viernes, 19 de abril de 2019

Genetics of Breast and Gynecologic Cancers (PDQ®) 7/10 —Health Professional Version - National Cancer Institute

Genetics of Breast and Gynecologic Cancers (PDQ®)—Health Professional Version - National Cancer Institute



National Cancer Institute



Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version

Low-Penetrance Genes and Loci

Polymorphisms underlying polygenic susceptibility to breast and gynecologic cancers are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to high-penetrance variants or alleles that are typically associated with more severe phenotypes, for example BRCA1/BRCA2 pathogenic variants leading to an autosomal dominant inheritance pattern in a family, and moderate-penetrance variants such as BRIP1, CHEK2, and RAD51C. (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes and the Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancer sections of this summary for more information.) Because these types of sequence variants (also called low-penetrance genes, alleles, variants, and polymorphisms) are relatively common in the general population, their overall contribution to cancer risk is estimated to be much greater than the attributable risk in the population from pathogenic variants in BRCA1 and BRCA2. For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible.[1] There are no known low-penetrance variants in BRCA1/BRCA2. The N372H variation in BRCA2, initially thought to be a low-penetrance allele, was not verified in a large combined analysis.[2]
Two strategies have attempted to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and then searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and, despite some confirmed associations (described below), has been relatively disappointing.[2,3] The candidate gene approach has largely been replaced by genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (approximately 1 million to 5 million) are chosen within the genome and tested, mostly without regard to their possible biological function, but instead to more uniformly capture all genetic variation throughout the genome.

Genome-Wide Searches

In contrast to assessing candidate genes and/or alleles, GWAS involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of as many as 5 million SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap and the 1000 Genomes Project.[4,5] By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained.[6-8] The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. Although this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is causal.
Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases,[9] including breast cancer.[10-13] The first study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the Breast Cancer Association Consortium.[10] Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. The 8q region and others may harbor multiple independent loci associated with risk. Subsequent genome-wide studies have replicated these loci and identified additional ones.[11,12,14,14-19] Numerous SNPs identified through large studies of sporadic breast cancer appear to be associated more strongly with estrogen receptor–positive disease;[20] however, some are associated primarily or exclusively with other subtypes, including triple-negative disease.[21,22] An online catalog is available of SNP-trait associations from published GWAS for use in investigating genomic characteristics of trait/disease-associated SNPs.
Although the statistical evidence for an association between genetic variation at these loci and breast and ovarian cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk (typically, an odds ratio [OR] <1.5), with more risk variants likely to be identified. No interaction between the SNPs and epidemiologic risk factors for breast cancer have been identified.[23,24] Furthermore, theoretical models have suggested that common moderate-risk SNPs have limited potential to improve models for individualized risk assessment.[25-27] These models used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC) as a measure of discriminatory accuracy. A subsequent study used ROC curve analysis to examine the utility of SNPs in a clinical dataset of more than 5,500 breast cancer cases and nearly 6,000 controls, using a model with traditional risk factors compared with a model using both standard risk factors and ten previously identified SNPs. The addition of genetic information modestly changed the AUC from 58% to 61.8%, a result that was not felt to be clinically significant. Despite this, 32.5% of patients were in a higher quintile of breast cancer risk when genetic information was included, and 20.4% were in a lower quintile of risk. Whether such information has clinical utility is unclear.[25,28]
More limited data are available regarding ovarian cancer risk. Three GWAS involving staged analysis of more than 10,000 cases and 13,000 controls have been carried out for ovarian cancer.[29-31] As in other GWAS, the ORs are modest, generally about 1.2 or weaker but implicate a number of genes with plausible biological ties to ovarian cancer, such as BABAM1, whose protein complexes with and may regulate BRCA1, and TIRAPR, which codes for a poly (ADP-ribose) polymerase, molecules that may be important inBRCA1/BRCA2-deficient cells.
Because the individual and collective influences of these SNPs on cancer risk have not been evaluated prospectively, they are not considered clinically relevant.
In addition to genome-wide studies interrogating common genetic variants, sequencing-based studies involving whole-genome or whole-exome sequencing [32] are also identifying genes associated with breast cancer, such as XRCC2, a rare, moderate-penetrance, breast cancer susceptibility gene.[33] (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for more information about whole-exome sequencing.)
References
  1. Pharoah PD, Antoniou A, Bobrow M, et al.: Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31 (1): 33-6, 2002. [PUBMED Abstract]
  2. Breast Cancer Association Consortium: Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Natl Cancer Inst 98 (19): 1382-96, 2006. [PUBMED Abstract]
  3. Dunning AM, Healey CS, Pharoah PD, et al.: A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8 (10): 843-54, 1999. [PUBMED Abstract]
  4. Thorisson GA, Smith AV, Krishnan L, et al.: The International HapMap Project Web site. Genome Res 15 (11): 1592-3, 2005. [PUBMED Abstract]
  5. Clarke L, Zheng-Bradley X, Smith R, et al.: The 1000 Genomes Project: data management and community access. Nat Methods 9 (5): 459-62, 2012. [PUBMED Abstract]
  6. Evans DM, Cardon LR: Genome-wide association: a promising start to a long race. Trends Genet 22 (7): 350-4, 2006. [PUBMED Abstract]
  7. Cardon LR: Genetics. Delivering new disease genes. Science 314 (5804): 1403-5, 2006. [PUBMED Abstract]
  8. Chanock SJ, Manolio T, Boehnke M, et al.: Replicating genotype-phenotype associations. Nature 447 (7145): 655-60, 2007. [PUBMED Abstract]
  9. Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661-78, 2007. [PUBMED Abstract]
  10. Easton DF, Pooley KA, Dunning AM, et al.: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447 (7148): 1087-93, 2007. [PUBMED Abstract]
  11. Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39 (7): 865-9, 2007. [PUBMED Abstract]
  12. Hunter DJ, Kraft P, Jacobs KB, et al.: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39 (7): 870-4, 2007. [PUBMED Abstract]
  13. Turnbull C, Ahmed S, Morrison J, et al.: Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42 (6): 504-7, 2010. [PUBMED Abstract]
  14. Gold B, Kirchhoff T, Stefanov S, et al.: Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A 105 (11): 4340-5, 2008. [PUBMED Abstract]
  15. Zheng W, Long J, Gao YT, et al.: Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41 (3): 324-8, 2009. [PUBMED Abstract]
  16. Kibriya MG, Jasmine F, Argos M, et al.: A pilot genome-wide association study of early-onset breast cancer. Breast Cancer Res Treat 114 (3): 463-77, 2009. [PUBMED Abstract]
  17. Murabito JM, Rosenberg CL, Finger D, et al.: A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study. BMC Med Genet 8 (Suppl 1): S6, 2007. [PUBMED Abstract]
  18. Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40 (6): 703-6, 2008. [PUBMED Abstract]
  19. Ahmed S, Thomas G, Ghoussaini M, et al.: Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41 (5): 585-90, 2009. [PUBMED Abstract]
  20. Reeves GK, Travis RC, Green J, et al.: Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci. JAMA 304 (4): 426-34, 2010. [PUBMED Abstract]
  21. Haiman CA, Chen GK, Vachon CM, et al.: A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer. Nat Genet 43 (12): 1210-4, 2011. [PUBMED Abstract]
  22. Stevens KN, Fredericksen Z, Vachon CM, et al.: 19p13.1 is a triple-negative-specific breast cancer susceptibility locus. Cancer Res 72 (7): 1795-803, 2012. [PUBMED Abstract]
  23. Campa D, Kaaks R, Le Marchand L, et al.: Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst 103 (16): 1252-63, 2011. [PUBMED Abstract]
  24. Milne RL, Gaudet MM, Spurdle AB, et al.: Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study. Breast Cancer Res 12 (6): R110, 2010. [PUBMED Abstract]
  25. Pharoah PD, Antoniou AC, Easton DF, et al.: Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358 (26): 2796-803, 2008. [PUBMED Abstract]
  26. Gail MH: Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk. J Natl Cancer Inst 100 (14): 1037-41, 2008. [PUBMED Abstract]
  27. Gail MH: Value of adding single-nucleotide polymorphism genotypes to a breast cancer risk model. J Natl Cancer Inst 101 (13): 959-63, 2009. [PUBMED Abstract]
  28. Wacholder S, Hartge P, Prentice R, et al.: Performance of common genetic variants in breast-cancer risk models. N Engl J Med 362 (11): 986-93, 2010. [PUBMED Abstract]
  29. Song H, Ramus SJ, Tyrer J, et al.: A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet 41 (9): 996-1000, 2009. [PUBMED Abstract]
  30. Goode EL, Chenevix-Trench G, Song H, et al.: A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 42 (10): 874-9, 2010. [PUBMED Abstract]
  31. Bolton KL, Tyrer J, Song H, et al.: Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat Genet 42 (10): 880-4, 2010. [PUBMED Abstract]
  32. Shendure J: Next-generation human genetics. Genome Biol 12 (9): 408, 2011. [PUBMED Abstract]
  33. Park DJ, Lesueur F, Nguyen-Dumont T, et al.: Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet 90 (4): 734-9, 2012. [PUBMED Abstract]

Clinical Management of Carriers of BRCA Pathogenic Variants

Increasing data are available on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast cancer or ovarian cancer.[1-7] As outlined in other sections of this summary, uncertainty is often considerable regarding the level of cancer risk associated with a positive family history or genetic test. In this setting, personal preferences are likely to be an important factor in patients’ decisions about risk reduction strategies.

Screening and Prevention Strategies

Breast cancer

Screening/surveillance
Refer to the PDQ summary on Breast Cancer Screening for information on screening in the general population, and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information on levels of evidence related to screening and prevention.
Breast self-examination
In the general population, evidence for the value of breast self-examination (BSE) is limited. Preliminary results have been reported from a randomized study of BSE being conducted in Shanghai, China.[8] At 5 years, no reduction in breast cancer mortality was seen in the BSE group compared with the control group of women, nor was a substantive stage shift seen in breast cancers that were diagnosed. (Refer to the PDQ summary on Breast Cancer Screening for more information.)
Little direct prospective evidence exists regarding BSE in individuals with an increased risk of breast cancer. In the Canadian National Breast Screening Study, women with first-degree relatives (FDRs) with breast cancer had statistically significantly higher BSE competency scores than those without a family history. In a study of 251 high-risk women at a referral center, five breast cancers were detected by self-examination less than a year after a previous screen (as compared with one cancer detected by clinician exam and 11 cancers detected as a result of mammography). Women in the cohort were instructed in self-examination, but it is not stated whether the interval cancers were detected as a result of planned self-examination or incidental discovery of breast masses.[9] In another series of carriers of BRCA1/BRCA2 pathogenic variants, four of nine incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting the potential value of self-examination.[10] A task force convened by the Cancer Genetics Studies Consortium has recommended “monthly self-examination beginning early in adult life (e.g., by age 18–21 y) to establish a regular habit and allow familiarity with the normal characteristics of breast tissue. Education and instruction in self-examination are recommended.”[11]
Level of evidence: 5
Clinical breast examination
Few prospective data exist regarding clinical breast examination (CBE).
The Cancer Genetics Studies Consortium task force concluded, “As with self-examination, the contribution of clinical examination may be particularly important for women at inherited risk of early breast cancer.” They recommended that female carriers of a BRCA1or BRCA2 high-risk pathogenic variant undergo annual or semiannual clinical examinations beginning at age 25 to 35 years.[11]
Level of evidence: 5
Mammography
In the general population, strong evidence suggests that regular mammography screening of women aged 50 to 59 years leads to a 25% to 30% reduction in breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.) For women who begin mammographic screening at age 40 to 49 years, a 17% reduction in breast cancer mortality is seen, which occurs 15 years after the start of screening.[12] Observational data from a cohort study of more than 28,000 women suggest that the sensitivity of mammography is lower for young women. In this study, the sensitivity was lowest for younger women (aged 30–49 y) who had a FDR with breast cancer. For these women, mammography detected 69% of breast cancers diagnosed within 13 months of the first screening mammography. By contrast, sensitivity for women younger than 50 years without a family history was 88% (P = .08). For women aged 50 years and older, sensitivity was 93% at 13 months and did not vary by family history.[13] Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers.[10] Subsequent observational studies have found that the positive predictive value (PPV) of mammography increases with age and is highest among older women and among women with a family history of breast cancer.[14] Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity.[15] One study found an association between the presence of pushing margins and false-negative mammograms in 28 women, 26 of whom had a BRCA1 pathogenic variant and two of whom had a BRCA2pathogenic variant. Pushing margins, characteristic of medullary histology, are associated with an absence of fibrotic reaction.[16] In addition, rapid tumor doubling times may lead to tumors presenting shortly after an apparently normal study. In one study, mean tumor doubling time in BRCA1/BRCA2 carriers was 45 days, compared with 84 days in noncarriers.[17] Another study that evaluated mammographic breast density in women with BRCApathogenic variants found no association between pathogenic variant status and mammographic density; however, in both carriers and noncarriers, increased breast density was associated with increased breast cancer risk.[18]
The randomized Canadian National Breast Screening Study-2 compared annual CBE plus mammography to CBE alone in women aged 50 to 59 years from the general population. Both groups were given instruction in BSE.[19] Although mammography detected smaller primary invasive tumors, more invasive cancers, and more ductal carcinoma in situ (DCIS) than CBE, the breast cancer mortality rates in the CBE-plus-mammography group and the CBE-alone group were nearly identical, and compared favorably with other breast cancer screening trials. After a mean follow-up of 13 years (range, 11.3–16.0 y), the cumulative breast cancer mortality ratio was 1.02 (95% confidence interval [CI], 0.78–1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.
Digital mammography refers to the use of a digital detector to find and record x-ray images. This technology improves contrast resolution [20] and has been proposed as a potential strategy for improving the sensitivity of mammography. A screening study comparing digital with routine mammography in 6,736 examinations of women aged 40 years and older found no difference in cancer detection rates;[21] however, digital mammography resulted in fewer recalls. In another study (ACRIN-6652) comparing digital mammography to plain-film mammography in 42,760 women, the overall diagnostic accuracy of the two techniques was similar.[22] When receiver operating characteristic curves were compared, digital mammography was more accurate in women younger than 50 years, in women with radiographically dense breasts, and in premenopausal or perimenopausal women.
In a prospective study of 251 individuals with BRCA pathogenic variants who received uniform recommendations regarding screening and risk-reducing surgery, annual mammography detected breast cancer in six women at a mean of 20.2 months after receipt of BRCA results.[9] The Cancer Genetics Studies Consortium task force has recommended for female carriers of a BRCA1 or BRCA2 high-risk pathogenic variant, “annual mammography, beginning at age 25 to 35 years. Mammograms should be done at a consistent location when possible, with prior films available for comparison.”[11] Data from prospective studies on the relative benefits and risks of screening with an ionizing radiation tool versus CBE or other nonionizing radiation tools would be useful.[23-25]
Certain observations have led to the concern that carriers of BRCA pathogenic variants may be more prone to radiation-induced breast cancer than women without pathogenic variants. The BRCA1 and BRCA2 proteins are known to be important in cellular mechanisms of DNA damage repair, including those involved in repairing radiation-induced damage. Some studies have suggested intermediate radiation sensitivity in cells that are heterozygous for a BRCA variant, but this is not consistent and varies by experimental system and endpoint.
Three studies have failed to find convincing evidence of an association between ionizing radiation exposure and breast cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants.[26-28] In contrast, two large international studies found evidence of an increased breast cancer risk due to chest x-rays [29] or estimates of total exposure to diagnostic radiation.[30] A large, international, case-control study of 1,601 carriers of pathogenic variants described an increased risk of breast cancer (hazard ratio [HR], 1.54) among women who were ever exposed to chest x-rays, with risk being highest in women aged 40 years and younger, born after 1949, and exposed to x-rays only before age 20 years.[29] Some of the subjects in this study were also included in a larger, more comprehensive analysis of carriers of pathogenic variants from three European centers.[30] In that study of 1,993 carriers of BRCA1 and BRCA2 pathogenic variants from the United Kingdom, France, and the Netherlands, age-specific total diagnostic radiation exposure (e.g., chest x-rays, mammography, fluoroscopy, and computed tomography) estimates were derived from self-reported questionnaires. Women exposed before age 30 years had an increased risk (HR, 1.90; 95% CI, 1.20–3.00), compared with those never exposed. This risk was primarily driven by nonmammographic radiation exposure in women younger than 20 years (HR, 1.62; 95% CI, 1.02–2.58). Subsequently, a prospective study of 1,844 BRCA1 carriers and 502 BRCA2 carriers without a breast cancer diagnosis at study entry, with an average follow-up time of 5.3 years, observed no significant association between prior mammography exposure and breast cancer risk.[28] Additional subgroup analyses in women younger than 30 years demonstrated no association with breast cancer risk.
With the routine use of magnetic resonance imaging (MRI) in carriers of BRCA1 and BRCA2pathogenic variants, any potential benefit of mammographic screening must be carefully weighed against potential risks, particularly in young women.[31] One study has suggested that the most cost-effective screening strategy in carriers of BRCA1 and BRCA2 pathogenic variants may be annual MRI beginning at age 25 years, with alternating MRI and digital mammography (so that each test is done annually but screening occurs every 6 months) beginning at age 30 years.[32] The National Comprehensive Cancer Network (NCCN) currently recommends annual breast MRI screening with contrast (or mammogram with consideration of tomosynthesis, only if MRI is unavailable) between ages 25 and 29 years and annual mammogram (with consideration of tomosynthesis and breast MRI screening with contrast) between ages 30 and 75 years.[33]
Magnetic resonance imaging
Because of the relative insensitivity of mammography in women with an inherited risk of breast cancer, a number of screening modalities have been proposed and investigated in high-risk women, including carriers of BRCA pathogenic variants. Many studies have described the experience with breast MRI screening in women at risk of breast cancer, including descriptions of relatively large multi-institutional trials.[34-42]
Despite some limitations of these studies, they consistently demonstrate that breast MRI is more sensitive than either mammography or ultrasound for the detection of hereditary breast cancer. The results of six large studies are presented in Table 11, Summary of MRI Screening Studies in Women at Hereditary Risk of Breast Cancer.[34,36,37,40,43,44] Most cancers in these programs were screen detected, with only 6% of cancers presenting in the interval between screenings. The sensitivity of MRI (as defined by the study methodology) ranged from 71% to 100%. Of the combined studies, 77% of cancers were identified by MRI, and 42% were identified by mammography.
Concerns have been raised about the reduced specificity of MRI compared with other screening modalities. In one study, after the initial MRI screen, 16.5% of patients were recalled for further evaluation and an additional 7.6% of patients were recommended to undergo a short-interval follow-up examination at 6 months.[37] These rates declined significantly during later screening rounds, with fewer than 10% of the subjects recalled for more detailed MRI and fewer than 3% recommended to have short interval follow-up. In a second study, Magnetic Resonance Imaging for Breast Screening (MARIBS), the recall rate for additional evaluation was 10.7% per year.[36] The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round.[37] In the MARIBS study, the aggregate surgical biopsy rate was 9 per 1,000 screening episodes, though this may underestimate the burden because follow-up ultrasounds, core-needle biopsies, and fine-needle aspirations have not been included in the numerator of the MARIBS calculation.[36] The PPV of MRI has been calculated differently in the various series and fluctuates somewhat, depending on whether all abnormal examinations or only the examinations that result in a biopsy are counted in the denominator. Generally, the PPV of a recommendation for tissue sampling (as opposed to further investigation) is in the range of 50% in most series.
These trials appear to establish that MRI is superior to mammography in the detection of hereditary breast cancer, and that women participating in these trials including annual MRI screening were less likely to have a cancer missed by screening.[45] However, mammography may identify some cancers, particularly DCIS, that are not identified by MRI.[46]
Regarding downstaging, one screening study demonstrated that patients at risk of hereditary breast cancer were more likely to be diagnosed with small tumors and node-negative disease than were women in two nonrandomized control groups.[34] Despite the apparent sensitivity of MRI screening, some women in MRI-based programs will develop life-threatening breast cancer. In a prospective study of 51 carriers of BRCA1 pathogenic variants and 41 carriers of BRCA2 pathogenic variants screened with yearly mammograms and MRIs (of whom 80 had risk-reducing oophorectomy), 11 breast cancers (9 invasive and 2 DCIS) were detected. Six cancers were first detected on MRI; three were first detected by mammogram; and two were interval cancers. All breast cancers occurred in carriers of BRCA1 pathogenic variants, suggesting a continued high risk of BRCA1-related breast cancer after oophorectomy in the short term. These results suggest that surveillance and prevention strategies may have differing outcomes in carriers of BRCA1 and BRCA2pathogenic variants.[41]
A publication combining results from three large studies (MARIBS, a Canadian study, and a Dutch MRI screening study) demonstrated that when MRI was added to mammography, 80% of cancers detected in carriers of BRCA2 pathogenic variants were either DCIS or invasive cancers smaller than 1 cm. In carriers of BRCA1 pathogenic variants, 49% of cancers were DCIS or small invasive cancers. In addition, the authors predicted mortality benefits with the addition of MRI for both carriers of BRCA1 and BRCA2 pathogenic variants. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening.[47] An additional study examining carriers of BRCA1/BRCA2 pathogenic variants undergoing MRI between 1997 and 2006 has demonstrated that 97% of incident cancers were stage 0 or stage I.[48] A 2015 Dutch case-control study further evaluated 2,308 high-risk patients, including 706 women with known BRCA pathogenic variants, who were screened with mammogram and compared them with those who had the addition of MRI.[49] Of the patients screened, 93 patients were detected to have 97 cancers, 33 patients had a BRCA1 pathogenic variant, and 18 patients had a BRCA2 pathogenic variant. With a median follow-up of 9 years, metastases-free survival was improved in the MRI-screened cohort (90% vs. 77%), but it did not reach statistical significance in the BRCA1 and BRCA2 subset because of very small numbers. MRI-screened patients in the entire cohort were more likely to be node-negative and receive less chemotherapy. The American Cancer Society and NCCN have recommended the use of annual MRI screening for women at hereditary risk of breast cancer.[33,50]
An additional question regarding the timing of mammography and MRI is whether they should be done simultaneously or in an alternating fashion (so that while each test is done annually, screening occurs every 6 months). One study has suggested that the most cost-effective screening strategy in carriers of BRCA1 and BRCA2 pathogenic variants may be annual MRI beginning at age 25 years, with alternating MRI and digital mammography beginning at age 30 years.[32]
In summary, evidence strongly supports the integral role of breast MRI in breast cancer surveillance for carriers of BRCA1/BRCA2 pathogenic variants.
Table 11. Summary of Magnetic Resonance Imaging (MRI) Screening Studies in Women at Hereditary Risk of Breast Cancer
ENLARGE
SeriesRijnsburger [42]Warner [37]MARIBS [36]Kuhl [40]Weinstein [43]Sardanelli [44]Totals
aBased on the first 1,909 women screened.[34]
bIncludes patients with invasive cancer only and patients with both invasive and in situ cancers.
cIncludes only 75 cancers detected in women who underwent both mammographic and MRI screening.
dRestricted to studies in which ultrasound was performed.
N PatientsOverall2,1572366496876095014,839
BRCA1/BRCA2Carriers59423612065443301,389
N Screening Episodes6,2534571,8811,679 1,59211,862
N CancersBaseline22a1320100065
Subsequent97915171852208
Invasiveb78162981144186
In situ199697858
Annual Incidence10.4/1,000 19/1,000    
Detected at Planned Screening782133271849226 (83%)
N Detected by Each ModalityMammography31c814972594 (42%)
MRI51c1727251242174 (77%)
Ultrasoundd 7 1032646 (41%)
Follow-upMedian of 4.9 yMinimum of 1 y2–7 yMedian of 29.09 mo2 y3 y 
Level of evidence: 3
Ultrasound
Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review.[51] In a pilot study of ultrasound as an adjunct to mammography in 149 women with moderately increased risk based on family history, one cancer was detected, based on ultrasound findings. Nine other biopsies of benign lesions were performed. One was based on abnormalities on both mammography and ultrasound, and the remaining eight were based on abnormalities on ultrasound alone.[51] A large study of 2,809 women with dense breast tissue (ACRIN-6666) demonstrated that ultrasound increased the detection rate due to breast cancer screening from 7.6 per 1,000 with mammography alone to 11.8 per 1,000 for combined mammography and ultrasound.[52] However, ultrasound screening increases false-positive rates and appears to have a limited benefit in combination with MRI. In a multicenter study of 171 women (92% of whom were carriers of BRCA1/BRCA2 pathogenic variants) undergoing simultaneous mammography, MRI, and ultrasound, no cancers were detected by ultrasound alone.[38] Uncertainties about ultrasound include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.
Level of evidence: None assigned
Other screening modalities
A number of other techniques are under active investigation, including tomosynthesis, contrast-enhanced mammography, thermography, and radionuclide scanning. Additional evidence is needed before these techniques can be incorporated into clinical practice.
Level of evidence: None assigned
Risk-reducing surgeries
Risk-reducing mastectomy
Risk-reducing mastectomy (RRM) is a management option for patients who are considered to be at high risk of developing breast cancer. The Society of Surgical Oncology has endorsed RRM as an option for women with BRCA1/BRCA2 pathogenic variants or strong family histories of breast cancer.[53] Historically, a total or simple mastectomy has been performed, which includes removal of all of the breast tissue, including the nipple and areolar complex (NAC). If the patient is interested, reconstruction can be performed simultaneously with the ablative portion of the procedure. Options for reconstruction include tissue expander and implant-based reconstructions or autologous reconstructions, in which the patient’s own tissue is used to reconstruct the breast. A number of different tissues can be used to reconstruct the breast, including flaps based on the latissimus dorsi muscle, the transverse rectus abdominis muscle, or the gluteus muscle. Muscle-sparing techniques such as the deep inferior epigastric perforator flap can also be used, but require advanced microvascular techniques. In the interest of improved cosmetic outcomes, skin-sparing techniques have been utilized in which the entire breast is removed with the NAC, but the entire skin envelope of the breast is preserved. In a further refinement, nipple-sparing techniques have been developed in which all of the breast skin and the nipple are preserved while the underlying glandular tissue is removed.
Risk-reducing mastectomy in unaffected women
Because there are no randomized, prospective trials of RRM versus observation, data are limited to cohort and case-control studies. The available data demonstrate that RRM does decrease breast cancer incidence in high-risk patients,[54-56] but overall survival (OS) correlates more closely with the overall risk from the primary incidence of breast cancer. Several studies have analyzed the impact of RRM on breast cancer risk and mortality. In one retrospective cohort study of 214 women considered to be at hereditary risk by virtue of a family history suggesting an autosomal dominant predisposition, three women were diagnosed with breast cancer after bilateral RRM, with a median follow-up of 14 years.[56] Because 37.4 cancers were expected, the calculated risk reduction was 92.0% (95% CI, 76.6%–98.3%). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent genetic testing for pathogenic variants in BRCA1 and BRCA2. Pathogenic variants were identified in 18 women, none of whom developed breast cancer after a median follow-up of 13.4 years.[54] Two of the three women diagnosed with breast cancer after RRM were tested, and neither carried a pathogenic variant. The calculated risk reduction among carriers of pathogenic variants was 89.5% to 100.0% (95% CI, 41.4%–100.0%), depending on the assumptions made about the expected numbers of cancers among carriers of pathogenic variants and the status of the untested woman who developed cancer despite mastectomy. The result of this retrospective cohort study has been supported by a prospective analysis of 76 carriers of pathogenic variants who underwent RRM and were monitored prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas eight were identified in women who underwent regular surveillance (HR for breast cancer after RRM, 0.00 [95% CI, 0.00–0.36]).[55]
The Prevention and Observation of Surgical Endpoints study group also estimated the degree of breast cancer risk reduction after RRM in carriers of BRCA1/BRCA2 pathogenic variants. The rate of breast cancer in 105 carriers of pathogenic variants who underwent bilateral RRM was compared with that in 378 carriers who did not choose surgery. Bilateral mastectomy reduced the risk of breast cancer by approximately 90% after a mean follow-up of 6.4 years.[3]
Theoretical models have also been utilized to assess the role of RRM in women with pathogenic variants in BRCA1 and BRCA2. Assuming risk reduction in the range of 90%, one model suggests that for a group of women, aged 30 years, with BRCA1 or BRCA2 pathogenic variants, RRM would result in an average increased life expectancy of 2.9 to 5.3 years.[57] A computer-simulated survival analysis using a Monte Carlo model included breast MRI, mammography, RRM, and risk-reducing salpingo-oophorectomy (RRSO) and examined the impact of each intervention separately on carriers of BRCA1 and BRCA2 pathogenic variants.[5] The most effective strategy was found to be RRSO at age 40 years and RRM at age 25 years, with survival at age 70 years approaching that of the general population. However, delaying mastectomy until age 40 years, or substituting RRM with screening with breast MRI and mammography, had little impact on survival estimates. For example, replacing RRM with MRI-based screening in women with RRSO at age 40 years led to a 3% to 5% decrement in survival compared with RRM at age 25 years.[58] As with any models, numerous assumptions cause uncertainty; however, these studies provide additional information for women and their providers who are making these difficult decisions.
Another study of at-risk women showed a 70% time–trade-off value for RRM, indicating that participants were willing to sacrifice 30% of life expectancy to avoid RRM.[59] A cost-effectiveness analysis study of RRM has also been performed. The investigators concluded that, compared with surveillance, risk-reducing surgery (mastectomy and oophorectomy) is cost-effective with regard to years of life saved, but not for improved quality of life.[60] While these data are interesting and may be useful for public policy decisions, they cannot be individualized for clinical care because they include assumptions that cannot be fully tested.
Level of evidence: 3ai
Contralateral risk-reducing mastectomy in affected women
If RRM is effective in lowering breast cancer risk in unaffected women, what is its role for women with unilateral breast cancer? This question often arises in discussions about surgical options with women who have unilateral breast cancer and hereditary risks. This section addresses the role of contralateral risk-reducing mastectomy (CRRM) in women being treated with mastectomy and will not discuss breast conservation therapy. Multiple studies have shown an increase in the rate of CRRM in women with unilateral breast cancer.[61,62] When the appropriateness of CRRM is being assessed for women with unilateral breast cancer, the first task is to determine the risk of contralateral breast cancer (CBC).
In the general population, current estimates of CBC risk after treatment for breast cancer are approximately 0.3% per year and are declining.[63] In carriers of BRCA pathogenic variants with a diagnosis of breast cancer, the risk of a second, unrelated breast cancer is related to age at initial diagnosis, biology, and systemic therapies used, but is clearly higher than that in the general population.[64] (Refer to the Contralateral breast cancer in carriers of BRCA pathogenic variants section in the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section of this summary for more information about the risk of CBC in this population.) In carriers of BRCA pathogenic variants whose first cancer has an excellent prognosis, estimating the risk of a second, unrelated breast cancer event is important for informing their decision to undergo risk-reducing surgery and has been described in this setting to improve survival.[65] The timing of genetic testing and knowledge of BRCA pathogenic variant status may influence surgical decision making, may prevent subsequent surgeries, and may influence follow-up care. Therefore, for individuals at increased risk of carrying a BRCA pathogenic variant, it is important that genetic testing be considered in advance of surgery, when possible.[66]
In a group of 148 carriers of BRCA1 and BRCA2 pathogenic variants with unilateral breast cancer, 79 of whom underwent CRRM, the risk of CBC was reduced by 91% and was independent of the effect of risk-reducing oophorectomy. Survival was better among women who underwent CRRM, but this result was likely associated with higher mortality caused by the index cancer or metachronous ovarian cancer in the group not undergoing surgery.[67] Data from ten European centers on 550 women (including 202 BRCA carriers) with 3,334 woman-years of follow-up indicated that RRM was highly effective. Bilateral RRMs were carried out on women with a lifetime risk of 25% to 80%, with an average expected incidence rate of 1% per year. No breast cancers occurred in this cohort over the follow-up period, though more than 34 breast cancers would have been expected.[68] A retrospective study of 593 carriers of BRCA1 and BRCA2 pathogenic variants included 105 women with unilateral breast cancer who underwent CRRM and had a 10-year survival rate of 89%, compared with 71% in the group who did not undergo contralateral risk-reducing surgery (P < .001).[4] This study was limited by several factors, such as the lack of information regarding breast cancer screening, grade, and estrogen receptor status in a large portion of this sample.
A Dutch cohort of 583 patients identified between 1980 and 2011, who had both a BRCApathogenic variant and a diagnosis of unilateral breast cancer, were evaluated for the effect of CRRM.[69] With a median follow-up of 11.4 years, 242 (42%) of the patients underwent RRM (193 carriers of BRCA1 pathogenic variants and 49 carriers of BRCA2pathogenic variants) at differing times after their diagnoses. Improved OS was observed in the RRM group compared with the surveillance group (HR, 0.49; 95% CI, 0.29–0.82), with improvements most pronounced in those diagnosed before age 40 years, with low tumor grade, and non–triple-negative subtype. In an attempt to control for the bias of time to surgery, the authors included a separate evaluation of women who were known to be disease free 2 years after the primary cancer diagnosis (HR, 0.55; 95% CI, 0.32–0.95). Additionally, the group who underwent RRM was more likely to undergo bilateral salpingo-oophorectomy and systemic chemotherapy, which may influence the significance of these survival findings.
A retrospective study of 390 women with early-stage breast cancer who were from families with a known BRCA1/BRCA2 pathogenic variant found a significant improvement in survival for women who underwent bilateral mastectomy compared with those who chose unilateral mastectomy.[65] Patients were followed for a median of 14.3 years (range, 0.1–20.0 y). A multivariate analysis controlling for age at diagnosis, year of diagnosis, treatment, and other prognostic factors found that CRRM was associated with a 48% reduction in death from breast cancer. This was a relatively small study, and although the authors adjusted for multiple factors, residual confounding factors may have influenced the results.
All of these studies are limited by the biases introduced in relatively small, retrospective studies among very select populations. There is often limited data on potential confounding variables such as socioeconomic status, comorbidities, and access to care. It has been suggested that women who elect to undergo RRM are healthier by virtue of being able to tolerate more extensive surgery. This theory is supported by one study that used Surveillance, Epidemiology, and End Results (SEER) Program data to examine the association between CRRM and outcomes among women with unilateral breast cancer stages I through III. Results showed a reduction in all-cause mortality and breast cancer–specific mortality, and also in noncancer event mortality, a finding that would not be expected to be related to CRRM.[70]
Level of evidence: 3ai
Nipple-sparing mastectomy
The option of nipple-sparing mastectomy (NSM) in carriers of BRCA pathogenic variants undergoing risk-reducing procedures has been controversial because of concerns about increased breast tissue left behind at surgery to keep the NAC viable. The ability to leave behind minimal residual tissue, however, may be related to experience and technique. In a retrospective review of NSM performed in carriers of BRCA pathogenic variants at two hospitals between 2007 and 2014, NSM was performed on 397 breasts in 201 carriers of BRCA pathogenic variants.[71] This study included both unaffected and affected women. Incidental cancers were found in 4 of 150 RRM patients (2.7%) and 2 of 51 cancer patients (3.9%). With a mean follow-up of 32.6 months (range, 1.0–76.0 months), there were four subsequent cancer events that included two patients with axillary recurrences, one with a local and distant recurrence 11 months after her original NSM, and one patient who developed a new cancer in the inferior portion of her breast, with no recurrences at the NAC. A study of 177 NSMs performed in 89 carriers of BRCA pathogenic variants between 2005 and 2013 reported similar, excellent local control rates. Sixty-three patients had risk-reducing NSM (median follow-up, 26 months; range, 11–42 months), and 26 patients had NSM and a diagnosis of breast cancer (median follow-up, 28 months; range, 15–43 months). Five patients required further nipple excision. There were no local recurrences or newly diagnosed breast cancers.[72]
Level of evidence: 3aii
Histopathology of RRM specimens
Studies describing histopathologic findings in RRM specimens from women with BRCA1 or BRCA2 pathogenic variants have been somewhat inconsistent. In two series, proliferative lesions associated with an increased risk of breast cancer (lobular carcinoma in situ, atypical lobular hyperplasia, atypical ductal hyperplasia, and DCIS) were noted in 37% to 46% of women with pathogenic variants who underwent either unilateral or bilateral RRM.[73-75] In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of risk-reducing bilateral or contralateral mastectomies performed in known carriers of BRCA1 or BRCA2 pathogenic variants from Australia, three (6%) cancers were detected at surgery.[76] In general, histopathologic findings in RRM specimens do not impact management.
Utilization
Individual psychological factors play an important role in decision-making about RRM by unaffected women and CRRM in women with unilateral breast cancer. (Refer to the Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer section in the Psychosocial Issues in Inherited Breast and Ovarian Cancer Syndromes section of this summary for information about uptake of RRM in BRCA carriers and the Psychosocial Outcome Studies section for information about psychosocial outcomes of RRM.)
Conclusion
In summary:
  • RRM in unaffected women with pathogenic BRCA variants decreases the incidence of breast cancer by approximately 90%, with a less clear impact on breast cancer mortality.
  • RRM in women with unilateral breast cancer (CRRM) has demonstrated decreased incidence of breast cancer and possible improved survival.
  • NSM is an option for RRM, although variation in surgical technique and expertise may leave behind some tissue in the NAC, which may impact the need for subsequent surgery and risk of subsequent cancer.
  • The predominant histopathologic findings at the time of RRM in unaffected women with pathogenic BRCA variants are proliferative lesions that do not require additional treatment.
Risk-reducing salpingo-oophorectomy (RRSO)
In the general population, removal of both ovaries has been associated with a reduction in breast cancer risk of up to 75%, depending on parity, weight, and age at time of artificial menopause. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) A Mayo Clinic study of 680 women at various levels of familial risk found that in women younger than 60 years who had bilateral oophorectomy, the likelihood of breast cancers developing was reduced for all risk groups.[77] Ovarian ablation, however, is associated with important side effects such as hot flashes, impaired sleep habits, vaginal dryness, dyspareunia, and increased risk of osteoporosis and heart disease. A variety of strategies may be necessary to counteract the adverse effects of ovarian ablation.
The evidence for the effect of RRSO on breast cancer has evolved. Early small studies suggested a protective benefit. Initial retrospective studies supported breast cancer and ovarian cancer risk reduction after RRSO in BRCA pathogenic variant–positive women.[78] In support of early small studies,[79,80] a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 variants found a significant reduction in risk of breast cancer (HR, 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR, 0.04; 95% CI, 0.01–0.16) after RRSO.[78] A prospective, single-institution study of 170 women with BRCA1 or BRCA2 pathogenic variants showed a similar trend. With RRSO, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74).[81] A prospective, multicenter study of 1,079 women followed up for a median of 30 to 35 months found that while RRSO was associated with reductions in breast cancer risk in both carriers of BRCA1 and BRCA2pathogenic variants, the risk reduction was more pronounced in BRCA2 carriers (HR, 0.28; 95% CI, 0.08–0.92).[6] A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in carriers of BRCA1/BRCA2 pathogenic variants confirmed that RRSO was associated with a significant reduction in breast cancer risk (overall: HR, 0.49; 95% CI, 0.37–0.65; BRCA1: HR, 0.47; 95% CI, 0.35–0.64; BRCA2: HR, 0.47; 95% CI, 0.26–0.84).[82] However, a cohort study of 822 carriers of BRCA1/BRCA2 pathogenic variants conducted in the Netherlands, where carrier screening is performed nationwide, did not observe a reduced risk of breast cancer after RRSO (HR, 1.09; 95% CI, 0.67–1.77).[83] The authors argued that the previous findings were driven by methodological issues including cancer-induced testing bias and immortal person time, and empirically evaluated this by using their own cohort and applying the same assumptions about counting person time from previous studies.[83] In a response, investigators from the U.S. studies analyzed their data using the assumptions of the Dutch study but still observed an inverse association with RRSO and breast cancer risk.[84] In a retrospective cohort of 676 women, carriers having an RRSO at the time of breast cancer diagnosis had a reduced risk of breast cancer–specific mortality (HR, 0.38; 95% CI, 0.19–0.77 for BRCA1 carriers and HR, 0.57; 95% CI, 0.23–1.43 for BRCA2 carriers).[85] A subsequent international, multi-institutional study of 3,722 BRCA1 and BRCA2 carriers using a similar methodology showed that oophorectomy performed before age 50 years was beneficial for preventing breast cancer in BRCA2carriers (HR, 0.18; 95% CI, 0.05–0.63; P = .007) but not in BRCA1 carriers.[86]
A prospective, multicenter, cohort study of 2,482 carriers of BRCA1/BRCA2 pathogenic variants has reported an association of RRSO with a reduction in all-cause mortality (HR, 0.40; 95% CI, 0.26–0.61), breast cancer–specific mortality (HR, 0.44; 95% CI, 0.26–0.76), and ovarian cancer–specific mortality (HR, 0.21; 95% CI, 0.06–0.80).[2] A subsequent meta-analysis confirmed the impact of RRSO on all-cause mortality (HR, 0.32; 95% CI, 0.27–0.38) in carriers of BRCA1 and BRCA2 pathogenic variants, including those with and without a personal history of breast cancer.[87]
Despite discordant findings regarding RRSO and breast cancer risk in the existing literature, aggregate data suggest that there is a benefit, although the magnitude of this benefit may not be fully understood. Further prospective studies are needed to confirm these findings.
Level of evidence: 3ai
Refer to the RRSO section in the Ovarian cancer section of this summary for more information about the effect of RRSO on ovarian cancer risk in carriers of BRCA pathogenic variants.
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