Curr Probl Cancer 38 (2014) 226–234
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
Hereditary breast and ovarian cancer syndrome: Considering the complexities Leigha Senter, MS, LGC
Introduction Hereditary breast and ovarian cancer syndrome (HBOC) is a well-described hereditary cancer predisposition syndrome caused by mutations in BRCA1 and BRCA2. Several studies have provided lifetime breast cancer risk estimates for women with HBOC, and most have suggested a risk between 50% and 80%.1 Men with BRCA mutations have a risk of up to 8% of developing breast cancer in their lifetimes.2 In women, the risk of developing breast cancer appears to be slightly higher in carriers of BRCA1 mutations compared with carriers of BRCA2 mutations, whereas the opposite is true regarding the risks for male breast cancer. The development of contralateral breast cancer is also more common in women with HBOC, with current estimates suggesting a risk of approximately 50% in the 25 years after initial breast cancer diagnosis. Women who are diagnosed with their first breast cancer at a younger age have the highest risk for contralateral disease.3 The risk for ovarian cancer is also substantially increased over that of the general population and is higher for carriers of BRCA1 mutations (approximately 40%) vs. BRCA2 mutations (11%).1 To manage these risks, guidelines for screening and risk reduction have been established.4 Malignancies of the pancreas and the prostate, as well as melanoma, have also been shown to be associated with BRCA gene mutations to a lesser degree.5-8 Although genetic testing for HBOC has been available since the mid-1990s, the number of patient-initiated discussions about testing for HBOC has been on the rise.9,10 This increase in consumer interest may potentially be the result of media coverage of celebrities with BRCA mutations, as well as related Supreme Court decisions regarding gene patenting. Along with this publicity, there has been a growing number of professional society recommendations regarding BRCA gene testing,4,11-13 as well as institutional accreditation standards that include requirements for the provision of genetic counseling, risk assessment, and testing.14,15 All of these factors have increased the need for health care providers to work together to play a role in identifying, counseling, testing, and managing patients with BRCA gene mutations.16 To emphasize the importance of this team approach, we use the following cases to represent common and important issues to be considered in risk assessment and genetic testing for HBOC.
http://dx.doi.org/10.1016/j.currproblcancer.2014.10.003 0147-0272/& 2014 Elsevier Inc. All rights reserved.
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Case 1 A healthy 24-year-old patient sought genetic counseling after learning that her mother, who had a previous diagnosis of breast cancer, was positive for a deleterious mutation in the BRCA1 gene. Family history information was obtained to construct a 3-generation pedigree (Fig. 1), and it indicated that her mother’s breast cancer diagnosis occurred at 40 years of age; her mother’s only sister had ovarian cancer at 50 years of age; and her maternal grandmother had breast cancer diagnosed at a young, unknown age. Additionally, her paternal family history was significant for ovarian cancer in 2 deceased paternal aunts and melanoma in her paternal grandmother. Because BRCA gene mutations are inherited in an autosomal dominant manner, the patient had a 50% chance of having inherited the identified BRCA1 mutation from her mother. Genetic testing The patient underwent single-site mutation analysis, which was negative, meaning that she did not inherit her mother’s BRCA1 mutation. Although this negative result clarified her risk based on her maternal family history of cancer, her paternal family history of ovarian cancer was also suggestive of HBOC. None of the patient’s paternal relatives had undergone BRCA gene testing, and the women diagnosed with ovarian cancer were deceased. Therefore, the optimal approach to cancer genetic testing, starting with an affected family member, was not possible. As such, additional testing to look for other BRCA gene mutations was recommended for this patient, and a different mutation in the BRCA2 gene was identified. This result not only established a diagnosis of HBOC in the patient, but also indicated that her father was an obligate carrier of the mutation. Postresult counseling included a discussion of management recommendations for the patients, as well as a communication plan for paternal family members to receive this new information. Had the paternal side of this patient’s family not been explored and further testing pursued, the patient would have falsely been reassured she was at low or general population risk. Medical management Although a comprehensive review of the evidence for medical management of BRCA1 and BRCA2 mutations is beyond the scope of this article, several publications and guidelines exist.4,11,12,17-19 Those of the National Comprehensive Cancer Network (NCCN) are updated annually and widely used.4 According to NCCN, this patient would be recommended to have annual screening with breast magnetic resonance imaging from 25-29 years of age, with the addition of annual mammography beginning at 30 years of age. Given this patient’s young age, she would be further counseled about additional risk reduction options such as prophylactic bilateral salpingo-oophorectomy (BSO) preferably by 35-40 years of age or when childbearing is complete.4 This patient’s test result, inadvertently provided information about her father’s BRCA status, as well—that he was an obligate carrier of the mutation in the family. Men with BRCA gene mutations are recommended to have clinical breast examination every 6-12 months beginning at 35 years of age and to consider baseline mammogram at 40 years of age. Prostate cancer screening is also recommended for men with BRCA2 mutations and should be considered by men with BRCA1 mutations beginning at 40 years of age.4 The relative risk of prostate cancer in men younger than 65 years in BRCA1 mutation carriers is 1.8, whereas the risk is increased 5-8fold for BRCA2 mutation carriers.7,20,21 Data have also suggested that BRCA2-related prostate cancers are more aggressive with poor survival rates.6,22,23 Familial implications When a person's test results are negative for a previously identified familial mutation, this is considered a “true negative” and increased screening is no longer indicated, unless there is
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Fig. 1. Pedigree for case 1 showing family history suggestive of HBOC on both sides of the patient’s family. d., Age at death, Ca, cancer. (Color version of figure is available online.)
concern based on the opposite side of the family (as in this case) or if there are cancers in the family that cannot be explained by the BRCA mutation. If there is no indication of a possible HBOC syndrome on the opposite side of the family, cancer screening recommendations for a person with a true negative test result would reflect what is recommended for the general population and thus would have been inappropriate for this patient.24 Reflex testing in this case, meant testing an unaffected patient for mutations in BRCA1 and BRCA2 based on cancers observed in her paternal family history. Although not ideal, this approach was warranted because her relatives with ovarian cancer were deceased. A negative result in this situation could mean that there is a BRCA gene mutation in the family that the patient did not inherit; or that the cancers in the family are due to a mutation in a different gene for which the patient was not tested; or that the cancers in the family are not hereditary. Because it is often impossible to distinguish between these possibilities in this situation, screening recommendations would be made based on the risk attributed to the family history. The identification of a paternally inherited BRCA gene mutation in this patient, by default, also indicates that her father carries the same mutation (he is an obligate carrier). Nonpaternity, which occurs when the man thought to be the biological father actually is not, is a possibility to be considered but this was not a concern for this family. We explained the importance of this information to the patient and encouraged her to notify her father and other paternal relatives as soon as possible. This patient’s brother and sister are at risk for having inherited a BRCA gene mutation from their mother and from their father. Each of her siblings has a 75% chance of having at least one of their parents’ BRCA gene mutations and a 25% chance of carrying neither mutation. Additionally, this patient’s other relatives on both sides of her family are also at risk of having one BRCA gene mutation. Achieving a negative test result in any relative would eliminate the need for that relative’s children to be tested for that specific mutation.
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Key points
Genetic test results should be interpreted in the context of a patient’s family history. It is preferred to initiate testing in a family with an individual who has been diagnosed with breast or ovarian cancer, because interpretation of a negative test result in an unaffected person is often not straightforward.24 Diagnosis of HBOC in a person who does not have a personal history of cancer allows for a personalized plan for risk reduction. Although not so in this case, genetic testing in a family can sometimes reveal nonpaternity.
Case 2 A 60-year-old woman was referred for genetic counseling and testing by her gynecologic oncologist. She was diagnosed with papillary serous ovarian cancer at 54 years of age and following surgical treatment and staging, she had undergone extensive chemotherapeutic treatment over the course of 6 years. Her disease continued to progress, and her oncology care team urged her to consider BRCA gene testing to determine whether she was eligible for a clinical trial open to BRCA-positive patients in whom previous platinum therapy had failed. A 3-generation pedigree did not reveal features suggestive of a hereditary cancer syndrome (Fig. 2). Genetic testing The patient underwent testing for mutations in the BRCA genes and was found to have a deleterious BRCA1 gene mutation. With the exception of the patient’s ovarian cancer, the family history in this case did not demonstrate other clinical features typical of HBOC. Data show that up to 15% of women with ovarian cancer have mutations in BRCA1 or BRCA2, regardless of family history.25 Further, Schrader et al26 reported that 5 of 26 BRCA mutation–positive patients with ovarian cancer did not have a positive family history of breast or ovarian cancer. Based on these data, the Society of Gynecologic Oncology recently released a clinical practice statement recommending genetic counseling with the consideration of BRCA gene testing for all women with epithelial ovarian, fallopian tube, and peritoneal cancers.27 Medical management The identification of a BRCA1 mutation allowed her to be enrolled in the clinical trial. In the past several years, studies have investigated the role of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARP inhibitors) in the treatment of ovarian cancers. PARPs work at a molecular level to repair single-strand DNA breaks. The inhibition of PARP leads to the accumulation of these defects, which leads to double-stranded breaks, which are typically repaired by genes like BRCA1 and BRCA2. Tumors of individuals with inherited BRCA gene mutations lack effective homologousrecombination DNA repair. When the repair mechanisms reliant on PARP and BRCA1 or BRCA2 are absent owing to treatment with a PARP inhibitor and germ-line BRCA gene mutation and subsequent loss of wild-type function, the affected tumor cells die. This can result in selectively induced cytotoxicity in tumor cells, while sparing normal cells in patients with BRCA-associated tumors.28 Available data have been promising in this population and also in non–BRCA-associated ovarian cancers.29 In a situation where a patient’s eligibility for a clinical trial is dependent upon the completion of BRCA gene testing, it is sometimes necessary to initiate testing quickly. Familial implications Single-site mutation analysis for family members, including her 4 adult children, was recommended based on this patient’s result. The patient notified her daughters, and they both
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Fig. 2. Pedigree for case 2 showing lack of HBOC-suggestive family history. d., Age at death, Ca, cancer. (Color version of figure is available online.)
underwent genetic testing but she did not notify her sons. The patient mistakenly thought that a BRCA gene mutation would not affect her sons’ medical management. Her lack of communication with male members of her family not only affects their ability to make decisions about genetic testing but also could lead to a lack of pertinent medical knowledge in her sons’ children.
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One daughter had negative test results for her mother’s mutation and would thus be considered at general population risk for breast and ovarian cancer. The other daughter had positive test results for her mother’s BRCA1 gene mutation. Unfortunately, screening for ovarian cancer is not a reliable long-term management plan for women with BRCA gene mutations.30,31 This daughter underwent prophylactic BSO and was found to have an occult cancer in her fallopian tube. Because occult, presymptomatic cancers of the ovaries and fallopian tubes have been identified at the time of risk-reducing BSO in up to 10% of BRCA mutation–positive women,32 pelvic washings and serial sectioning with microscopic examination are recommended for women with a BRCA mutation undergoing this surgery.12 The patient’s 52-year-old sister also underwent a test for the BRCA1 mutation. She had previously undergone prophylactic BSO given her sister’s history of the disease. She did not have the familial BRCA1 mutation. If she had this information before considering prophylactic BSO, she would have chosen to forgo surgery.
Key points
Although in the past, the primary reason for genetic testing in a patient like this would primarily be for risk information for her family. With the advent of newer treatment options such as PARP inhibitors, the identification of a BRCA mutation in a patient with advanced cancer has the potential to directly affect their medical care. A diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer warrants genetic counseling and consideration of BRCA gene testing. Once a BRCA mutation is identified in a family, it is crucial that the result and its implications be communicated to all male and female relatives. Occult, presymptomatic cancers of the ovaries and fallopian tubes have been identified at the time of risk-reducing BSO in up to 10% of BRCA mutation–positive women.32
Case 3 A previously healthy woman diagnosed with breast cancer diagnosed at 35 years of age was referred for genetic counseling and testing before making decisions about surgical treatment of her breast cancer. The patient’s family history revealed that her sister had papillary thyroid cancer at 40 years of age, and her maternal aunt had an unknown type of leukemia at 15 years of age (Fig. 3). Genetic testing She underwent BRCA genetic testing and was found to have a variant of uncertain significance (VOUS) in the BRCA2 gene. The VOUS had not been previously observed by the testing laboratory and was not reported in the literature. This means that the genetic alteration identified in her sample could not be further classified as deleterious or benign. As such, this VOUS could not be used to aid the patient and her care team in management decision making. The rate at which VOUSs occur in practice is difficult to quantify given the differences in testing laboratories and lack of public data. According to testing laboratory advertisements at the time of publication, 2%-10% of BRCA tests ordered singularly result in a VOUS. Given the patient’s age of diagnosis, she was counseled about additional options for genetic testing using a multigene panel including other genes known to be associated with hereditary breast cancer including TP53 and PTEN. This was particularly prudent for her given her family history of leukemia which can be associated with Li-Fraumeni syndrome,33 and papillary thyroid cancer, which can be associated with Cowden syndrome.34 She opted to initiate this testing and received negative panel results a month later.
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Fig. 3. Pedigree for case 3 showing other early-onset cancers in the family. d., Age at death, Ca, cancer. (Color version of figure is available online.)
Medical management Based on her test result, the patient considered her options and ultimately decided to have a unilateral mastectomy to surgically treat her cancer. It is not uncommon for women to be referred for genetic counseling and testing shortly upon receiving a diagnosis of early-onset breast cancer to facilitate decisions about surgical treatment.35 One primary motivator of this practice is the increased risk of contralateral breast cancers in BRCA mutation–positive women. Contralateral breast cancer risk in BRCA gene mutation carriers has been estimated to be as high as 50% in some women.3 This is compared with approximately 10% in nonmutation carriers.36 Because some patients may be overwhelmed by the circumstances surrounding their cancer diagnosis, careful counseling should include the option to decline genetic testing.
Familial implications In this circumstance, because a VOUS was identified, a hereditary cancer syndrome diagnosis has not been made and genetic testing for this VOUS would not be appropriate for family members. However, given the patient’s diagnosis of breast cancer at a young age, her close female relatives’ risks for breast cancer are still elevated over the general population. Risk models37-40 can be used to estimate the magnitude of risk that family history and hormonal factors might impart to allow for personalized risk management for her unaffected relatives. The American Cancer Society and the NCCN recommend that individuals with at least a 20% lifetime
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risk of breast cancer consider breast magnetic resonance imaging in addition to mammography as part of their annual imaging.4,41 Given the rapidly changing landscape of cancer genetic testing, the family should be encouraged to follow-up periodically and to keep their contact information current so that they may be contacted in the event that the testing laboratory reclassifies the VOUS. A VOUS can be upgraded to “likely deleterious” or “deleterious” or downgraded to “likely benign” or “benign.” Genetic testing laboratories have different policies for reporting these changes in VOUS interpretation, which places differing degrees of responsibility on the ordering clinician. In some cases, a laboratory may only notify the ordering provider when a VOUS changes from uncertain to deleterious and not from uncertain to benign. Key points
It is not uncommon for women to be referred for genetic counseling and testing shortly upon receiving a diagnosis of early-onset breast cancer to facilitate decisions about surgical treatment.35 Multigene panels can be particularly useful when a patient’s family has features of more than one hereditary cancer syndrome,42 but specific recommendations for the conditions in which multigene panel tests are appropriate are lacking. Care should be taken to address the increased complexity inherent to this testing with patients, including a higher likelihood of finding a VOUS. When genetic testing fails to reveal a deleterious mutation in a known hereditary cancer gene, risks for family members should be provided based on empiric models and periodic follow-up with genetics is recommended.
Summary HBOC is the most common and well-described hereditary breast cancer syndrome and is often at the center of professional recommendations, accreditation standards, and insurance company coverage policies. A person’s BRCA gene mutation status may alter their decisions about surgical treatment, eligibility for a clinical trial, and their approach to cancer risk reduction and screening. The potential for knowledge gained from undergoing BRCA gene testing is great, but there are limitations and pitfalls of which patients should be aware before providing informed consent, including the possibility of uncertain or uninformative results, potential for psychological distress, and effect on family members. As such, it is important for clinicians across the health care spectrum to be able to appropriately identify patients at risk of having HBOC, understand the effect that this diagnosis has on their patients with and without cancer, and be able to identify resources to support their patients throughout genetic testing process. References 1. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72(5):1117–1130. 2. Evans DG, Susnerwala I, Dawson J, Woodward E, Maher ER, Lalloo F. Risk of breast cancer in male BRCA2 carriers. J Med Genet 2010;47(10):710–711. 3. Graeser MK, Engel C, Rhiem K, et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2009;27(35):5887–5892. 4. National Comprehensive Cancer Network. NCCN Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/breast-scre ening.pdf; 2014 Accessed 01.09.14. 5. Iqbal J, Ragone A, Lubinski J, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2012;107(12):2005–2009. 6. 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. J Clin Oncol 2013;31(14):1748–1757. 7. 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. Br J Cancer 2011;105(8):1230–1234.
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8. Ginsburg OM, Kim-Sing C, Foulkes WD, et al. BRCA1 and BRCA2 families and the risk of skin cancer. Fam Cancer 2010;9(4):489–493. 9. Evans DGR, Barwell J, Eccle DM, et al. The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services. Breast Cancer Res 2014;16:442. [Epub ahead of print]. 10. Radford C, Prince A, Lewis K, Pal T. Factors which impact the delivery of genetic risk assessment services focused on inherited cancer genomics: expanding the role and reach of certified genetics professionals. J Genet Counsel 2014;23(4):522–530. 11. Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2010;28(5):893–901. 12. ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol 2009;113:957–966. 13. Berliner JL, Fay AM, Cummings SA, Burnett B, Tillmanns T. NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Counsel 2013;22(2):155–163. 14. Commission on Cancer. Cancer Program Standards 2012: ensuring patient-centered care V1.1. http://www.facs.org/ cancer/coc/programstandards2012.pdf; 2012 Accessed 01.09.14. 15. American College of Surgeons 2013. National Accreditation Program for Breast Centers NAPBC. Breast Center Standards Manual. https://www.facs.org/ /media/files/quality%20programs/cancer/napbc/2013standardsmanual.ashx Accessed 01.09.14. 16. Borzekowski DL, Guan Y, Smith KC, Erby LH, Roter DL. The Angelina effect: immediate reach, grasp, and impact of going public. Genet Med 2014;16(7):516–521. 17. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007;57(2):75–89. 18. Robson ME, Offit K. Management of an inherited predisposition to breast cancer. N Engl J Med 2007;357:154–162. 19. Pruthi S, Gostout BS, Lindor NM. Identification and management of women with BRCA mutations or hereditary predisposition for breast and ovarian cancer. Mayo Clin Proc 2010;85(12):1111–1120. 20. Thompson D, Easton DF. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 2001;68(2):410–419. 21. Thompson D, Easton DF. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 2002;94(18):1358–1365. 22. Edwards SM, Evans DG, Hope Q. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer 2010;103(6):918–924. 23. Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, et al. Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 2007;99(12):929–935. 24. 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 Counsel 2012;21(2):151–161. 25. Ramus SJ, Gayther SA. The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol Oncol 2009;3(2):138–150. 26. Schrader KA, Hurlburt J, Kalloger SE, et al. Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy. Obstet Gynecol 2012;120(2):235–240. 27. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. https://www.sgo. org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/; 2014 Accessed 01.09.14. 28. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361(2):123–134. 29. Chen Y, Zhang L, Hao Q. Olaparib: a promising PARP inhibitor in ovarian cancer therapy. Arch Gynecol Obstet 2013;288(2):367–374. 30. Evans DG, Gaarenstroom KN, Stirling D, et al. Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers. J Med Genet 2009;46(9):593–597. 31. Woodward ER, Sleightholme HV, Considine AM, Williamson S, McHugo JM, Cruger DG. Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both high-risk and population risk women is ineffective. BJOG 2007;114:1500–1509. 32. Powell CB, Chen LM, McLennan J, et al. Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol. Int J Gynecol Cancer 2011;21(5):846–851. 33. McBride KA, Ballinger ML, Killick E, et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol 2014;11(5):260–271. 34. Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst 2013;105(21):1607–1616. 35. Schwartz MD, Lerman C, Brogan B, et al. Utilization of BRCA1/BRCA2 mutation testing in newly diagnosed breast cancer patients. Cancer Epidemiol Biomarkers Prev 2005;14(4):1003–1007. 36. Obedian E, Fischer DB, Haffty BG. Second malignancies after treatment of early-stage breast cancer: lumpectomy and radiation therapy versus mastectomy. J Clin Oncol 2000;18(12):2406–2412. 37. Claus EB, Schildkraut J, Iversen ES Jr., Berry D, Parmigiani G. Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history. J Natl Cancer Inst 1998;90(23):1824–1829. 38. Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 1998;62(1):145–158. 39. MacInnis RJ, Bickerstaffe A, Apicella C, et al. Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre. Br J Cancer 2013;109(5):1296–1301. 40. Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 2004;23(7):1111–1130. 41. American Cancer Society. American Cancer Society recommendations for early breast cancer detection in women without breast symptoms. http://www.cancer.org/cancer/breastcancer/moreinformation/breastcancerearlydetec tion/breast-cancer-early-detection-acs-recs; 2014 Accessed 01.10.14. 42. 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(19):2001–2009.
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
Hereditary breast and ovarian cancer syndrome: Considering the complexities Leigha Senter, MS, LGC
Introduction Hereditary breast and ovarian cancer syndrome (HBOC) is a well-described hereditary cancer predisposition syndrome caused by mutations in BRCA1 and BRCA2. Several studies have provided lifetime breast cancer risk estimates for women with HBOC, and most have suggested a risk between 50% and 80%.1 Men with BRCA mutations have a risk of up to 8% of developing breast cancer in their lifetimes.2 In women, the risk of developing breast cancer appears to be slightly higher in carriers of BRCA1 mutations compared with carriers of BRCA2 mutations, whereas the opposite is true regarding the risks for male breast cancer. The development of contralateral breast cancer is also more common in women with HBOC, with current estimates suggesting a risk of approximately 50% in the 25 years after initial breast cancer diagnosis. Women who are diagnosed with their first breast cancer at a younger age have the highest risk for contralateral disease.3 The risk for ovarian cancer is also substantially increased over that of the general population and is higher for carriers of BRCA1 mutations (approximately 40%) vs. BRCA2 mutations (11%).1 To manage these risks, guidelines for screening and risk reduction have been established.4 Malignancies of the pancreas and the prostate, as well as melanoma, have also been shown to be associated with BRCA gene mutations to a lesser degree.5-8 Although genetic testing for HBOC has been available since the mid-1990s, the number of patient-initiated discussions about testing for HBOC has been on the rise.9,10 This increase in consumer interest may potentially be the result of media coverage of celebrities with BRCA mutations, as well as related Supreme Court decisions regarding gene patenting. Along with this publicity, there has been a growing number of professional society recommendations regarding BRCA gene testing,4,11-13 as well as institutional accreditation standards that include requirements for the provision of genetic counseling, risk assessment, and testing.14,15 All of these factors have increased the need for health care providers to work together to play a role in identifying, counseling, testing, and managing patients with BRCA gene mutations.16 To emphasize the importance of this team approach, we use the following cases to represent common and important issues to be considered in risk assessment and genetic testing for HBOC.
http://dx.doi.org/10.1016/j.currproblcancer.2014.10.003 0147-0272/& 2014 Elsevier Inc. All rights reserved.
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Case 1 A healthy 24-year-old patient sought genetic counseling after learning that her mother, who had a previous diagnosis of breast cancer, was positive for a deleterious mutation in the BRCA1 gene. Family history information was obtained to construct a 3-generation pedigree (Fig. 1), and it indicated that her mother’s breast cancer diagnosis occurred at 40 years of age; her mother’s only sister had ovarian cancer at 50 years of age; and her maternal grandmother had breast cancer diagnosed at a young, unknown age. Additionally, her paternal family history was significant for ovarian cancer in 2 deceased paternal aunts and melanoma in her paternal grandmother. Because BRCA gene mutations are inherited in an autosomal dominant manner, the patient had a 50% chance of having inherited the identified BRCA1 mutation from her mother. Genetic testing The patient underwent single-site mutation analysis, which was negative, meaning that she did not inherit her mother’s BRCA1 mutation. Although this negative result clarified her risk based on her maternal family history of cancer, her paternal family history of ovarian cancer was also suggestive of HBOC. None of the patient’s paternal relatives had undergone BRCA gene testing, and the women diagnosed with ovarian cancer were deceased. Therefore, the optimal approach to cancer genetic testing, starting with an affected family member, was not possible. As such, additional testing to look for other BRCA gene mutations was recommended for this patient, and a different mutation in the BRCA2 gene was identified. This result not only established a diagnosis of HBOC in the patient, but also indicated that her father was an obligate carrier of the mutation. Postresult counseling included a discussion of management recommendations for the patients, as well as a communication plan for paternal family members to receive this new information. Had the paternal side of this patient’s family not been explored and further testing pursued, the patient would have falsely been reassured she was at low or general population risk. Medical management Although a comprehensive review of the evidence for medical management of BRCA1 and BRCA2 mutations is beyond the scope of this article, several publications and guidelines exist.4,11,12,17-19 Those of the National Comprehensive Cancer Network (NCCN) are updated annually and widely used.4 According to NCCN, this patient would be recommended to have annual screening with breast magnetic resonance imaging from 25-29 years of age, with the addition of annual mammography beginning at 30 years of age. Given this patient’s young age, she would be further counseled about additional risk reduction options such as prophylactic bilateral salpingo-oophorectomy (BSO) preferably by 35-40 years of age or when childbearing is complete.4 This patient’s test result, inadvertently provided information about her father’s BRCA status, as well—that he was an obligate carrier of the mutation in the family. Men with BRCA gene mutations are recommended to have clinical breast examination every 6-12 months beginning at 35 years of age and to consider baseline mammogram at 40 years of age. Prostate cancer screening is also recommended for men with BRCA2 mutations and should be considered by men with BRCA1 mutations beginning at 40 years of age.4 The relative risk of prostate cancer in men younger than 65 years in BRCA1 mutation carriers is 1.8, whereas the risk is increased 5-8fold for BRCA2 mutation carriers.7,20,21 Data have also suggested that BRCA2-related prostate cancers are more aggressive with poor survival rates.6,22,23 Familial implications When a person's test results are negative for a previously identified familial mutation, this is considered a “true negative” and increased screening is no longer indicated, unless there is
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Fig. 1. Pedigree for case 1 showing family history suggestive of HBOC on both sides of the patient’s family. d., Age at death, Ca, cancer. (Color version of figure is available online.)
concern based on the opposite side of the family (as in this case) or if there are cancers in the family that cannot be explained by the BRCA mutation. If there is no indication of a possible HBOC syndrome on the opposite side of the family, cancer screening recommendations for a person with a true negative test result would reflect what is recommended for the general population and thus would have been inappropriate for this patient.24 Reflex testing in this case, meant testing an unaffected patient for mutations in BRCA1 and BRCA2 based on cancers observed in her paternal family history. Although not ideal, this approach was warranted because her relatives with ovarian cancer were deceased. A negative result in this situation could mean that there is a BRCA gene mutation in the family that the patient did not inherit; or that the cancers in the family are due to a mutation in a different gene for which the patient was not tested; or that the cancers in the family are not hereditary. Because it is often impossible to distinguish between these possibilities in this situation, screening recommendations would be made based on the risk attributed to the family history. The identification of a paternally inherited BRCA gene mutation in this patient, by default, also indicates that her father carries the same mutation (he is an obligate carrier). Nonpaternity, which occurs when the man thought to be the biological father actually is not, is a possibility to be considered but this was not a concern for this family. We explained the importance of this information to the patient and encouraged her to notify her father and other paternal relatives as soon as possible. This patient’s brother and sister are at risk for having inherited a BRCA gene mutation from their mother and from their father. Each of her siblings has a 75% chance of having at least one of their parents’ BRCA gene mutations and a 25% chance of carrying neither mutation. Additionally, this patient’s other relatives on both sides of her family are also at risk of having one BRCA gene mutation. Achieving a negative test result in any relative would eliminate the need for that relative’s children to be tested for that specific mutation.
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Key points
Genetic test results should be interpreted in the context of a patient’s family history. It is preferred to initiate testing in a family with an individual who has been diagnosed with breast or ovarian cancer, because interpretation of a negative test result in an unaffected person is often not straightforward.24 Diagnosis of HBOC in a person who does not have a personal history of cancer allows for a personalized plan for risk reduction. Although not so in this case, genetic testing in a family can sometimes reveal nonpaternity.
Case 2 A 60-year-old woman was referred for genetic counseling and testing by her gynecologic oncologist. She was diagnosed with papillary serous ovarian cancer at 54 years of age and following surgical treatment and staging, she had undergone extensive chemotherapeutic treatment over the course of 6 years. Her disease continued to progress, and her oncology care team urged her to consider BRCA gene testing to determine whether she was eligible for a clinical trial open to BRCA-positive patients in whom previous platinum therapy had failed. A 3-generation pedigree did not reveal features suggestive of a hereditary cancer syndrome (Fig. 2). Genetic testing The patient underwent testing for mutations in the BRCA genes and was found to have a deleterious BRCA1 gene mutation. With the exception of the patient’s ovarian cancer, the family history in this case did not demonstrate other clinical features typical of HBOC. Data show that up to 15% of women with ovarian cancer have mutations in BRCA1 or BRCA2, regardless of family history.25 Further, Schrader et al26 reported that 5 of 26 BRCA mutation–positive patients with ovarian cancer did not have a positive family history of breast or ovarian cancer. Based on these data, the Society of Gynecologic Oncology recently released a clinical practice statement recommending genetic counseling with the consideration of BRCA gene testing for all women with epithelial ovarian, fallopian tube, and peritoneal cancers.27 Medical management The identification of a BRCA1 mutation allowed her to be enrolled in the clinical trial. In the past several years, studies have investigated the role of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARP inhibitors) in the treatment of ovarian cancers. PARPs work at a molecular level to repair single-strand DNA breaks. The inhibition of PARP leads to the accumulation of these defects, which leads to double-stranded breaks, which are typically repaired by genes like BRCA1 and BRCA2. Tumors of individuals with inherited BRCA gene mutations lack effective homologousrecombination DNA repair. When the repair mechanisms reliant on PARP and BRCA1 or BRCA2 are absent owing to treatment with a PARP inhibitor and germ-line BRCA gene mutation and subsequent loss of wild-type function, the affected tumor cells die. This can result in selectively induced cytotoxicity in tumor cells, while sparing normal cells in patients with BRCA-associated tumors.28 Available data have been promising in this population and also in non–BRCA-associated ovarian cancers.29 In a situation where a patient’s eligibility for a clinical trial is dependent upon the completion of BRCA gene testing, it is sometimes necessary to initiate testing quickly. Familial implications Single-site mutation analysis for family members, including her 4 adult children, was recommended based on this patient’s result. The patient notified her daughters, and they both
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Fig. 2. Pedigree for case 2 showing lack of HBOC-suggestive family history. d., Age at death, Ca, cancer. (Color version of figure is available online.)
underwent genetic testing but she did not notify her sons. The patient mistakenly thought that a BRCA gene mutation would not affect her sons’ medical management. Her lack of communication with male members of her family not only affects their ability to make decisions about genetic testing but also could lead to a lack of pertinent medical knowledge in her sons’ children.
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One daughter had negative test results for her mother’s mutation and would thus be considered at general population risk for breast and ovarian cancer. The other daughter had positive test results for her mother’s BRCA1 gene mutation. Unfortunately, screening for ovarian cancer is not a reliable long-term management plan for women with BRCA gene mutations.30,31 This daughter underwent prophylactic BSO and was found to have an occult cancer in her fallopian tube. Because occult, presymptomatic cancers of the ovaries and fallopian tubes have been identified at the time of risk-reducing BSO in up to 10% of BRCA mutation–positive women,32 pelvic washings and serial sectioning with microscopic examination are recommended for women with a BRCA mutation undergoing this surgery.12 The patient’s 52-year-old sister also underwent a test for the BRCA1 mutation. She had previously undergone prophylactic BSO given her sister’s history of the disease. She did not have the familial BRCA1 mutation. If she had this information before considering prophylactic BSO, she would have chosen to forgo surgery.
Key points
Although in the past, the primary reason for genetic testing in a patient like this would primarily be for risk information for her family. With the advent of newer treatment options such as PARP inhibitors, the identification of a BRCA mutation in a patient with advanced cancer has the potential to directly affect their medical care. A diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer warrants genetic counseling and consideration of BRCA gene testing. Once a BRCA mutation is identified in a family, it is crucial that the result and its implications be communicated to all male and female relatives. Occult, presymptomatic cancers of the ovaries and fallopian tubes have been identified at the time of risk-reducing BSO in up to 10% of BRCA mutation–positive women.32
Case 3 A previously healthy woman diagnosed with breast cancer diagnosed at 35 years of age was referred for genetic counseling and testing before making decisions about surgical treatment of her breast cancer. The patient’s family history revealed that her sister had papillary thyroid cancer at 40 years of age, and her maternal aunt had an unknown type of leukemia at 15 years of age (Fig. 3). Genetic testing She underwent BRCA genetic testing and was found to have a variant of uncertain significance (VOUS) in the BRCA2 gene. The VOUS had not been previously observed by the testing laboratory and was not reported in the literature. This means that the genetic alteration identified in her sample could not be further classified as deleterious or benign. As such, this VOUS could not be used to aid the patient and her care team in management decision making. The rate at which VOUSs occur in practice is difficult to quantify given the differences in testing laboratories and lack of public data. According to testing laboratory advertisements at the time of publication, 2%-10% of BRCA tests ordered singularly result in a VOUS. Given the patient’s age of diagnosis, she was counseled about additional options for genetic testing using a multigene panel including other genes known to be associated with hereditary breast cancer including TP53 and PTEN. This was particularly prudent for her given her family history of leukemia which can be associated with Li-Fraumeni syndrome,33 and papillary thyroid cancer, which can be associated with Cowden syndrome.34 She opted to initiate this testing and received negative panel results a month later.
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Fig. 3. Pedigree for case 3 showing other early-onset cancers in the family. d., Age at death, Ca, cancer. (Color version of figure is available online.)
Medical management Based on her test result, the patient considered her options and ultimately decided to have a unilateral mastectomy to surgically treat her cancer. It is not uncommon for women to be referred for genetic counseling and testing shortly upon receiving a diagnosis of early-onset breast cancer to facilitate decisions about surgical treatment.35 One primary motivator of this practice is the increased risk of contralateral breast cancers in BRCA mutation–positive women. Contralateral breast cancer risk in BRCA gene mutation carriers has been estimated to be as high as 50% in some women.3 This is compared with approximately 10% in nonmutation carriers.36 Because some patients may be overwhelmed by the circumstances surrounding their cancer diagnosis, careful counseling should include the option to decline genetic testing.
Familial implications In this circumstance, because a VOUS was identified, a hereditary cancer syndrome diagnosis has not been made and genetic testing for this VOUS would not be appropriate for family members. However, given the patient’s diagnosis of breast cancer at a young age, her close female relatives’ risks for breast cancer are still elevated over the general population. Risk models37-40 can be used to estimate the magnitude of risk that family history and hormonal factors might impart to allow for personalized risk management for her unaffected relatives. The American Cancer Society and the NCCN recommend that individuals with at least a 20% lifetime
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risk of breast cancer consider breast magnetic resonance imaging in addition to mammography as part of their annual imaging.4,41 Given the rapidly changing landscape of cancer genetic testing, the family should be encouraged to follow-up periodically and to keep their contact information current so that they may be contacted in the event that the testing laboratory reclassifies the VOUS. A VOUS can be upgraded to “likely deleterious” or “deleterious” or downgraded to “likely benign” or “benign.” Genetic testing laboratories have different policies for reporting these changes in VOUS interpretation, which places differing degrees of responsibility on the ordering clinician. In some cases, a laboratory may only notify the ordering provider when a VOUS changes from uncertain to deleterious and not from uncertain to benign. Key points
It is not uncommon for women to be referred for genetic counseling and testing shortly upon receiving a diagnosis of early-onset breast cancer to facilitate decisions about surgical treatment.35 Multigene panels can be particularly useful when a patient’s family has features of more than one hereditary cancer syndrome,42 but specific recommendations for the conditions in which multigene panel tests are appropriate are lacking. Care should be taken to address the increased complexity inherent to this testing with patients, including a higher likelihood of finding a VOUS. When genetic testing fails to reveal a deleterious mutation in a known hereditary cancer gene, risks for family members should be provided based on empiric models and periodic follow-up with genetics is recommended.
Summary HBOC is the most common and well-described hereditary breast cancer syndrome and is often at the center of professional recommendations, accreditation standards, and insurance company coverage policies. A person’s BRCA gene mutation status may alter their decisions about surgical treatment, eligibility for a clinical trial, and their approach to cancer risk reduction and screening. The potential for knowledge gained from undergoing BRCA gene testing is great, but there are limitations and pitfalls of which patients should be aware before providing informed consent, including the possibility of uncertain or uninformative results, potential for psychological distress, and effect on family members. As such, it is important for clinicians across the health care spectrum to be able to appropriately identify patients at risk of having HBOC, understand the effect that this diagnosis has on their patients with and without cancer, and be able to identify resources to support their patients throughout genetic testing process. References 1. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72(5):1117–1130. 2. Evans DG, Susnerwala I, Dawson J, Woodward E, Maher ER, Lalloo F. Risk of breast cancer in male BRCA2 carriers. J Med Genet 2010;47(10):710–711. 3. Graeser MK, Engel C, Rhiem K, et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2009;27(35):5887–5892. 4. National Comprehensive Cancer Network. NCCN Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/breast-scre ening.pdf; 2014 Accessed 01.09.14. 5. Iqbal J, Ragone A, Lubinski J, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2012;107(12):2005–2009. 6. 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. J Clin Oncol 2013;31(14):1748–1757. 7. 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. Br J Cancer 2011;105(8):1230–1234.
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NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Counsel 2013;22(2):155–163. 14. Commission on Cancer. Cancer Program Standards 2012: ensuring patient-centered care V1.1. http://www.facs.org/ cancer/coc/programstandards2012.pdf; 2012 Accessed 01.09.14. 15. American College of Surgeons 2013. National Accreditation Program for Breast Centers NAPBC. Breast Center Standards Manual. https://www.facs.org/ /media/files/quality%20programs/cancer/napbc/2013standardsmanual.ashx Accessed 01.09.14. 16. Borzekowski DL, Guan Y, Smith KC, Erby LH, Roter DL. The Angelina effect: immediate reach, grasp, and impact of going public. Genet Med 2014;16(7):516–521. 17. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007;57(2):75–89. 18. Robson ME, Offit K. Management of an inherited predisposition to breast cancer. 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A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 2004;23(7):1111–1130. 41. American Cancer Society. American Cancer Society recommendations for early breast cancer detection in women without breast symptoms. http://www.cancer.org/cancer/breastcancer/moreinformation/breastcancerearlydetec tion/breast-cancer-early-detection-acs-recs; 2014 Accessed 01.10.14. 42. 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(19):2001–2009.
