.
      • et al.
      Adding in silico assessment of potential splice aberration to the integrated evaluation of BRCA gene unclassified variants.
      This additional information has proven important for the classification of a large number of BRCA1/2 VUS as neutral/benign variants.
      Large numbers of VUS in non-BRCA1/2, non-MMR predisposition genes, have also been identified by clinical multigene panel testing and reported in ClinVar (eg, TP53). Classification of these VUS is more challenging than for BRCA1/2 or MMR genes because the lower penetrance of mutations in these other genes limits the use of family history and segregation information. Furthermore, standardization of functional assays and estimation of sensitivity and specificity for the assays is difficult in the absence of known pathogenic and known neutral missense variants. Efforts to develop sequence-based prediction models, multifactorial models, and functional methods for VUS classification in these genes are ongoing.

      Working With a Genetics Clinic or Genetic Counselor

      If a patient’s personal and/or family history is suggestive of a hereditary predisposition, referral to a genetics clinic and/or genetic counselor can provide an in-depth assessment of personal and family history in the context of hereditary colon and breast-ovarian cancer (referral indications are outlined in Table 3).
      • Zhang S.
      • Folsom A.R.
      • Sellers T.A.
      • Kushi L.H.
      • Potter J.D.
      Better breast cancer survival for postmenopausal women who are less overweight and eat less fat: the Iowa Women’s Health Study.
      Genetic counselors are specially trained to perform personalized risk assessments based on a combination of both personal factors and family history. Genetic counselors may use mathematical risk assessment tools such as MMRPro, PREMM, BRCAPRO, PENNI, and LAMBDA to identify individuals at high risk of having a hereditary cancer syndrome, incorporating a 3-generation family history as well as the patient’s personal medical history.
      Genetic counselors can also assist with the logistical aspects of genetic testing, including obtaining additional medical and family history to ensure appropriate testing is ordered, initiating insurance preauthorization and peer-to-peer reviews, interpreting the results in the context of a patient’s medical and family history, and providing personalized medical management recommendations. Consultation with a genetics specialist can allow the patient to discuss not only the risks associated with genetic cancer syndromes but also the psychological or emotional impact these syndromes may have on families. Pre- and posttest counseling is recommended by the American Society of Clinical Oncology as part of the germline genetic testing process.
      • Lu K.H.
      • Wood M.E.
      • Daniels M.
      • et al.
      American Society of Clinical Oncology
      American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
      This ensures that informed consent is obtained and that genetic test results are communicated to both the patient and their providers. A study conducted by Sussner et al
      • Sussner K.M.
      • Jandorf L.
      • Valdimarsdottir H.B.
      Educational needs about cancer family history and genetic counseling for cancer risk among frontline healthcare clinicians in New York City.
      found that of the 143 clinicians, only 1.7% felt confident in their ability to interpret risk based on family history and to provide a patient with screening, treatment, and/or risk reduction recommendations. Increased patient understanding may lead to improved communication between family members who are at risk and may also increase adherence to screening and/or risk reduction recommendations.
      • Stoffel E.M.
      • Mercado R.C.
      • Kohlmann W.
      • et al.
      Prevalence and predictors of appropriate colorectal cancer surveillance in Lynch syndrome.
      In addition, many major insurance companies now require documentation of genetic counseling to cover the cost of genetic testing. Genetic counselors can also discuss genetic discrimination and current protections that are in place for patients who undergo genetic testing (Genetic Information Nondiscrimination Act), which is a patient and provider perceived barrier to genetic evaluation.
      • Kushi L.H.
      • Potter J.D.
      • Bostick R.M.
      • et al.
      Dietary fat and risk of breast cancer according to hormone receptor status.
      • Wood M.E.
      • Kadlubek P.
      • Pham T.H.
      • et al.
      Quality of cancer family history and referral for genetic counseling and testing among oncology practices: a pilot test of quality measures as part of the American Society of Clinical Oncology Quality Oncology Practice Initiative.

      Patient Support Groups

      Patient groups are pillars of hereditary tumor syndrome patient care, and providers should notify patients of their existence and services. Although the term support group is commonly used, we prefer the term patient groups because of the many roles they play (including supporting patients, educating patients and providers, counseling on medical care, formulating treatment algorithms, raising and allocating funds for research and patient assistance, and advocating for patients in many forums). Social media platforms have greatly reduced the barriers to creating these groups, and some exist exclusively on social media (eg, Facebook and PTEN World). Although no systematic research has been published on the benefits of hereditary tumor patient groups, research on cancer patient support groups has found improvements in quality of life.
      • Gottlieb B.H.
      • Wachala E.D.
      Cancer support groups: a critical review of empirical studies.

      Conclusion

      The diagnosis and management of patients with high-risk breast-ovarian cancer is complex, requiring early detection and intensive surveillance. We have provided the busy clinician with an overview of the genetics, surveillance, and management of common HBOC syndromes. We have also provided the reader with an overview of working with genetic counselors, VUS, and patient support groups. The second part of this series will focus on the hereditary gastrointestinal cancer syndromes and provide an overview of their genetics, surveillance, and management options.

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      • In the Limelight: June 2019
        Mayo Clinic ProceedingsVol. 94Issue 6
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          This monthly feature highlights five articles in the current print and online issue of Mayo Clinic Proceedings. These articles are also featured on the Mayo Clinic Proceedings' YouTube Channel ( https://youtu.be/yHIJsTUi_u0 ).
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