BRCA1 and BRCA2: Cancer Risks and Management (PDQ®): Genetics - Health Professional Information [NCI]
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BRCA1 and BRCA2: Cancer Risks and Management (PDQ®): Genetics - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Genetics

Germline pathogenic variants in BRCA1/BRCA2 are associated with ovarian cancer, fallopian tube cancer, primary peritoneal cancer, male breast cancer, prostate cancer, pancreatic cancer, and early-onset breast cancer. BRCA1/BRCA2-associated cancer risks are inherited in an autosomal dominant manner.

Prevalence ofBRCA1/2Pathogenic Variants

Several studies have assessed the frequency of BRCA1 or BRCA2 pathogenic variants in women with breast or ovarian cancers.[1,2] Approximately 1 in 400 to 1 in 800 individuals in the general population (excluding those with Ashkenazi Jewish [AJ] ancestry) may carry a germline pathogenic variant in BRCA1 or BRCA2.[3,4,5]

Among the general population, the likelihood of having any BRCA pathogenic variant is as follows:

  • Women with breast cancer (at any age): 1 in 50 (2%).[6]
  • Women with breast cancer (younger than age 40 y): 1 in 10 (10%).[2,7,8]
  • Men with breast cancer (at any age): 1 in 20 (5%).[9]
  • Women with ovarian cancer (at any age): 1 in 8 to 1 in 10 (10%–15%).[10,11,12]

BRCA1/2 pathogenic variants are not currently associated with genetic anticipation, despite suggestive findings from a few studies.[13,14,15]

BRCA1/2founder pathogenic variants

The same pathogenic variant can be found in multiple unrelated families due to the founder effect (a pathogenic variant identified in a contemporary population that can be traced to a small group of founders isolated by geographic, cultural, or other factors). The presence of these founder pathogenic variants have practical implications for genetic testing.

Founder pathogenic variants have been observed in multiple population groups. In individuals with AJ ancestry, two specific BRCA1 pathogenic variants (185delAG and 5382insC) and one BRCA2 pathogenic variant (6174delT) are common. However, nonfounder BRCA pathogenic variants have also been reported at a rate of 3% to 15% in the AJ population.[16,17,18]

Among AJ individuals, the likelihood of having a BRCA pathogenic variant is as follows:

  • General AJ population: 1 in 40 (1.1%–2.5%).[19,20,21]
  • Women with breast cancer (at any age): 1 in 10 (10%).[22]
  • Women with breast cancer (younger than age 40 y): 1 in 3 (30%–35%).[22,23,24]
  • Men with breast cancer (at any age): 1 in 5 (19%).[25]
  • Women with ovarian cancer or primary peritoneal cancer (at any age): 1 in 3 (36%–41%).[26,27,28]

Some laboratories offer testing for ethnic-specific variants (particularly the three AJ founder variants). However, searching only for the AJ founder variants increases the risk of receiving a false-negative genetic test result (i.e., missing a nonfounder BRCA1/2 pathogenic variant or a pathogenic variant in another cancer susceptibility gene).[16,17,18]

Founder pathogenic variants have been observed in other non-AJ racial and ethnic groups, such as groups of Icelandic, Hispanic, West African, French Canadian, Polish, Sephardic Jewish, and Bahamian descent.[29,30,31,32,33,34,35,36]

BRCA1/2de novo pathogenic variant rate

The spontaneous pathogenic variant rate (de novo pathogenic variant rate) in the BRCA genes is thought to be 5% or less, based on data from limited studies.[37,38,39,40,41,42,43,44,45] However, these estimates of spontaneous pathogenic variant rates in the BRCA genes seem to overlap with the estimates of nonpaternity rates in various populations (0.6%–3.3%),[46,47,48] making the de novo pathogenic variant rate for these genes relatively low.

Detection ofBRCA1/2Variants

Variant-screening methods have differing sensitivities. Large genomic alterations such as translocations, inversions, deletions, or insertions are missed by most variant-screening techniques, including direct DNA sequencing. However, testing for these alterations is commercially available. Such rearrangements may be responsible for 12% to 18% of BRCA1 inactivating variants but are seen less frequently in the BRCA2 gene and in individuals of AJ descent.[49,50,51,52,53,54,55] Furthermore, studies have suggested that these rearrangements may be seen more frequently in Hispanic and Caribbean populations.[30,53,55]

Indications forBRCA1/2Genetic Testing

Several professional organizations and expert panels, including the American Society of Clinical Oncology,[56] the National Comprehensive Cancer Network,[57] the American Society of Human Genetics,[58] the American College of Medical Genetics and Genomics,[59] the National Society of Genetic Counselors,[59] the U.S. Preventive Services Task Force,[60] and the Society of Gynecologic Oncologists,[61] have developed clinical criteria and practice guidelines that can help health care providers identify individuals who may have a BRCA1 or BRCA2 pathogenic variant. For more information, see the Indications for hereditary breast and gynecologic cancers genetic testing section in Genetics of Breast and Gynecologic Cancers. For more information about models that can be used to estimate an individual's chance of carrying a BRCA1 or BRCA2 pathogenic variant, see the Models for Predicting the Likelihood of a BRCA1/BRCA2 Pathogenic Variant section in Genetics of Breast and Gynecologic Cancers.

Related Conditions

Fanconi anemia, a rare inherited condition, may be associated with biallelic pathogenic variants in some breast cancer susceptibility genes, including BRCA2. For more information, see the Fanconi anemia genes section in Genetics of Breast and Gynecologic Cancers.

References:

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  25. Struewing JP, Coriaty ZM, Ron E, et al.: Founder BRCA1/2 mutations among male patients with breast cancer in Israel. Am J Hum Genet 65 (6): 1800-2, 1999.
  26. Hirsh-Yechezkel G, Chetrit A, Lubin F, et al.: Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in Israel. Gynecol Oncol 89 (3): 494-8, 2003.
  27. Moslehi R, Chu W, Karlan B, et al.: BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66 (4): 1259-72, 2000.
  28. Levine DA, Argenta PA, Yee CJ, et al.: Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol 21 (22): 4222-7, 2003.
  29. Weitzel JN, Lagos V, Blazer KR, et al.: Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev 14 (7): 1666-71, 2005.
  30. Weitzel JN, Lagos VI, Herzog JS, et al.: Evidence for common ancestral origin of a recurring BRCA1 genomic rearrangement identified in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev 16 (8): 1615-20, 2007.
  31. Mefford HC, Baumbach L, Panguluri RC, et al.: Evidence for a BRCA1 founder mutation in families of West African ancestry. Am J Hum Genet 65 (2): 575-8, 1999.
  32. Tonin PN, Mes-Masson AM, Futreal PA, et al.: Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet 63 (5): 1341-51, 1998.
  33. Gal I, Gershoni Baruch R, Haber D, et al.: The 1100delAT BRCA1 and the 8765delAG BRCA2 mutations: occurrence in high-risk non-Ashkenazi Jews and haplotype comparison of Jewish and non-Jewish carriers. Fam Cancer 3 (1): 11-4, 2004.
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  35. Sagi M, Eilat A, Ben Avi L, et al.: Two BRCA1/2 founder mutations in Jews of Sephardic origin. Fam Cancer 10 (1): 59-63, 2011.
  36. Donenberg T, Lunn J, Curling D, et al.: A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas. Breast Cancer Res Treat 125 (2): 591-6, 2011.
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  38. Diez O, Gutiérrez-Enríquez S, Mediano C, et al.: A novel de novo BRCA2 mutation of paternal origin identified in a Spanish woman with early onset bilateral breast cancer. Breast Cancer Res Treat 121 (1): 221-5, 2010.
  39. Garcia-Casado Z, Romero I, Fernandez-Serra A, et al.: A de novo complete BRCA1 gene deletion identified in a Spanish woman with early bilateral breast cancer. BMC Med Genet 12: 134, 2011.
  40. Hansen TV, Bisgaard ML, Jønson L, et al.: Novel de novo BRCA2 mutation in a patient with a family history of breast cancer. BMC Med Genet 9: 58, 2008.
  41. Kwong A, Ng EK, Tang EY, et al.: A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer. Fam Cancer 10 (2): 233-7, 2011.
  42. Marshall M, Solomon S, Lawrence Wickerham D: Case report: de novo BRCA2 gene mutation in a 35-year-old woman with breast cancer. Clin Genet 76 (5): 427-30, 2009.
  43. Robson M, Scheuer L, Nafa K, et al.: Unique de novo mutation of BRCA2 in a woman with early onset breast cancer. J Med Genet 39 (2): 126-8, 2002.
  44. Tesoriero A, Andersen C, Southey M, et al.: De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet 65 (2): 567-9, 1999.
  45. van der Luijt RB, van Zon PH, Jansen RP, et al.: De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer. J Med Genet 38 (2): 102-5, 2001.
  46. Anderson KG: How well does paternity confidence match actual paternity? Evidence from worldwide nonpaternity rates. Curr Anthropol 47 (3): 513-20, 2006. Also available online. Last accessed May 24, 2024.
  47. Sasse G, Müller H, Chakraborty R, et al.: Estimating the frequency of nonpaternity in Switzerland. Hum Hered 44 (6): 337-43, 1994 Nov-Dec.
  48. Voracek M, Haubner T, Fisher ML: Recent decline in nonpaternity rates: a cross-temporal meta-analysis. Psychol Rep 103 (3): 799-811, 2008.
  49. Unger MA, Nathanson KL, Calzone K, et al.: Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet 67 (4): 841-50, 2000.
  50. Walsh T, Casadei S, Coats KH, et al.: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295 (12): 1379-88, 2006.
  51. Palma MD, Domchek SM, Stopfer J, et al.: The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 68 (17): 7006-14, 2008.
  52. Stadler ZK, Saloustros E, Hansen NA, et al.: Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families. Breast Cancer Res Treat 123 (2): 581-5, 2010.
  53. Judkins T, Rosenthal E, Arnell C, et al.: Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer 118 (21): 5210-6, 2012.
  54. Shannon KM, Rodgers LH, Chan-Smutko G, et al.: Which individuals undergoing BRACAnalysis need BART testing? Cancer Genet 204 (8): 416-22, 2011.
  55. Jackson SA, Davis AA, Li J, et al.: Characteristics of individuals with breast cancer rearrangements in BRCA1 and BRCA2. Cancer 120 (10): 1557-64, 2014.
  56. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010.
  57. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed October 31, 2023.
  58. Statement of the American Society of Human Genetics on genetic testing for breast and ovarian cancer predisposition. Am J Hum Genet 55 (5): i-iv, 1994.
  59. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015.
  60. Owens DK, Davidson KW, Krist AH, et al.: Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 322 (7): 652-665, 2019.
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Cancer Risks, Spectrum, and Characteristics

The proportion of individuals who carry a hereditary cancer syndrome pathogenic variant and develop cancer is called penetrance. (Refer to the Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers section of Genetics of Breast and Gynecologic Cancers for more information.) While numerous studies have estimated cancer risks in carriers of BRCA1 and BRCA2 pathogenic variants, making precise penetrance estimates in an individual carrier is difficult.

Table 1. Spectrum of Cancers in Carriers ofBRCA1andBRCA2Pathogenic Variants
Cancer Sites[1,2,3,4,5,6,7,8,9] BRCA1 BRCA2
a For more information on the association betweenBRCA1/BRCA2and prostate cancer, see the BRCA1 and BRCA2section in Genetics of Prostate Cancer.
+++ Multiple studies demonstrated association and are relatively consistent.
++ Multiple studies and the predominance of the evidence are positive.
+ May be an association, predominantly single studies; smaller limited studies and/or inconsistent but weighted toward positive.
  Strength of Evidence Lifetime Risk Strength of Evidence Lifetime Risk
Breast (female) +++ 55% to 65% +++ 45% to 47%
Ovary, fallopian tube, peritoneum +++ 39% +++ 11% to 17%
Breast (male) + 1% to 2% +++ 5% to 10%
Pancreas ++ Lower thanBRCA2 +++ 3% to 5%
Prostatea + Undefined +++ 27%

The risk to develop both breast and ovarian cancers is consistently higher in BRCA1 pathogenic variant carriers than in BRCA2 pathogenic variant carriers.[7,8] While the average penetrances of breast cancer and ovarian cancer in BRCA1/2 carriers may not be as high as initially estimated, they are substantial, both in relative and absolute terms, particularly in women born after 1940.[10,11,12]

Table 2. Estimated Cumulative Breast and Ovarian Cancer Risks in Carriers ofBRCA1andBRCA2Pathogenic Variants
Study Breast Cancer Risk (95% CI) Ovarian Cancer Risk (95% CI)
CI = confidence interval.
a Risk estimate calculated up to age 70 years.
b Risk estimate calculated up to age 80 years.
  BRCA1 BRCA2 BRCA1 BRCA2
Antoniou et al. (2003)[7] 65% (44–78)a 45% (31–56)a 39% (18–54)a 11% (2.4–19)a
Chen et al. (2007)[8] 55% (50–59)a 47% (42–51)a 39% (34–45)a 17% (13–21)a
Kuchenbaecker et al. (2017)[13] 72% (65–79)b 69% (61–77)b 44% (36–53)b 17% (11–25)b

Female Breast Cancer Risks

First primary breast cancer risks

The estimated cumulative risks of breast cancer by age 70 years in two meta-analyses were 55% to 65% for carriers of BRCA1 pathogenic variants and 45% to 47% for carriers of BRCA2 pathogenic variants.[7,8] One of these studies provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages.[8] For more information, see Table 2.

Contralateral breast cancer (CBC) risk

Most studies that assess second primary breast cancer risk use CBCs, since it can be challenging to determine if ipsilateral breast cancers are recurrences or second primary breast cancers.

As early as 1995, the Breast Cancer Linkage Consortium estimated the risk of CBC in BRCA1 carriers to be as high as 60% by age 60 years.[14] More recent studies have confirmed an increased risk of CBC among both BRCA1 and BRCA2 carriers. Due to variability in study designs and populations studied, risk estimates vary considerably. The estimated cumulative 10-year risk for CBC ranges from 18.5% to 34.2% in BRCA1 carriers and from 10.8% to 29.9% in BRCA2 carriers.[15] Most studies report CBC rates exceeding 50% in BRCA1/BRCA2 carriers after 20 years of follow-up, which translates to a relatively constant incidence rate of 2% to 3% per year (which persists for at least 20 years).[16,17] The largest CBC study to date, the CARRIERS study, included 15,104 women. Results showed that after a median follow-up period of 11 years, BRCA1 carriers had a 2.7-fold increased rate of CBC when compared with noncarriers, and BRCA2 carriers had a 3.0-fold increased rate of CBC when compared with noncarriers.[18] The CBC risk was similar in women with estrogen receptor (ER)–positive and ER-negative cancers.

Several factors can increase CBC risk. These factors may help explain the variability of CBC rates observed in BRCA1/BRCA2 carriers:

  • Age : Women whose first breast cancer was diagnosed at or before age 40 years have a significantly higher risk of developing a second breast cancer than women whose first breast cancer was diagnosed at a later age.[19]
  • Family history : A family history of breast cancer, particularly in first- and/or second-degree relatives, is also associated with a significantly increased risk of CBC.
  • Other genetics factors : The association between CBC risk and family history may be partially explained by other genetic factors. Data from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) have identified an association between CBC and polygenic risk scores (PRS) (which were based on 313 single nucleotide polymorphisms [SNPs] in this study).[15] Although the relative risks (RRs) for CBC were modest, they could have a strong influence on absolute risk, particularly in young women in whom the risks for CBC were the highest.

The following treatment options may have an impact on CBC risk in BRCA1/BRCA2 carriers:

  • Chemotherapy : Research on homologous recombination pathway impairment in BRCA-related breast cancers suggests that chemotherapy regimens that cause double-stranded DNA breaks may reduce CBC risk by eliminating precancerous lesions in the contralateral breast. A large, Dutch cohort study found that BRCA1 carriers who were treated with chemotherapy had greater than a 50% reduction in CBCs when compared with those who did not receive chemotherapy.[20] A similar trend was seen in BRCA2 carriers, in which CBC risk reduction was greatest for women who received anthracycline- and taxane-based chemotherapies.
  • Endocrine therapy : Retrospective data suggests that endocrine therapy has a protective effect when it is taken for primary breast cancer in BRCA1/BRCA2 carriers. However, these individuals still have a high absolute risk for CBC.[21]
  • Radiation therapy : The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study did not find an elevated CBC risk among BRCA1/BRCA2 carriers treated with radiation therapy.[22]

Women who are planning their initial surgery for breast cancer treatment weigh the risks and benefits of risk-reducing bilateral mastectomy. During this process, factors that contribute to CBC risk may help optimize decision making when they are combined in a multifactorial risk model.

Breast cancer risks after ovarian cancer diagnosis

Key points:

  • Treatment for ovarian cancer, namely oophorectomy and platinum-based chemotherapy, may confer protection against subsequent breast cancers.

Studies have explored the risk of primary breast cancer after BRCA-related ovarian cancer. In one study, 164 BRCA1/BRCA2 carriers with primary epithelial ovarian, fallopian tube, or primary peritoneal cancers were followed for subsequent events.[23] The risk of metachronous breast cancer at 5 years after a diagnosis of ovarian cancer was lower than previously reported for unaffected BRCA1/BRCA2 carriers. In this series, overall survival was dominated by ovarian cancer-related deaths. A similar study compared the risk of primary breast cancer in BRCA-related ovarian cancer patients and unaffected carriers.[24] The 2-year, 5-year, and 10-year risks of primary breast cancer were all statistically significantly lower in patients with ovarian cancer. The risk of CBC among women with a unilateral breast cancer before their ovarian cancer diagnosis was also lower than in women without ovarian cancer, although the difference did not reach statistical significance. These studies suggest that treatment for ovarian cancer, namely oophorectomy and platinum-based chemotherapy, may confer protection against subsequent breast cancers. In a single-institution cohort study of 364 patients with epithelial ovarian cancer who underwent BRCA pathogenic variant testing, 135 (37.1%) were found to carry a germline BRCA1 or BRCA2 pathogenic variant. Of the 135 BRCA1/BRCA2 carriers, 12 (8.9%) developed breast cancers. All breast cancers were stage 0 to stage II and diagnosed as follows: mammogram (7), palpable mass (3), and incidental finding during risk-reducing mastectomy (2). After a median follow-up period of 6.3 years, of the 12 patients with breast cancer after ovarian cancer, three died of recurrent ovarian cancer and one died of metastatic breast cancer.[25] Most of these cancers were detected with mammogram or clinical breast exam, suggesting that additional breast surveillance with other modalities or risk-reducing surgery may be of questionable value.

BRCA1/2-associated breast cancer pathology

Key point:

  • Ductal carcinoma in situ (DCIS) is part of the spectrum of BRCA1/BRCA2-associated breast cancers, particularly in BRCA2 carriers.

Overall evidence suggests DCIS is part of the BRCA1/BRCA2 cancer spectrum, particularly in BRCA2 carriers. However, the prevalence of BRCA1/2 pathogenic variants in DCIS patients, unselected for family history, is less than 5%.[26,27]

There is growing evidence that preinvasive lesions are a component of the BRCA phenotype. The Breast Cancer Linkage Consortium initially reported a relative lack of an in situ component in BRCA1-associated breast cancers.[28] This has also been seen in two subsequent studies of BRCA1/BRCA2 carriers.[29,30] However, in a study of 369 DCIS cases, BRCA1 and BRCA2 pathogenic variants were detected in 0.8% and 2.4%, respectively, which is only slightly lower than previously reported prevalence in studies of invasive breast cancer patients.[26] A retrospective study of breast cancer cases in a high-risk clinic found similar rates of preinvasive lesions, particularly DCIS, among 73 BRCA-associated breast cancers and 146 pathogenic variant–negative cases.[31,32] A study of Ashkenazi Jewish (AJ) women, stratified by whether they were referred to a high-risk clinic or were unselected, showed similar prevalence of DCIS and invasive breast cancers in referred patients compared with one-third lower DCIS cases among unselected subjects.[27] Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased [33,34] and decreased prevalence.[30] Similar to invasive breast cancer, DCIS diagnosed at an early age and/or with a family history of breast and/or ovarian cancer is more likely to be associated with a BRCA1/BRCA2 pathogenic variant.[35]

BRCA1-associated breast cancer pathology

Key point:

  • Most BRCA1-associated breast cancers have triple negative and/or basal subtypes.

Several studies evaluating pathological patterns seen in BRCA1-associated breast cancers have suggested an association with adverse pathological and biological features. These findings include higher than expected frequencies of medullary histology, high histological grades, areas of necrosis, trabecular growth patterns, aneuploidy, high S-phase fractions, high mitotic indexes, and frequent TP53 variants.[28,36,37,38,39,40,41,42] In a large international series of 3,797 carriers of BRCA1 pathogenic variants, the median age at breast cancer diagnosis was 40 years.[42] Of breast tumors arising in BRCA1 carriers, 78% were ER-negative, 79% were progesterone receptor (PR)–negative, 90% were human epidermal growth factor two (HER2)–negative, and 69% were triple-negative. These findings were consistent with multiple smaller series.[38,43,44,45,46] In addition, the proportion of ER-negative tumors significantly decreased as the age at breast cancer diagnosis increased.[42]

There is considerable, but not complete, overlap between the triple-negative and basal-like subtype cancers, both of which are common in BRCA1-associated breast cancers,[47,48] particularly in women diagnosed before age 50 years.[45,49,50] A small proportion of BRCA1-related breast cancers are ER-positive, which are associated with later ages of onset.[51,52] These ER-positive cancers have clinical behavioral features that are intermediate between ER-negative BRCA1 cancers and ER-positive sporadic breast cancers, raising the possibility that there may be a unique mechanism by which they develop.

The prevalence of germline BRCA1 pathogenic variants in women with triple-negative breast cancer (TNBC) is significant, both in women undergoing clinical genetic testing (and thus, selected in large part for family history) and in unselected triple-negative patients, with pathogenic variants reported in 9% to 35%.[43,50,53,54,55,56,57] Notably, studies have demonstrated a high rate of BRCA1 pathogenic variants in unselected women with TNBC, particularly in those diagnosed before age 50 years. A large report of 1,824 patients with TNBC unselected for family history, recruited through 12 studies, identified 14.6% with a pathogenic variant in an inherited cancer susceptibility gene.[57]BRCA1 pathogenic variants accounted for the largest proportion (8.5%), followed by BRCA2 (2.7%); PALB2 (1.2%); and BARD1, RAD51D, RAD51C and BRIP1 (0.3%–0.5% for each gene). In this study, those with pathogenic variants in BRCA1/BRCA2 or other inherited cancer genes were diagnosed at an earlier age and had higher grade tumors than those without pathogenic variants. Specifically, among carriers of BRCA1 pathogenic variants, the average age at diagnosis was 44 years, and 94% had high-grade tumors. One study examined 308 individuals with TNBC. BRCA1 pathogenic variants were present in 45 of these individuals. Pathogenic variants were seen both in women unselected for family histories of breast cancer (11 of 58; 19%) and in those with family histories of breast cancer (26 of 111; 23%).[58] A meta-analysis based on 2,533 patients from 12 studies was conducted to assess the risk of a BRCA1 pathogenic variant in high-risk women with TNBC.[59] Results indicated that the RR of a BRCA1 pathogenic variant among women with versus without TNBC is 5.65 (95% CI, 4.15–7.69), and approximately two in nine women with triple-negative disease harbor a BRCA1 pathogenic variant. Interestingly, a study of 77 unselected patients with TNBC in which 15 (19.5%) had a germline pathogenic variant or somatic BRCA1/BRCA2mutation demonstrated a lower risk of relapse in those with BRCA1 pathogenic variant–associated TNBC than in those with non-BRCA1-associated TNBC; this study was limited by its size.[54] A second study on BRCA1-associated versus non-BRCA1–associated TNBCs showed no differences in clinical outcomes between these groups. However, there was a trend toward more brain metastases in those with BRCA1-associated breast cancers. In both of these studies, all but one carrier of BRCA1 pathogenic variants received chemotherapy.[60] In contrast, HER2 positivity and young age at breast cancer diagnosis alone in the absence of family history or a second primary cancer does not increase the likelihood of a pathogenic variant in BRCA1, BRCA2, or TP53.[61]

It has been hypothesized that many BRCA1 tumors are derived from the basal epithelial layer of cells of the normal mammary gland, which account for 3% to 15% of unselected invasive ductal cancers. If the basal epithelial cells of the breast represent the breast stem cells, the regulatory role suggested for wild-type BRCA1 may partly explain the aggressive phenotype of BRCA1-associated breast cancer when BRCA1 function is damaged.[62] Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes.

The most accurate method for identifying basal-like breast cancers is through gene expression studies, which have been used to classify breast cancers into biologically and clinically meaningful groups.[44,63,64] This technology has also been shown to correctly differentiate BRCA1- and BRCA2-associated tumors from sporadic tumors in a high proportion of cases.[65,66,67] Notably, among a set of breast tumors studied by gene expression array to determine molecular phenotype, all tumors with BRCA1 alterations fell within the basal tumor subtype;[44] however, this technology is not in routine use due to its high cost. Instead, immunohistochemical markers of basal epithelium have been proposed to identify basal-like breast cancers, which are typically negative for ER, PR, and HER2, and stain positive for cytokeratin 5/6, or epidermal growth factor receptor.[68,69,70,71] Based on these methods to measure protein expression, a number of studies have shown that most BRCA1-associated breast cancers are positive for basal epithelial markers.[38,45,70]

BRCA2-associated breast cancer pathology

Key point:

  • Most BRCA2-associated breast cancers are hormone receptor (HR)–positive, although TNBCs are also overrepresented in BRCA2 carriers.

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1, although they are generally ER- and PR-positive.[28,72,73] A large international series of 2,392 carriers of BRCA2 pathogenic variants found that only 23% of tumors arising in carriers of BRCA2 pathogenic variants were ER-negative; 36% were PR-negative; 87% were HER2-negative; and 16% were triple-negative.[42] A large report of 1,824 patients with TNBC unselected for family history, recruited through 12 studies, identified 2.7% with a BRCA2 pathogenic variant.[57] (Refer to the BRCA1-associated breast cancer pathology section of this summary for more information about this study.) A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors than in sporadic controls; however, a single BRCA2 founder pathogenic variant (999del5) accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation.[74] A large case series from North America and Europe described a greater proportion of BRCA2-associated tumors with continuous pushing margins (a histopathological description of a pattern of invasion), fewer tubules, and lower mitotic counts.[75] Other reports suggest that BRCA2-related tumors include an excess of lobular and tubulolobular histologies.[37,72] In summary, histological characteristics associated with BRCA2 pathogenic variants have been inconsistent.

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Risks

Key points:

  • Cumulative ovarian cancer risk is 39% in BRCA1 carriers and ranges from 11% to 17% in BRCA2 carriers.
  • Having a BRCA1/BRCA2 pathogenic variant elevates risks for fallopian tube and primary peritoneal cancers. However, specific risks for these cancers are not yet known.

The estimated cumulative risks of ovarian cancer by age 70 years in two meta-analyses were 39% for carriers of BRCA1 pathogenic variants and 11% to 17% for carriers of BRCA2 pathogenic variants.[7,8] One of these studies provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages.[8]

BRCA pathogenic variants also confer an increased risk of fallopian tube and primary peritoneal carcinomas. One large study from a familial registry of carriers of BRCA1 pathogenic variants has found a 120-fold RR of fallopian tube cancer among carriers of BRCA1 pathogenic variants compared with the general population.[2] The risk of primary peritoneal cancer among carriers of BRCA pathogenic variants with intact ovaries is increased but remains poorly quantified, despite a residual risk of 3% to 4% 20 years after risk-reducing salpingo-oophorectomy.[76,77] A study of 108 women with fallopian tube cancer identified pathogenic variants in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall).[78] Estimates of the frequency of fallopian tube cancer in carriers of BRCA pathogenic variants are limited by the lack of precision in the assignment of site of origin for high-grade, metastatic, serous carcinomas at initial presentation.[2,78,79,80]

Pathologies ofBRCA1/2-associated ovarian, fallopian tube, and primary peritoneal cancers

Key points:

  • BRCA1/2-associated ovarian cancers are more likely to have high-grade serous adenocarcinoma histologies.
  • Occult lesions found in the fallopian tubes of BRCA carriers suggest that many BRCA-associated ovarian cancers may originate in the fallopian tubes.

Ovarian cancers in women with BRCA1 and BRCA2 pathogenic variants are more likely to be high-grade serous adenocarcinomas and are less likely to be mucinous or borderline tumors.[81,82,83,84,85] Fallopian tube cancers and peritoneal carcinomas are also part of the BRCA-associated disease spectrum.[79,86]

Histopathological examinations of fallopian tubes removed from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that are suggestive of a premalignant phenotype.[87,88] Occult carcinomas have been reported in 2% to 11% of adnexa removed from carriers of BRCA pathogenic variants at the time of risk-reducing surgery.[89,90,91] Most of these occult lesions are seen in the fallopian tubes, which has led to the hypothesis that many BRCA-associated ovarian cancers may actually have originated in the fallopian tubes. Specifically, the distal segment of the fallopian tubes (containing the fimbriae) has been implicated as a common origin of the high-grade serous cancers seen in BRCA pathogenic variant carriers, based on the close proximity of the fimbriae to the ovarian surface, exposure of the fimbriae to the peritoneal cavity, and the broad surface area in the fimbriae.[92] Because of the multicentric origin of high-grade serous carcinomas from Müllerian-derived tissue, staging of ovarian, tubal, and peritoneal carcinomas is now considered collectively by the International Federation of Gynecology and Obstetrics. The term high-grade serous ovarian carcinoma may be used to represent high-grade pelvic serous carcinoma for consistency in language.[93]

High-grade serous ovarian carcinomas have a higher incidence of somatic TP53 variants.[81,94] DNA microarray technology suggests distinct molecular pathways of carcinogenesis between BRCA1, BRCA2, and sporadic ovarian cancers.[95] Furthermore, data suggest that BRCA-related ovarian cancers metastasize more frequently to the viscera, while sporadic ovarian cancers remain confined to the peritoneum.[96]

Unlike high-grade serous carcinomas, low-grade serous ovarian cancers are less likely to be part of the BRCA1/BRCA2 spectrum.[97,98]

Uterine Cancer Risk

Key point:

  • Serous uterine cancer risk may be elevated in BRCA1 carriers who used tamoxifen. However, there is mixed evidence on this topic.

Some reports have suggested an increased incidence of uterine carcinoma in BRCA1/2 pathogenic variant carriers,[99] whereas others have not confirmed an elevated risk of serous uterine cancer.[100] A prospective study of 857 women suggested that any increased incidence of uterine cancer appeared to be among carriers of BRCA1 pathogenic variants who used tamoxifen;[101] this was confirmed by the same group in a later study of 4,456 carriers of BRCA1/BRCA2 pathogenic variants.[102] Even with tamoxifen use, the excess risk of endometrial cancer was small, with a 10-year cumulative risk of 2%.[102] In addition, the use of tamoxifen can now be minimized, given the options of raloxifene (which does not increase the risk of uterine cancer) and aromatase inhibitors for breast cancer prevention in postmenopausal women.

Male Breast Cancer Risk

Men with BRCA2 pathogenic variants, and to a lesser extent BRCA1 pathogenic variants, have an increased risk to develop breast cancer, with lifetime risks ranging from 5% to 10% and 1% to 2%, respectively.[2,3,9,103,104]

Prostate Cancer Risk

Key points:

  • BRCA2 carriers have up to a sevenfold increased risk of developing prostate cancer when compared with individuals in the general population.
  • BRCA2-associated prostate cancers are more likely to be aggressive than sporadic prostate cancers.

Men carrying BRCA2 pathogenic variants, and to a lesser extent BRCA1 pathogenic variants, have an approximately threefold to sevenfold increased risk of developing prostate cancer.[1,3,5,6,9,105,106,107,108]BRCA2-associated prostate cancers also appear to be more aggressive than sporadic prostate cancers.[109,110,111,112,113,114] For more information, see the BRCA1 and BRCA2 section in Genetics of Prostate Cancer.

Pancreatic Cancer Risk

Key point:

  • The lifetime risk of pancreatic cancer in BRCA2 carriers is estimated to be 3% to 5%, with lower risks in BRCA1 carriers.

Studies of familial pancreatic cancer (FPC) [115,116,117,118,119] and unselected series of pancreatic cancer [120,121,122] have also supported an association with BRCA2, and to a lesser extent, BRCA1.[5] Overall, it appears that between 3% to 15% of families with FPC may have germline BRCA2 pathogenic variants, with pancreatic cancer risk increasing as individuals have a greater number of affected relatives.[115,116,117] Similarly, studies of unselected pancreatic cancers have reported BRCA2 pathogenic variant frequencies between 3% to 7%, with these numbers approaching 10% in individuals of AJ descent.[120,121,123] The lifetime risk of pancreatic cancer in BRCA2 carriers is estimated to be 3% to 5%,[1,3,9] compared with an estimated lifetime risk of 0.5% by age 70 years in the general population.[124] A large, single-institution study of more than 1,000 carriers of pathogenic variants found a 21-fold increased risk of pancreatic cancer among BRCA2 carriers and a 4.7-fold increased risk among carriers of BRCA1 pathogenic variants, compared with incidence in the general population.[108]

Melanoma Risk

Melanoma is another cancer that is associated with BRCA2 pathogenic variants in some, but not all, studies.[1] It is unclear if BRCA1 and BRCA2 pathogenic variants increase melanoma risk based on the current evidence.[125,126] For more information, see the BRCA1 and BRCA2 section in Genetics of Skin Cancer.

Other Cancer Risks

Taken together, there are insufficient data to support an increased risk of colorectal cancer (CRC) in BRCA1 and BRCA2 carriers. Therefore, at this time, carriers of BRCA1 pathogenic variants should adhere to population-screening recommendations for CRC.[2,3,4,5,105,127,128,129,130,131,132,133,134]

There is mounting evidence supporting an association between BRCA1/BRCA2 pathogenic variants and increased gastric cancer risk. Multigene panel testing of over 80 genes (hereditary cancer syndrome genes, including hereditary gastric cancer) in 34 patients with gastric cancer demonstrated that six patients had a pathogenic variant (17.6%), half of which were pathogenic variants in BRCA1/BRCA2.[135] In a similar study, 515 patients with esophagogastric cancers participated in genetic testing that searched for pathogenic variants in up to 88 hereditary cancer syndrome genes. Results indicated that 48 of 243 patients with gastric cancer (19.8%) had a pathogenic variant in one of these genes.[136] Twelve patients with either a gastric cancer or a gastroesophageal junction cancer had a BRCA1/BRCA2 pathogenic variant. Incidences of 26 cancers in a group of 3,184 BRCA1 and 2,157 BRCA2 families were compared with the incidences of these cancers in the general population and were matched by age, country, birth cohort, and RRs (which were equivalent to standardized incidence ratios).[9] The RRs of developing gastric cancer were 2.17 and 3.69 in BRCA1 and BRCA2 carriers, respectively. Furthermore, female BRCA2 carriers had a RR of 6.89 for developing gastric cancer, while male BRCA2 carriers had a RR of 2.76 for developing gastric cancer. Studies have demonstrated that gastric cancers in patients with BRCA1/BRCA2 pathogenic variants have mutational signatures consistent with defects in DNA double-stranded break repair (via homologous recombination). This provides biological plausibility for the link between gastric cancer and BRCA1/BRCA2 pathogenic variants.[137,138] On the contrary, a meta-analysis of five studies did not find an association between BRCA1 pathogenic variants and increased gastric cancer risk (RR, 1.70; 95% CI, 0.93–3.09). However, this meta-analysis did find an association between BRCA2 pathogenic variants and increased gastric cancer risk over six studies (RR, 2.15; 95% CI, 1.98–2.33).[139] Taken together, these data suggest that there is an association between BRCA2 pathogenic variants and gastric cancer risk and a possible association between BRCA1 pathogenic variants and gastric cancer risk. Currently, gastric cancer screening is not indicated for BRCA1/BRCA2 carriers.

Risk Modifiers

The observed variation in penetrance has led to the hypothesis that other genetic and/or environmental factors modify cancer risk in carriers of BRCA1/2 pathogenic variants. There is a growing body of literature identifying genetic and nongenetic factors that contribute to the observed variation in cancer rates seen in families with BRCA1/BRCA2 pathogenic variants.

Genetic modifiers

The largest studies investigating genetic modifiers of breast and ovarian cancer risk to date have come from the CIMBA, a large international effort with genotypic and phenotypic data on more than 15,000 BRCA1 and 10,000 BRCA2 carriers.[140] Using candidate gene analysis and genome-wide association studies, CIMBA has identified several loci associated both with increased and decreased risks of breast cancer and ovarian cancer. Some of the single nucleotide variants (SNVs) are related to subtypes of breast cancer, such as HR and HER2/neu statuses. The risks conferred are all modest but if operating in a multiplicative fashion could significantly impact risk of cancer in carriers of BRCA1/BRCA2 pathogenic variants. Currently, clinicians do not test for SNVs, and they are not currently being used in clinical decision making.

Lifestyle factors, reproductive factors, and other modifiers of cancer risks

For more information about risk factors that may increase cancer risks in BRCA1/2 carriers, see the following sections in the Genetics of Breast and Gynecologic Cancers summary:

  • Risk Factors for Breast Cancer
  • Risk Factors for Ovarian Cancer

Genotype-Phenotype Correlations

Some genotype -phenotype correlations have been identified in both BRCA1 and BRCA2 pathogenic variant families. None of the studies have had sufficient numbers of pathogenic variant–positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management. Studies have identified ovarian cancer cluster regions and breast cancer cluster regions in BRCA1 and BRCA2.[141,142,143,144,7,145,146,147,148] Data from CIMBA also found breast cancer cluster regions and ovarian cancer cluster regions in both genes. The data, which consisted of 19,581 BRCA1 pathogenic variant carriers and 11,900 BRCA2 pathogenic variant carriers, were analyzed to estimate hazard ratios (HRs) for breast cancer and ovarian cancer by pathogenic variant type, function, and nucleotide position.[149] Incidence of breast cancer, incidence of ovarian cancer, and age at diagnosis differed by variant class. Further evaluation of these findings is needed before they can be translated into clinical practice.

In an Australian study of 122 families with a pathogenic variant in BRCA1, large genomic rearrangement variants were associated with higher-risk features in breast and ovarian cancers, including younger age at breast cancer diagnosis and higher incidence of bilateral breast cancers.[150]

Studies of penetrance for carriers of specific individual variants are not usually large enough to provide stable estimates, but numerous studies of the AJ founder pathogenic variants have been conducted. One group of researchers analyzed the subset of families with one of the AJ founder pathogenic variants from its larger meta-analyses and found that the estimated penetrance for the individual pathogenic variants was very similar to the corresponding estimates among all carriers.[151] A later study of 4,649 women with BRCA pathogenic variants reported significantly lower RRs for breast cancer in those with the BRCA2 6174delT variant than in those with other BRCA2 variants (HR, 0.35; 95% confidence interval [CI], 0.18–0.69).[152]

Another study from the CIMBA group looked at the phenotype of women with breast cancer who had inherited pathogenic variants in both BRCA1 and BRCA2.[153] The majority of women in this study carried common AJ pathogenic variants. Compared with women who were heterozygous for the same pathogenic variant (heterozygote controls), women who were heterozygous for both BRCA1 and BRCA2 were more likely to be diagnosed with breast cancer than women who were heterozygote controls, and more likely to be diagnosed with ovarian cancer than women who were heterozygote controls with BRCA2, but not those with BRCA1 pathogenic variants. Similarly, age at breast cancer onset was younger in carriers of both variants compared with women who were heterozygote controls with BRCA2, but not compared with those with BRCA1 pathogenic variants. The percentage of women with both variants and ER-positive and PR-positive breast cancers was intermediate between the heterozygote controls with BRCA1 pathogenic variants and those with BRCA2 pathogenic variants. The authors concluded that women who inherit pathogenic variants in both BRCA1 and BRCA2 may be managed similarly to carriers of only a BRCA1 variant.

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Management of Cancer Risks in BRCA1 / 2 Carriers

Increasing data are available on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast cancer or ovarian cancer.[1,2,3,4,5,6,7] As outlined in other sections of this summary, there is considerable uncertainty 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.

Breast Cancer Screening, Surveillance, and Risk-Reduction Strategies forBRCA1/2Carriers

Screening and surveillance for breast cancer

Refer to the PDQ summary on Breast Cancer Screening for information on screening in the general population.

Breast self-examination

In the general population, evidence for the value of breast self-examination (BSE) is limited.

Little direct prospective evidence exists regarding BSE in individuals with an increased risk of breast cancer.[8]

Level of evidence: 5

Clinical breast examination (CBE)

Few prospective data exist regarding the utility of CBE in detection of early breast cancer.[8]

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.)

Certain observations raise concerns 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 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 end point.

Three studies have failed to find convincing evidence of an association between ionizing radiation exposure and increased breast cancer risk in BRCA1 and BRCA2 pathogenic variant carriers.[9,10,11] In contrast, two large international studies found evidence of an increased breast cancer risk due to chest x-rays [12] or estimates of total exposure to diagnostic radiation.[13] 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.[12] 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.[13] In this 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 who were exposed to radiation before age 30 years had an increased risk (HR, 1.90; 95% confidence interval [CI], 1.20–3.00) when compared with those who were 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.[11] 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 BRCA2 pathogenic variants, any potential benefit of mammographic screening must be carefully weighed against potential risks, particularly in young women.[14] 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.[15] The National Comprehensive Cancer Network (NCCN) recommends annual breast MRI screening with and without contrast (or mammogram if MRI is unavailable) between the ages of 25 and 29 years in BRCA1/2 carriers. If a breast cancer was diagnosed prior to age 30 years in a patient's relative, individualized breast cancer screening may be warranted. Annual mammogram and breast MRI with and without contrast are recommended between ages 30 and 75 years.[16]

Level of evidence: 2

Magnetic resonance imaging

Because of the relative insensitivity of mammography alone in women with inherited breast cancer risk, a number of screening modalities have been investigated in high-risk women, including in BRCA1/2 carriers. Many studies, including relatively large multi-institutional trials, have described breast MRI screening in women at elevated risk for breast cancer.[17,18,19]

Despite some limitations, these studies consistently demonstrate that breast MRI is more sensitive than mammography or ultrasound at detecting breast cancer in high-risk women.[17,18,20,21,22,23] Most cancers in these programs were detected via screening, 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%. In the combined studies, 77% of cancers were identified by MRI, and 42% were identified by mammography.

However, breast MRI may have reduced specificity when compared with other breast cancer screening methods.[20,21] For example, in one study, 16.5% of participants were recalled for additional screening after receiving breast MRI, and 11% of the first-round biopsies in this group were benign.[20] These rates declined significantly during later screening rounds. The benign biopsy rates were 6.6% in the second round and 4.7% in the third round. In a second study, Magnetic Resonance Imaging for Breast Screening (MARIBS), the recall rate was 10.7% per year.[21] The aggregate surgical biopsy rate was 9 per 1,000 screening episodes, though this figure may underestimate the burden because follow-up ultrasounds, core-needle biopsies, and fine-needle aspirations were not included in the numerator of the MARIBS calculation.[21] The positive predictive value (PPV) of MRI has been calculated differently in various series and fluctuates somewhat, depending on whether all abnormal examinations or only 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.

A systematic review has also shown that breast MRI is better at detecting breast cancer than mammography alone in young women with high breast cancer risk. However, mammogram may detect some lesions (i.e., DCIS) that are not easily identified by MRI.[24,25] In turn, the American Cancer Society and NCCN have recommended annual breast MRI screening with and without contrast starting at age 25 years and annual mammogram screening starting at age 30 years for women who are BRCA1 or BRCA2 carriers. If a breast cancer was diagnosed prior to age 30 years in a patient's relative, individualized MRI screening may be warranted.[16,26]

Despite the apparent sensitivity of MRI screening, some women screened with MRI 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 annual mammograms and MRIs, 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 BRCA2 pathogenic variants.[27]

It is unclear whether mammography and MRI should be done simultaneously or in an alternating fashion (each test is done annually but 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.[15]

Evidence does not support the use of routine MRI after risk-reducing mastectomy (RRM). A retrospective review of 159 women (including 58 BRCA1/2 carriers) who underwent RRM reported a low yield of breast cancers detected by annual MRI screening over an 8-year period. MRI was negative in 98% of patients and was associated with a false-positive rate of 90%.[28]

In summary, evidence strongly supports the integral role of breast MRI in breast cancer surveillance for carriers of BRCA1/BRCA2 pathogenic variants.

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.[29] 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.[30] 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: 3

Breast cancer screening in individuals diagnosed with ovarian cancer

Mathematical modeling suggests that for women with BRCA-associated ovarian cancers, breast cancer screening should consist of mammography and CBE. The consideration of MRI and/or risk-reducing mastectomy may be beneficial for women with early-stage ovarian cancers or for long-term ovarian cancer survivors.[31]

Risk-reducing strategies for breast cancer

Risk-reducing mastectomy (RRM) for unaffected females

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,[32,33,34] but overall survival (OS) correlates more closely with the overall risk from the primary incidence of breast cancer.

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 of 378 carriers who did not choose surgery. Bilateral mastectomy reduced the risk of breast cancer by approximately 90% after a mean follow-up period of 6.4 years.[3]

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 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 breast MRI and mammography screening, 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.[35] 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.

Level of evidence: 3ai

RRM for affected females

If RRM is effective at lowering breast cancer risk in unaffected women, what is its role in 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. 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 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 (approximately 0.3% per year in the general population).[36,37] (Refer to the Contralateral breast cancer (CBC) risk section of this summary for more information about CBC risk in individuals with BRCA pathogenic variants.) In carriers of BRCA pathogenic variants whose first cancer has an excellent prognosis, estimating the risk of a second, unrelated breast cancer is important for informing their decision to undergo risk-reducing surgery and has been described in this setting to improve survival.[38] 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.[39]

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 that 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 (ER) status in a large portion of this sample.

A Dutch cohort of 583 patients identified between 1980 and 2011, who had both a BRCA pathogenic variant and a diagnosis of unilateral breast cancer, were evaluated for the effect of CRRM.[40] With a median follow-up period of 11.4 years, 242 of the patients (42%) underwent RRM (193 carriers of BRCA1 pathogenic variants and 49 carriers of BRCA2 pathogenic variants) at differing times after their diagnoses. Improved OS was observed in the RRM group when 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 grades, and non–triple-negative subtypes. 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 RRM when compared with those who chose unilateral mastectomy.[38] 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.[41]

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 nipple-areolar complex (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.[42] 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 period of 32.6 months (range, 1.0–76.0 months), there were four subsequent cancer events that included two patients with axillary recurrences, one patient 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 period, 26 months; range, 11–42 months), and 26 patients had NSM and a diagnosis of breast cancer (median follow-up period, 28 months; range, 15–43 months). Five patients required further nipple excision. There were no local recurrences or newly diagnosed breast cancers.[43] Although the median follow-up time was short (34 months), NSM appeared to be a safe alternative to traditional mastectomy in appropriately selected patients with BRCA pathogenic variants.[44]

Level of evidence: 3aii

Incidence of breast cancer or other lesions in RRM

The predominant histopathological findings at the time of RRM in unaffected women with pathogenic BRCA variants are proliferative lesions that do not require additional treatment. Studies describing histopathological 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.[45,46,47] In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of RRM or contralateral mastectomies performed in known carriers of BRCA1 or BRCA2 pathogenic variants from Australia, three (6%) cancers were detected at the time of surgery.[48] In general, histopathologic findings in RRM specimens do not impact management.

Risk-reducing salpingo-oophorectomy (RRSO) for breast cancer risk reduction

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.[49]

Evidence regarding the effect of RRSO on breast cancer risk has evolved. Early small studies suggested RRSO provided a protective benefit against developing breast cancer. A meta-analysis of RRSO and breast and ovarian/fallopian tube cancers in carriers of BRCA1/BRCA2 pathogenic variants reported 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).[50] However, a cohort study of 822 BRCA1/BRCA2 pathogenic variant carriers conducted in the Netherlands (where carrier screening is performed nationwide) did not observe a reduction in breast cancer risk after RRSO (HR, 1.09; 95% CI, 0.67–1.77).[51] The authors presented evidence of methodological biases from earlier studies regarding RRSO and breast cancer risk. Discussion of this bias has led to additional reanalyses of data [52] and new studies, some of which support a decreased association in breast cancer from RRSO.[53,54] Other cohort studies have not found an association between RRSO and breast cancer risk.[55]

A prospective, multicenter, cohort study of 2,482 carriers of BRCA1/BRCA2 pathogenic variants reported an association between RRSO and 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 histories of breast cancer.[56]

For more information, see the Hormone Replacement Therapy in Carriers of BRCA1/2 Pathogenic Variants section.

Level of evidence: 3ai

Chemopreventive agents for reducing breast cancer risk

Tamoxifen (a synthetic antiestrogen) increases breast-cell growth inhibitory factors and concomitantly reduces breast-cell growth stimulatory factors. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP-P-1), a prospective, randomized, double-blind trial, compared tamoxifen (20 mg/day) with placebo for 5 years in high-risk women (defined by a Gail model risk score >1.66, age >60 y, or lobular carcinoma in situ). Tamoxifen was shown to reduce the risk of invasive breast cancer by 49%. The protective effect was largely confined to ER-positive breast cancer, which was reduced by 69%. The incidence of ER-negative cancer was not significantly reduced.[57] Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted both among women with a family history of breast cancer and among those without a family history. An increased incidence of endometrial cancers and thrombotic events occurred among women older than 50 years. Interim data from two European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months [58] or 70 months,[59] respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used hormone replacement therapy (HRT).[58] These trials varied considerably in study design and populations. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

Subsequently, the International Breast Cancer Intervention Study 1 (IBIS-1) breast cancer prevention trial randomly assigned 7,154 women between the ages of 35 and 70 years to receive tamoxifen or placebo for 5 years. Eligibility for the trial was based on family history or abnormal benign breast disease. At a median follow-up of 16 years, there was a 29% reduction in risk of breast cancer in the tamoxifen arm (HR, 0.71; 95% CI, 0.60–0.83). There was a 43% reduction in risk for invasive ER-positive breast cancer (HR, 0.66; 95% CI, 0.54–0.81) and a 35% reduction in risk for DCIS (HR, 0.65; 95% CI 0.43–1.00). There was no reduction in risk of invasive ER-negative breast cancer.[60] These findings confirm those of the Breast Cancer Prevention Trial (P-1).[57]

Level of evidence (tamoxifen in a high-risk population): 1aii

A substudy of the NSABP-P-1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in carriers of BRCA1/BRCA2 pathogenic variants older than 35 years. BRCA2-positive women benefited from tamoxifen to the same extent as BRCA1/BRCA2 pathogenic variant–negative participants; however, tamoxifen use among healthy women with BRCA1 pathogenic variants did not appear to reduce breast cancer incidence. These data must be viewed with caution because of the small number of carriers of pathogenic variants in the sample (8 BRCA1 carriers and 11 BRCA2 carriers).[61]

Level of evidence: 1aii

In contrast to the very limited data on primary prevention in carriers of BRCA1 and BRCA2 pathogenic variants with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of CBC.[62,63,64] In one study involving approximately 600 carriers of BRCA1/BRCA2 pathogenic variants, tamoxifen use was associated with a 51% reduction in CBC.[62] An update to this report examined 285 carriers of BRCA1/BRCA2 pathogenic variants with bilateral breast cancer and 751 carriers of BRCA1/BRCA2 pathogenic variants with unilateral breast cancer (40% of these patients were included in their initial study). Tamoxifen was associated with a 50% reduction in CBC risk in carriers of BRCA1 pathogenic variants and a 58% reduction in carriers of BRCA2 pathogenic variants. Tamoxifen did not appear to confer benefit in women who had undergone an oophorectomy, although the numbers in this subgroup were quite small.[64] Another study that involved 160 carriers of BRCA1/BRCA2 pathogenic variants demonstrated that tamoxifen use after the treatment of breast cancer with lumpectomy and radiation was associated with a 69% reduction in the risk of CBC.[63] In another study, 2,464 carriers of BRCA1/BRCA2 pathogenic variants with a personal history of breast cancer were identified from three family cohorts. Using both retrospective and prospective data, researchers found a significant decrease in the risk of CBC among women who received adjuvant tamoxifen therapy after their diagnosis. This association persisted after researchers adjusted for age at diagnosis and the ER status of the first cancer. A major limitation of this study is the lack of information on ER status of the first breast cancer in 56% of the women.[65] These studies are limited by their retrospective, case-control designs and the absence of information regarding ER status in the primary tumor.

The STAR trial (NSABP-P-2) included more than 19,000 women and compared 5 years of raloxifene versus tamoxifen in reducing the risk of invasive breast cancer.[66] There was no difference in incidence of invasive breast cancer at a mean follow-up period of 3.9 years. However, there were fewer noninvasive cancers in the tamoxifen group. The incidence of thromboembolic events and hysterectomy was significantly lower in the raloxifene group. Detailed quality-of-life (QOL) data demonstrate slight differences between the two arms.[67] Data regarding efficacy in carriers of BRCA1 or BRCA2 pathogenic variants are not available. (Refer to the PDQ summary on Breast Cancer Prevention for more information about the use of selective ER modulators and aromatase inhibitors in the general population, including postmenopausal women.)

Another case-control study of carriers of pathogenic variants and noncarriers identified through ascertainment of women with bilateral breast cancer found that systemic adjuvant chemotherapy reduced CBC risk among carriers of pathogenic variants (RR, 0.5; 95% CI, 0.2–1.0). Tamoxifen was associated with a nonsignificant risk reduction (RR, 0.7; 95% CI, 0.3–1.8). Similar risk reduction was seen in noncarriers. However, given the higher absolute CBC risk in carriers, there is potentially a greater impact of adjuvant treatment in risk reduction.[68]

The effect of tamoxifen on ovarian cancer risk was studied in 714 carriers of BRCA1 pathogenic variants. All subjects had a prior histories of breast cancer. Use of tamoxifen was not associated with an increased risk of subsequent ovarian cancers (odds ratio [OR], 0.78; 95% CI, 0.46–1.33).[69]

Ovarian Cancer Screening, Surveillance, and Risk-Reduction Strategies forBRCA1/2Carriers

Risk-reducing strategies for ovarian cancer

Risk-reducing salpingo-oophorectomy for ovarian cancer risk reduction

RRSO in BRCA1/2 carriers is an effective strategy to reduce the risk of ovarian and tubal cancers. Numerous studies have found that women with an inherited risk of breast and ovarian cancer have a decreased risk of ovarian cancer after RRSO. (Refer to the RRSO for breast cancer risk reduction section for more information on RRSO's effect on breast cancer risk.) A prospective, single-institution study of 170 women with BRCA1 or BRCA2 pathogenic variants showed the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancers. The HR was 0.32 (95% CI, 0.08–1.2) for breast cancers after bilateral salpingo-oophorectomy.[70] The HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective multicenter study of 1,079 women who were followed up for a median period of 30 to 35 months found that RRSO is highly effective in reducing ovarian cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants. This study also showed that RRSO was associated with reductions in breast cancer risk in both carriers of BRCA1 and BRCA2 pathogenic variants. However, the breast cancer 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 cancers in carriers of BRCA1/BRCA2 pathogenic variants confirmed that RRSO was associated with a significant reduction in risk of ovarian or fallopian tube cancers (HR, 0.21; 95% CI, 0.12–0.39). The study also found a significant reduction in risk of breast cancer (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).[50] Subsequently, a matched case-control study of 2,854 pairs of women with a BRCA1 or BRCA2 pathogenic variant with or without breast cancer showed a greater breast cancer risk reduction with surgical menopause (OR, 0.52; 95% CI, 0.40–0.66) than with natural menopause (OR, 0.81; 95% CI, 0.62–1.07). This study also reported a highly significant reduction in breast cancer risk among women who had an oophorectomy after natural menopause (OR, 0.13; 95% CI, 0.02–0.54; P = .006).[71] Another study of 5,783 women with BRCA1 or BRCA2 pathogenic variants who were followed up for an average of 5.6 years reported that 68 of 186 women who developed either ovarian, fallopian, or peritoneal cancers had died. The HR for these cancers with bilateral oophorectomy was 0.20 (95% CI, 0.13–0.30; P = .001). In carriers of BRCA pathogenic variants without a history of cancer, the HR for all-cause mortality to age 70 years associated with oophorectomy was 0.23 (95% CI, 0.13–0.39; P < .001).[7]

In addition to a reduction in risk of ovarian and breast cancer, RRSO may also significantly improve OS and breast and ovarian cancer–specific survival. A prospective cohort study of 666 women with germline pathogenic variants in BRCA1 and BRCA2 found an HR for overall mortality of 0.24 (95% CI, 0.08–0.71) in women who had RRSO compared with women who did not.[72] This study provides the first evidence to suggest a survival advantage among women undergoing RRSO.

Level of evidence: 2aii

Occult cancers and premalignant lesions found during RRSO

Studies on the associations between RRSO and cancer risk reduction have begun to clarify the spectrum of occult cancers that can be discovered at the time of surgery. Primary fallopian tube cancers, primary peritoneal cancers, and occult ovarian cancers have all been reported. Several case series have reported on the prevalence of malignant findings in pathogenic variant carriers undergoing risk-reducing oophorectomies. In studies with 50 or more subjects, prevalence of malignant findings ranged from 1.2% to 11%.[70,73,74,75,76,77,78,79,80,81,82] In the Gynecologic Oncology Group (GOG)–199 study of 966 women who were at high risk of ovarian cancer, the incidence of occult cancers was highest in BRCA1 carriers (4.6%), followed by BRCA2 carriers (3.5%), and noncarriers (0.5%).[83] The odds of an occult pathological finding was also four times higher in postmenopausal women. Performing RRSOs at specialty gynecologic cancer centers may decrease risk for subsequent primary peritoneal cancers. A study from the United Kingdom found an occult cancer rate of 2.4% and a HR of 0.03 for peritoneal cancers (95% CI, 0.001–0.13) when surgery was performed at a specialty center.[84] In contrast, the HR for peritoneal cancers was 0.11 (95% CI, 0.02–0.37) when surgery was performed at a nonspecialty center.

In addition to occult cancers, premalignant lesions have also been described in fallopian tube tissue removed during RRSO. These pathological findings were consistent with the identification of germline BRCA1 and BRCA2 pathogenic variants in women affected with both fallopian tube and primary peritoneal cancers.[77,85,86,87,88,89,90] In a series of 12 women with BRCA1 pathogenic variants undergoing risk-reducing surgeries, 11 had hyperplastic or dysplastic lesions identified in the epithelium of the fallopian tubes.[91] Lesions were multifocal in several cases. One study suggested that there was a causal relationship between early/intraepithelial fallopian tube carcinomas and subsequent invasive serous carcinomas of the fallopian tubes, ovaries, or peritoneum.[92] For more information, see the Pathologies of BRCA1/2-associated ovarian, fallopian tube, and primary peritoneal cancers section.

Evidence shows that RRSO best practices include routine collection of peritoneal washings and careful adherence to comprehensive pathological evaluation of the entire adnexa with the use of serial sectioning.[79,93,94]

The peritoneum appears to remain at low risk for Müllerian-type adenocarcinoma, even after RRSO.[95] Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomies, six (1.8%) subsequently developed primary peritoneal carcinomas.[96] A follow-up period was not specified in this study. A total of 238 individuals in the Creighton Registry with BRCA1/BRCA2 pathogenic variants underwent risk-reducing oophorectomies.[97] Five of these individuals (2.1%) subsequently developed intra-abdominal carcinomatosis. Notably, all five of them had BRCA1 pathogenic variants. A study of 1,828 women with a BRCA1 or BRCA2 pathogenic variant found that they had a 4.3% risk of developing primary peritoneal cancer 20 years after undergoing RRSO.[98]

Outcomes of occult lesions after RRSO

There are limited data regarding outcomes of BRCA1 and BRCA2 carriers with occult lesions found during RRSO. In a multi-institution study of 32 women with invasive carcinomas (n = 15) or serous tubal intraepithelial carcinomas (STIC) (n = 17), 47% of women with invasive cancer had a recurrence at a median time of 32.5 months after RRSO, with an OS rate of 73%.[99] A subsequent single-institution study of 26 occult, invasive ovarian carcinomas found that 31% of patients had stage I disease after surgical staging.[100] None of these patients had recurrent disease after a median follow-up period of 67.3 months.

Another study confirmed the malignant potential of STIC lesions. While 3 of 243 women (1.2%) with benign pathology found during RRSO subsequently developed primary peritoneal carcinomas, 2 of 9 women (22%) with STIC lesions developed high-grade, serous pelvic carcinomas after a median follow-up time of 63 months.[101] Of the women with intraepithelial lesions, one patient (approximately 6%) had a recurrence after 43 months, suggesting that these two entities have different disease processes. The largest series of STIC lesions was collected in a meta-analysis of 17 RRSO studies that included individual data on 115 patients. This study found that the HR for developing peritoneal carcinomas was 33.9 (95% CI, 15.6–73.9).[95] The 5- and 10-year risks of peritoneal carcinoma after developing a STIC lesion were 10.5% and 27.5%, respectively. The 5- and 10-year risks of peritoneal carcinoma when participants did not have a STIC lesion were 0.3% and 0.9%, respectively.

Timing of RRSO

Given current ovarian cancer screening limitations and the high risk of disease associated with BRCA1 and BRCA2 pathogenic variants, NCCN guidelines recommend RRSO as an effective risk-reducing option. Ovarian cancer onset typically occurs 8 to 10 years later in patients with a BRCA2 pathogenic variant than in patients with a BRCA1 pathogenic variant. Hence, NCCN states that it is reasonable to postpone RRSO until age 40 to 45 years in most patients with a BRCA2 pathogenic variant. However, RRSO may be performed at a younger age if individuals with a BRCA2 pathogenic variant have a family member who had ovarian cancer at a young age.[102] Optimal timing for RRSO is individualized, but evaluating a woman's risk of ovarian cancer based on pathogenic variant status can be helpful in the decision-making process. In a large study of American BRCA1 and BRCA2 families, age-specific cumulative risk of ovarian cancer at age 40 years was 4.7% for BRCA1 carriers and 1.9% for BRCA2 carriers.[103] In a combined analysis of 22 studies of BRCA1 and BRCA2 carriers, risk of ovarian cancer for BRCA1 carriers increased the most from the ages of 40 to 50 years. The risk of ovarian cancer for BRCA2 carriers increased sharply from the ages of 50 to 60 years.[104] A Markov model studying a hypothetical cohort of patients with BRCA1/BRCA2 pathogenic variants found that the optimal strategy for improving survival was to proceed with RRSO as early as possible.[105] However, this mathematical model did not consider patient decision making. In this model, the ovarian cancer cluster region may be associated with lower life expectancy estimates when compared with the breast cancer cluster regions or the noncluster regions. However, this did not significantly change life expectancy outcomes unless RRSO was significantly delayed. In summary, women with BRCA1 pathogenic variants may want to consider RRSO for ovarian cancer risk reduction at an earlier age than women with BRCA2 pathogenic variants.

Concomitant hysterectomy at time of RRSO

The role of concomitant hysterectomy at the time of RRSO in BRCA1/BRCA2 carriers is controversial. Some reports have suggested an increased incidence of uterine carcinoma in BRCA1/BRCA2 carriers,[106] whereas others have not confirmed an elevated risk of serous uterine cancer.[107] A prospective study of 857 women suggested that an increased incidence of uterine cancer occurred in BRCA1 carriers who used tamoxifen.[108] The same research group confirmed this finding in a later study of 4,456 BRCA1/BRCA2 carriers.[109] Even with tamoxifen use, the excess risk of endometrial cancer was small, with a 10-year cumulative risk of 2%.[109] In addition, the use of tamoxifen can now be minimized, given the options of raloxifene (which does not increase the risk of uterine cancer) and aromatase inhibitors for breast cancer prevention in postmenopausal women. Concomitant hysterectomy can simplify the hormone replacement regimen for BRCA1/BRCA2 carriers who take hormones. After hysterectomy, women can take estrogen alone (which does not increase the risk of breast cancer), without progestins, eliminating the risk of endometrial pathology. For more information, see the HRT in Carriers of BRCA1/2 Pathogenic Variants section.

Studies have shown that removing the uterus is not necessary to reduce cancer risk. BRCA1/BRCA2 pathogenic variant prevalence was not increased in 200 Ashkenazi Jewish women with endometrial carcinomas or in 56 unselected women with uterine papillary serous carcinomas.[107,110] The cumulative risk of endometrial cancer in BRCA1/BRCA2 carriers with ER-positive breast cancer (all treated with tamoxifen) may be one factor to consider when counseling this population about risk-reducing hysterectomy.[108,111] Hysterectomy may also be considered in young, unaffected BRCA1/BRCA2 carriers who may desire HRT but for whom hysterectomy would offer a simplified hormone regimen (i.e., given estrogen only). In addition, aggregate data suggest that risk from residual fallopian tube tissue after RRSO is the least compelling reason to suggest hysterectomy.

Morbidity, mortality, and quality of life (QOL) considerations after RRSO

For more information, see the Psychosocial outcomes associated with RRSO section in Genetics of Breast and Gynecologic Cancers.

For women who are premenopausal at the time of RRSO, the symptoms of surgical menopause (e.g., hot flashes, mood swings, weight gain, and genitourinary complaints) can cause a significant impairment in their QOL. To reduce the impact of these symptoms, providers often prescribe a time-limited course of systemic HRT after surgery. In one longitudinal cohort, 61% of patients (mean age, 42 y) reported using HRT after having RRSO.[112] Factors associated with the use of HRT included young age at surgery, a high level of education, and RRM. For more information, see the HRT in Carriers of BRCA1/2 Pathogenic Variants section.

Studies have examined the effect of RRSO on QOL. One study examined 846 high-risk women, of whom 44% underwent RRSO and 56% participated in periodic screening.[113] Of the 368 BRCA1/BRCA2 carriers, 72% underwent RRSO. No significant differences were observed in QOL scores (as assessed by the Short Form-36) between those who underwent RRSO, those who underwent screening, or those in the general population. However, women who underwent RRSO had fewer breast and ovarian cancer worries (P < .001) and more favorable cancer risk perception (P < .05). These individuals also had more endocrine symptoms (P < .001) and decreased sexual functioning (P < .05). Of note, 37% of women used HRT after RRSO, although 62% were either perimenopausal or postmenopausal.[113] Researchers then examined 450 premenopausal high-risk women who had chosen either RRSO (36%) or screening (64%). Forty-seven percent of individuals in the RRSO group used HRT. HRT users (n = 77) had fewer vasomotor symptoms than nonusers (n = 87; P < .05), but they had more vasomotor symptoms than women in the screening group (n = 286). Likewise, women who underwent RRSO and used HRT had more sexual discomfort due to vaginal dryness and dyspareunia than those in the screening group (P < .01). While such symptoms improved with HRT use, HRT was not completely effective. Additional research is warranted to address these important issues.

The long-term nononcologic effects of RRSO in BRCA1/BRCA2 carriers are unknown. In the general population, RRSO has been associated with increased risks of cardiovascular disease, dementia, death from lung cancer, and overall mortality.[114,115,116,117,118] When age at oophorectomy was analyzed, the most detrimental effects were seen in women who underwent RRSO before age 45 years and did not take estrogen replacement therapy.[114] In addition, BRCA1/BRCA2 carriers who undergo RRSO may have increased risk of metabolic syndrome.[119] RRSO has also been associated with an improvement in short-term mortality in this population.[72] The benefits related to cancer risk reduction after RRSO are clear, but further data are needed on the long-term nononcologic risks and benefits.

Chemopreventive agents for reducing ovarian cancer risk

Oral contraceptives (OCs) have been shown to have a protective effect against ovarian cancer in the general population.[120] Several studies, including a large, multicenter, case-control study, showed a protective effect,[121,122,123,124,125] while one population-based study from Israel failed to demonstrate a protective effect.[126]

There has been great interest in determining whether a similar benefit extends to women who are at increased genetic risk of ovarian cancer. A multicenter study of 799 ovarian cancer patients with BRCA1 or BRCA2 pathogenic variants, and 2,424 control patients without ovarian cancer but with a BRCA1 or BRCA2 pathogenic variant, showed a significant reduction in ovarian cancer risk with use of OCs (OR, 0.56; 95% CI, 0.45–0.71). Compared with never-use of OCs, duration up to 1 year was associated with an OR of 0.67 (95% CI, 0.50–0.89). The OR for each year of OC use was 0.95 (95% CI, 0.92–0.97), with a maximum observed protection at 3 years to 5 years of use.[125] This study included women from a prior study by the same authors and confirmed the results of that prior study.[121] A population-based case-control study of ovarian cancer did not find a protective benefit of OC use in carriers of BRCA1 or BRCA2 pathogenic variants (OR, 1.07 for ≥5 years of use), although they were protective, as expected, among noncarriers (OR, 0.53 for ≥5 years of use).[126] A small, population-based, case-control study of 36 carriers of BRCA1 pathogenic variants, however, observed a similar protective effect in both carriers of pathogenic variants and noncarriers (OR, approximately 0.5).[124] A larger case-control study of women with pathogenic variants in BRCA1 demonstrated maximum benefit after 5 years of OC use, while women with pathogenic variants in BRCA2 seemed to reach maximum benefit after 3 years of OC use.[127] A multicenter study of subjects drawn from numerous registries observed a protective effect of OCs among the 147 carriers of BRCA1 or BRCA2 pathogenic variants, with ovarian cancer compared with the 304 matched carriers of pathogenic variants without cancer (OR, 0.62 for ≥6 years of use).[123] Finally, a meta-analysis of 18 studies that included 13,627 carriers of BRCA pathogenic variants, 2,855 of whom had breast cancer and 1,503 of whom had ovarian cancer, reported a significantly reduced risk of ovarian cancer (summary RR, 0.50; 95% CI, 0.33–0.75) associated with OC use. The authors also reported significantly higher risk reductions with longer duration of OC use (36% reduction in risk for each additional 10 years of OC use). There was no association with breast cancer risk and use of OC pills formulated after 1975.[128]

Level of evidence: 3aii

Risk-reducing bilateral salpingectomy

Risk-reducing bilateral salpingectomy with delayed oophorectomy has been suggested as an interim procedure to reduce risk in BRCA1/BRCA2 carriers.[129,130] There are no data available on the efficacy of salpingectomy as a risk-reducing procedure. The procedure preserves ovarian function and spares the premenopausal patient the adverse effects of a premature menopause. The procedure can be performed using a minimally invasive approach, and a subsequent bilateral oophorectomy could be deferred until the patient approaches menopause. While the data make a compelling argument that some pelvic serous cancers in carriers of BRCA pathogenic variants originate in the fallopian tube, some cancers clearly arise in the ovary. Furthermore, bilateral salpingectomy could give patients a false sense of security that they have eliminated their cancer risk as completely as if they had undergone a bilateral salpingo-oophorectomy. A small study of 14 young carriers of BRCA pathogenic variants documented the procedure as feasible.[131] However, efficacy and impact on ovarian function was not assessed in this study. Future prospective trials are needed to establish the validity of the procedure as a risk-reducing intervention.

In a statistical Markov model using Monte Carlo simulation, risk-reducing salpingectomy with delayed oophorectomy was a cost-effective strategy considering quality-adjusted life expectancy for women with pathogenic variants in BRCA1/BRCA2.[132] Another study modeling ovarian cancer risk and effects of RRSO and salpingectomy found that the difference in estimated ovarian cancer risk is small when salpingectomy is performed on women of childbearing age and oophorectomy is performed 5 to 10 years later.[133]

Prospective studies are under way evaluating the impact of bilateral salpingectomy with delayed oophorectomy on patient satisfaction and the reduction in ovarian cancer.[134] A prospective, nonrandomized, controlled trial from the Netherlands compared quality of life (QOL) in women who underwent salpingectomy versus those who underwent standard RRSO. After 1 year of follow-up, women whose ovaries were retained had better QOL, even when compared with women who took estrogen after RRSO.[135]

Level of evidence: 4b

Screening and surveillance

Effective ovarian cancer screening is particularly important for women carrying pathogenic variants in BRCA1, BRCA2, and mismatch repair genes (e.g., MLH1, MSH2, MSH6, PMS2) because these pathogenic variants increase ovarian cancer risk.

While this is an active area of research with a number of promising new biomarkers in early development, at present, none of these biomarkers alone or in combination have been sufficiently well studied to justify their routine clinical use for screening purposes, either in the general population or in women at increased genetic risk.

Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancers Screening for information on screening in the general population.

Clinical examination

In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early-stage ovarian cancer. No data exist regarding the benefit of clinical examination of the ovaries (bimanual pelvic examination) in women at inherited risk of ovarian cancer.

Level of evidence: Insufficient evidence

Transvaginal ultrasound (TVUS)

The first prospective study of TVUS and cancer antigen–125 (CA-125) with survival as the primary outcome was completed in 2009. Of the 3,532 high-risk women screened, 981 were carriers of BRCA pathogenic variants, 49 of whom developed ovarian cancer. The 5- and 10-year survival rates were 58.6% (95% CI, 50.9%–66.3%) and 36% (95% CI, 27%–45%), respectively, and there were no differences in survival rates between carriers and noncarriers. A major limitation of the study was the absence of a control group. Despite limitations, this study suggests that annual surveillance by TVUS and CA-125 level appears to be ineffective in detecting tumors at an early stage to substantially influence survival.[136]

In the United Kingdom Familial Ovarian Cancer Screening Study, 3,563 women with an estimated 10% or higher lifetime risk of ovarian cancer were screened with annual ultrasound and serum CA-125 measurements for a mean of 3.2 years. Four of 13 screen-detected cancers were stage I or II. Women screened within the previous year were less likely to have higher than stage IIIC disease; there was also a trend towards better rates of optimal cytoreduction and improved OS. Furthermore, most of the cancers occurred in women with known ovarian cancer susceptibility genes, identifying a cohort at highest cancer risk for consideration of screening.[137] Phase II of this study increased the frequency of screening to every 4 months; the impact of this is not yet available.

Level of evidence: 4

Serum CA-125

A novel modification of CA-125 screening is based on the hypothesis that rising CA-125 levels over time may provide better ovarian cancer screening performance characteristics than simply classifying CA-125 as normal or abnormal based on an arbitrary cut-off value. This has been implemented in the form of the risk of ovarian cancer algorithm (ROCA), an investigational statistical model that incorporates serial CA-125 test results and other covariates into a computation that produces an estimate of the likelihood that ovarian cancer is present in the screened subject. The first report of this strategy, based on reanalysis of 5,550 average-risk women from the Stockholm Ovarian Cancer screening trial, suggested that ovarian cancer cases and controls could be distinguished with 99.7% sensitivity, 83% specificity, and a PPV of 16%. That PPV represents an eightfold increase over the 2% PPV reported with a single measure of CA-125.[138] This report was followed by applying the ROCA to 33,621 serial CA-125 values obtained from the 9,233 average-risk postmenopausal women in a prospective British ovarian cancer screening trial.[139] The area under the receiver operator curve increased from 84% to 93% (P = .01) for ROCA compared with a fixed CA-125 cutoff. These observations represented the first evidence that preclinical detection of ovarian cancer might be improved using this screening strategy. A prospective study of 13,000 healthy volunteers aged 50 years and older in England used serial CA-125 values and the ROCA to stratify participants into low, intermediate, and elevated risk subgroups.[140] Each had its own prescribed management strategy, including TVUS and repeat CA-125 either annually (low risk) or at 3 months (intermediate risk). Using this protocol, ROCA was found to have a specificity of 99.8% and a PPV of 19%.

Two prospective trials in England used the ROCA. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) randomly assigned normal-risk women to either (1) no screening, (2) annual ultrasound, or (3) multimodal screening (N = 202,638; accrual completed; follow-up ended in 2014), and the U.K. Familial Ovarian Cancer Screening Study (UKFOCSS) targeted high-risk women (accrual completed). There are also two high-risk cohorts using the ROCA under evaluation in the United States: the Cancer Genetics Network ROCA Study (N = 2,500; follow-up complete; analysis under way) and the Gynecologic Oncology Group Protocol 199 (GOG-0199; enrollment complete; follow-up ended in 2011).[141] Thus, additional data regarding the utility of this currently investigational screening strategy will become available.

Level of evidence: 4

HRT in Carriers ofBRCA1/2Pathogenic Variants

The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 pathogenic variant has been examined in two studies. In a prospective study of 462 carriers of BRCA1 and BRCA2 pathogenic variants, bilateral RRSO (n = 155) was significantly associated with breast cancer risk-reduction overall (HR, 0.40; 95% CI, 0.18–0.92). When carriers of pathogenic variants without bilateral RRSO or HRT were used as the comparison group, HRT use (n = 93) did not significantly alter the reduction in breast cancer risk associated with bilateral RRSO (HR, 0.37; 95% CI, 0.14–0.96).[142] In a matched case-control study of 472 postmenopausal women with BRCA1 pathogenic variants, HRT use was associated with an overall reduction in breast cancer risk (OR, 0.58; 95% CI, 0.35–0.96; P = .03). A nonsignificant reduction in risk was observed both in women who had undergone bilateral oophorectomy and in those who had not. Women taking estrogen alone had an OR of 0.51 (95% CI, 0.27–0.98; P = .04), while the association with estrogen and progesterone was not statistically significant (OR, 0.66; 95% CI, 0.34–1.27; P = .21).[143] A case-control study of 432 matched pairs of postmenopausal women with a BRCA1 pathogenic variant who had a personal history of cancer were compared with unaffected BRCA1 carriers. The use of HRT was not associated with an increased risk of developing breast cancer (OR, 0.80; P = .24).[144] Especially given the differences in estimated risks associated with HRT between observational studies and the Women's Health Initiative (WHI), these findings should be confirmed in randomized prospective studies,[145] but they suggest that HRT in carriers of BRCA1/BRCA2 pathogenic variants neither increases breast cancer risk nor negates the protective effect of oophorectomy.

Level of evidence: 3aii

Male Breast Cancer Screening and Surveillance forBRCA1/2Carriers

Male breast cancer patients have historically presented with advanced-stage disease, which was thought to occur due to a lack of screening. While data on breast cancer screening (via mammogram) in men with inherited risk is limited, recent studies have suggested that the detection rate for male breast cancer is similar to or better than detection rates for breast cancer in women at population risk.[146,147,148] Specifically, 41 breast cancers were diagnosed in 1,869 men (median age, 55 y; range, 18–96 y) who underwent 2,052 mammograms at a single institution.[146] Participants included 165 men who underwent screening mammograms due to the following: (1) personal or family histories of breast cancer, or (2) genetic predispositions to breast cancer. In these individuals, five node-negative cancers were detected, yielding a cancer detection rate of 18 cancers per 1,000 examinations. In comparison, 36 cancers were diagnosed on 1,781 diagnostic exams performed on symptomatic men with a cancer detection rate of 20 cancers per 1,000 examinations. In 24 of these 36 cases the researchers had records about the cancer diagnoses (i.e., tumor type, tumor size, status of lymph nodes, etc.). These 24 cases had tumors that measured an average of 2.1 cm, and most of the tumors had nodal metastases. Mammography sensitivity, mammography specificity, and PPV of breast biopsies were 100%, 95%, and 50%, respectively. In another cohort, 806 screening mammograms were conducted in 163 asymptomatic males at increased risk for breast cancer based on personal and/or family histories of breast cancer or genetic predispositions.[147] The breast cancer detection rate was reported as 4.9 cancers per 1,000 examinations, which is similar to the cancer detection rate for screening mammography in women (5.4 cancers per 1,000 examinations). Collectively, these studies suggest that screening mammography may help detect breast cancer in males with increased breast cancer risk. Of note, gynecomastia is not a risk factor for male breast cancer, and screening based on the presence of gynecomastia is not recommended.[149]

NCCN guidelines recommend that men with a BRCA pathogenic variant learn how to perform BSEs at age 35 years.[16] CBEs are also recommended every 12 months, beginning at age 35 years. NCCN guidelines recommend that annual mammogram screenings be considered in male BRCA1/2 carriers, especially in BRCA2 carriers. Screening is recommended to begin at age 50 years or 10 years prior to the youngest known male breast cancer in the family (whichever comes first).

Prostate Cancer Screening and Surveillance forBRCA1/2Carriers

For more information, see the Screening in carriers of BRCA pathogenic variants section in Genetics of Prostate Cancer.

Management Guidelines forBRCA1/2Carriers

Table 3 lists several organizations that have published recommendations for cancer risk assessment and genetic counseling, genetic testing, and/or management for hereditary breast and ovarian cancers.

Table 3. Available Clinical Practice Guidelines for Hereditary Breast and Ovarian Cancer (HBOC)
Organization Referral Recommendations Risk Assessment and Genetic Counseling Recommendations Genetic Testing Recommendations Management Recommendations
ACMG/NSGC = American College of Medical Genetics and Genomics/National Society of Genetic Counselors; ACOG = American College of Obstetricians and Gynecologists; ASCO = American Society of Clinical Oncology; ESMO = European Society for Medical Oncology; NAPBC = National Accreditation Program for Breast Centers; NCCN = National Comprehensive Cancer Network; NSGC = National Society of Genetic Counselors; SGO = Society of Gynecologic Oncology; USPSTF = U.S. Preventive Services Task Force.
a The USPSTF guidelines apply to individuals without a prior cancer diagnosis.
ACMG/NSGC (2015 and 2019)[150,151] Addressed Risk Assessment: Addressed Not addressed Not addressed
Genetic Counseling: Addressed
ACOG (2017)[152] Addressed Risk Assessment: Addressed Addressed Addressed
Genetic Counseling: Addressed
ASCO (2015)[153] Not addressed Risk Assessment: General recommendations; not specific to HBOC General recommendations; not specific to HBOC Not addressed
Genetic Counseling: Addressed
ESMO (2023)[154] Refers to other published guidelines Risk Assessment: Refers to other published guidelines Addressed Addressed
Genetic Counseling: Addressed
NSGC (2021)[155] Addressed Risk Assessment: Addressed Addressed Refers to other published guidelines
Genetic Counseling: Addressed
NCCN (2024)[16] Addressed Risk Assessment: Addressed Addressed Addressed
Genetic Counseling: Addressed
SGO (2015, 2017)[152,156] Addressed Risk Assessment: Addressed Addressed Addressed
Genetic Counseling: Addressed
USPSTFa(2019)[157] Addressed Risk Assessment: Addressed Addressed in general terms and other guidelines referenced Addressed in general terms and other guidelines referenced
Genetic Counseling: Addressed

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Cancer Treatment for BRCA1 / 2 Carriers

Breast Cancer Treatment Strategies

Unique clinical and molecular features ofBRCA1/2-associated breast cancers

BRCA1-associated breast cancers are more likely to be subtyped as triple negative (TNBC), (e.g., lacking hormone receptors [HRs] or human epidermal growth factor receptor 2 [HER2] receptors). BRCA2-associated breast cancers are more likely to be HR-positive, although TNBCs are overrepresented when compared with sporadic breast cancers.[1,2,3]

In translational studies of primary breast cancers, genes with the highest frequencies of somatic alterations in BRCA1/2-mutated breast cancers include TP53 and PIK3CA.[4] Microsatellite instability appears to be mutually exclusive to these cancers.[5]

Biomarkers relevant in cancer care, such as measures of homologous recombination deficiency (HRD) or tumor mutational burden, appear to be consistent across trajectory of BRCA1/2-associated breast cancers, although datasets are currently limited.[6]

Systemic therapy forBRCA1/2-related breast cancer

Chemotherapy

BRCA1/2-related breast cancers are currently treated with standard chemotherapy agents. Newer agents, such as lurbinectedin, are under investigation.[7]

An active question is the use of platinum chemotherapy for TNBCs in both the neoadjuvant and metastatic settings.

Multiple studies in the early-stage breast cancer setting have not shown a clear benefit of cisplatin for germline BRCA1/2 carriers.

  • Fifty subjects with BRCA1/2 pathogenic variants participated in the GeparSixto trial. Adding platinum-based chemotherapy did not improve the pathological complete response (PCR) rate for these patients (interaction test: odds ratio [OR], 0.68; 95% confidence interval [CI], 0.17–2.68; P = .58).[8]
  • The BrighTNess trial matched subjects with germline BRCA1/2 pathogenic variants and early-stage TNBCs in a 1:2 ratio to controls with breast cancer and no BRCA1/2 variants to assess the benefit of platinum chemotherapy with a poly (ADP-ribose) polymerase (PARP) inhibitor (veliparib). PCR rates for BRCA1/2 carriers did not improve with carboplatin (OR, 0.24; 95% CI, 0.04–1.24; P = .09) or with a combination of carboplatin and veliparib (OR, 0.44; 95% CI, 0.10–1.84; P = .26).[9]
  • A retrospective, real-world analysis of the Epidemiological Strategy and Medical Economics (ESME) cohort found that first-line, platinum-based chemotherapy was associated with better survival metrics when used prior to PARP inhibitors in 300 patients with germline BRCA1/2 variants.[10]
  • One meta-analysis reported a difference in PCR rates among germline BRCA carriers in trials using cisplatin monotherapy and in trials using cisplatin combination therapies.[11]

In the metastatic breast cancer setting, the Triple Negative Breast Cancer Trial (TNT trial) compared carboplatin with docetaxel in 43 subjects with BRCA1/2 germline pathogenic variants. These patients had greater responses to carboplatin than to docetaxel (objective response rate [ORR], 68% in 17 of 25 carboplatin-treated subjects vs. 33.3% in 6 of 18 docetaxel-treated subjects; absolute difference, 34.7%; P = .03). The progression-free survival (PFS) was 6.8 months in participants who received carboplatin and 4.4 months in participants who received docetaxel (interaction test: P = .002). Overall survival (OS) values did not differ between the two groups.[12]

While the efficacy of platinum therapy is under investigation in this patient population, patients with BRCA1/2-associated breast cancers are more likely to receive platinum therapy from oncologists, per Surveillance, Epidemiology, and End Results (SEER) Program data.[13]

Chemotherapeutic toxicities are not known to be increased in BRCA1/2 carriers.[14] A real-world analysis of 543 BRCA1/2 carriers with breast cancer from the United States, Europe, and Israel found that nausea and neutropenia rates were similar in those who received platinum and nonplatinum-based chemotherapies.[15] However, rates of anemia increased in patients who received nonplatinum-based chemotherapy (nonplatinum-based chemotherapy, 38%; platinum-based chemotherapy, 20%).

Level of evidence: 1

Targeted therapy: PARP inhibitors for breast cancer

PARP inhibitors have demonstrated an OS benefit for patients with BRCA-related breast cancers in the adjuvant setting and a PFS benefit (but not OS) in the metastatic setting.[16]

Olaparib is approved by the U.S. Food and Drug Administration (FDA) for the adjuvant treatment of patients with high-risk TNBCs/HR-positive breast cancers and a germline BRCA1/2 pathogenic variant. This approval is based on the OlympiA trial: a randomized, placebo-controlled, phase III study of 1,836 patients with high-risk TNBCs/HR-positive breast cancers who completed neoadjuvant/adjuvant chemotherapy, surgery, and radiation therapies.[17] The primary end point of the trial was invasive disease-free survival (IDFS) after 3 years. IDFS occurred in 87.5% of participants in the olaparib group and 80.4% of participants in the placebo group (hazard ratio [HR] for distant disease or death, 0.57; 99.5% CI, 0.39–0.83; P < .001). In 2022, the OlympiA trial reported an OS benefit as well (HR, 0.68; 98.5% CI, 0.47–0.97; P = .009), with 4-year survival rates of 89.8% in the olaparib group and 86.4% in the placebo group.[18]

The FDA approved olaparib and talazoparib for the treatment of BRCA1/2-associated metastatic breast cancer. These approvals were granted based on the OlympiAD and EMBRACA trials:

  • OlympiAD (2017): Randomized phase III study of olaparib 302 patients with metastatic breast cancer. The control arm received the physician's choice of chemotherapy (capecitabine, vinorelbine, or eribulin).[19] The primary end point of the trial was PFS, which was improved in patients who received olaparib (HR for disease progression or death, 0.58; 95% CI, 0.43–0.80; P < .001). In the 2019 follow-up study, the trial reported no significant differences in OS (HR, 0.90; 95% CI, 0.66–1.23; P = .513), although survival results were better in patients who did not receive chemotherapy.[20]
  • EMBRACA (2017): Randomized phase III study of talazoparib in 431 patients with metastatic breast cancer. The control arm received the physician's choice of chemotherapy (capecitabine, eribulin, vinorelbine, or gemcitabine).[21] The primary endpoint of the trial was PFS, which improved in patients who received talazoparib (HR for disease progression or death, 0.54; 95% CI, 0.41–0.71; P < .001). In the 2020 follow-up study, the trial also reported no significant differences in OS (HR, 0.848; 95% CI, 0.67–1.073; P = .17).[22]

Veliparib demonstrated promising early results in this patient population in the phase III BROCADE3 study.[23,24] Pamiparib was also evaluated in a phase II study and showed initial promising results.[25] The BRAVO phase III study of niraparib was terminated due to informative censoring in the control arm.[26]

Numerous clinical trials involving patients with both early and metastatic breast cancers are studying the use of PARP inhibitors in combination with other DNA damage repair agents, immunotherapies, and other targeted therapies to improve responses, as well as to broaden the patient population who may benefit.[27]

An active question is the risk of myelodysplastic syndrome (MDS)/acute leukemia associated with PARP inhibitor therapy. In a safety meta-analysis of randomized controlled trials using PARP inhibitor therapy (including the OlympiAD and EMBRACA trials), 5% of the treatment-related MDS/leukemia cases occurred in patients with breast cancer.[28] These results will likely evolve with further follow-up and more studies.

For more information about PARP inhibitor use in BRCA carriers with ovarian cancer, see the Systemic therapy with PARP inhibitors for ovarian cancer section.

Level of evidence: 1

Other targeted therapy

BRCA1/2-associated breast cancers are currently treated with standard targeted therapy agents.

Early studies suggest that patients who have germline BRCA1- and BRCA2-associated breast cancers may not respond as well to first-line cyclin-dependent kinase (CDK) 4/6 inhibitors that are given to individuals with metastatic breast cancers.[29] However, this remains an active area of research.

Immunotherapy

BRCA1/2-associated breast cancers are currently treated with immunotherapy, in accordance with the standard of care. However, it is unknown how best to integrate existing FDA approvals for immunotherapy in patients with TNBC who take PARP inhibitors and have germline BRCA1/2-associated breast cancers.[30]

Several small combination trials have been conducted in individuals with breast cancer. Although some patients respond to a combination of a PARP inhibitor and immunotherapy, conclusions regarding benefit are limited by nonrandomized designs and different PARP inhibitors/immunotherapy agents.[31,32,33]

The use of immunotherapy in patients with BRCA1/2 pathogenic variants and in combination with PARP inhibitors remains a major area of active research.[34]

Level of evidence: 2

Breast conservation and radiation therapy inBRCA1/2carriers

While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early-stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is more complicated. Initial concerns about the potential for therapeutic radiation to induce tumors or cause excess toxicity in carriers of BRCA1/BRCA2 pathogenic variants were unfounded.[35,36,37,38] Despite this, an increased rate of second primary breast cancer exists, which could impact treatment decisions.

Because of the established increased risk of second primary breast cancers, which may be up to 60% in younger women with BRCA1 pathogenic variants,[39]BRCA1/BRCA2 carriers frequently choose bilateral mastectomy at the time of their initial cancer diagnosis. For more information about genetic testing after a breast cancer diagnosis and uptake of risk-reducing mastectomy (RRM), see the Psychosocial Issues in Hereditary Breast and Gynecologic Cancers section in Genetics of Breast and Gynecologic Cancers. However, several studies support the use of breast conservation therapy as a reasonable option to treat the primary tumor.[40,41,42] The risk of ipsilateral recurrence at 10 years has been estimated to be between 10% to 15% and is similar to that seen in noncarriers.[39,40,41,42,43] Studies with longer periods of follow-up demonstrate risks of ipsilateral breast events at 15 years to be as high as 24%, largely resulting from ipsilateral second breast cancers (rather than relapse of the primary tumor).[40,42,44] In a study of 1,947 consecutive Chinese women treated with breast conservation for primary breast cancer (103 with pathogenic variants in BRCA1/BRCA2 and 1,844 noncarriers), the rate of ipsilateral breast tumor development (new primary or recurrent disease) was 3.9% in pathogenic variant carriers and 2% in noncarriers (P = .16). In these cases, however, the new primary rate was significantly higher in those with a pathogenic variant compared with noncarriers (3.9% vs. 0.6%, respectively; P < .01).[44] Although not entirely consistent across studies, radiation therapy, chemotherapy, oophorectomy, and tamoxifen are associated with a decreased risk of ipsilateral events,[40,41,42,43] as is the case in sporadic breast cancer. The risk of contralateral breast cancer (CBC) does not appear to differ in women undergoing breast conservation therapy versus unilateral mastectomy, suggesting no added risk of CBC from scattered radiation.[40] This finding is supported by a population-based case-control study of women diagnosed with breast cancer before the age of 55 years.[45] All women were genotyped for BRCA1/BRCA2. Although there was a significant fourfold risk of CBC in carriers compared with noncarriers, carriers who were exposed to radiation therapy for the first primary were not at increased risk of CBC compared with carriers who were not exposed. (Refer to the Mammography section for more information about radiation and breast cancer risk.) Finally, no difference in OS at 15 years has been seen between carriers of BRCA1/BRCA2 pathogenic variants choosing breast conservation therapy and carriers choosing mastectomy.[40]

Level of evidence: 3a

Ovarian Cancer Treatment Strategies

The molecular mechanisms that explain the improved prognosis in hereditary BRCA-associated ovarian cancers are unknown but may be related to the function of BRCA genes. BRCA genes play an important role in cell-cycle checkpoint activation and in the repair of damaged DNA via homologous recombination.[46,47] In addition to BRCA, other genes maintain homologous recombination, such as ATM, BARD1, PALB2, BRIP1, RAD51, BLM, CHEK2, and NBN. Comprehensive genetic testing of larger numbers of ovarian cancers has shown that approximately 50% of serous ovarian tumors may have somatic variants or germline variants leading to a defective homologous recombination.[48]

Deficiencies in homologous repair can impair the cells' ability to repair DNA cross-links that result from certain chemotherapy agents, such as cisplatin. Preclinical data has demonstrated BRCA1 impacts chemosensitivity in breast cancer and ovarian cancer cell lines. Reduced BRCA1 protein expression has been shown to enhance cisplatin chemosensitivity.[49] Patients with BRCA-associated ovarian cancer have shown improved responses to both first-line and subsequent platinum-based chemotherapy compared with patients with sporadic cancers, which may contribute to their better outcome.[50,51] Women with ovarian cancer whose tumors have HRD, resulting from either germline variants or somatic variants, have improved survival compared with women with an intact homologous recombination. Most homologous recombination repair gene variants consist of somatic variants or germline variants in BRCA1 and BRCA2, with one-third contributed by variants in other homologous repair genes.[52,53]

PARP pathway inhibitors have been studied for the treatment of BRCA1- or BRCA2-deficient ovarian cancers. (Refer to the Systemic therapy with PARP inhibitors for ovarian cancer section for more information about PARP inhibitors.) While PARP is involved in the repair of single-stranded breaks by base excision repair, BRCA1 and BRCA2 are active in the repair of double-stranded DNA breaks by homologous recombination. Therefore, it was hypothesized that inhibiting base excision repair with PARP inhibition in BRCA1- or BRCA2-deficient tumors leads to enhanced cell death, as two separate repair mechanisms would be compromised—the concept of synthetic lethality. The same concept may apply to tumors with HRD, and consequently, PARP inhibitors may have expanded use in women whose tumors have any homologous recombination defects beyond pathogenic variants in BRCA genes. In clinical practice, there are different tumor assays available to determine HRD tumors, which vary by method and definition. More study of PARP inhibitors in HRD ovarian cancers is ongoing.

Systemic therapy with PARP inhibitors for ovarian cancer

Olaparib

Studies have used PARP inhibitors in ovarian cancer after platinum-based chemotherapy. A phase I study of olaparib, an oral PARP inhibitor, demonstrated tolerability and activity in carriers of BRCA1 and BRCA2 pathogenic variants with ovarian, breast, and prostate cancers.[54] A phase II trial of two different doses of olaparib demonstrated tolerability and efficacy in patients with recurrent ovarian cancer and BRCA1 or BRCA2 pathogenic variants.[55] The overall response rate was 33% (11 of 33 patients) in the cohort receiving 400 mg twice daily and 13% (3 of 24 patients) in the cohort receiving 100 mg twice daily (i.e., 16 capsules daily). The most frequent side effects were mild nausea and fatigue.[56] In addition to patients with germline BRCA1 or BRCA2 pathogenic variants, PARP inhibitors also may be useful in patients with ovarian cancer and somatic BRCA1 or BRCA2 mutations or with epigenetic silencing of the genes.[57]

Several phase II treatment studies have explored the efficacy of olaparib in patients with recurrent ovarian cancer, in both platinum-sensitive and platinum-resistant disease. Olaparib at 400 mg twice daily was used in a single-arm study to treat a spectrum of 298 BRCA-associated cancers, including breast, pancreas, prostate, and ovarian. Of the 193 women with ovarian cancer treated with olaparib, 31% had a response, and 40.4% had stable disease that persisted for at least 8 weeks.[58] Among the 154 women previously treated with at least three lines of chemotherapy, a similar overall response rate of 30% was seen, with comparable median durations of response of 8.2 months for platinum-sensitive disease and 8.0 months for platinum-resistant disease.[59] Another study of 173 patients with platinum-sensitive disease were treated with paclitaxel/carboplatin plus olaparib versus paclitaxel/carboplatin alone. The PFS was significantly longer in the olaparib group than the control group (12.2 vs. 9.6 months) (HR, 0.51; 95% CI, 0.34–0.77), especially in the subgroup of patients with BRCA pathogenic variants (HR, 0.21; 95% CI, 0.08–0.55). There were no differences in OS between the olaparib and control groups.[60]

In contrast, other studies found that BRCA status did not predict survival advantage in women with platinum-sensitive ovarian cancer treated with olaparib. A randomized open-label trial assigned 90 women with recurrent platinum-sensitive ovarian cancer to either olaparib or cediranib and olaparib. Median PFS was significantly longer with the combination (17.7 mo vs. 9 mo) (HR, 0.42; 95% CI, 0.23–0.76). Subset analysis showed that combination cediranib and olaparib resulted in significantly longer PFS in the 43 BRCA wild-type/unknown patients than did single agent olaparib (16.5 mo vs. 5.7 mo) (HR, 0.32; P = .008) and a smaller trend toward increased PFS in 47 women with BRCA pathogenic variants (19.4 mo vs. 16.5 mo) (HR, 0.55; P = .16).[61]

In another study, women with BRCA1/BRCA2 pathogenic variants and recurrent ovarian cancer within 12 months of a prior platinum-based regimen were randomly assigned to receive doxorubicin hydrochloride liposome (Doxil) (n = 33) versus olaparib at 200 mg twice daily (n = 32) versus olaparib at 400 mg twice daily (n = 32). This study did not show a difference in PFS between the groups, which was the primary endpoint.[62] Of interest, the doxorubicin hydrochloride liposome arm had a higher response rate than anticipated, consistent with other studies demonstrating that BRCA1/BRCA2-associated ovarian cancers may be more sensitive to this drug than sporadic ovarian cancers are.[63,64] Another study demonstrated significant responses to olaparib in patients with recurrent ovarian cancer, including patients with a BRCA1/BRCA2 pathogenic variant (ORR, 41%) and patients without a BRCA1/BRCA2 pathogenic variant (ORR, 24%).[65] This study emphasizes that certain sporadic ovarian cancers, particularly those of high-grade serous histology, may have properties similar to tumors related to a BRCA1/BRCA2 pathogenic variant.

As maintenance treatment, olaparib has shown significantly improved PFS in platinum-sensitive recurrent ovarian cancer. In a randomized controlled study of 265 patients (Study 19), those who received olaparib had a PFS of 8.4 months compared with 4.8 months in those who received the placebo (HR, 0.35; 95% CI, 0.25–0.49).[66] Within the cohort, the 136 patients with BRCA pathogenic variants demonstrated the most benefit with olaparib compared with placebo, with a PFS of 11.2 versus 4.3 months (HR, 0.18; 95% CI, 0.1–0.31).[67] There was no OS difference observed in the entire cohort, or in the carriers of BRCA pathogenic variants. A subsequent post hoc exploratory analysis excluded patients with BRCA pathogenic variants who received a PARP inhibitor at the time of progression to minimize the confounding influence on OS. In this group of 97 patients, an improved OS HR of 0.52 (95% CI, 0.28–0.97) was associated with olaparib, compared with placebo.[68] The more mature Study 19 data, after more than 5 years of follow-up, showed a trend towards OS benefit but did not meet the a priori significance threshold of P < .0001 with olaparib compared with placebo in the entire cohort (29.8 mo vs. 27.8 mo; HR, 0.73; 95% CI, 0.55–0.96), or among BRCA pathogenic variant carriers treated with olaparib (24.5 mo vs. 26.6 mo; HR, 0.62; 95% CI, 0.41–0.94).[69] Olaparib tablets have been shown to be effective maintenance therapy, compared with placebo, in a similar population of women with recurrent, platinum-sensitive ovarian cancer and BRCA pathogenic variants (SOLO2 trial). Olaparib resulted in a median PFS of 19.1 months versus 5.5 months for placebo (HR, 0.30; 95% CI, 0.22–0.41). Olaparib tablets offer the advantage of a reduced daily pill burden (two tablets twice daily) compared with 16 capsules daily.[70]

Olaparib has demonstrated significant benefit as maintenance treatment in women with newly diagnosed advanced-stage, BRCA-associated ovarian cancer following response to primary treatment. The SOLO-1 trial randomly assigned 391 women with BRCA pathogenic variants to receive either olaparib 300 mg twice daily (n = 260) or placebo (n = 131) for 2 years after their primary surgeries and platinum-based chemotherapy. After a median follow-up of 41 months, women receiving olaparib had a 70% lower risk of disease progression or death compared with women receiving placebo with an estimated improved PFS of approximately 3 years.[71] Within 3 years, disease progression or death occurred in 102 of 260 women (39%) in the olaparib group and 96 of 131 women (73%) in the placebo group. There was a durable survival benefit for up to 5 years of follow-up.[72] Side effects resulted in a dose reduction in 28% of patients and dose interruptions in more than half of patients. Fatigue and nausea were common side effects and reasons for dose reductions.

Rucaparib

Rucaparib is a small molecule inhibitor of PARP-1, -2, and -3 and was approved in the United States for the treatment of advanced germline BRCA1/BRCA2-associated ovarian cancer in December 2016. A phase II study found that continuous dosing provided better response rates than intermittent dosing in women with pathogenic BRCA-associated breast and ovarian cancer.[73] A subsequent phase I/II dose-finding study selected a dose of 600 mg twice daily on the basis of manageable toxicity and a response rate of 59.5% in 42 women with recurrent, germline BRCA-associated, high-grade serous cancer who had received between two and four prior treatment regimens. Common grade 3 toxicities included fatigue, nausea, and anemia.[74]

The ARIEL-2 phase II study found that rucaparib was effective in the treatment of recurrent, high-grade, platinum-sensitive ovarian cancer in women with BRCA variants, but also in BRCA wild-type women with high genomic loss of heterozygosity (LOH), which is a likely marker of HRD cancers. The study enrolled 206 women, of whom 40 had germline pathogenic variants or somatic variants in BRCA. An additional 82 were BRCA wild-type but had high LOH. Median PFS was significantly longer in the BRCA variant subgroup (12.8 mo) (HR, 0.27; 95% CI, 0.16–44), and the high LOH subgroup (5.8 mo) (HR, 0.62; 95% CI, 0.42–0.90), compared with the low LOH subgroup (5.2 mo). The authors concluded that both BRCA variant status and LOH score, as a surrogate for HRD, were molecular predictors of rucaparib sensitivity in women with recurrent, platinum-sensitive, high-grade ovarian cancer.[75]

A phase III trial assessed rucaparib versus placebo in 576 women with recurrent, platinum-sensitive, high-grade ovarian cancer after response to second line, or greater, platinum chemotherapy. The study found that 196 women had BRCA pathogenic variants: 130 germline variants and 56 somatic variants. Median PFS of women in the rucaparib group was 10.8 versus 5.4 months (HR, 0.35; 95% CI, 0.30–0.45). Median PFS was the most prolonged in BRCA-associated ovarian cancer: 16.6 months in the rucaparib group versus 5.4 months in the placebo group (HR, 0.23; 95% CI, 0.16–0.34). In women with HRD cancers, the median PFS was 13.6 versus 5.4 months (HR, 0.32; 95% CI, 0.24–0.42). On the basis of these data, the authors concluded that platinum sensitivity alone was a sufficient marker to predict benefit from rucaparib in women with advanced high-grade ovarian cancer, without requiring additional HRD or BRCA testing.[76]

Niraparib

Niraparib is a selective inhibitor of PARP-1 and -2. A phase I dose-finding study observed a response rate of 42% with 300 mg daily in women with recurrent, BRCA-associated solid tumors.[77] In a cohort of 500 patients with platinum-sensitive, recurrent ovarian cancer, 234 received niraparib maintenance treatment and 116 received placebo (NOVA trial).[78] Niraparib maintenance resulted in improved PFS in BRCA pathogenic variant carriers (at 21 mo) and in wild-type patients with HRD positivity (at 12 mo) compared with wild-type patients without HRD tumor positivity (at 9 mo). Consistent with prior data, patients with germline BRCA pathogenic variants had the longest PFS of the three groups. Based upon the broad activity of niraparib maintenance in heavily pretreated women with ovarian cancer, regardless of platinum response or variant status, the QUADRA phase II trial studied the antitumor activity of niraparib in 463 women with recurrent, measurable ovarian cancer. Women had received a median of four prior lines of treatment. Twenty-eight percent of women had an overall response with a median duration of 9 months, which was improved in platinum sensitive, HRD-positive women.[79]

More mature data are necessary to determine whether platinum sensitivity alone is a marker of response to PARP inhibitors in women with BRCA pathogenic variants, and the optimal timing of PARP inhibitors as treatment or as maintenance therapy. HRD status may also be used to predict response to PARP treatment on the basis of a better understanding of the multiple genes involved in homologous repair pathways.

Level of evidence: 3dii

Treatment Strategies for Prostate Cancer

For more information on treating BRCA1/BRCA2 carriers diagnosed with prostate cancer, see the BRCA1 and BRCA2 and the Impact of Germline Genetics on Management and Treatment of Metastatic Prostate Cancer sections in Genetics of Prostate Cancer.

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Reproductive Considerations for BRCA1 / 2 Carriers

For more information, see the Prenatal diagnosis and preimplantation genetic testing section in Genetics of Breast and Gynecologic Cancers.

Prognosis and Outcomes for BRCA1 / 2 Carriers

Prognosis and Outcomes forBRCA1/2-Associated Female Breast Cancer

BRCA1- and BRCA2-associated breast cancers seem to have similar prognoses as sporadic breast cancers. Although BRCA1 carriers with breast cancer show slightly worse overall survival (OS) outcomes across multiple meta-analyses (for more information, see Table 4), the clinical relevance of this information is not yet clear. Future studies are needed to analyze prognosis after routine use of poly (ADP-ribose) polymerase inhibitor therapy.

Table 4. Meta-Analyses on Prognosis and Outcomes ofBRCA1/BRCA2-Associated Breast Cancers
Study Citation Total Number of Studies Total Number of Patients BRCA1/BRCA2Carrier Breakdown Follow-up Period OS Values:BRCA1Carriers OS Values:BRCA2 Carriers Other Studied Survival Values Study Caveats
BCSS = breast cancer–specific survival; CI = confidence interval; DFS = disease-free survival; DMFS = distant metastasis–free survival; EFS = event-free survival; HR = hazard ratio; OS = overall survival; PFS = progression-free survival; RFS = relapse-free survival.
Zhong et al. (Clinical Cancer Research, 2015)[1] 13 10,016 890BRCA1 carriers, 342BRCA2carriers, 8,784 noncarriers Follow-up period of 4.5 to 7.9 y BRCA1carriers had slightly worse OS values than noncarriers (HR, 1.5; 95% CI, 1.11–2.04) BRCA2carriers did not have a significant difference in OS when compared with noncarriers (HR, 0.97; 95% CI, 0.78–1.22) PFS Studies were conducted from 2000 to 2013.BRCA1 carriers did not have consistently worse OS values when taking treatment into account
Zhu et al. (Oncotarget, 2016)[2] 34 297,402 29,402BRCA1/BRCA2carriers BRCA1: 7 studies with follow-up periods of <5 y, 10 studies with follow-up periods of >5 y;BRCA2: 3 studies with follow-up periods of <5 y, 5 studies with follow-up periods of >5 y BRCA1carriers had slightly worse OS values than non-carriers (HR, 1.69; 95% CI, 1.35–2.12) BRCA2 carriers had slightly worse OS values than noncarriers (HR, 1.50; 95% CI, 1.03–2.19) BCSS, EFS Studies were conducted from 1996 to 2014
Baretta et al. (Medicine [Baltimore], 2016)[3] 60 105,220 3,588BRCA1/BRCA2 carriers Follow-up period not discussed in study BRCA1carriers had slightly worse OS values than noncarriers (HR, 1.3; 95% CI, 1.11–1.52) BRCA2 carriers did not have a significant difference in OS when compared with noncarriers (HR, 0.98; 95% CI, 0.76–1.25) BCSS, RFS, DMFS Studies were conducted from 1996 to 2013. An association was found betweenBRCA1/BRCA2carriers and decreased OS values (HR, 1.19; 95% CI, 1.04–1.35)
Liu et al. (Breast Cancer Research and Treatment, 2021)[4] 30 35,972 3,402BRCA1/BRCA2 carriers 4 studies with follow-up periods of <5 y, 8 studies with follow-up periods of >5 y BRCA1carriers had slightly worse OS values than noncarriers (HR, 1.2; 95% CI, 1.08–1.33) BRCA2 carriers did not have a significant difference in OS when compared with noncarriers (HR, 1.17; 95% CI, 0.99–1.39) DFS, BCSS, DMFS Studies were conducted from 2007 to 2017

Associations between BRCA pathogenic variants and prognosis may be specific to a breast cancer's hormone receptor (HR) subtype (i.e., HR-positive, triple negative, etc.). In a real-world study of patients with metastatic breast cancer from 2008 to 2016, BRCA variants were associated with improved progression-free survival (PFS) and OS values in triple-negative breast cancers (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.60–0.97; P = .027), but worse PFS values in HR-positive breast cancers (HR, 1.23; 95% CI, 1.03–1.46; P = .024).[5] This trend was also observed in the POSH (Prospective Outcomes in Sporadic versus Hereditary breast cancer) cohort study of 2,733 women with germline BRCA1/BRCA2 pathogenic variants and breast cancer diagnosed at age 40 years or younger.[6]

Prognosis and Outcomes forBRCA1/2-Associated Ovarian Cancer

Key points:

  • Compelling data suggest a short-term survival advantage in BRCA1/BRCA2 carriers. However, long-term outcomes are yet to be established.
  • Optimal surgery remains a cornerstone of care in this patient population. Larger studies, including the use of maintenance poly (ADP-ribose) polymerase (PARP) inhibitors with longer follow-up time, are needed.

While ovarian cancer associated with BRCA1/BRCA2 pathogenic variants is typically associated with poor prognostic factors, several studies have found an improved survival rate in these individuals. A meta-analysis, which included literature up to 2021, compared BRCA-positive and BRCA-negative patients.[7] It found that patients with BRCA1/BRCA2 pathogenic variants were younger, presented with stage III/stage IV disease more often, and typically had high-grade serous carcinomas. Surgical outcomes of complete and optimal cytoreduction were not different between carriers and noncarriers. However, patients with BRCA1/BRCA2 pathogenic variants were more sensitive to platinum-based chemotherapies than noncarriers, with BRCA2-positive patients showing more sensitivity than BRCA1-positive patients. While most literature on survival outcomes predates the era of PARP-inhibitor maintenance, the responsiveness of BRCA-positive patients to PARP-inhibitors will likely improve PFS outcomes. What is less clear is the prognosis of BRCA-associated ovarian cancer after platinum resistance occurs.

Optimal treatment for ovarian cancer includes a combination of surgery and chemotherapy. In a study of consecutive patients with ovarian cancer in which germline BRCA1/BRCA2 statuses were available, 71.8% of patients with stage III/stage IV disease underwent primary debulking surgery, with 70.4% of patients achieving complete macroscopic tumor resection (R0 resection).[8] There were no differences in disease presentation, surgical complexity, or the amount of residual tumor found in carriers and noncarriers. In this single-institution study, a multivariate analysis suggested that interval debulking surgery was associated with adverse outcomes when compared with primary debulking surgery (odds ratio [OR], 2.41; 95% CI, 1.29–3.64; P < .001).

In 2011, a significant survival advantage was seen in a case-control study among women with non-AJ BRCA1/BRCA2 pathogenic variants.[9] A study from the Netherlands also showed a better response to platinum-based primary chemotherapy in 112 BRCA1/BRCA2 carriers than in 220 sporadic ovarian cancer patients.[10] Furthermore, a pooled analysis of 26 observational studies that included 1,213 carriers of BRCA pathogenic variants and 2,666 noncarriers with epithelial ovarian cancer showed more favorable survival in carriers of pathogenic variants (BRCA1: HR, 0.73; 95% CI, 0.64–0.84; P < .001; BRCA2: HR, 0.49; 95% CI, 0.39–0.61; P < .001).[11] Thus, 5-year survival in both BRCA1 and BRCA2 carriers with epithelial ovarian cancers was better than that observed in noncarriers, with BRCA2 carriers having the best prognosis.

In contrast, several studies have not found improved OS among ovarian cancer patients with BRCA1/BRCA2 pathogenic variants. A large series of unselected Canadian and American patients were tested for BRCA1 and BRCA2 pathogenic variants.[12]BRCA1/BRCA2 carriers had better prognoses after 3 years but no difference in prognosis was seen after 10 years. A total of 4,320 women with ovarian cancer were recruited through the Georgia and California Surveillance Epidemiology and End Results (SEER) program registry.[13] This study had a median follow-up period of 41 months. The short-term mortality rates were lower in BRCA1/BRCA2 carriers than in noncarriers. After 20 years, BRCA1/BRCA2–pathogenic variant status was not predictive of long-term survival in patients with stage III/stage IV serous cancers.[14] However, residual disease found during surgery remained statistically significant for 20-year survival (HR, 2.91; 95% CI, 2.12–4.09; P < .0001).

Compelling data suggest a short-term survival advantage in BRCA1/BRCA2 carriers. However, long-term outcomes are yet to be established. Optimal surgery remains a cornerstone of care in this patient population. Larger studies, including the use of maintenance PARP inhibitors with longer follow-up time, are needed.

References:

  1. Zhong Q, Peng HL, Zhao X, et al.: Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis. Clin Cancer Res 21 (1): 211-20, 2015.
  2. Zhu Y, Wu J, Zhang C, et al.: BRCA mutations and survival in breast cancer: an updated systematic review and meta-analysis. Oncotarget 7 (43): 70113-70127, 2016.
  3. Baretta Z, Mocellin S, Goldin E, et al.: Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis. Medicine (Baltimore) 95 (40): e4975, 2016.
  4. Liu M, Xie F, Liu M, et al.: Association between BRCA mutational status and survival in patients with breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat 186 (3): 591-605, 2021.
  5. Mailliez A, D'Hondt V, Lusque A, et al.: Survival outcomes of metastatic breast cancer patients by germline BRCA1/2 status in a large multicenter real-world database. Int J Cancer 152 (5): 921-931, 2023.
  6. Copson ER, Maishman TC, Tapper WJ, et al.: Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol 19 (2): 169-180, 2018.
  7. Wang Y, Li N, Ren Y, et al.: Association of BRCA1/2 mutations with prognosis and surgical cytoreduction outcomes in ovarian cancer patients: An updated meta-analysis. J Obstet Gynaecol Res 48 (9): 2270-2284, 2022.
  8. Ataseven B, Tripon D, Schwameis R, et al.: Clinical outcome in patients with primary epithelial ovarian cancer and germline BRCA1/2-mutation - real life data. Gynecol Oncol 163 (3): 569-577, 2021.
  9. Lacour RA, Westin SN, Meyer LA, et al.: Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations. Gynecol Oncol 121 (2): 358-63, 2011.
  10. Vencken PM, Kriege M, Hoogwerf D, et al.: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22 (6): 1346-52, 2011.
  11. Bolton KL, Chenevix-Trench G, Goh C, et al.: Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307 (4): 382-90, 2012.
  12. McLaughlin JR, Rosen B, Moody J, et al.: Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2. J Natl Cancer Inst 105 (2): 141-8, 2013.
  13. Kurian AW, Abrahamse P, Bondarenko I, et al.: Association of Genetic Testing Results With Mortality Among Women With Breast Cancer or Ovarian Cancer. J Natl Cancer Inst 114 (2): 245-253, 2022.
  14. Kotsopoulos J, Zamani N, Rosen B, et al.: Impact of germline mutations in cancer-predisposing genes on long-term survival in patients with epithelial ovarian cancer. Br J Cancer 127 (5): 879-885, 2022.

Molecular Biology of BRCA1 / 2

While not homologous genes, both BRCA1 and BRCA2 have an unusually large exon 11 and translational start sites in exon 2. BRCA1 and BRCA2 appear to behave like tumor suppressor genes. In tumors associated with both BRCA1 and BRCA2 pathogenic variants, there is often loss of the wild-type allele.

Discovery and Historical Overview

In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21.[1] The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed.[2] The BRCA1 gene was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids.

A second breast cancer susceptibility gene, BRCA2, was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to BRCA1. BRCA2 is a large gene with 27 exons that encode a protein of 3,418 amino acids.[3]

BRCA1/2Function

Most BRCA1 and BRCA2 pathogenic variants are predicted to produce a truncated protein product, and thus loss of protein function, although some missense pathogenic variants cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, individuals with a BRCA1 or BRCA2 pathogenic variant on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from carriers of pathogenic variants, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitination, chromatin remodeling, and cell cycle control.[4,5]

References:

  1. Hall JM, Lee MK, Newman B, et al.: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250 (4988): 1684-9, 1990.
  2. Narod SA, Feunteun J, Lynch HT, et al.: Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 338 (8759): 82-3, 1991.
  3. Tonin P, Weber B, Offit K, et al.: Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 2 (11): 1179-83, 1996.
  4. Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108 (2): 171-82, 2002.
  5. Narod SA, Foulkes WD: BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4 (9): 665-76, 2004.

Latest Updates to This Summary (03 / 08 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Genetics

Added text to state that BRCA1/BRCA2-associated cancer risks are inherited in an autosomal dominant manner.

Added Related Conditions as a new subsection.

Management of Cancer Risks in BRCA1/2 Carriers

Added level of evidence 2aii.

Added Occult cancers and premalignant lesions found during risk-reducing salpingo-oophorectomy (RRSO) as a new subsection.

Added Outcomes of occult lesions after RRSO as a new subsection.

Added Timing of RRSO as a new subsection.

Added Concomitant hysterectomy at time of RRSO as a new subsection.

Added Morbidity, mortality, and quality of life considerations after RRSO as a new subsection.

The Risk-reducing bilateral salpingectomy subsection was renamed from Bilateral salpingectomy.

Added text to state that a prospective, nonrandomized, controlled trial from the Netherlands compared quality of life in women who underwent salpingectomy versus those who underwent standard RRSO. After 1 year of follow-up, women whose ovaries were retained had better quality of life, even when compared with women who took estrogen after RRSO (cited Steenbeek et al. as reference 135).

Added level of evidence 4b.

Updated Table 3, Available Clinical Practice Guidelines for Hereditary Breast and Ovarian Cancer, with new recommendations from the European Society for Medical Oncology and the National Society of Genetic Counselors (cited Sessa et al. as reference 154 and Berliner et al. as reference 155).

Prognosis and Outcomes for BRCA1/2 Carriers

The Prognosis and Outcomes for BRCA1/2-Associated Ovarian Cancer subsection was extensively revised.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about BRCA1/BRCA2 (hereditary breast and ovarian cancer) cancer risks and management. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for BRCA1 and BRCA2 are:

  • Doreen Agnese, MD (The Ohio State University)
  • Ilana Cass, MD (Dartmouth-Hitchcock Medical Center)
  • Lee-may Chen, MD (UCSF Helen Diller Family Comprehensive Cancer Center)
  • Mary B. Daly, MD, PhD (Fox Chase Cancer Center)
  • Megan Frone, MS, CGC (National Cancer Institute)
  • Joanne Kotsopoulos, PhD (University of Toronto and Women's College Hospital)
  • Tuya Pal, MD, FACMG, FCCMG (Vanderbilt-Ingram Cancer Center)
  • Padma Sheila Rajagopal, MD, MPH, MSC (National Cancer Institute)
  • Mary Beth Terry, PhD (Columbia University Mailman School of Public Health)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Cancer Genetics Editorial Board. PDQ BRCA1 and BRCA2. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/publications/pdq/information-summaries/genetics/brca-genes-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 36881687]

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Last Revised: 2024-03-08

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