Curr Probl Cancer 38 (2014) 209–215
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
The changing landscape of genetic testing for hereditary breast and ovarian cancer Cecelia A. Bellcross, PhD, MS, CGC
A bit of history It took Angelina Jolie’s announcement in 2013 to bring broad awareness of hereditary breast and ovarian cancer (HBOC) to the general public. However, it has been 25 years since MaryClaire King mapped BRCA1 to chromosome 17 through linkage analysis involving painstaking collection of a large number of families with multiple cases of early-onset breast cancer.1 Though familial “clusters” of breast cancer had been described since the early 1800s, the concept that cancer can result from inheritance of a single faulty gene first made its way into the scientific literature when Knudson2 published his famous “2-hit hypothesis” in 1971. Lynch et al3 were one of the first to describe the association of breast with ovarian cancer in a 1978 article entitled “Familial Association of Breast and Ovarian.” However, it was the pioneering work of Gardner and Stephens4 initiated in the mid-1940s identifying and following large Mormon kindreds in Utah that ultimately drove the search for the “breast cancer gene.” Despite the work of Knudson, Lynch, Gardner, and others, the research and clinical communities remained skeptical well into the early 1980s that breast cancer could be hereditary, as opposed to primarily the result of environmental and lifestyle factors. The race to isolate the BRCA1 gene was ultimately won by Mark Skolnick, founder of Myriad Genetic Laboratories, Inc, in 1994, followed closely by the cloning of BRCA2 in 1995.5-7 At that time, despite the evidence of increased incidence of ovarian cancer in BRCA1 and BRCA2 families, many still believed there was an ovarian cancer–only gene that was responsible for pedigrees segregating multiple ovarian cancer cases, but no breast cancer. However, further study confirmed that there was not an “OVCA1” gene, and that BRCA1 and BRCA2 accounted for most familial site-specific ovarian cancer.8 In addition, the failure to find a BRCA1 and BRCA2 mutation in many apparently classic HBOC families led to the search for “BRCA3.” Ultimately it was determined that there likely did not exist another single major hereditary cancer gene responsible for most BRCA1- and BRCA2-negative families.9,10
Enter commercial testing and cancer genetic counseling As commercial testing for BRCA1 and BRCA2 quickly followed the isolation of BRCA2 in 1996, the medical genetics community struggled with how best to identify and counsel at-risk women. http://dx.doi.org/10.1016/j.currproblcancer.2014.10.001 0147-0272/& 2014 Elsevier Inc. All rights reserved.
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There was concern that knowing one who carried a BRCA1 and BRCA2 mutation would impose a psychosocial burden similar to that of Huntington disease. Fears about insurance discrimination were widespread, and many women and families struggled with the decision of whether to undergo BRCA1 and BRCA2 testing, or even to come see a genetic counselor. We had very little evidence-based information to offer women in terms of what screening protocols should be initiated at what age, whether they were effective in reducing morbidity or mortality, and to what extent prophylactic surgeries were warranted. Such issues led some to advocate that BRCA1 and BRCA2 testing only be offered in the context of clinical research.11 Referrals for HBOC genetic counseling and testing were fairly uncommon in the mid-to-late 1990s. This was in part because practitioners did not routinely collect essential family history information and had limited understanding of the red flags that indicate an individual at risk for HBOC. Provider knowledge and awareness of hereditary cancer have improved substantially over the last 20 years, with a concomitant steady increase in use of counseling and testing. However, there does remain concerning evidence of failure to appropriately identify and refer patients for cancer genetics services.12 Early protocols for providing cancer genetic counseling were based on the uncertain psychosocial influence and clinical utility of BRCA testing. The process was extensive and typically involved 3 in-person appointments. Now cancer genetic counseling is usually streamlined into appointment, though patients are often encouraged to return for in-person posttest counseling in the advent of a positive result. Several studies have suggested that undergoing genetic counseling and BRCA testing is not associated with substantial increases in depression or anxiety.13 Currently, there are hundreds of hereditary cancer clinics in a wide variety of institutions across the United States, and cancer genetic counseling is a wellrecognized subspecialty. In addition, provision of cancer genetic counseling by phone or video conferencing is helping to address the increased demand and lack access to local cancer genetic services.14
Our knowledge improves As the number of patients being tested for BRCA1 and BRCA2 mutations grew steadily in the late 90s and early 2000s, there was a clearly recognized need for outcome data to provide evidence-based risk counseling and management recommendations. The number of articles published regarding BRCA1 and BRCA2 has grown exponentially from less than 200 in 1995, to more than 13,000 by 2014. These data have demonstrated the clinical utility of BRCA1 and BRCA2 genetic testing and provided more accurate cancer risk estimates for mutation carriers. Despite newer data, the misconceptions of the original penetrance estimates indicating an 87% lifetime risk for breast cancer remain in use in many situations today.15 This is evidenced by what Angelina Jolie quoted to the news media as her risk for breast cancer (87%), as well as the fact that Myriad still uses these 1994 cancer risk figures in their BRCA mutation–positive reports. More recent population-based data do not support these more extreme-risk estimates. In 2007, Chen and Parmigiani16 reported longitudinal risks for breast and ovarian cancer based on a woman's age and which gene is involved. A 30 year-old woman with a BRCA1 mutation has a risk for breast cancer of 54% by 70 years of age, whereas her risk to develop breast cancer by 40 years of age is 10%. Providing accurate, longitudinal, and age-adjusted risks is critical for women with a BRCA1 or BRCA2 mutation, as they seek to make decisions about medical management and riskreducing surgeries. In addition to better cancer penetrance figures, there is now evidence supporting the clinical utility of BRCA1 and BRCA2 testing, including reduction in morbidity and mortality associated with identification and management of mutation carriers.17-21 The United States Preventive Services Task Force (USPSTF) found sufficient evidence in 2005 to recommend “women whose family history is associated with an increased risk for deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing,” though the evidence of reduced mortality at the time was just emerging.22 The USPSTF recently affirmed their original
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recommendation, with a focus on primary care providers using screening tools to identify at-risk women for referral.23 One of the more recent articles published regarding the effect of riskreducing surgery on mortality is that of Finch et al, reporting on 5783 women. Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.24
Variants and patents Along with the fear of insurance discrimination, lack of provider awareness, and uncertainty regarding the effectiveness of management strategies, the first decade of cancer genetic counseling and testing for HBOC was also plagued by the limitations of the testing itself. Not only were variants of uncertain significance (VOUS) found in upward of 10-15% of cases, but the technology at the time also did not allow for the detection of deletions and duplications in BRCA1 and BRCA2, which account for approximately 20% of deleterious mutations in these genes depending on the population studied.25 In addition, the 1994 and 1995 Myriad patents of BRCA1 and BRCA2 eliminated the possibility of other laboratories working to improve detection rates and prevented the market competition that would have helped to keep costs reasonable. This of course changed with the June 13, 2013 Supreme Court decision in the case of the American Molecular Pathologist vs Myriad with the ruling that the process of isolating naturally occurring DNA is insufficient to transform the natural phenomenon into a patentable inventions.26 There is no doubt that this patent decision has affected both the cost and the availability of BRCA1 and BRCA2 testing. Very soon after, multiple laboratories began offering BRCA testing, driving the cost from more than $4000 to as low as $1000. However, cost is not the only issue. Practitioners must carefully consider the quality of the laboratory, turnaround times, and rates of VOUS. Throughout its years of testing, Myriad maintained a proprietary database of more than 14,000 variants, which ultimately allowed them to reduce their VOUS rate to 2.5%. Without access to information regarding these 14,000 variants, new laboratories offering BRCA1 and BRCA2 testing must rely on their own limited data, or data otherwise in the public domain to make decisions regarding variant classification, and as such, have higher rates of VOUS. Furthermore, not all laboratories will make the same call regarding these variants, meaning the same variant may be reported as likely benign by one laboratory, and likely pathogenic by another. This places the burden on the clinician receiving the report, especially from lesserknown laboratories, to confirm the variant call through other sources.
Insurance and discrimination A substantial barrier to patient's accessing cancer genetic counseling and testing in those early years was the lack of insurance coverage. In the beginning, most carriers considered BRCA1 and BRCA2 testing to be “experimental,” as there were no randomized control trials to demonstrate its usefulness. Many insurance carriers denied genetic testing because of impressions of excessive cost, not necessarily considering the fact that cost of testing and management was substantially less than long-term treatment for advanced stage cancer. Now most health insurance companies cover testing, but typically have policies determining which patients qualify. CIGNA recently instituted a policy that requires genetic counseling for testing to be covered, recognizing that indiscriminate testing without appropriate risk assessment and follow-up can result in unnecessary expenditures.27 In 2008, the Genetic Information Non-Discrimination act was passed, prohibiting health insurers from denying or charging higher rates based on either family history or genetic test results.28 Although this 14-year effort was a tremendous victory and provided needed reassurance to worried families, very little evidence of overt discrimination based on a positive result for HBOC had emerged since testing began.28 Now, with the advent of the Affordable Care Act, not only
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those with predisposing mutations are protected from discrimination, but also those who have already manifest cancer or precancerous lesions are covered.29 In addition, the Affordable Care Act stipulates that insurance must cover any screening or preventive services that have been endorsed by independent bodies such as the USPSTF. Thus, the 2005 and 2013 grade B USPSTF recommendations regarding BRCA1 and BRCA2 counseling and testing should increase the availability of these services to at-risk individuals who might otherwise have been denied.30
New genes, single-nucleotide polymorphisms, and panels Though the initial identification of BRCA1 and BRCA2 and the other early discovered major hereditary cancer genes (APC, P53, MLH1, MSH2, etc) was a long and arduous process, rapidly advancing technology resulted in the identification of many more genes predisposing to cancer in the decade that followed. Some of these genes such as PTEN and STK11 are classic hereditary cancer genes in the sense that they are associated with substantially increased risk for cancer (high-penetrance), though they each account for a much smaller percentage of hereditary cancers.31 What has emerged in the continued search for additional hereditary cancer genes and chemotherapeutic targets are genes that are clearly linked to an increased incidence of cancer, but with relative risks in the range of 2-4-fold general population (moderate penetrance).32 Genome-wide association studies led to the identification of several single-nucleotide polymorphisms associated with breast and other cancers, with marginal effect sizes in the range of 1.1-1.3-fold general population risks.33,34 Direct-to-consumer (DTC) genetic testing companies sprouted in the wake of the numerous genome-wide association studies publications, offering genomic risk profiles for breast and other cancers, as well as other common diseases, with a click of your mouse and a swish and spit. In addition to concerns about consumers understanding and interpreting results on their own, these single-nucleotide polymorphism–based risk profiles explained little of the known familial risk for breast cancer (or other diseases), and ignored both family history and lifestyle factors.35 Ultimately, enough concerns were raised about the validity of the risk information provided, and the manner in which these tests were being sold to the public, that the Government Accountability Office became involved.36 By 2012, the many DTC companies that had originally popped up was whittled down to 2 or 3, and the holdout—23andMe—was ordered by the Food and Drug Administration to stop offering health-based testing in 2013. Perhaps the most profound change to affect the provision of cancer genetics services has occurred in just the last few years, which was made possible by the emergence of nextgeneration sequencing (NGS). This technology allows for rapid and simultaneous testing for mutations in multiple genes with a single test. Rather than testing one hereditary cancer gene at a time, providers can order gene panels, including 6, 18, 28, 39, and soon up to 100 genes or more in personally designed panels.37 The smaller panels focus on the high-penetrance genes for which some evidence base exists to guide medical management and testing of at-risk family members. There are panels specific for breast cancer, ovarian cancer, colon cancer, pancreatic cancer, and “all cancers.” Sequencing and deletion or duplication analysis of 28 genes cost less than what Myriad used to charge for BRCA1 and BRCA2 testing alone—without full deletion or duplication analysis. Although on the surface, this sounds great—why not get tested for as many genes as possible?—there are multiple issues to consider. Many of the genes included on the larger breast cancer panels are relatively newly described moderate-penetrance genes such as ATM, CHEK2, BARD1, BRIP1, and NBN, or genes such as MRE11 and RAD50 where their inclusion is based on reports of identification in only a few families or for which actual cancer risks remain undetermined, or both.38 In addition to uncertainty about cancer penetrance, we do not know the extent to which we can assume that a mutation in one of these genes fully explains the cancer in a family. One of the major benefits of identifying a BRCA1 or BRCA2 mutation (or other well-characterized hereditary cancer genes) in a family is the availability of mutation-specific testing of at-risk family members. A woman with a strong maternal family history of breast or ovarian cancer or both
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whose test results are negative for the BRCA1 mutation identified in her mother is considered a “true negative” and no longer at an increased risk for breast or ovarian cancer beyond the general population (assuming paternal history is not significant). Identification of a familial mutation allows individuals who do not carry it to avoid unnecessary screening or surgical procedures, targeting this management only to the mutation carriers in the family. For most moderate-penetrance cancer genes on these panels, we have insufficient information to determine whether a mutation is acting alone, or in concert with other low-to-moderate penetrance genes not tested. Thus, we are limited in our ability to offer mutation-specific testing to at-risk family members, as absence of the mutation cannot be assumed to indicate the person is at population risk. Additionally, for most moderate-penetrance cancer genes evaluated in these panels, there is no consensus regarding appropriate screening and management for individuals who carry a mutation, and effect on morbidity and mortality is essentially unknown.37-39 Furthermore, each time a gene is sequenced; there is the possibility of finding a VOUS. Although we have been dealing with the issue of VOUS for more than 20 years, it has up until recently been one at a time and for a relatively low percentage of individuals undergoing testing. When multiple genes are tested simultaneously, a substantial percentage of results obtained will contain one or more VOUS. Ambry recently reported on the outcome of their first 2000 cancer gene panels, with rates of VOUS for their larger gene panels (BreastNext—18 genes and CancerNext—28 genes) of 20% and 24%, respectively.40 Ambry has also reported that 42% of nonBRCA mutations detected by their BRCAplus panel and 30% of mutations in high-penetrance genes on their ColoNext panel were in individuals who did not meet existing clinical criteria for the associated syndromes. Although perhaps this can be considered a victory, as these individuals might not have otherwise been identified, it raises the question of whether we counsel them regarding the same cancer risks and management strategies developed on the basis of high-penetrance families. As an example, the BreastPlus panel includes the CDH1 gene, associated with lobular breast cancer (40% lifetime risk) as well as gastric cancer (70%-80% lifetime risk).41 Do we recommend gastrectomy, the standard for individuals with CDH1 mutations, for a woman with a personal or family history of breast cancer only, and no evidence of gastric cancer? Also, given the large number of genes that may be tested in these panels, patients will be found to carry mutations in more than one gene. Little data exist at this juncture regarding the potential interactive effect on cancer risk of multiple mutations involving various combinations of moderate- and high-penetrance genes. Cancer gene panels can be very helpful and are appropriate in specific circumstances. However, at minimum, application of these panels requires careful pretest and posttest counseling by qualified individuals regarding possible results and the remaining uncertainty of how to interpret them in terms of cancer risks, management, and familial implications. Further data are needed to assess the effect of widespread use of these panels on hereditary cancer morbidity and mortality, as well as the psychosocial impact on patients and families.
What is next? The final piece in the changing landscape of cancer genetic testing is the emergence of NGS of tumors to identify possible chemotherapeutic targets.42 Given that 5%-10% of all cancers are hereditary (and probably more are associated with low-to-moderate penetrance cancer genes), routine use of tumor NGS will undoubtedly lead to the identification of germline mutations in hereditary cancer genes for many patients with cancer. How patients with cancer will be told of this possibility up front? The extent to which pretest and posttest genetic counseling should be offered is just beginning to be explored.43 Furthermore, promising therapeutic options for BRCArelated cancers, such as PARP inhibitors, may lead to testing all individuals with breast or ovarian cancer for BRCA1 and BRCA2 mutations through tumor NGS.44,45 Therefore, Mary-Claire King recently made the argument that all women, regardless of personal or family history of cancer, should be offered screening for known disease-causing mutations in BRCA1 and BRCA2.46
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There is no question that the next decade of cancer genetic testing holds the promise of improved cancer prevention and treatment, and the possibility of such advances is definitely exciting. However, oncologists, pathologists, laboratories, primary care providers, and genetic professionals must work together to ensure it is evidence of clinical utility, and not the latest technology, that drives what we offer to our patients. References 1. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250(4988):1684–1689. 2. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A Apr 1971;68(4): 820–823. 3. Lynch HT, Harris RE, Guirgis HA, Maloney K, Carmody LL, Lynch JF. Familial association of breast/ovarian carcinoma. Cancer 1978;41(4):1543–1549. 4. Gardner EJ, Stephens FE. Breast cancer in one family group. Am J Hum Genet 1950;2(1):30–40. 5. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266(5182):66–71. 6. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995;378 (6559):789–792. 7. Goldgar DE, Fields P, Lewis CM, et al. A large kindred with 17q-linked breast and ovarian cancer: genetic, phenotypic, and genealogical analysis. J Natl Cancer Inst 1994;86(3):200–209. 8. Gayther SA, Russell P, Harrington P, Antoniou AC, Easton DF, Ponder BA. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am J Hum Genet 1999;65(4):1021–1029. 9. Hopper JL. More breast cancer genes? Breast Cancer Res 2001;3(3):154–157. 10. Thompson D, Szabo CI, Mangion J, et al. Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. Proc Natl Acad Sci U S A. 2002;99(2):827–831. 11. Collins FS. BRCA1—lots of mutations, lots of dilemmas. N Engl J Med 1996;334(3):186–188. 12. Bellcross CA, Kolor K, Goddard KA, Coates RJ, Reyes M, Khoury MJ. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med 2011;40(1):61–66. 13. 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(4):510–518. 14. 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(7):618–626. 15. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994;343(8899):692–695. 16. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25(11):1329–1333. 17. Domchek SM, Friebel TM, Neuhausen SL, et al. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Lancet Oncol 2006;7(3):223–229. 18. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. J Am Med Assoc 2010;304(9):967–975. 19. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 2008;26(8): 1331–1337. 20. Kurian AW, Sigal BM, Plevritis SK. Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol 2010;28(2):222–231. 21. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst 2009;101(2):80–87. 22. United States Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med Sep 6 2005;143(5):355–361. 23. Moyer VA. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160(4):271–281. 24. Finch AP, Lubinski J, Moller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014;32(15):1547–1553. 25. Sluiter MD, van Rensburg EJ. Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation. Breast Cancer Res Treat Jan 2011;125(2):325–349. 26. Offit K, Bradbury A, Storm C, Merz JF, Noonan KE, Spence R. Gene patents and personalized cancer care: impact of the Myriad case on clinical oncology. J Clin Oncol 2013;31(21):2743–2748. 27. Cragun D, Camperlengo L, Robinson E, et al. Differences in BRCA counseling and testing practices based on ordering provider type. Genet Med. June 13, 2014; http://dx.doi.org/10.1038/gim.2014. 28. National Human Genome Research Institute. Genetic discrimination. http://www.genome.gov/10002077 Accessed 01.09.14. 29. Hall JP, Moore JM. The Affordable Care Act's pre-existing condition insurance plan: enrollment, costs, and lessons for reform. Issue Brief (Commonw Fund) 2012;24:1–13. 30. United States Preventive Services Task Force. USPSTF A and B recommendations. http://www.uspreventiveservices taskforce.org/uspstf/uspsabrecs.htm Accessed 01.09.14.
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31. Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med Nov 13 2008;359(20):2143–2153. 32. Bogdanova N, Helbig S, Dork T. Hereditary breast cancer: ever more pieces to the polygenic puzzle. Hered Cancer Clin Pract 2013;11(1):12. 33. Khoury MJ, McBride CM, Schully SD, et al. The Scientific Foundation for personal genomics: recommendations from a National Institutes of Health-Centers for Disease Control and Prevention multidisciplinary workshop. Genet Med 2009;11(8):559–567. 34. Janssens AC, Gwinn M, Bradley LA, Oostra BA, van Duijn CM, Khoury MJ. A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions. Am J Hum Genet 2008;82(3):593–599. 35. Bellcross CA, Page PZ, Meaney-Delman D. Direct-to-consumer personal genome testing and cancer risk prediction. Cancer J 2012;18(4):293–302. 36. U.S. Government Accountability Office. Direct-to-consumer genetic tests: misleading test results are further complicated by deceptive marketing and other questionable practices. http://www.gao.gov/products/GAO-10-847T; 2012 Accessed 01.09.14. 37. Domchek SM, Bradbury A, Garber JE, Offit K, Robson ME. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol 2013;31(10):1267–1270. 38. Rainville IR, Rana HQ. Next-generation sequencing for inherited breast cancer risk: counseling through the complexity. Curr Oncol Rep 2014;16(3):371. 39. Mauer CB, Pirzadeh-Miller SM, Robinson LD, Euhus DM. The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience. Genet Med 2014;16(5):407–412. 40. 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(11):830–837. (Epub ahead of print). 41. Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001;121(6):1348–1353. 42. Roukos DH, Ku CS. Clinical cancer genome and precision medicine. Ann Surg Oncol 2012;19(12):3646–3650. 43. Everett JN, Gustafson SL, Raymond VM. Traditional roles in a non-traditional setting: genetic counseling in precision oncology. J Genet Counse 2014;23(4):655–660. 44. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010;376(9737):235–244. 45. Lee JM, Ledermann JA, Kohn EC. PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. AnnOncol 2014;25(1):32–40. 46. King MC, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. J Am Med Assoc 2014;312(11):1091–1092.
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
The changing landscape of genetic testing for hereditary breast and ovarian cancer Cecelia A. Bellcross, PhD, MS, CGC
A bit of history It took Angelina Jolie’s announcement in 2013 to bring broad awareness of hereditary breast and ovarian cancer (HBOC) to the general public. However, it has been 25 years since MaryClaire King mapped BRCA1 to chromosome 17 through linkage analysis involving painstaking collection of a large number of families with multiple cases of early-onset breast cancer.1 Though familial “clusters” of breast cancer had been described since the early 1800s, the concept that cancer can result from inheritance of a single faulty gene first made its way into the scientific literature when Knudson2 published his famous “2-hit hypothesis” in 1971. Lynch et al3 were one of the first to describe the association of breast with ovarian cancer in a 1978 article entitled “Familial Association of Breast and Ovarian.” However, it was the pioneering work of Gardner and Stephens4 initiated in the mid-1940s identifying and following large Mormon kindreds in Utah that ultimately drove the search for the “breast cancer gene.” Despite the work of Knudson, Lynch, Gardner, and others, the research and clinical communities remained skeptical well into the early 1980s that breast cancer could be hereditary, as opposed to primarily the result of environmental and lifestyle factors. The race to isolate the BRCA1 gene was ultimately won by Mark Skolnick, founder of Myriad Genetic Laboratories, Inc, in 1994, followed closely by the cloning of BRCA2 in 1995.5-7 At that time, despite the evidence of increased incidence of ovarian cancer in BRCA1 and BRCA2 families, many still believed there was an ovarian cancer–only gene that was responsible for pedigrees segregating multiple ovarian cancer cases, but no breast cancer. However, further study confirmed that there was not an “OVCA1” gene, and that BRCA1 and BRCA2 accounted for most familial site-specific ovarian cancer.8 In addition, the failure to find a BRCA1 and BRCA2 mutation in many apparently classic HBOC families led to the search for “BRCA3.” Ultimately it was determined that there likely did not exist another single major hereditary cancer gene responsible for most BRCA1- and BRCA2-negative families.9,10
Enter commercial testing and cancer genetic counseling As commercial testing for BRCA1 and BRCA2 quickly followed the isolation of BRCA2 in 1996, the medical genetics community struggled with how best to identify and counsel at-risk women. http://dx.doi.org/10.1016/j.currproblcancer.2014.10.001 0147-0272/& 2014 Elsevier Inc. All rights reserved.
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There was concern that knowing one who carried a BRCA1 and BRCA2 mutation would impose a psychosocial burden similar to that of Huntington disease. Fears about insurance discrimination were widespread, and many women and families struggled with the decision of whether to undergo BRCA1 and BRCA2 testing, or even to come see a genetic counselor. We had very little evidence-based information to offer women in terms of what screening protocols should be initiated at what age, whether they were effective in reducing morbidity or mortality, and to what extent prophylactic surgeries were warranted. Such issues led some to advocate that BRCA1 and BRCA2 testing only be offered in the context of clinical research.11 Referrals for HBOC genetic counseling and testing were fairly uncommon in the mid-to-late 1990s. This was in part because practitioners did not routinely collect essential family history information and had limited understanding of the red flags that indicate an individual at risk for HBOC. Provider knowledge and awareness of hereditary cancer have improved substantially over the last 20 years, with a concomitant steady increase in use of counseling and testing. However, there does remain concerning evidence of failure to appropriately identify and refer patients for cancer genetics services.12 Early protocols for providing cancer genetic counseling were based on the uncertain psychosocial influence and clinical utility of BRCA testing. The process was extensive and typically involved 3 in-person appointments. Now cancer genetic counseling is usually streamlined into appointment, though patients are often encouraged to return for in-person posttest counseling in the advent of a positive result. Several studies have suggested that undergoing genetic counseling and BRCA testing is not associated with substantial increases in depression or anxiety.13 Currently, there are hundreds of hereditary cancer clinics in a wide variety of institutions across the United States, and cancer genetic counseling is a wellrecognized subspecialty. In addition, provision of cancer genetic counseling by phone or video conferencing is helping to address the increased demand and lack access to local cancer genetic services.14
Our knowledge improves As the number of patients being tested for BRCA1 and BRCA2 mutations grew steadily in the late 90s and early 2000s, there was a clearly recognized need for outcome data to provide evidence-based risk counseling and management recommendations. The number of articles published regarding BRCA1 and BRCA2 has grown exponentially from less than 200 in 1995, to more than 13,000 by 2014. These data have demonstrated the clinical utility of BRCA1 and BRCA2 genetic testing and provided more accurate cancer risk estimates for mutation carriers. Despite newer data, the misconceptions of the original penetrance estimates indicating an 87% lifetime risk for breast cancer remain in use in many situations today.15 This is evidenced by what Angelina Jolie quoted to the news media as her risk for breast cancer (87%), as well as the fact that Myriad still uses these 1994 cancer risk figures in their BRCA mutation–positive reports. More recent population-based data do not support these more extreme-risk estimates. In 2007, Chen and Parmigiani16 reported longitudinal risks for breast and ovarian cancer based on a woman's age and which gene is involved. A 30 year-old woman with a BRCA1 mutation has a risk for breast cancer of 54% by 70 years of age, whereas her risk to develop breast cancer by 40 years of age is 10%. Providing accurate, longitudinal, and age-adjusted risks is critical for women with a BRCA1 or BRCA2 mutation, as they seek to make decisions about medical management and riskreducing surgeries. In addition to better cancer penetrance figures, there is now evidence supporting the clinical utility of BRCA1 and BRCA2 testing, including reduction in morbidity and mortality associated with identification and management of mutation carriers.17-21 The United States Preventive Services Task Force (USPSTF) found sufficient evidence in 2005 to recommend “women whose family history is associated with an increased risk for deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing,” though the evidence of reduced mortality at the time was just emerging.22 The USPSTF recently affirmed their original
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recommendation, with a focus on primary care providers using screening tools to identify at-risk women for referral.23 One of the more recent articles published regarding the effect of riskreducing surgery on mortality is that of Finch et al, reporting on 5783 women. Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.24
Variants and patents Along with the fear of insurance discrimination, lack of provider awareness, and uncertainty regarding the effectiveness of management strategies, the first decade of cancer genetic counseling and testing for HBOC was also plagued by the limitations of the testing itself. Not only were variants of uncertain significance (VOUS) found in upward of 10-15% of cases, but the technology at the time also did not allow for the detection of deletions and duplications in BRCA1 and BRCA2, which account for approximately 20% of deleterious mutations in these genes depending on the population studied.25 In addition, the 1994 and 1995 Myriad patents of BRCA1 and BRCA2 eliminated the possibility of other laboratories working to improve detection rates and prevented the market competition that would have helped to keep costs reasonable. This of course changed with the June 13, 2013 Supreme Court decision in the case of the American Molecular Pathologist vs Myriad with the ruling that the process of isolating naturally occurring DNA is insufficient to transform the natural phenomenon into a patentable inventions.26 There is no doubt that this patent decision has affected both the cost and the availability of BRCA1 and BRCA2 testing. Very soon after, multiple laboratories began offering BRCA testing, driving the cost from more than $4000 to as low as $1000. However, cost is not the only issue. Practitioners must carefully consider the quality of the laboratory, turnaround times, and rates of VOUS. Throughout its years of testing, Myriad maintained a proprietary database of more than 14,000 variants, which ultimately allowed them to reduce their VOUS rate to 2.5%. Without access to information regarding these 14,000 variants, new laboratories offering BRCA1 and BRCA2 testing must rely on their own limited data, or data otherwise in the public domain to make decisions regarding variant classification, and as such, have higher rates of VOUS. Furthermore, not all laboratories will make the same call regarding these variants, meaning the same variant may be reported as likely benign by one laboratory, and likely pathogenic by another. This places the burden on the clinician receiving the report, especially from lesserknown laboratories, to confirm the variant call through other sources.
Insurance and discrimination A substantial barrier to patient's accessing cancer genetic counseling and testing in those early years was the lack of insurance coverage. In the beginning, most carriers considered BRCA1 and BRCA2 testing to be “experimental,” as there were no randomized control trials to demonstrate its usefulness. Many insurance carriers denied genetic testing because of impressions of excessive cost, not necessarily considering the fact that cost of testing and management was substantially less than long-term treatment for advanced stage cancer. Now most health insurance companies cover testing, but typically have policies determining which patients qualify. CIGNA recently instituted a policy that requires genetic counseling for testing to be covered, recognizing that indiscriminate testing without appropriate risk assessment and follow-up can result in unnecessary expenditures.27 In 2008, the Genetic Information Non-Discrimination act was passed, prohibiting health insurers from denying or charging higher rates based on either family history or genetic test results.28 Although this 14-year effort was a tremendous victory and provided needed reassurance to worried families, very little evidence of overt discrimination based on a positive result for HBOC had emerged since testing began.28 Now, with the advent of the Affordable Care Act, not only
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those with predisposing mutations are protected from discrimination, but also those who have already manifest cancer or precancerous lesions are covered.29 In addition, the Affordable Care Act stipulates that insurance must cover any screening or preventive services that have been endorsed by independent bodies such as the USPSTF. Thus, the 2005 and 2013 grade B USPSTF recommendations regarding BRCA1 and BRCA2 counseling and testing should increase the availability of these services to at-risk individuals who might otherwise have been denied.30
New genes, single-nucleotide polymorphisms, and panels Though the initial identification of BRCA1 and BRCA2 and the other early discovered major hereditary cancer genes (APC, P53, MLH1, MSH2, etc) was a long and arduous process, rapidly advancing technology resulted in the identification of many more genes predisposing to cancer in the decade that followed. Some of these genes such as PTEN and STK11 are classic hereditary cancer genes in the sense that they are associated with substantially increased risk for cancer (high-penetrance), though they each account for a much smaller percentage of hereditary cancers.31 What has emerged in the continued search for additional hereditary cancer genes and chemotherapeutic targets are genes that are clearly linked to an increased incidence of cancer, but with relative risks in the range of 2-4-fold general population (moderate penetrance).32 Genome-wide association studies led to the identification of several single-nucleotide polymorphisms associated with breast and other cancers, with marginal effect sizes in the range of 1.1-1.3-fold general population risks.33,34 Direct-to-consumer (DTC) genetic testing companies sprouted in the wake of the numerous genome-wide association studies publications, offering genomic risk profiles for breast and other cancers, as well as other common diseases, with a click of your mouse and a swish and spit. In addition to concerns about consumers understanding and interpreting results on their own, these single-nucleotide polymorphism–based risk profiles explained little of the known familial risk for breast cancer (or other diseases), and ignored both family history and lifestyle factors.35 Ultimately, enough concerns were raised about the validity of the risk information provided, and the manner in which these tests were being sold to the public, that the Government Accountability Office became involved.36 By 2012, the many DTC companies that had originally popped up was whittled down to 2 or 3, and the holdout—23andMe—was ordered by the Food and Drug Administration to stop offering health-based testing in 2013. Perhaps the most profound change to affect the provision of cancer genetics services has occurred in just the last few years, which was made possible by the emergence of nextgeneration sequencing (NGS). This technology allows for rapid and simultaneous testing for mutations in multiple genes with a single test. Rather than testing one hereditary cancer gene at a time, providers can order gene panels, including 6, 18, 28, 39, and soon up to 100 genes or more in personally designed panels.37 The smaller panels focus on the high-penetrance genes for which some evidence base exists to guide medical management and testing of at-risk family members. There are panels specific for breast cancer, ovarian cancer, colon cancer, pancreatic cancer, and “all cancers.” Sequencing and deletion or duplication analysis of 28 genes cost less than what Myriad used to charge for BRCA1 and BRCA2 testing alone—without full deletion or duplication analysis. Although on the surface, this sounds great—why not get tested for as many genes as possible?—there are multiple issues to consider. Many of the genes included on the larger breast cancer panels are relatively newly described moderate-penetrance genes such as ATM, CHEK2, BARD1, BRIP1, and NBN, or genes such as MRE11 and RAD50 where their inclusion is based on reports of identification in only a few families or for which actual cancer risks remain undetermined, or both.38 In addition to uncertainty about cancer penetrance, we do not know the extent to which we can assume that a mutation in one of these genes fully explains the cancer in a family. One of the major benefits of identifying a BRCA1 or BRCA2 mutation (or other well-characterized hereditary cancer genes) in a family is the availability of mutation-specific testing of at-risk family members. A woman with a strong maternal family history of breast or ovarian cancer or both
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whose test results are negative for the BRCA1 mutation identified in her mother is considered a “true negative” and no longer at an increased risk for breast or ovarian cancer beyond the general population (assuming paternal history is not significant). Identification of a familial mutation allows individuals who do not carry it to avoid unnecessary screening or surgical procedures, targeting this management only to the mutation carriers in the family. For most moderate-penetrance cancer genes on these panels, we have insufficient information to determine whether a mutation is acting alone, or in concert with other low-to-moderate penetrance genes not tested. Thus, we are limited in our ability to offer mutation-specific testing to at-risk family members, as absence of the mutation cannot be assumed to indicate the person is at population risk. Additionally, for most moderate-penetrance cancer genes evaluated in these panels, there is no consensus regarding appropriate screening and management for individuals who carry a mutation, and effect on morbidity and mortality is essentially unknown.37-39 Furthermore, each time a gene is sequenced; there is the possibility of finding a VOUS. Although we have been dealing with the issue of VOUS for more than 20 years, it has up until recently been one at a time and for a relatively low percentage of individuals undergoing testing. When multiple genes are tested simultaneously, a substantial percentage of results obtained will contain one or more VOUS. Ambry recently reported on the outcome of their first 2000 cancer gene panels, with rates of VOUS for their larger gene panels (BreastNext—18 genes and CancerNext—28 genes) of 20% and 24%, respectively.40 Ambry has also reported that 42% of nonBRCA mutations detected by their BRCAplus panel and 30% of mutations in high-penetrance genes on their ColoNext panel were in individuals who did not meet existing clinical criteria for the associated syndromes. Although perhaps this can be considered a victory, as these individuals might not have otherwise been identified, it raises the question of whether we counsel them regarding the same cancer risks and management strategies developed on the basis of high-penetrance families. As an example, the BreastPlus panel includes the CDH1 gene, associated with lobular breast cancer (40% lifetime risk) as well as gastric cancer (70%-80% lifetime risk).41 Do we recommend gastrectomy, the standard for individuals with CDH1 mutations, for a woman with a personal or family history of breast cancer only, and no evidence of gastric cancer? Also, given the large number of genes that may be tested in these panels, patients will be found to carry mutations in more than one gene. Little data exist at this juncture regarding the potential interactive effect on cancer risk of multiple mutations involving various combinations of moderate- and high-penetrance genes. Cancer gene panels can be very helpful and are appropriate in specific circumstances. However, at minimum, application of these panels requires careful pretest and posttest counseling by qualified individuals regarding possible results and the remaining uncertainty of how to interpret them in terms of cancer risks, management, and familial implications. Further data are needed to assess the effect of widespread use of these panels on hereditary cancer morbidity and mortality, as well as the psychosocial impact on patients and families.
What is next? The final piece in the changing landscape of cancer genetic testing is the emergence of NGS of tumors to identify possible chemotherapeutic targets.42 Given that 5%-10% of all cancers are hereditary (and probably more are associated with low-to-moderate penetrance cancer genes), routine use of tumor NGS will undoubtedly lead to the identification of germline mutations in hereditary cancer genes for many patients with cancer. How patients with cancer will be told of this possibility up front? The extent to which pretest and posttest genetic counseling should be offered is just beginning to be explored.43 Furthermore, promising therapeutic options for BRCArelated cancers, such as PARP inhibitors, may lead to testing all individuals with breast or ovarian cancer for BRCA1 and BRCA2 mutations through tumor NGS.44,45 Therefore, Mary-Claire King recently made the argument that all women, regardless of personal or family history of cancer, should be offered screening for known disease-causing mutations in BRCA1 and BRCA2.46
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There is no question that the next decade of cancer genetic testing holds the promise of improved cancer prevention and treatment, and the possibility of such advances is definitely exciting. However, oncologists, pathologists, laboratories, primary care providers, and genetic professionals must work together to ensure it is evidence of clinical utility, and not the latest technology, that drives what we offer to our patients. References 1. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250(4988):1684–1689. 2. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A Apr 1971;68(4): 820–823. 3. Lynch HT, Harris RE, Guirgis HA, Maloney K, Carmody LL, Lynch JF. Familial association of breast/ovarian carcinoma. Cancer 1978;41(4):1543–1549. 4. Gardner EJ, Stephens FE. Breast cancer in one family group. Am J Hum Genet 1950;2(1):30–40. 5. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266(5182):66–71. 6. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995;378 (6559):789–792. 7. Goldgar DE, Fields P, Lewis CM, et al. A large kindred with 17q-linked breast and ovarian cancer: genetic, phenotypic, and genealogical analysis. J Natl Cancer Inst 1994;86(3):200–209. 8. Gayther SA, Russell P, Harrington P, Antoniou AC, Easton DF, Ponder BA. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am J Hum Genet 1999;65(4):1021–1029. 9. Hopper JL. More breast cancer genes? Breast Cancer Res 2001;3(3):154–157. 10. Thompson D, Szabo CI, Mangion J, et al. Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. Proc Natl Acad Sci U S A. 2002;99(2):827–831. 11. Collins FS. BRCA1—lots of mutations, lots of dilemmas. N Engl J Med 1996;334(3):186–188. 12. Bellcross CA, Kolor K, Goddard KA, Coates RJ, Reyes M, Khoury MJ. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med 2011;40(1):61–66. 13. 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(4):510–518. 14. 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(7):618–626. 15. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994;343(8899):692–695. 16. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25(11):1329–1333. 17. 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United States Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med Sep 6 2005;143(5):355–361. 23. Moyer VA. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160(4):271–281. 24. Finch AP, Lubinski J, Moller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014;32(15):1547–1553. 25. Sluiter MD, van Rensburg EJ. Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation. Breast Cancer Res Treat Jan 2011;125(2):325–349. 26. Offit K, Bradbury A, Storm C, Merz JF, Noonan KE, Spence R. Gene patents and personalized cancer care: impact of the Myriad case on clinical oncology. J Clin Oncol 2013;31(21):2743–2748. 27. Cragun D, Camperlengo L, Robinson E, et al. Differences in BRCA counseling and testing practices based on ordering provider type. Genet Med. June 13, 2014; http://dx.doi.org/10.1038/gim.2014. 28. National Human Genome Research Institute. Genetic discrimination. http://www.genome.gov/10002077 Accessed 01.09.14. 29. Hall JP, Moore JM. The Affordable Care Act's pre-existing condition insurance plan: enrollment, costs, and lessons for reform. Issue Brief (Commonw Fund) 2012;24:1–13. 30. United States Preventive Services Task Force. USPSTF A and B recommendations. http://www.uspreventiveservices taskforce.org/uspstf/uspsabrecs.htm Accessed 01.09.14.
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