Genetic counseling and testing for hereditary breast and ovarian cancer
- Beth N Peshkin, MS, CGC
Beth N Peshkin, MS, CGC
- Professor of Oncology, Senior Genetic Counselor
- Georgetown University Medical School
- Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research
- Claudine Isaacs, MD
Claudine Isaacs, MD
- Professor of Medicine and Oncology
- Georgetown University Medical School
- Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research
- Section Editors
- Anees B Chagpar, MD, MSc, MA, MPH, MBA, FACS, FRCS(C)
Anees B Chagpar, MD, MSc, MA, MPH, MBA, FACS, FRCS(C)
- Section Editor — Breast Surgery
- Associate Professor, Department of Surgery
- Yale University School of Medicine
- Barbara Goff, MD
Barbara Goff, MD
- Section Editor — Gynecologic Oncology
- Professor of Gynecologic Oncology
- University of Washington
The most common cause for hereditary breast and ovarian cancers is the presence of germline mutations in the tumor suppressor genes and breast cancer type 1 and 2 susceptibility genes (BRCA1 and BRCA2). However, in clinical practice, the vast majority of women who undergo genetic testing do not have a mutation in either one of these genes.
Genetic analysis is performed at various commercial laboratories nationally and internationally . Since 2013, when the Supreme Court of the United States invalidated key patents on BRCA1 and BRCA2 held by a commercial company, more testing options have become available. In addition to BRCA1 and BRCA2 tests, next-generation sequencing (NGS) multigene panels are also available to evaluate a wider array of potential mutations that might predispose to breast and/or ovarian cancer.
For patients who meet criteria for genetic testing (and those who desire genetic testing), expertise is required to ensure that the test will be adequately interpreted and that the results will aid in diagnosis or influence management of the patient or family members at risk for hereditary cancer . The complexity involved in pre- and post-test risk assessment underscores the importance of genetic counseling both before and after testing.
This topic reviews the genetic testing and the interpretation of genetic tests for hereditary breast and ovarian cancer syndrome suspected as being associated with mutations in BRCA1 or BRCA2.
CRITERIA FOR GENETIC RISK EVALUATION
While unaffected women often present with concerns about their hereditary cancer risk, whenever possible, it is ideal to initiate genetic testing in a family member who is most likely to test positive for a mutation, which is usually a woman affected by early breast cancer or ovarian cancer (any age). Most hereditary breast and ovarian cancers (HBOC) are due to highly penetrant germline BRCA mutations, which are inherited in an autosomal-dominant fashion. Data regarding clinical characteristics associated with BRCA mutations are discussed elsewhere (See "BRCA1 and BRCA2-associated hereditary breast and ovarian cancer", section on 'Clinical characteristics associated with BRCA mutations'.)
- GeneTests: http://www.genetests.org/laboratories/ (Accessed on March 25, 2015).
- Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 2015; 33:3660.
- NCCN Guidelines for Detection, Prevention, & Risk Reduction Genetic/Familial High-risk Assessment: Breast and Ovarian, v 2.2016. http://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf.
- Hampel H, Bennett RL, Buchanan A, et al. 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. Genet Med 2015; 17:70.
- Hamilton JG, Lobel M, Moyer A. Emotional distress following genetic testing for hereditary breast and ovarian cancer: a meta-analytic review. Health Psychol 2009; 28:510.
- Graves KD, Vegella P, Poggi EA, et al. Long-term psychosocial outcomes of BRCA1/BRCA2 testing: differences across affected status and risk-reducing surgery choice. Cancer Epidemiol Biomarkers Prev 2012; 21:445.
- Halbert CH, Stopfer JE, McDonald J, et al. Long-term reactions to genetic testing for BRCA1 and BRCA2 mutations: does time heal women's concerns? J Clin Oncol 2011; 29:4302.
- Bleiker E, Wigbout G, van Rens A, et al. Withdrawal from genetic counselling for cancer. Hered Cancer Clin Pract 2005; 3:19.
- Riley BD, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 2012; 21:151.
- Amir E, Freedman OC, Seruga B, Evans DG. Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst 2010; 102:680.
- Ready K, Litton JK, Arun BK. Clinical application of breast cancer risk assessment models. Future Oncol 2010; 6:355.
- Green MJ, Peterson SK, Baker MW, et al. Effect of a computer-based decision aid on knowledge, perceptions, and intentions about genetic testing for breast cancer susceptibility: a randomized controlled trial. JAMA 2004; 292:442.
- Wakefield CE, Meiser B, Homewood J, et al. A randomized controlled trial of a decision aid for women considering genetic testing for breast and ovarian cancer risk. Breast Cancer Res Treat 2008; 107:289.
- Platten U, Rantala J, Lindblom A, et al. The use of telephone in genetic counseling versus in-person counseling: a randomized study on counselees' outcome. Fam Cancer 2012; 11:371.
- Peshkin BN, Demarco TA, Graves KD, et al. Telephone genetic counseling for high-risk women undergoing BRCA1 and BRCA2 testing: rationale and development of a randomized controlled trial. Genet Test 2008; 12:37.
- Wang C, Gonzalez R, Milliron KJ, et al. Genetic counseling for BRCA1/2: a randomized controlled trial of two strategies to facilitate the education and counseling process. Am J Med Genet A 2005; 134A:66.
- Schwartz MD, Valdimarsdottir HB, Peshkin BN, et al. Randomized noninferiority trial of telephone versus in-person genetic counseling for hereditary breast and ovarian cancer. J Clin Oncol 2014; 32:618.
- Kinney AY, Butler KM, Schwartz MD, et al. Expanding access to BRCA1/2 genetic counseling with telephone delivery: a cluster randomized trial. J Natl Cancer Inst 2014; 106.
- NCCN Clinical Practice Guidelines in Oncology. “Genetic/Familial High-Risk Assessment: Breast and Ovarian.” Version 1.2015. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf (Accessed on March 25, 2015).
- CancerGene with BRCAPRO, MMRpro, PancPRO, and MelaPRO www4.utsouthwestern.edu/breasthealth/cagene/ (Accessed on March 25, 2015).
- Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Centre for Cancer Genetic Epidemiology ccge.medschl.cam.ac.uk/boadicea/ (Accessed on March 25, 2015).
- IBIS Breast Cancer Risk Evaluation Tool. Centre for Cancer Prevention. London www.ems-trials.org/riskevaluator/ (Accessed on March 25, 2015).
- Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 1994; 73:643.
- Claus EB, Risch N, Thompson WD. The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Res Treat 1993; 28:115.
- Breast Cancer Risk Assessment Tool. National Cancer Institute and National Surgical Adjuvant Breast and Bowel Project. www.cancer.gov/bcrisktool/ (Accessed on March 25, 2015).
- Breast Cancer Surveillance Consortium Risk Calculator tools.bcsc-scc.org/BC5yearRisk/intro.htm (Accessed on March 25, 2015).
- Allain DC, Friedman S, Senter L. Consumer awareness and attitudes about insurance discrimination post enactment of the Genetic Information Nondiscrimination Act. Fam Cancer 2012; 11:637.
- Genetic Discrimination and Other Laws. http://www.genome.gov/10002077#al-3 (Accessed on February 04, 2015).
- McInerney-Leo A, Biesecker BB, Hadley DW, et al. BRCA1/2 testing in hereditary breast and ovarian cancer families II: impact on relationships. Am J Med Genet A 2005; 133A:165.
- Green RM, Thomas AM. Whose gene is it? A case discussion about familial conflict over genetic testing for breast cancer. J Genet Couns 1997; 6:245.
- Loud JT, Weissman NE, Peters JA, et al. Deliberate deceit of family members: a challenge to providers of clinical genetics services. J Clin Oncol 2006; 24:1643.
- Segal J, Esplen MJ, Toner B, et al. An investigation of the disclosure process and support needs of BRCA1 and BRCA2 carriers. Am J Med Genet A 2004; 125A:267.
- Patenaude AF, Dorval M, DiGianni LS, et al. Sharing BRCA1/2 test results with first-degree relatives: factors predicting who women tell. J Clin Oncol 2006; 24:700.
- Bradbury AR, Dignam JJ, Ibe CN, et al. How often do BRCA mutation carriers tell their young children of the family's risk for cancer? A study of parental disclosure of BRCA mutations to minors and young adults. J Clin Oncol 2007; 25:3705.
- Rosenthal E, Moyes K, Arnell C, et al. Incidence of BRCA1 and BRCA2 non-founder mutations in patients of Ashkenazi Jewish ancestry. Breast Cancer Res Treat 2015; 149:223.
- Judkins T, Rosenthal E, Arnell C, et al. Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer 2012; 118:5210.
- Arnold AG, Otegbeye E, Fleischut MH, et al. Assessment of individuals with BRCA1 and BRCA2 large rearrangements in high-risk breast and ovarian cancer families. Breast Cancer Res Treat 2014; 145:625.
- Stadler ZK, Saloustros E, Hansen NA, et al. Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families. Breast Cancer Res Treat 2010; 123:581.
- Jackson SA, Davis AA, Li J, et al. Characteristics of individuals with breast cancer rearrangements in BRCA1 and BRCA2. Cancer 2014; 120:1557.
- Tung N, Lin NU, Kidd J, et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. J Clin Oncol 2016; 34:1460.
- Chong HK, Wang T, Lu HM, et al. The validation and clinical implementation of BRCAplus: a comprehensive high-risk breast cancer diagnostic assay. PLoS One 2014; 9:e97408.
- LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med 2014; 16:830.
- Tung N, Battelli C, Allen B, 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; 121:25.
- Desmond A, Kurian AW, Gabree M, et al. Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment. JAMA Oncol 2015; 1:943.
- Fecteau H, Vogel KJ, Hanson K, Morrill-Cornelius S. The evolution of cancer risk assessment in the era of next generation sequencing. J Genet Couns 2014; 23:633.
- Domchek SM, Bradbury A, Garber JE, et al. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol 2013; 31:1267.
- Walsh T, Casadei S, Lee MK, 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; 108:18032.
- Couch FJ, Nathanson KL, Offit K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science 2014; 343:1466.
- Stadler ZK, Schrader KA, Vijai J, et al. Cancer genomics and inherited risk. J Clin Oncol 2014; 32:687.
- Facio FM, Lee K, O'Daniel JM. A genetic counselor's guide to using next-generation sequencing in clinical practice. J Genet Couns 2014; 23:455.
- Sie AS, Prins JB, van Zelst-Stams WA, et al. Patient experiences with gene panels based on exome sequencing in clinical diagnostics: high acceptance and low distress. Clin Genet 2015; 87:319.
- Schwartz MD, Peshkin BN, Hughes C, et al. Impact of BRCA1/BRCA2 mutation testing on psychologic distress in a clinic-based sample. J Clin Oncol 2002; 20:514.
- Kinney AY, Bloor LE, Mandal D, et al. The impact of receiving genetic test results on general and cancer-specific psychologic distress among members of an African-American kindred with a BRCA1 mutation. Cancer 2005; 104:2508.
- Smith A, Moran A, Boyd MC, et al. Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet 2007; 44:10.
- Katki HA, Gail MH, Greene MH. Breast-cancer risk in BRCA-mutation-negative women from BRCA-mutation-positive families. Lancet Oncol 2007; 8:1042.
- Metcalfe KA, Finch A, Poll A, et al. Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation. Br J Cancer 2009; 100:421.
- Korde LA, Mueller CM, Loud JT, et al. No evidence of excess breast cancer risk among mutation-negative women from BRCA mutation-positive families. Breast Cancer Res Treat 2011; 125:169.
- Lindor NM, Goldgar DE, Tavtigian SV, et al. BRCA1/2 sequence variants of uncertain significance: a primer for providers to assist in discussions and in medical management. Oncologist 2013; 18:518.
- Eggington JM, Bowles KR, Moyes K, et al. A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes. Clin Genet 2014; 86:229.
- Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014; 32:2001.
- https://connect.patientcrossroads.org/?org=prompt (Accessed on March 18, 2015).
- Sawyer S, Mitchell G, McKinley J, et al. A role for common genomic variants in the assessment of familial breast cancer. J Clin Oncol 2012; 30:4330.
- Comen E, Balistreri L, Gönen M, et al. Discriminatory accuracy and potential clinical utility of genomic profiling for breast cancer risk in BRCA-negative women. Breast Cancer Res Treat 2011; 127:479.
- Tice JA, Cummings SR, Smith-Bindman R, et al. Using clinical factors and mammographic breast density to estimate breast cancer risk: development and validation of a new predictive model. Ann Intern Med 2008; 148:337.
- Berry DA, Parmigiani G, Sanchez J, et al. Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst 1997; 89:227.
- Berry DA, Iversen ES Jr, Gudbjartsson DF, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 2002; 20:2701.
- Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 2004; 23:1111.
- Mann GJ, Thorne H, Balleine RL, et al. Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource. Breast Cancer Res 2006; 8:R12.
- Ozanne EM, Drohan B, Bosinoff P, et al. Which risk model to use? Clinical implications of the ACS MRI screening guidelines. Cancer Epidemiol Biomarkers Prev 2013; 22:146.
- Curtis RE, Freedman DM, Ron E, Ries LAG, Hacker DG, Edwards BK, Tucker MA, Fraumeni JF Jr. (eds). New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973-2000. National Cancer Institute, NIH Publ. No. 05-5302. Bethesda, MD, 2006. http://seer.cancer.gov/archive/publications/mpmono/MPMonograph_complete.pdf (Accessed on March 25, 2015).
- Graeser MK, Engel C, Rhiem K, et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2009; 27:5887.
- Rhiem K, Engel C, Graeser M, et al. The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study. Breast Cancer Res 2012; 14:R156.
- Reiner AS, John EM, Brooks JD, et al. Risk of asynchronous contralateral breast cancer in noncarriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: a report from the Women's Environmental Cancer and Radiation Epidemiology Study. J Clin Oncol 2013; 31:433.
- Mazzola E, Chipman J, Cheng SC, Parmigiani G. Recent BRCAPRO upgrades significantly improve calibration. Cancer Epidemiol Biomarkers Prev 2014; 23:1689.
- Schonfeld SJ, Berrington de Gonzalez A, Visvanathan K, et al. Declining second primary ovarian cancer after first primary breast cancer. J Clin Oncol 2013; 31:738.
- Metcalfe KA, Lynch HT, Ghadirian P, et al. The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol Oncol 2005; 96:222.
- Kauff ND, Mitra N, Robson ME, et al. Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families. J Natl Cancer Inst 2005; 97:1382.
- Ingham SL, Warwick J, Buchan I, et al. Ovarian cancer among 8,005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2. J Med Genet 2013; 50:368.
- Kerlikowske K, Brown JS, Grady DG. Should women with familial ovarian cancer undergo prophylactic oophorectomy? Obstet Gynecol 1992; 80:700.
- Jervis S, Song H, Lee A, et al. Ovarian cancer familial relative risks by tumour subtypes and by known ovarian cancer genetic susceptibility variants. J Med Genet 2014; 51:108.
- La Vecchia C. Oral contraceptives and ovarian cancer: an update, 1998-2004. Eur J Cancer Prev 2006; 15:117.
- Fischer C, Engel C, Sutter C, et al. BRCA1/2 testing: uptake, phenocopies, and strategies to improve detection rates in initially negative families. Clin Genet 2012; 82:478.
- Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 2006; 38:873.
- Thompson D, Duedal S, Kirner J, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 2005; 97:813.
- Kurian AW, Gong GD, John EM, et al. Breast cancer risk for noncarriers of family-specific BRCA1 and BRCA2 mutations: findings from the Breast Cancer Family Registry. J Clin Oncol 2011; 29:4505.
- Domchek SM, Gaudet MM, Stopfer JE, et al. Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2. Breast Cancer Res Treat 2010; 119:409.
- Evans DG, Ingham SL, Buchan I, et al. Increased rate of phenocopies in all age groups in BRCA1/BRCA2 mutation kindred, but increased prospective breast cancer risk is confined to BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2013; 22:2269.
- CRITERIA FOR GENETIC RISK EVALUATION
- GENETIC COUNSELING
- Pre-test counseling
- - Pedigree evaluation
- Risk assessment models
- Issues for patients considering testing
- Post-test counseling
- OPTIONS FOR GENETIC TESTING
- BRCA1 and BRCA2 testing
- Assessment of large genomic rearrangements in BRCA
- Next-generation panel testing
- Other options
- INTERPRETATION OF TEST RESULTS
- Positive results
- True negative results
- Uninformative (negative) result
- Variants of uncertain significance
- APPROACH TO PATIENTS WITH UNINFORMATIVE RESULTS
- Cancer risk assessment of patients with uninformative (negative) test results
- - No personal history of cancer
- - Personal history of breast cancer
- - Personal or family history of ovarian cancer
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS