Genetics of Breast and Gynecologic Cancers (PDQ®) 4/5 —Health Professional Version - National Cancer Institute

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

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

Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancer

In This Section

• Background
• Breast and Gynecologic Cancer Susceptibility Genes Identified Through Candidate Gene Approaches
  • Fanconi anemia genes
  • CHEK2
  • ATM
  • CASP8 and TGFB1
  • RAD51
  • Abraxas
  • RECQL
  • SMARCA4

Background

Pathogenic variants in BRCA1, BRCA2, PALB2, and the genes involved in other rare syndromes discussed in the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section of this summary account for less than 25% of the familial risk of breast cancer.[1] Despite intensive genetic linkage studies, there do not appear to be other high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters.[2] However, several moderate-penetrance genes associated with breast and/or gynecologic cancers have been identified. Genes such as CHEK2 and ATM are associated with a 20% or higher lifetime risk of breast cancer;[3,4] similarly, genes such as RAD51C, RAD51D, and BRIP1 are associated with a 5% to 10% risk of ovarian cancer.[5,6] Many of these genes are now included on multigene panels, although the clinical actionability of these findings remains uncertain and under investigation.

Breast and Gynecologic Cancer Susceptibility Genes Identified Through Candidate Gene Approaches

There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several studies or are supported by robust meta-analyses. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.

Fanconi anemia genes

Fanconi anemia (FA) is a rare, inherited condition characterized by bone marrow failure, increased risk of malignancy, and physical abnormalities. To date, 16 FA-related genes, including BRCA1 and BRCA2, have been identified (as outlined in Table 10). FA is mainly an autosomal recessive condition, except when caused by pathogenic variants in FANCB, which is X-linked recessive. FANCA accounts for 60% to 70% of pathogenic variants, FANCCaccounts for approximately 14%, and the remaining genes each account for 3% or fewer.[7]

Table 10. Fanconi Anemia Genes and Breast Cancer Risk

aRefer to the BRCA1 and BRCA2 section of this summary for information about the cumulative risk of breast cancer in carriers of BRCA1 and BRCA2 pathogenic variants.

bRefer to the PALB2 section of this summary for information about the cumulative risk of breast cancer in carriers of PALB2 pathogenic variants.

cModerate risk is defined as a statistically significant, twofold or lower increased risk estimate.

High-Risk Genes

– BRCA1 (FANCS)a

– BRCA2 (FANCD1)a

– PALB2 (FANCN)b

Moderate-Risk Genes c

– BRIP1 (FANCJ/BACH1)

– FANCD2

– RAD51C (FANCO)

Genes With Uncertain or No Significantly Increased Risk

– FANCA

– FANCB

– FANCC

– FANCE

– FANCF

– FANCG (XRCC9)

– FANCI (KIAA1794)

– FANCL

– SLX4 (FANCP)

– ERCC4 (FANCQ/XPF)

Progressive bone marrow failure typically occurs in the first decade, with patients often presenting with thrombocytopenia or leucopenia. The incidence of bone marrow failure is 90% by age 40 to 50 years. The incidence is 10% to 30% for hematologic malignancies (primarily acute myeloid leukemia) and 25% to 30% for nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, gastrointestinal [GI] tract, and genital tract). Physical abnormalities, including short stature, abnormal skin pigmentation, radial ray defects (including malformation of the thumbs), abnormalities of the urinary tract, eyes, ears, heart, GI system, and central nervous system, hypogonadism, and developmental delay are present in 60% to 75% of affected individuals.[7]

Variants in some of the FA genes, most notably BRCA1 and BRCA2, but also PALB2, RAD51C(in the RAD51 family of genes), and BRIP1, among others, may predispose to breast cancer in heterozygotes. Given the widespread availability of multigene (panel) tests, genetic testing of many of the FA genes is frequently performed despite uncertain cancer risks and the lack of available evidence-based medical management recommendations for many of these genes.

FA gene pathogenic variant carrier status can have implications for reproductive decision making because pathogenic variants in these genes can lead to serious childhood onset of disease if both parents are carriers of pathogenic variants in the same gene. Partner testing may be considered.

BRIP1

BRIP1 (also known as BACH1) encodes a helicase that interacts with the BRCA1 C-terminal (BRCT) domain. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallelic pathogenic variants in BRIP1 are a cause of FA,[8-10] much like such pathogenic variants in BRCA2. Inactivating variants of BRIP1 are associated with an increased risk of breast cancer. In one study, more than 3,000 individuals from BRCA1/BRCA2 pathogenic variant–negative families were examined for BRIP1 variants. Pathogenic variants were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls (P = .003). The relative risk (RR) of breast cancer was estimated to be 2.0 (95% confidence interval [CI], 1.2–3.2; P = .012). Of note, in families with BRIP1 pathogenic variants and multiple cases of breast cancer, there was incomplete segregation of the pathogenic variant with breast cancer, consistent with a low-penetrance allele and similar to that seen with CHEK2.[11] In a case-control study of 3,236 women with ovarian cancer, BRIP1 pathogenic variants were more frequently associated with ovarian cancer risk (RR, 11.2; 95% CI, 3.2–34.1).[12]

CHEK2

CHEK2 (OMIM) is a gene involved in the DNA damage repair response pathway. Based on numerous studies, a polymorphism, 1100delC, appears to be a rare, moderate-penetrance cancer susceptibility allele.[13-18] One study identified the pathogenic variant in 1.2% of the European controls, 4.2% of the European BRCA1/BRCA2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases.[13] In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC pathogenic variant.[19] In additional European and U.S. (where the pathogenic variant appears to be slightly less common) studies, including a large prospective study,[20] the frequency of CHEK2 pathogenic variants detected in familial breast or ovarian cancer cases has ranged from 0% [21] to 11%; overall, these studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer.[20,22-25] A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among carriers of pathogenic variants.[26] A subsequent meta-analysis based on 29,154 cases and 37,064 controls from 25 case-control studies found a significant association between CHEK21100delC heterozygotes and breast cancer risk (odds ratio [OR], 2.75; 95% CI, 2.25–3.36). The ORs and CIs in unselected, familial, and early-onset breast cancer subgroups were 2.33 (1.79–3.05), 3.72 (2.61–5.31), and 2.78 (2.28–3.39), respectively. However, study limitations included pooling of populations without subgroup analysis, using a mix of population-based and hospital-based controls, and basing results on unadjusted estimates (as cases and controls were matched on only a few common factors); therefore, results should be interpreted in the context of these limitations.[27] In a series of male breast cancer patients, the CHEK2 1100delC variant was significantly more frequently identified than in controls, suggesting that this variant is also associated with an increased risk of male breast cancer.[28]

Two studies have suggested that the risk associated with a CHEK2 1100delC pathogenic variant was stronger in the families of probands ascertained because of bilateral breast cancer.[29,30] Furthermore, a meta-analysis of carriers of 1100delC pathogenic variants estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer.[31] Similarly, a Polish study reported that CHEK2 truncating pathogenic variants confer breast cancer risks based on a family history of breast cancer as follows: no family history: 20%; one second-degree relative: 28%; one first-degree relative: 34%; and both first- and second-degree relatives: 44%.[3] Moreover, a Dutch study suggested that female homozygotes for the CHEK2 1100delC variant have a greater-than-twofold increased breast cancer risk compared with heterozygotes.[32] Although there have been conflicting reports regarding cancers other than breast cancer associated with CHEK2 pathogenic variants, this may be dependent on variant type (i.e., missense vs. truncating) or population studied and is not currently of clinical utility.[18,23,33-38] The contribution of CHEK2 variants to breast cancer may depend on the population studied, with a potentially higher variant prevalence in Poland.[39] Carriers of CHEK2 variants in Poland may be more susceptible to estrogen receptor (ER)–positive breast cancer.[40]

Currently, the clinical applicability of CHEK variants remains uncertain because of low variant prevalence and lack of guidelines for clinical management.[41]

A large Dutch study of 86,975 individuals reported an increased risk of cancers other than breast and colon for carriers of the CHEK2 1100delC pathogenic variant,[42] although additional studies are needed to further refine these risks.

(Refer to the CHEK2 section in the PDQ summary on Genetics of Colorectal Cancer for more information.)

ATM

Ataxia telangiectasia (AT) (OMIM) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of ATM variants (OMIM).[43] More than 300 variants in the gene have been identified, most of which are truncating variants.[44] ATM proteins have been shown to play a role in cell cycle control.[45-47] In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[48] There is insufficient evidence to recommend against radiation therapy in carriers of a single ATM pathogenic variant (heterozygotes).

Initial studies searching for an excess of ATM pathogenic variants among breast cancer patients provided conflicting results, perhaps due to study design and variant testing strategies.[49-59] However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated RR of approximately 2.0.[4,59] A meta-analysis modeled the risk of breast cancer to be 6.02% by age 50 years and 32.83% by age 80 years.[60] Given these risks, increased screening and other recommendations based on family history and age may be considered.

CASP8 and TGFB1

The Breast Cancer Association Consortium (BCAC), an international group of investigators, investigated single nucleotide polymorphisms (SNPs) identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, CASP8 D302H and TGFB1 L10P, were associated with invasive breast cancer with RRs of 0.88 (95% CI, 0.84–0.92) and 1.08 (95% CI, 1.04–1.11), respectively.[61]

RAD51

RAD51 and the family of RAD51-related genes, also known as RAD51 paralogs, are thought to encode proteins that are involved in DNA damage repair through homologous recombination and interaction with numerous other DNA repair proteins, including BRCA1 and BRCA2. RAD51 protein plays a central role in single-strand annealing in the DNA damage response. RAD51 recruitment to break sites and recombinational DNA repair depend on the RAD51 paralogs, although their precise cellular functions are poorly characterized.[62] Variants in these genes are thought to result in loss of RAD51 focus formation in response to DNA damage.[63]

One of five RAD51-related genes, RAD51C has been reported to be linked to both FA-like disorders and familial breast and ovarian cancers. The literature, however, has produced contradictory findings. In a study of 480 German families characterized by breast and ovarian cancers who were negative for BRCA1 and BRCA2 pathogenic variants, six monoallelic variants in RAD51C were found (frequency of 1.3%).[64] Another study screened 286 BRCA1/BRCA2-negative patients with breast cancer and/or ovarian cancer and found one likely pathogenic variant in RAD51C-G153D.[65] RAD51C pathogenic variants have also been reported in Australian, British, Finnish, and Spanish non-BRCA1/BRCA2ovarian cancer–only and breast/ovarian cancer families, and in unselected ovarian cancer cases, with frequencies ranging from 0% to 3% in these populations.[5,12,66-71] In a sample of 206 high-risk Jewish women (including 79 of Ashkenazi origin) previously tested for the common Jewish pathogenic variants, two previously described and possibly pathogenic missense variants were detected.[72] Four additional studies were unable to confirm an association between the RAD51C gene and hereditary breast cancer or ovarian cancer.[73-76]

In addition to carriers of RAD51C pathogenic variants, there are other RAD51 paralogs, including RAD51B, RAD51D, and RAD51L1, that may be associated with breast and/or ovarian cancer risk,[6,12,77-80] although the clinical significance of these findings is unknown. In a case-control study of 3,429 ovarian cancer patients, RAD51C and RAD51Dpathogenic variants were more commonly found in ovarian cancer cases (0.82%) than in controls (0.11%, P < .001).[81]

In addition to germline variants, different polymorphisms of RAD51 have been hypothesized to have reduced capacity to repair DNA defects, resulting in increased susceptibility to familial breast cancer. The Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) pooled data from 8,512 carriers of BRCA1 and BRCA2 pathogenic variants and found evidence of an increased risk of breast cancer among women who were BRCA2 carriers and who were homozygous for CC at the RAD51 135G→C SNP (hazard ratio, 1.17; 95% CI, 0.91–1.51).[82]

Several meta-analyses have investigated the association between the RAD51 135G→C polymorphism and breast cancer risk. There is significant overlap in the studies reported in these meta-analyses, significant variability in the characteristics of the populations included, and significant methodologic limitations to their findings.[83-86] A meta-analysis of nine epidemiologic studies involving 13,241 cases and 13,203 controls of unknown BRCA1/BRCA2 status found that women carrying the CC genotype had an increased risk of breast cancer compared with women with the GG or GC genotype (OR, 1.35; 95% CI, 1.04–1.74). A meta-analysis of 14 case-control studies involving 12,183 cases and 10,183 controls confirmed an increased risk only for women who were known BRCA2 carriers (OR, 4.92; 95% CI, 1.10–21.83).[87] Another meta-analysis of 12 studies included only studies of known BRCA-negative cases and found no association between RAD51 135G→C and breast cancer.[88]

In summary, among this conflicting data is substantial evidence for a modest association between germline variants in RAD51C and breast cancer and ovarian cancer. There is also evidence of an association between polymorphisms in RAD51 135G→C among women with homozygous CC genotypes and breast cancer, particularly among BRCA2 carriers. These associations are plausible given the known role of RAD51 in the maintenance of genomic stability.

Abraxas

Pathogenic variants in the BRCA1-interacting gene Abraxas were found in three Finnish breast cancer families and no controls.[89] The significance of this finding outside of this population is not yet known.

RECQL

Through full exome sequencing among high-risk Polish and Quebec-based French Canadian families, the RECQL gene was discovered to harbor multiple rare truncating variants in both populations.[90] (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for more information about whole-exome sequencing.) In the same populations, truncating variants in this gene were also identified in two subsequent validation phases among additional breast cancer patients from high-risk families, and among additional breast cancer cases in which the variant frequency was higher than that observed among controls. A case-control study from Belarus and Germany looked at the most common pathogenic variant, c.1667_1667+3delA GTA, and found it to be linked to ER-positive breast cancer. The OR in this study alone was 1.23 (95% CI, 0.44–3.47; P = .69), but in a meta-analysis with a Polish study, the OR was 2.51 (95% CI, 1.13–5.57, P = .02).[91] Although study results suggest that truncating germline RECQLpathogenic variants are associated with an increased risk of breast cancer, the exact magnitude of risk remains uncertain, and future studies are needed to determine clinical usefulness. Furthermore, the significance of this finding outside of these two populations is not yet known.

SMARCA4

SMARCA4 encodes BRG1 and is a catalytic subunit of the SWI/SNF chromatin remodeling complex, which plays a major role in rendering chromatin accessible to regulation of gene expression.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive tumor that has an early age at onset (before age 40 y) and a poor prognosis.[92-94] Familial clustering is sometimes present. SCCOHT tumors may be unilateral or bilateral and have been characterized histologically by the presence of small hyperchromatic cells with brisk mitotic activity.[93] A multimodality approach including surgery, chemotherapy, and radiation therapy has been suggested for the treatment of SCCOHT.[93,94] Given the paraneoplastic phenomenon of hypercalcemia in 60% of cases, tracking calcium levels is useful in monitoring the course of disease. With a wide range of differential diagnoses including germ cell tumors, sex cord–stromal tumors, and undifferentiated carcinomas, SCCOHT remains classified by the World Health Organization as a "miscellaneous tumor" but more recently has been sequenced to be a malignant rhabdoid tumor.[95] Through exome sequencing, most cases of SCCOHT have been found to lack functional SMARCA4/BRG1; in fact, pathogenic variants in SMARCA4 may be the sole variants responsible for SCCOHT.

Despite only approximately 300 cases in the literature, three separate research groups showed SCCOHT to be associated with germline and somatic pathogenic variants in the SMARCA4 gene. In one study of 12 young women with SCCOHT, sequencing of paired tumor and normal samples identified inactivating biallelic SMARCA4 pathogenic variants in each case.[96] Only four additional nonrecurrent somatic genes were identified in any of the other 278 genes sequenced. Immunohistochemistry demonstrated loss of SMARCA4 protein expression in seven of nine tested cases, consistent with a tumor-suppressor genefunction. In a second study of another 12 patients, next-generation sequencing also identified SMARCA4 as the only recurrently variant gene, with the majority of variants predicted to result in a truncated protein.[97] A third study included three families in whom whole-exome sequencing with Sanger sequencing confirmation identified at least one germline or somatic pathogenic variant in 24 of 26 cases.[98] Overall, 38 of 43 (88%) of SCCOHT tumors showed loss of SMARCA4 expression, in comparison to only 1 of 139 (0.7%) other ovarian tumor types.

Because of the rarity of this tumor, the penetrance of SMARCA4 is unknown. There is currently no consensus for management, yet SMARCA4 is on the larger multigene panels currently available for genetic testing, and risk-reducing surgery has been offered to pathogenic variant carriers.[99]

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48. Gilad S, Chessa L, Khosravi R, et al.: Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 62 (3): 551-61, 1998. [PUBMED Abstract]
49. FitzGerald MG, Bean JM, Hegde SR, et al.: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 15 (3): 307-10, 1997. [PUBMED Abstract]
50. Chen J, Birkholtz GG, Lindblom P, et al.: The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 58 (7): 1376-9, 1998. [PUBMED Abstract]
51. Bay JO, Grancho M, Pernin D, et al.: No evidence for constitutional ATM mutation in breast/gastric cancer families. Int J Oncol 12 (6): 1385-90, 1998. [PUBMED Abstract]
52. Laake K, Vu P, Andersen TI, et al.: Screening breast cancer patients for Norwegian ATM mutations. Br J Cancer 83 (12): 1650-3, 2000. [PUBMED Abstract]
53. Dörk T, Bendix R, Bremer M, et al.: Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61 (20): 7608-15, 2001. [PUBMED Abstract]
54. Teraoka SN, Malone KE, Doody DR, et al.: Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 92 (3): 479-87, 2001. [PUBMED Abstract]
55. Chenevix-Trench G, Spurdle AB, Gatei M, et al.: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94 (3): 205-15, 2002. [PUBMED Abstract]
56. Thorstenson YR, Roxas A, Kroiss R, et al.: Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63 (12): 3325-33, 2003. [PUBMED Abstract]
57. Cavaciuti E, Laugé A, Janin N, et al.: Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families. Genes Chromosomes Cancer 42 (1): 1-9, 2005. [PUBMED Abstract]
58. Olsen JH, Hahnemann JM, Børresen-Dale AL, et al.: Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br J Cancer 93 (2): 260-5, 2005. [PUBMED Abstract]
59. Renwick A, Thompson D, Seal S, et al.: ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38 (8): 873-5, 2006. [PUBMED Abstract]
60. Marabelli M, Cheng SC, Parmigiani G: Penetrance of ATM Gene Mutations in Breast Cancer: A Meta-Analysis of Different Measures of Risk. Genet Epidemiol 40 (5): 425-31, 2016. [PUBMED Abstract]
61. Cox Angela, Dunning Alison, Garcia-Closas Montserrat, et al.: Nature genetics. Nat Genet 39 (5): 352-8, 2007.
62. Suwaki N, Klare K, Tarsounas M: RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. Semin Cell Dev Biol 22 (8): 898-905, 2011. [PUBMED Abstract]
63. Vaz F, Hanenberg H, Schuster B, et al.: Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42 (5): 406-9, 2010. [PUBMED Abstract]
64. Meindl A, Hellebrand H, Wiek C, et al.: Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42 (5): 410-4, 2010. [PUBMED Abstract]
65. Clague J, Wilhoite G, Adamson A, et al.: RAD51C germline mutations in breast and ovarian cancer cases from high-risk families. PLoS One 6 (9): e25632, 2011. [PUBMED Abstract]
66. Thompson ER, Boyle SE, Johnson J, et al.: Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat 33 (1): 95-9, 2012. [PUBMED Abstract]
67. Vuorela M, Pylkäs K, Hartikainen JM, et al.: Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility. Breast Cancer Res Treat 130 (3): 1003-10, 2011. [PUBMED Abstract]
68. Romero A, Pérez-Segura P, Tosar A, et al.: A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families. Breast Cancer Res Treat 129 (3): 939-46, 2011. [PUBMED Abstract]
69. Osorio A, Endt D, Fernández F, et al.: Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Hum Mol Genet 21 (13): 2889-98, 2012. [PUBMED Abstract]
70. Blanco A, Gutiérrez-Enríquez S, Santamariña M, et al.: RAD51C germline mutations found in Spanish site-specific breast cancer and breast-ovarian cancer families. Breast Cancer Res Treat 147 (1): 133-43, 2014. [PUBMED Abstract]
71. Norquist BM, Harrell MI, Brady MF, et al.: Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2 (4): 482-90, 2016. [PUBMED Abstract]
72. Kushnir A, Laitman Y, Shimon SP, et al.: Germline mutations in RAD51C in Jewish high cancer risk families. Breast Cancer Res Treat 136 (3): 869-74, 2012. [PUBMED Abstract]
73. Wong MW, Nordfors C, Mossman D, et al.: BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. Breast Cancer Res Treat 127 (3): 853-9, 2011. [PUBMED Abstract]
74. Zheng Y, Zhang J, Hope K, et al.: Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast Cancer Res Treat 124 (3): 857-61, 2010. [PUBMED Abstract]
75. Akbari MR, Tonin P, Foulkes WD, et al.: RAD51C germline mutations in breast and ovarian cancer patients. Breast Cancer Res 12 (4): 404, 2010. [PUBMED Abstract]
76. De Leeneer K, Van Bockstal M, De Brouwer S, et al.: Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing. Breast Cancer Res Treat 133 (1): 393-8, 2012. [PUBMED Abstract]
77. Thomas G, Jacobs KB, Kraft P, et al.: A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41 (5): 579-84, 2009. [PUBMED Abstract]
78. Figueroa JD, Garcia-Closas M, Humphreys M, et al.: Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20 (23): 4693-706, 2011. [PUBMED Abstract]
79. Osher DJ, De Leeneer K, Michils G, et al.: Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families. Br J Cancer 106 (8): 1460-3, 2012. [PUBMED Abstract]
80. Pelttari LM, Kiiski J, Nurminen R, et al.: A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer. J Med Genet 49 (7): 429-32, 2012. [PUBMED Abstract]
81. Song H, Dicks E, Ramus SJ, et al.: Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J Clin Oncol 33 (26): 2901-7, 2015. [PUBMED Abstract]
82. Antoniou AC, Sinilnikova OM, Simard J, et al.: RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet 81 (6): 1186-200, 2007. [PUBMED Abstract]
83. He XF, Su J, Zhang Y, et al.: Need for clarification of data in the recent meta-analysis about RAD51 135G>C polymorphism and breast cancer risk. Breast Cancer Res Treat 129 (2): 649-51; author reply 652-3, 2011. [PUBMED Abstract]
84. Lu W, Wang X, Lin H, et al.: Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer 11 (3): 381-5, 2012. [PUBMED Abstract]
85. Wang WW, Spurdle AB, Kolachana P, et al.: A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10 (9): 955-60, 2001. [PUBMED Abstract]
86. Wang Z, Dong H, Fu Y, et al.: RAD51 135G>C polymorphism contributes to breast cancer susceptibility: a meta-analysis involving 26,444 subjects. Breast Cancer Res Treat 124 (3): 765-9, 2010. [PUBMED Abstract]
87. Zhou GW, Hu J, Peng XD, et al.: RAD51 135G>C polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 125 (2): 529-35, 2011. [PUBMED Abstract]
88. Yu KD, Yang C, Fan L, et al.: RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers: evidence from a meta-analysis of 12 studies. Breast Cancer Res Treat 126 (2): 365-71, 2011. [PUBMED Abstract]
89. Solyom S, Aressy B, Pylkäs K, et al.: Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions. Sci Transl Med 4 (122): 122ra23, 2012. [PUBMED Abstract]
90. Cybulski C, Carrot-Zhang J, Kluźniak W, et al.: Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet 47 (6): 643-6, 2015. [PUBMED Abstract]
91. Bogdanova N, Pfeifer K, Schürmann P, et al.: Analysis of a RECQL splicing mutation, c.1667_1667+3delAGTA, in breast cancer patients and controls from Central Europe. Fam Cancer 16 (2): 181-186, 2017. [PUBMED Abstract]
92. Dickersin GR, Kline IW, Scully RE: Small cell carcinoma of the ovary with hypercalcemia: a report of eleven cases. Cancer 49 (1): 188-97, 1982. [PUBMED Abstract]
93. Harrison ML, Hoskins P, du Bois A, et al.: Small cell of the ovary, hypercalcemic type -- analysis of combined experience and recommendation for management. A GCIG study. Gynecol Oncol 100 (2): 233-8, 2006. [PUBMED Abstract]
94. Callegaro-Filho D, Gershenson DM, Nick AM, et al.: Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT): A review of 47 cases. Gynecol Oncol 140 (1): 53-7, 2016. [PUBMED Abstract]
95. Foulkes WD, Clarke BA, Hasselblatt M, et al.: No small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. J Pathol 233 (3): 209-14, 2014. [PUBMED Abstract]
96. Jelinic P, Mueller JJ, Olvera N, et al.: Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet 46 (5): 424-6, 2014. [PUBMED Abstract]
97. Ramos P, Karnezis AN, Craig DW, et al.: Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet 46 (5): 427-9, 2014. [PUBMED Abstract]
98. Witkowski L, Carrot-Zhang J, Albrecht S, et al.: Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet 46 (5): 438-43, 2014. [PUBMED Abstract]
99. Berchuck A, Witkowski L, Hasselblatt M, et al.: Prophylactic oophorectomy for hereditary small cell carcinoma of the ovary, hypercalcemic type. Gynecol Oncol Rep 12: 20-2, 2015. [PUBMED Abstract]

Low-Penetrance Genes and Loci

In This Section

• Genome-Wide Searches

Polymorphisms underlying polygenic susceptibility to breast and gynecologic cancers are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to high-penetrance variants or alleles that are typically associated with more severe phenotypes, for example BRCA1/BRCA2 pathogenic variants leading to an autosomal dominant inheritance pattern in a family, and moderate-penetrance variants such as BRIP1, CHEK2, and RAD51C. (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes and the Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancer sections of this summary for more information.) Because these types of sequence variants (also called low-penetrance genes, alleles, variants, and polymorphisms) are relatively common in the general population, their overall contribution to cancer risk is estimated to be much greater than the attributable risk in the population from pathogenic variants in BRCA1 and BRCA2. For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible.[1] There are no known low-penetrance variants in BRCA1/BRCA2. The N372H variation in BRCA2, initially thought to be a low-penetrance allele, was not verified in a large combined analysis.[2]

Two strategies have attempted to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and then searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and, despite some confirmed associations (described below), has been relatively disappointing.[2,3] The candidate gene approach has largely been replaced by genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (approximately 1 million to 5 million) are chosen within the genome and tested, mostly without regard to their possible biological function, but instead to more uniformly capture all genetic variation throughout the genome.

Genome-Wide Searches

In contrast to assessing candidate genes and/or alleles, GWAS involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of as many as 5 million SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap and the 1000 Genomes Project.[4,5] By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained.[6-8] The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. Although this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is causal.

Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases,[9] including breast cancer.[10-13] The first study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the Breast Cancer Association Consortium.[10] Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. The 8q region and others may harbor multiple independent loci associated with risk. Subsequent genome-wide studies have replicated these loci and identified additional ones.[11,12,14,14-19] Numerous SNPs identified through large studies of sporadic breast cancer appear to be associated more strongly with estrogen receptor–positive disease;[20] however, some are associated primarily or exclusively with other subtypes, including triple-negative disease.[21,22] An online catalogExit Disclaimer is available of SNP-trait associations from published GWAS for use in investigating genomic characteristics of trait/disease-associated SNPs.

Although the statistical evidence for an association between genetic variation at these loci and breast and ovarian cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk (typically, an odds ratio [OR] <1.5), with more risk variants likely to be identified. No interaction between the SNPs and epidemiologic risk factors for breast cancer have been identified.[23,24] Furthermore, theoretical models have suggested that common moderate-risk SNPs have limited potential to improve models for individualized risk assessment.[25-27] These models used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC) as a measure of discriminatory accuracy. A subsequent study used ROC curve analysis to examine the utility of SNPs in a clinical dataset of more than 5,500 breast cancer cases and nearly 6,000 controls, using a model with traditional risk factors compared with a model using both standard risk factors and ten previously identified SNPs. The addition of genetic information modestly changed the AUC from 58% to 61.8%, a result that was not felt to be clinically significant. Despite this, 32.5% of patients were in a higher quintile of breast cancer risk when genetic information was included, and 20.4% were in a lower quintile of risk. Whether such information has clinical utility is unclear.[25,28]

More limited data are available regarding ovarian cancer risk. Three GWAS involving staged analysis of more than 10,000 cases and 13,000 controls have been carried out for ovarian cancer.[29-31] As in other GWAS, the ORs are modest, generally about 1.2 or weaker but implicate a number of genes with plausible biological ties to ovarian cancer, such as BABAM1, whose protein complexes with and may regulate BRCA1, and TIRAPR, which codes for a poly (ADP-ribose) polymerase, molecules that may be important inBRCA1/BRCA2-deficient cells.

Because the individual and collective influences of these SNPs on cancer risk have not been evaluated prospectively, they are not considered clinically relevant.

In addition to genome-wide studies interrogating common genetic variants, sequencing-based studies involving whole-genome or whole-exome sequencing [32] are also identifying genes associated with breast cancer, such as XRCC2, a rare, moderate-penetrance, breast cancer susceptibility gene.[33] (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for more information about whole-exome sequencing.)

References

1. Pharoah PD, Antoniou A, Bobrow M, et al.: Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31 (1): 33-6, 2002. [PUBMED Abstract]
2. Breast Cancer Association Consortium: Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Natl Cancer Inst 98 (19): 1382-96, 2006. [PUBMED Abstract]
3. Dunning AM, Healey CS, Pharoah PD, et al.: A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8 (10): 843-54, 1999. [PUBMED Abstract]
4. Thorisson GA, Smith AV, Krishnan L, et al.: The International HapMap Project Web site. Genome Res 15 (11): 1592-3, 2005. [PUBMED Abstract]
5. Clarke L, Zheng-Bradley X, Smith R, et al.: The 1000 Genomes Project: data management and community access. Nat Methods 9 (5): 459-62, 2012. [PUBMED Abstract]
6. Evans DM, Cardon LR: Genome-wide association: a promising start to a long race. Trends Genet 22 (7): 350-4, 2006. [PUBMED Abstract]
7. Cardon LR: Genetics. Delivering new disease genes. Science 314 (5804): 1403-5, 2006. [PUBMED Abstract]
8. Chanock SJ, Manolio T, Boehnke M, et al.: Replicating genotype-phenotype associations. Nature 447 (7145): 655-60, 2007. [PUBMED Abstract]
9. Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661-78, 2007. [PUBMED Abstract]
10. Easton DF, Pooley KA, Dunning AM, et al.: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447 (7148): 1087-93, 2007. [PUBMED Abstract]
11. Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39 (7): 865-9, 2007. [PUBMED Abstract]
12. Hunter DJ, Kraft P, Jacobs KB, et al.: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39 (7): 870-4, 2007. [PUBMED Abstract]
13. Turnbull C, Ahmed S, Morrison J, et al.: Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42 (6): 504-7, 2010. [PUBMED Abstract]
14. Gold B, Kirchhoff T, Stefanov S, et al.: Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A 105 (11): 4340-5, 2008. [PUBMED Abstract]
15. Zheng W, Long J, Gao YT, et al.: Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41 (3): 324-8, 2009. [PUBMED Abstract]
16. Kibriya MG, Jasmine F, Argos M, et al.: A pilot genome-wide association study of early-onset breast cancer. Breast Cancer Res Treat 114 (3): 463-77, 2009. [PUBMED Abstract]
17. Murabito JM, Rosenberg CL, Finger D, et al.: A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study. BMC Med Genet 8 (Suppl 1): S6, 2007. [PUBMED Abstract]
18. Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40 (6): 703-6, 2008. [PUBMED Abstract]
19. Ahmed S, Thomas G, Ghoussaini M, et al.: Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41 (5): 585-90, 2009. [PUBMED Abstract]
20. Reeves GK, Travis RC, Green J, et al.: Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci. JAMA 304 (4): 426-34, 2010. [PUBMED Abstract]
21. Haiman CA, Chen GK, Vachon CM, et al.: A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer. Nat Genet 43 (12): 1210-4, 2011. [PUBMED Abstract]
22. Stevens KN, Fredericksen Z, Vachon CM, et al.: 19p13.1 is a triple-negative-specific breast cancer susceptibility locus. Cancer Res 72 (7): 1795-803, 2012. [PUBMED Abstract]
23. Campa D, Kaaks R, Le Marchand L, et al.: Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst 103 (16): 1252-63, 2011. [PUBMED Abstract]
24. Milne RL, Gaudet MM, Spurdle AB, et al.: Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study. Breast Cancer Res 12 (6): R110, 2010. [PUBMED Abstract]
25. Pharoah PD, Antoniou AC, Easton DF, et al.: Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358 (26): 2796-803, 2008. [PUBMED Abstract]
26. Gail MH: Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk. J Natl Cancer Inst 100 (14): 1037-41, 2008. [PUBMED Abstract]
27. Gail MH: Value of adding single-nucleotide polymorphism genotypes to a breast cancer risk model. J Natl Cancer Inst 101 (13): 959-63, 2009. [PUBMED Abstract]
28. Wacholder S, Hartge P, Prentice R, et al.: Performance of common genetic variants in breast-cancer risk models. N Engl J Med 362 (11): 986-93, 2010. [PUBMED Abstract]
29. Song H, Ramus SJ, Tyrer J, et al.: A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet 41 (9): 996-1000, 2009. [PUBMED Abstract]
30. Goode EL, Chenevix-Trench G, Song H, et al.: A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 42 (10): 874-9, 2010. [PUBMED Abstract]
31. Bolton KL, Tyrer J, Song H, et al.: Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat Genet 42 (10): 880-4, 2010. [PUBMED Abstract]
32. Shendure J: Next-generation human genetics. Genome Biol 12 (9): 408, 2011. [PUBMED Abstract]
33. Park DJ, Lesueur F, Nguyen-Dumont T, et al.: Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet 90 (4): 734-9, 2012. [PUBMED Abstract]

Clinical Management of Carriers of BRCA Pathogenic Variants

In This Section

• Screening and Prevention Strategies
  • Breast cancer
  • Ovarian cancer
• Management of Male Carriers of BRCA Pathogenic Variants
• Reproductive Considerations in Carriers of BRCA Pathogenic Variants
• Treatment Strategies
  • Breast cancer
  • Ovarian cancer
• Available Clinical Practice Guidelines for Hereditary Breast and Ovarian Cancer

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

Screening and Prevention Strategies

Breast cancer

Screening/surveillance

Refer to the PDQ summary on Breast Cancer Screening for information on screening in the general population, and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information on levels of evidence related to screening and prevention.

Breast self-examination

In the general population, evidence for the value of breast self-examination (BSE) is limited. Preliminary results have been reported from a randomized study of BSE being conducted in Shanghai, China.[8] At 5 years, no reduction in breast cancer mortality was seen in the BSE group compared with the control group of women, nor was a substantive stage shift seen in breast cancers that were diagnosed. (Refer to the PDQ summary on Breast Cancer Screening for more information.)

Little direct prospective evidence exists regarding BSE in individuals with an increased risk of breast cancer. In the Canadian National Breast Screening Study, women with first-degree relatives (FDRs) with breast cancer had statistically significantly higher BSE competency scores than those without a family history. In a study of 251 high-risk women at a referral center, five breast cancers were detected by self-examination less than a year after a previous screen (as compared with one cancer detected by clinician exam and 11 cancers detected as a result of mammography). Women in the cohort were instructed in self-examination, but it is not stated whether the interval cancers were detected as a result of planned self-examination or incidental discovery of breast masses.[9] In another series of carriers of BRCA1/BRCA2 pathogenic variants, four of nine incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting the potential value of self-examination.[10] A task force convened by the Cancer Genetics Studies Consortium has recommended “monthly self-examination beginning early in adult life (e.g., by age 18–21 y) to establish a regular habit and allow familiarity with the normal characteristics of breast tissue. Education and instruction in self-examination are recommended.”[11]

Level of evidence: 5

Clinical breast examination

Few prospective data exist regarding clinical breast examination (CBE).

The Cancer Genetics Studies Consortium task force concluded, “As with self-examination, the contribution of clinical examination may be particularly important for women at inherited risk of early breast cancer.” They recommended that female carriers of a BRCA1or BRCA2 high-risk pathogenic variant undergo annual or semiannual clinical examinations beginning at age 25 to 35 years.[11]

Level of evidence: 5

Mammography

In the general population, strong evidence suggests that regular mammography screening of women aged 50 to 59 years leads to a 25% to 30% reduction in breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.) For women who begin mammographic screening at age 40 to 49 years, a 17% reduction in breast cancer mortality is seen, which occurs 15 years after the start of screening.[12] Observational data from a cohort study of more than 28,000 women suggest that the sensitivity of mammography is lower for young women. In this study, the sensitivity was lowest for younger women (aged 30–49 y) who had a FDR with breast cancer. For these women, mammography detected 69% of breast cancers diagnosed within 13 months of the first screening mammography. By contrast, sensitivity for women younger than 50 years without a family history was 88% (P = .08). For women aged 50 years and older, sensitivity was 93% at 13 months and did not vary by family history.[13] Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers.[10] Subsequent observational studies have found that the positive predictive value (PPV) of mammography increases with age and is highest among older women and among women with a family history of breast cancer.[14] Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity.[15] One study found an association between the presence of pushing margins and false-negative mammograms in 28 women, 26 of whom had a BRCA1 pathogenic variant and two of whom had a BRCA2pathogenic variant. Pushing margins, characteristic of medullary histology, are associated with an absence of fibrotic reaction.[16] In addition, rapid tumor doubling times may lead to tumors presenting shortly after an apparently normal study. In one study, mean tumor doubling time in BRCA1/BRCA2 carriers was 45 days, compared with 84 days in noncarriers.[17] Another study that evaluated mammographic breast density in women with BRCApathogenic variants found no association between pathogenic variant status and mammographic density; however, in both carriers and noncarriers, increased breast density was associated with increased breast cancer risk.[18]

The randomized Canadian National Breast Screening Study-2 compared annual CBE plus mammography to CBE alone in women aged 50 to 59 years from the general population. Both groups were given instruction in BSE.[19] Although mammography detected smaller primary invasive tumors, more invasive cancers, and more ductal carcinoma in situ (DCIS) than CBE, the breast cancer mortality rates in the CBE-plus-mammography group and the CBE-alone group were nearly identical, and compared favorably with other breast cancer screening trials. After a mean follow-up of 13 years (range, 11.3–16.0 y), the cumulative breast cancer mortality ratio was 1.02 (95% confidence interval [CI], 0.78–1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.

Digital mammography refers to the use of a digital detector to find and record x-ray images. This technology improves contrast resolution [20] and has been proposed as a potential strategy for improving the sensitivity of mammography. A screening study comparing digital with routine mammography in 6,736 examinations of women aged 40 years and older found no difference in cancer detection rates;[21] however, digital mammography resulted in fewer recalls. In another study (ACRIN-6652) comparing digital mammography to plain-film mammography in 42,760 women, the overall diagnostic accuracy of the two techniques was similar.[22] When receiver operating characteristic curves were compared, digital mammography was more accurate in women younger than 50 years, in women with radiographically dense breasts, and in premenopausal or perimenopausal women.

In a prospective study of 251 individuals with BRCA pathogenic variants who received uniform recommendations regarding screening and risk-reducing surgery, annual mammography detected breast cancer in six women at a mean of 20.2 months after receipt of BRCA results.[9] The Cancer Genetics Studies Consortium task force has recommended for female carriers of a BRCA1 or BRCA2 high-risk pathogenic variant, “annual mammography, beginning at age 25 to 35 years. Mammograms should be done at a consistent location when possible, with prior films available for comparison.”[11] Data from prospective studies on the relative benefits and risks of screening with an ionizing radiation tool versus CBE or other nonionizing radiation tools would be useful.[23-25]

Certain observations have led to the concern that carriers of BRCA pathogenic variants may be more prone to radiation-induced breast cancer than women without pathogenic variants. The BRCA1 and BRCA2 proteins are known to be important in cellular mechanisms of DNA damage repair, including those involved in repairing radiation-induced damage. Some studies have suggested intermediate radiation sensitivity in cells that are heterozygous for a BRCA variant, but this is not consistent and varies by experimental system and endpoint.

Three studies have failed to find convincing evidence of an association between ionizing radiation exposure and breast cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants.[26-28] In contrast, two large international studies found evidence of an increased breast cancer risk due to chest x-rays [29] or estimates of total exposure to diagnostic radiation.[30] A large, international, case-control study of 1,601 carriers of pathogenic variants described an increased risk of breast cancer (hazard ratio [HR], 1.54) among women who were ever exposed to chest x-rays, with risk being highest in women aged 40 years and younger, born after 1949, and exposed to x-rays only before age 20 years.[29] Some of the subjects in this study were also included in a larger, more comprehensive analysis of carriers of pathogenic variants from three European centers.[30] In that study of 1,993 carriers of BRCA1 and BRCA2 pathogenic variants from the United Kingdom, France, and the Netherlands, age-specific total diagnostic radiation exposure (e.g., chest x-rays, mammography, fluoroscopy, and computed tomography) estimates were derived from self-reported questionnaires. Women exposed before age 30 years had an increased risk (HR, 1.90; 95% CI, 1.20–3.00), compared with those never exposed. This risk was primarily driven by nonmammographic radiation exposure in women younger than 20 years (HR, 1.62; 95% CI, 1.02–2.58). Subsequently, a prospective study of 1,844 BRCA1 carriers and 502 BRCA2 carriers without a breast cancer diagnosis at study entry, with an average follow-up time of 5.3 years, observed no significant association between prior mammography exposure and breast cancer risk.[28] Additional subgroup analyses in women younger than 30 years demonstrated no association with breast cancer risk.

With the routine use of magnetic resonance imaging (MRI) in carriers of BRCA1 and BRCA2pathogenic variants, any potential benefit of mammographic screening must be carefully weighed against potential risks, particularly in young women.[31] One study has suggested that the most cost-effective screening strategy in carriers of BRCA1 and BRCA2 pathogenic variants may be annual MRI beginning at age 25 years, with alternating MRI and digital mammography (so that each test is done annually but screening occurs every 6 months) beginning at age 30 years.[32] The National Comprehensive Cancer Network (NCCN) currently recommends annual breast MRI screening with contrast (or mammogram with consideration of tomosynthesis, only if MRI is unavailable) between ages 25 and 29 years and annual mammogram (with consideration of tomosynthesis and breast MRI screening with contrast) between ages 30 and 75 years.[33]

Magnetic resonance imaging

Because of the relative insensitivity of mammography in women with an inherited risk of breast cancer, a number of screening modalities have been proposed and investigated in high-risk women, including carriers of BRCA pathogenic variants. Many studies have described the experience with breast MRI screening in women at risk of breast cancer, including descriptions of relatively large multi-institutional trials.[34-42]

Despite some limitations of these studies, they consistently demonstrate that breast MRI is more sensitive than either mammography or ultrasound for the detection of hereditary breast cancer. The results of six large studies are presented in Table 11, Summary of MRI Screening Studies in Women at Hereditary Risk of Breast Cancer.[34,36,37,40,43,44] Most cancers in these programs were screen detected, with only 6% of cancers presenting in the interval between screenings. The sensitivity of MRI (as defined by the study methodology) ranged from 71% to 100%. Of the combined studies, 77% of cancers were identified by MRI, and 42% were identified by mammography.

Concerns have been raised about the reduced specificity of MRI compared with other screening modalities. In one study, after the initial MRI screen, 16.5% of patients were recalled for further evaluation and an additional 7.6% of patients were recommended to undergo a short-interval follow-up examination at 6 months.[37] These rates declined significantly during later screening rounds, with fewer than 10% of the subjects recalled for more detailed MRI and fewer than 3% recommended to have short interval follow-up. In a second study, Magnetic Resonance Imaging for Breast Screening (MARIBS), the recall rate for additional evaluation was 10.7% per year.[36] The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round.[37] In the MARIBS study, the aggregate surgical biopsy rate was 9 per 1,000 screening episodes, though this may underestimate the burden because follow-up ultrasounds, core-needle biopsies, and fine-needle aspirations have not been included in the numerator of the MARIBS calculation.[36] The PPV of MRI has been calculated differently in the various series and fluctuates somewhat, depending on whether all abnormal examinations or only the examinations that result in a biopsy are counted in the denominator. Generally, the PPV of a recommendation for tissue sampling (as opposed to further investigation) is in the range of 50% in most series.

These trials appear to establish that MRI is superior to mammography in the detection of hereditary breast cancer, and that women participating in these trials including annual MRI screening were less likely to have a cancer missed by screening.[45] However, mammography may identify some cancers, particularly DCIS, that are not identified by MRI.[46]

Regarding downstaging, one screening study demonstrated that patients at risk of hereditary breast cancer were more likely to be diagnosed with small tumors and node-negative disease than were women in two nonrandomized control groups.[34] Despite the apparent sensitivity of MRI screening, some women in MRI-based programs will develop life-threatening breast cancer. In a prospective study of 51 carriers of BRCA1 pathogenic variants and 41 carriers of BRCA2 pathogenic variants screened with yearly mammograms and MRIs (of whom 80 had risk-reducing oophorectomy), 11 breast cancers (9 invasive and 2 DCIS) were detected. Six cancers were first detected on MRI; three were first detected by mammogram; and two were interval cancers. All breast cancers occurred in carriers of BRCA1 pathogenic variants, suggesting a continued high risk of BRCA1-related breast cancer after oophorectomy in the short term. These results suggest that surveillance and prevention strategies may have differing outcomes in carriers of BRCA1 and BRCA2pathogenic variants.[41]

A publication combining results from three large studies (MARIBS, a Canadian study, and a Dutch MRI screening study) demonstrated that when MRI was added to mammography, 80% of cancers detected in carriers of BRCA2 pathogenic variants were either DCIS or invasive cancers smaller than 1 cm. In carriers of BRCA1 pathogenic variants, 49% of cancers were DCIS or small invasive cancers. In addition, the authors predicted mortality benefits with the addition of MRI for both carriers of BRCA1 and BRCA2 pathogenic variants. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening.[47] An additional study examining carriers of BRCA1/BRCA2 pathogenic variants undergoing MRI between 1997 and 2006 has demonstrated that 97% of incident cancers were stage 0 or stage I.[48] A 2015 Dutch case-control study further evaluated 2,308 high-risk patients, including 706 women with known BRCA pathogenic variants, who were screened with mammogram and compared them with those who had the addition of MRI.[49] Of the patients screened, 93 patients were detected to have 97 cancers, 33 patients had a BRCA1 pathogenic variant, and 18 patients had a BRCA2 pathogenic variant. With a median follow-up of 9 years, metastases-free survival was improved in the MRI-screened cohort (90% vs. 77%), but it did not reach statistical significance in the BRCA1 and BRCA2 subset because of very small numbers. MRI-screened patients in the entire cohort were more likely to be node-negative and receive less chemotherapy. The American Cancer Society and NCCN have recommended the use of annual MRI screening for women at hereditary risk of breast cancer.[33,50]

An additional question regarding the timing of mammography and MRI is whether they should be done simultaneously or in an alternating fashion (so that while each test is done annually, screening occurs every 6 months). One study has suggested that the most cost-effective screening strategy in carriers of BRCA1 and BRCA2 pathogenic variants may be annual MRI beginning at age 25 years, with alternating MRI and digital mammography beginning at age 30 years.[32]

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

Table 11. Summary of Magnetic Resonance Imaging (MRI) Screening Studies in Women at Hereditary Risk of Breast Cancer

ENLARGE

Series		Rijnsburger [42]	Warner [37]	MARIBS [36]	Kuhl [40]	Weinstein [43]	Sardanelli [44]	Totals
aBased on the first 1,909 women screened.[34]
bIncludes patients with invasive cancer only and patients with both invasive and in situ cancers.
cIncludes only 75 cancers detected in women who underwent both mammographic and MRI screening.
dRestricted to studies in which ultrasound was performed.
N Patients	Overall	2,157	236	649	687	609	501	4,839
	BRCA1/BRCA2Carriers	594	236	120	65	44	330	1,389
N Screening Episodes		6,253	457	1,881	1,679		1,592	11,862
N Cancers	Baseline	22a	13	20	10	0	0	65
	Subsequent	97	9	15	17	18	52	208
	Invasiveb	78	16	29	8	11	44	186
	In situ	19	9	6	9	7	8	58
Annual Incidence		10.4/1,000		19/1,000
Detected at Planned Screening		78	21	33	27	18	49	226 (83%)
N Detected by Each Modality	Mammography	31c	8	14	9	7	25	94 (42%)
	MRI	51c	17	27	25	12	42	174 (77%)
	Ultrasoundd		7		10	3	26	46 (41%)
Follow-up		Median of 4.9 y	Minimum of 1 y	2–7 y	Median of 29.09 mo	2 y	3 y

Level of evidence: 3

Ultrasound

Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review.[51] In a pilot study of ultrasound as an adjunct to mammography in 149 women with moderately increased risk based on family history, one cancer was detected, based on ultrasound findings. Nine other biopsies of benign lesions were performed. One was based on abnormalities on both mammography and ultrasound, and the remaining eight were based on abnormalities on ultrasound alone.[51] A large study of 2,809 women with dense breast tissue (ACRIN-6666) demonstrated that ultrasound increased the detection rate due to breast cancer screening from 7.6 per 1,000 with mammography alone to 11.8 per 1,000 for combined mammography and ultrasound.[52] However, ultrasound screening increases false-positive rates and appears to have a limited benefit in combination with MRI. In a multicenter study of 171 women (92% of whom were carriers of BRCA1/BRCA2 pathogenic variants) undergoing simultaneous mammography, MRI, and ultrasound, no cancers were detected by ultrasound alone.[38] Uncertainties about ultrasound include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.

Level of evidence: None assigned

Other screening modalities

A number of other techniques are under active investigation, including tomosynthesis, contrast-enhanced mammography, thermography, and radionuclide scanning. Additional evidence is needed before these techniques can be incorporated into clinical practice.

Level of evidence: None assigned

Risk-reducing surgeries

Risk-reducing mastectomy

Risk-reducing mastectomy (RRM) is a management option for patients who are considered to be at high risk of developing breast cancer. The Society of Surgical Oncology has endorsed RRM as an option for women with BRCA1/BRCA2 pathogenic variants or strong family histories of breast cancer.[53] Historically, a total or simple mastectomy has been performed, which includes removal of all of the breast tissue, including the nipple and areolar complex (NAC). If the patient is interested, reconstruction can be performed simultaneously with the ablative portion of the procedure. Options for reconstruction include tissue expander and implant-based reconstructions or autologous reconstructions, in which the patient’s own tissue is used to reconstruct the breast. A number of different tissues can be used to reconstruct the breast, including flaps based on the latissimus dorsi muscle, the transverse rectus abdominis muscle, or the gluteus muscle. Muscle-sparing techniques such as the deep inferior epigastric perforator flap can also be used, but require advanced microvascular techniques. In the interest of improved cosmetic outcomes, skin-sparing techniques have been utilized in which the entire breast is removed with the NAC, but the entire skin envelope of the breast is preserved. In a further refinement, nipple-sparing techniques have been developed in which all of the breast skin and the nipple are preserved while the underlying glandular tissue is removed.

Risk-reducing mastectomy in unaffected women

Because there are no randomized, prospective trials of RRM versus observation, data are limited to cohort and case-control studies. The available data demonstrate that RRM does decrease breast cancer incidence in high-risk patients,[54-56] but overall survival (OS) correlates more closely with the overall risk from the primary incidence of breast cancer. Several studies have analyzed the impact of RRM on breast cancer risk and mortality. In one retrospective cohort study of 214 women considered to be at hereditary risk by virtue of a family history suggesting an autosomal dominant predisposition, three women were diagnosed with breast cancer after bilateral RRM, with a median follow-up of 14 years.[56] Because 37.4 cancers were expected, the calculated risk reduction was 92.0% (95% CI, 76.6%–98.3%). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent genetic testing for pathogenic variants in BRCA1 and BRCA2. Pathogenic variants were identified in 18 women, none of whom developed breast cancer after a median follow-up of 13.4 years.[54] Two of the three women diagnosed with breast cancer after RRM were tested, and neither carried a pathogenic variant. The calculated risk reduction among carriers of pathogenic variants was 89.5% to 100.0% (95% CI, 41.4%–100.0%), depending on the assumptions made about the expected numbers of cancers among carriers of pathogenic variants and the status of the untested woman who developed cancer despite mastectomy. The result of this retrospective cohort study has been supported by a prospective analysis of 76 carriers of pathogenic variants who underwent RRM and were monitored prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas eight were identified in women who underwent regular surveillance (HR for breast cancer after RRM, 0.00 [95% CI, 0.00–0.36]).[55]

The Prevention and Observation of Surgical Endpoints study group also estimated the degree of breast cancer risk reduction after RRM in carriers of BRCA1/BRCA2 pathogenic variants. The rate of breast cancer in 105 carriers of pathogenic variants who underwent bilateral RRM was compared with that in 378 carriers who did not choose surgery. Bilateral mastectomy reduced the risk of breast cancer by approximately 90% after a mean follow-up of 6.4 years.[3]

Theoretical models have also been utilized to assess the role of RRM in women with pathogenic variants in BRCA1 and BRCA2. Assuming risk reduction in the range of 90%, one model suggests that for a group of women, aged 30 years, with BRCA1 or BRCA2 pathogenic variants, RRM would result in an average increased life expectancy of 2.9 to 5.3 years.[57] A computer-simulated survival analysis using a Monte Carlo model included breast MRI, mammography, RRM, and risk-reducing salpingo-oophorectomy (RRSO) and examined the impact of each intervention separately on carriers of BRCA1 and BRCA2 pathogenic variants.[5] The most effective strategy was found to be RRSO at age 40 years and RRM at age 25 years, with survival at age 70 years approaching that of the general population. However, delaying mastectomy until age 40 years, or substituting RRM with screening with breast MRI and mammography, had little impact on survival estimates. For example, replacing RRM with MRI-based screening in women with RRSO at age 40 years led to a 3% to 5% decrement in survival compared with RRM at age 25 years.[58] As with any models, numerous assumptions cause uncertainty; however, these studies provide additional information for women and their providers who are making these difficult decisions.

Another study of at-risk women showed a 70% time–trade-off value for RRM, indicating that participants were willing to sacrifice 30% of life expectancy to avoid RRM.[59] A cost-effectiveness analysis study of RRM has also been performed. The investigators concluded that, compared with surveillance, risk-reducing surgery (mastectomy and oophorectomy) is cost-effective with regard to years of life saved, but not for improved quality of life.[60] While these data are interesting and may be useful for public policy decisions, they cannot be individualized for clinical care because they include assumptions that cannot be fully tested.

Level of evidence: 3ai

Contralateral risk-reducing mastectomy in affected women

If RRM is effective in lowering breast cancer risk in unaffected women, what is its role for women with unilateral breast cancer? This question often arises in discussions about surgical options with women who have unilateral breast cancer and hereditary risks. This section addresses the role of contralateral risk-reducing mastectomy (CRRM) in women being treated with mastectomy and will not discuss breast conservation therapy. Multiple studies have shown an increase in the rate of CRRM in women with unilateral breast cancer.[61,62] When the appropriateness of CRRM is being assessed for women with unilateral breast cancer, the first task is to determine the risk of contralateral breast cancer (CBC).

In the general population, current estimates of CBC risk after treatment for breast cancer are approximately 0.3% per year and are declining.[63] In carriers of BRCA pathogenic variants with a diagnosis of breast cancer, the risk of a second, unrelated breast cancer is related to age at initial diagnosis, biology, and systemic therapies used, but is clearly higher than that in the general population.[64] (Refer to the Contralateral breast cancer in carriers of BRCA pathogenic variants section in the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section of this summary for more information about the risk of CBC in this population.) In carriers of BRCA pathogenic variants whose first cancer has an excellent prognosis, estimating the risk of a second, unrelated breast cancer event is important for informing their decision to undergo risk-reducing surgery and has been described in this setting to improve survival.[65] The timing of genetic testing and knowledge of BRCA pathogenic variant status may influence surgical decision making, may prevent subsequent surgeries, and may influence follow-up care. Therefore, for individuals at increased risk of carrying a BRCA pathogenic variant, it is important that genetic testing be considered in advance of surgery, when possible.[66]

In a group of 148 carriers of BRCA1 and BRCA2 pathogenic variants with unilateral breast cancer, 79 of whom underwent CRRM, the risk of CBC was reduced by 91% and was independent of the effect of risk-reducing oophorectomy. Survival was better among women who underwent CRRM, but this result was likely associated with higher mortality caused by the index cancer or metachronous ovarian cancer in the group not undergoing surgery.[67] Data from ten European centers on 550 women (including 202 BRCA carriers) with 3,334 woman-years of follow-up indicated that RRM was highly effective. Bilateral RRMs were carried out on women with a lifetime risk of 25% to 80%, with an average expected incidence rate of 1% per year. No breast cancers occurred in this cohort over the follow-up period, though more than 34 breast cancers would have been expected.[68] A retrospective study of 593 carriers of BRCA1 and BRCA2 pathogenic variants included 105 women with unilateral breast cancer who underwent CRRM and had a 10-year survival rate of 89%, compared with 71% in the group who did not undergo contralateral risk-reducing surgery (P < .001).[4] This study was limited by several factors, such as the lack of information regarding breast cancer screening, grade, and estrogen receptor status in a large portion of this sample.

A Dutch cohort of 583 patients identified between 1980 and 2011, who had both a BRCApathogenic variant and a diagnosis of unilateral breast cancer, were evaluated for the effect of CRRM.[69] With a median follow-up of 11.4 years, 242 (42%) of the patients underwent RRM (193 carriers of BRCA1 pathogenic variants and 49 carriers of BRCA2pathogenic variants) at differing times after their diagnoses. Improved OS was observed in the RRM group compared with the surveillance group (HR, 0.49; 95% CI, 0.29–0.82), with improvements most pronounced in those diagnosed before age 40 years, with low tumor grade, and non–triple-negative subtype. In an attempt to control for the bias of time to surgery, the authors included a separate evaluation of women who were known to be disease free 2 years after the primary cancer diagnosis (HR, 0.55; 95% CI, 0.32–0.95). Additionally, the group who underwent RRM was more likely to undergo bilateral salpingo-oophorectomy and systemic chemotherapy, which may influence the significance of these survival findings.

A retrospective study of 390 women with early-stage breast cancer who were from families with a known BRCA1/BRCA2 pathogenic variant found a significant improvement in survival for women who underwent bilateral mastectomy compared with those who chose unilateral mastectomy.[65] Patients were followed for a median of 14.3 years (range, 0.1–20.0 y). A multivariate analysis controlling for age at diagnosis, year of diagnosis, treatment, and other prognostic factors found that CRRM was associated with a 48% reduction in death from breast cancer. This was a relatively small study, and although the authors adjusted for multiple factors, residual confounding factors may have influenced the results.

All of these studies are limited by the biases introduced in relatively small, retrospective studies among very select populations. There is often limited data on potential confounding variables such as socioeconomic status, comorbidities, and access to care. It has been suggested that women who elect to undergo RRM are healthier by virtue of being able to tolerate more extensive surgery. This theory is supported by one study that used Surveillance, Epidemiology, and End Results (SEER) Program data to examine the association between CRRM and outcomes among women with unilateral breast cancer stages I through III. Results showed a reduction in all-cause mortality and breast cancer–specific mortality, and also in noncancer event mortality, a finding that would not be expected to be related to CRRM.[70]

Level of evidence: 3ai

Nipple-sparing mastectomy

The option of nipple-sparing mastectomy (NSM) in carriers of BRCA pathogenic variants undergoing risk-reducing procedures has been controversial because of concerns about increased breast tissue left behind at surgery to keep the NAC viable. The ability to leave behind minimal residual tissue, however, may be related to experience and technique. In a retrospective review of NSM performed in carriers of BRCA pathogenic variants at two hospitals between 2007 and 2014, NSM was performed on 397 breasts in 201 carriers of BRCA pathogenic variants.[71] This study included both unaffected and affected women. Incidental cancers were found in 4 of 150 RRM patients (2.7%) and 2 of 51 cancer patients (3.9%). With a mean follow-up of 32.6 months (range, 1.0–76.0 months), there were four subsequent cancer events that included two patients with axillary recurrences, one with a local and distant recurrence 11 months after her original NSM, and one patient who developed a new cancer in the inferior portion of her breast, with no recurrences at the NAC. A study of 177 NSMs performed in 89 carriers of BRCA pathogenic variants between 2005 and 2013 reported similar, excellent local control rates. Sixty-three patients had risk-reducing NSM (median follow-up, 26 months; range, 11–42 months), and 26 patients had NSM and a diagnosis of breast cancer (median follow-up, 28 months; range, 15–43 months). Five patients required further nipple excision. There were no local recurrences or newly diagnosed breast cancers.[72]

Level of evidence: 3aii

Histopathology of RRM specimens

Studies describing histopathologic findings in RRM specimens from women with BRCA1 or BRCA2 pathogenic variants have been somewhat inconsistent. In two series, proliferative lesions associated with an increased risk of breast cancer (lobular carcinoma in situ, atypical lobular hyperplasia, atypical ductal hyperplasia, and DCIS) were noted in 37% to 46% of women with pathogenic variants who underwent either unilateral or bilateral RRM.[73-75] In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of risk-reducing bilateral or contralateral mastectomies performed in known carriers of BRCA1 or BRCA2 pathogenic variants from Australia, three (6%) cancers were detected at surgery.[76] In general, histopathologic findings in RRM specimens do not impact management.

Utilization

Individual psychological factors play an important role in decision-making about RRM by unaffected women and CRRM in women with unilateral breast cancer. (Refer to the Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer section in the Psychosocial Issues in Inherited Breast and Ovarian Cancer Syndromes section of this summary for information about uptake of RRM in BRCA carriers and the Psychosocial Outcome Studies section for information about psychosocial outcomes of RRM.)

Conclusion

In summary:

• RRM in unaffected women with pathogenic BRCA variants decreases the incidence of breast cancer by approximately 90%, with a less clear impact on breast cancer mortality.
• RRM in women with unilateral breast cancer (CRRM) has demonstrated decreased incidence of breast cancer and possible improved survival.
• NSM is an option for RRM, although variation in surgical technique and expertise may leave behind some tissue in the NAC, which may impact the need for subsequent surgery and risk of subsequent cancer.
• The predominant histopathologic findings at the time of RRM in unaffected women with pathogenic BRCA variants are proliferative lesions that do not require additional treatment.

Risk-reducing salpingo-oophorectomy (RRSO)

In the general population, removal of both ovaries has been associated with a reduction in breast cancer risk of up to 75%, depending on parity, weight, and age at time of artificial menopause. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) A Mayo Clinic study of 680 women at various levels of familial risk found that in women younger than 60 years who had bilateral oophorectomy, the likelihood of breast cancers developing was reduced for all risk groups.[77] Ovarian ablation, however, is associated with important side effects such as hot flashes, impaired sleep habits, vaginal dryness, dyspareunia, and increased risk of osteoporosis and heart disease. A variety of strategies may be necessary to counteract the adverse effects of ovarian ablation.

The evidence for the effect of RRSO on breast cancer has evolved. Early small studies suggested a protective benefit. Initial retrospective studies supported breast cancer and ovarian cancer risk reduction after RRSO in BRCA pathogenic variant–positive women.[78] In support of early small studies,[79,80] a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 variants found a significant reduction in risk of breast cancer (HR, 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR, 0.04; 95% CI, 0.01–0.16) after RRSO.[78] A prospective, single-institution study of 170 women with BRCA1 or BRCA2 pathogenic variants showed a similar trend. With RRSO, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74).[81] A prospective, multicenter study of 1,079 women followed up for a median of 30 to 35 months found that while RRSO was associated with reductions in breast cancer risk in both carriers of BRCA1 and BRCA2pathogenic variants, the risk reduction was more pronounced in BRCA2 carriers (HR, 0.28; 95% CI, 0.08–0.92).[6] A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in carriers of BRCA1/BRCA2 pathogenic variants confirmed that RRSO was associated with a significant reduction in breast cancer risk (overall: HR, 0.49; 95% CI, 0.37–0.65; BRCA1: HR, 0.47; 95% CI, 0.35–0.64; BRCA2: HR, 0.47; 95% CI, 0.26–0.84).[82] However, a cohort study of 822 carriers of BRCA1/BRCA2 pathogenic variants conducted in the Netherlands, where carrier screening is performed nationwide, did not observe a reduced risk of breast cancer after RRSO (HR, 1.09; 95% CI, 0.67–1.77).[83] The authors argued that the previous findings were driven by methodological issues including cancer-induced testing bias and immortal person time, and empirically evaluated this by using their own cohort and applying the same assumptions about counting person time from previous studies.[83] In a response, investigators from the U.S. studies analyzed their data using the assumptions of the Dutch study but still observed an inverse association with RRSO and breast cancer risk.[84] In a retrospective cohort of 676 women, carriers having an RRSO at the time of breast cancer diagnosis had a reduced risk of breast cancer–specific mortality (HR, 0.38; 95% CI, 0.19–0.77 for BRCA1 carriers and HR, 0.57; 95% CI, 0.23–1.43 for BRCA2 carriers).[85] A subsequent international, multi-institutional study of 3,722 BRCA1 and BRCA2 carriers using a similar methodology showed that oophorectomy performed before age 50 years was beneficial for preventing breast cancer in BRCA2carriers (HR, 0.18; 95% CI, 0.05–0.63; P = .007) but not in BRCA1 carriers.[86]

A prospective, multicenter, cohort study of 2,482 carriers of BRCA1/BRCA2 pathogenic variants has reported an association of RRSO with a reduction in all-cause mortality (HR, 0.40; 95% CI, 0.26–0.61), breast cancer–specific mortality (HR, 0.44; 95% CI, 0.26–0.76), and ovarian cancer–specific mortality (HR, 0.21; 95% CI, 0.06–0.80).[2] A subsequent meta-analysis confirmed the impact of RRSO on all-cause mortality (HR, 0.32; 95% CI, 0.27–0.38) in carriers of BRCA1 and BRCA2 pathogenic variants, including those with and without a personal history of breast cancer.[87]

Despite discordant findings regarding RRSO and breast cancer risk in the existing literature, aggregate data suggest that there is a benefit, although the magnitude of this benefit may not be fully understood. Further prospective studies are needed to confirm these findings.

Level of evidence: 3ai

Refer to the RRSO section in the Ovarian cancer section of this summary for more information about the effect of RRSO on ovarian cancer risk in carriers of BRCA pathogenic variants.

Chemoprevention

Tamoxifen

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. 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.[88] 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 in 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 [89] or 70 months,[90] respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used hormone replacement therapy (HRT).[89] 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.[91] These findings confirm those of the Breast Cancer Prevention Trial (P-1).[88]

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 BRCA1pathogenic variants did not appear to reduce breast cancer incidence. These data must be viewed with caution in view of the small number of carriers of pathogenic variants in the sample (8 BRCA1 carriers and 11 BRCA2 carriers).[92]

Level of evidence: 1aii

In contrast to the very limited data on primary prevention in carriers of BRCA1 and BRCA2pathogenic variants with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of contralateral breast cancer.[93-95] In one study involving approximately 600 carriers of BRCA1/BRCA2 pathogenic variants, tamoxifen use was associated with a 51% reduction in contralateral breast cancer.[93] 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 contralateral breast cancer 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.[95] Another study that involved 160 carriers of BRCA1/BRCA2pathogenic 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 contralateral breast cancer.[94] 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 contralateral breast cancer 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.[96] 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.[97] There was no difference in incidence of invasive breast cancer at a mean follow-up 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 data demonstrate slight differences between the two arms.[98] 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.[99]

The effect of tamoxifen on ovarian cancer risk was studied in 714 carriers of BRCA1pathogenic variants. All subjects had a prior history of breast cancer; use of tamoxifen was not associated with an increased risk of subsequent ovarian cancer (odds ratio [OR], 0.78; 95% CI, 0.46–1.33).[100]

Reproductive factors

In the general population, breast cancer risk increases with early menarche and late menopause, and is reduced at early first full-term pregnancy. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) In the Nurses’ Health Study, these were risk factors among women who did not have a mother or sister with breast cancer.[101] Among women with a family history of breast cancer, pregnancy at any age appeared to be associated with an increase in risk of breast cancer, persisting to age 70 years.

One study evaluated risk modifiers among 333 female carriers of a BRCA1 high-risk pathogenic variant. In women with known pathogenic variants of the BRCA1 gene, early age at first live birth and parity of three or more have been associated with a lowered risk of breast cancer. A RR of 0.85 was estimated for each additional birth, up to five or more; however, increasing parity appeared to be associated with an increased risk of ovarian cancer.[102,103] In a case-control study from New Zealand, investigators noted no difference in the impact of parity on the risk of breast cancer between women with a family history of breast cancer and those without a family history.[104]

Studies of the effect of pregnancy on breast cancer risk have revealed complex results and the relationship with parity has been inconsistent and may vary between carriers of BRCA1and BRCA2 pathogenic variants.[105-107] Parity has more consistently been associated with a reduced risk of breast cancer in carriers of BRCA1 pathogenic variants.[105-109] Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.[107,110]

Level of evidence: 4aii

In the general population, breastfeeding has been associated with a slight reduction in breast cancer risk in a few studies, including a large collaborative reanalysis of multiple epidemiologic studies,[111] and at least one study suggests that it may be protective in carriers of BRCA1 pathogenic variants. In a multicenter, case-control study of 685 carriers of BRCA1 pathogenic variants with breast cancer and 280 carriers of BRCA2 pathogenic variants with breast cancer and 965 carriers without breast cancer drawn from multiple-case families, among carriers of BRCA1 pathogenic variants, breastfeeding for 1 year or more was associated with approximately a 45% reduced risk of breast cancer.[112] No such reduced risk was observed among carriers of BRCA2 pathogenic variants. A second study failed to confirm this association.[110]

Oral contraceptives

There is no consistent evidence that the use of oral contraceptives (OCs) increases the risk of breast cancer in the general population.[113] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

Although several smaller studies have reported a slightly increased risk of breast cancer with OC use in carriers of BRCA1/BRCA2 pathogenic variants,[114,115] a meta-analysis concluded that the associated risk is not significant with more recent OC formulations.[116] However, OCs formulated before 1975 were associated with an increased risk of breast cancer.[116] A large proportion of patients on whom this meta-analysis was based were drawn from three large studies summarized in Table 12.[117-119]

Table 12. Oral Contraceptive (OC) Use and Breast Cancer Risk in Carriers of BRCA1/BRCA2 Pathogenic Variants

		Kotsopoulos et al. (2014)a[120]	Brohet et al. (2007)b[117]	Haile et al. (2006)a,c[118]	Narod et al. (2002)a[119]
CI = confidence interval.
aReports risk estimates in the form of odds ratios with 95% CIs.
bReports risk estimates in the form of hazard ratios with 95% CIs.
cRisk estimates restricted to carriers of BRCA pathogenic variants younger than 40 years.
Study population	BRCA1carriers with breast cancer	N = 2,492	N = 597	N = 195; diagnosis < age 50 y	N = 981
	BRCA2carriers with breast cancer	Not applicable	N = 249	N = 128; diagnosis < age 50 y	N = 330
Ever use OC	BRCA1	1.18 [CI 1.03–1.36] P = .02	1.47 [CI 1.13–1.91]	0.64 [CI 0.35–1.16]	1.38 [CI 1.11–1.72] P= .003
	BRCA2	Not applicable	1.49 [Cl 0.8–2.7]	1.29 [Cl 0.61–2.76]	0.94 [Cl 0.72–1.24]
Age use <20 y	BRCA1	1.45 [CI 1.20–1.75] P = .0001	1.41 [Cl 0.99–2.01]	0.84 [Cl 0.45–1.55]	1.36 [Cl 1.11–1.67] P= .003
	BRCA2	Not applicable	1.25 [Cl 0.57–2.74]	1.64 [Cl 0.77–3.46]	Not reported
Total duration	BRCA1	<5 y: 1.14 [CI 0.97–1.35]	<9 y: 1.51 [Cl 1.1–2.08]	<5 y: 0.61 [Cl 0.31–1.17]	<10 y: 1.36 [Cl 1.11–1.67] P = .003
		>5 y: 1.22 [CI 1.04–1.49] P= .02
	BRCA2	Not applicable	<9 y: 2.27 [Cl 1.1–4.65]	<5 y: 0.79 [Cl 0.26–2.37]	<10 y: 0.82 [Cl 0.56–1.91]
Use before full-term pregnancy	BRCA1	Not applicable	>4 y: 1.49 [Cl 1.05–2.11]	>4 y: 0.69 [Cl 0.41–1.16]	Not evaluated
	BRCA2	Not applicable	>4 y: 2.58 [Cl 1.21–5.49]	>4 y: 2.08 [Cl 1.02–4.25] trend per y: 1.11; P trend = .01

When patients are counseled about contraceptive options and preventive actions, the potential impact of OC use on the risk of breast cancer and ovarian cancer and other health-related effects of OCs need to be considered. A number of important issues remain unresolved, including the potential differences between carriers of BRCA1 or BRCA2pathogenic variants, effect of age and duration of exposure, and effect of OCs on families with highly penetrant early-onset breast cancer.

Level of evidence: 3aii

(Refer to the Oral contraceptives section in the Chemoprevention section of this summary for a discussion of OC use and ovarian cancer in this population.)

Hormone replacement therapy (HRT)

Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with HRT in the general population.[121-124] The Women’s Health Initiative (WHI) was a randomized controlled trial of approximately 160,000 postmenopausal women that investigated the risks and benefits of dietary interventions and hormone therapy to reduce the incidence of heart disease, breast cancer, colorectal cancer, and fractures. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits.[123,124] One of the adverse outcomes prompting closure was a significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150) breast cancers (RR, 1.24; 95% CI, 1.02–1.50; P < .001) in women randomly assigned to receive estrogen and progestin.[124] Results of a follow-up study suggest that the recent reduction in breast cancer incidence, especially among women aged 50 to 69 years, is predominantly related to decrease in use of combined estrogen plus progestin HRT.[125] HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.[124]

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [126-128] or unaffected by a family history of breast cancer;[102,129,130] risk did not vary by family history in the meta-analysis.[113] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 pathogenic variants.[124] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.[131]

HRT in carriers of BRCA1/BRCA2 pathogenic 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 BRCA1and 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).[132] 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).[133] 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).[134] Especially given the differences in estimated risk associated with HRT between observational studies and the WHI, these findings should be confirmed in randomized prospective studies,[135] 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

Ovarian cancer

Screening/surveillance

Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening for information on screening in the general population and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information about levels of evidence related to screening and prevention. The latter also outlines the five requirements that must be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice.

Clinical examination

In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early 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: None assigned

Transvaginal ultrasound

In the general population, transvaginal ultrasound (TVUS) appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries (e.g., transient corpus luteum cysts) that can cause difficulty in interpretation. The randomized prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO-1) found no reduction in mortality with the annual use of combined TVUS and cancer antigen 125 (CA-125) in screening asymptomatic postmenopausal women at general-population risk of ovarian cancer.[136]

Data are limited regarding the potential benefit of TVUS in screening women at inherited risk of ovarian cancer. A number of retrospective studies have reported experience with ovarian cancer screening in high-risk women using TVUS with or without CA-125.[9,137-147] However, there is little uniformity in the definition of high-risk criteria and compliance with screening, and in whether cancers detected were incident or prevalent. One of the largest reported studies included 888 carriers of BRCA1/BRCA2 pathogenic variants who were screened annually with TVUS and CA-125. Ten women developed ovarian cancer; five of the ten developed interval cancers after normal screening results within 3 to 10 months before diagnosis. Five of the ten ovarian cancers were screen-detected incident cases, which had normal screening results within 6 to 14 months before diagnosis. Of these five cases, four were stage IIIB or IV.[137]

A similar study reported the results of annual TVUS and CA-125 in a cohort of 312 high-risk women (152 carriers of BRCA1/BRCA2 pathogenic variants).[139] Of the four cancers that were detected due to abnormal TVUS and CA-125, all four patients were symptomatic, and three had advanced-stage disease. Annual screening of carriers of BRCA1/BRCA2pathogenic variants with pelvic ultrasound, TVUS, and CA-125 failed to detect early-stage ovarian cancer among 241 carriers of BRCA1/BRCA2 pathogenic variants in a study from the Netherlands.[148] Three cancers were detected over the course of the study, all advanced stage IIIC disease.[148] Finally, a study of 1,100 moderate- and high-risk women who underwent annual TVUS and CA-125 reported that ten of 13 ovarian tumors were detected due to screening. Only five of ten were stage I or II.[138] There are limited data related to the efficacy of semiannual screening with TVUS and CA-125.[9,146]

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.[149] Phase II of this study increased the frequency of screening to every 4 months; the impact of this is not yet available.

The first prospective study of TVUS and CA-125 with survival as the primary outcome was completed in 2009. Of the 3,532 high-risk women screened, 981 were carriers of BRCApathogenic variants, 49 of whom developed ovarian cancer. The 5- and 10-year survival was 58.6% (95% CI, 50.9%–66.3%) and 36% (95% CI, 27–45), respectively, and there was no difference in survival 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 appear to be ineffective in detecting tumors at an early stage to substantially influence survival.[150]

Level of evidence: 4

Serum CA-125

Serum CA-125 screening for ovarian cancer in high-risk women has been evaluated in combination with TVUS in a number of retrospective studies, as described in the previous section.[9,137-146]

The National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA-125. (Refer to the Prostate, Lung, Colorectal and Ovarian [PLCO] Cancer Screening Trial: Single-threshold CA-125 levels and TVU section in the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening for more information.) The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA-125 screening every 6 to 12 months, beginning at age 35 years.[151] The Cancer Genetics Studies Consortium task force has recommended that female carriers of a BRCA1 pathogenic variant undergo annual or semiannual screening using TVUS and serum CA-125 levels, beginning at age 25 to 35 years.[11] Both recommendations are based solely on expert opinion and best clinical judgment.

Level of evidence: 5

Other candidate ovarian cancer biomarkers

The need for effective ovarian cancer screening is particularly important for women carrying BRCA1 and BRCA2 pathogenic variants, and the mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, PMS2), disorders in which the risk of ovarian cancer is high. There is a special sense of urgency for carriers of BRCA1 pathogenic variants, in whom cumulative lifetime risks of ovarian cancer may exceed 40%.

Thus, it is expected that many new ovarian cancer biomarkers (either singly or in combination) will be proposed as ovarian cancer screening strategies during the next 5 to 10 years. 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.

Before information related to emerging ovarian cancer biomarkers is addressed, it is important to consider the several steps that are required to develop and, more importantly, validate a new biomarker. One useful framework is that published by the National Cancer Institute Early Detection Research Network investigators.[152] They indicated that the goal of a cancer-screening program is to detect tumors at an early stage so that treatment is likely to be successful. The gold standard by which such programs are judged is whether the death rate from the cancer for which screening is performed is reduced among those being screened. In addition, the screening test must be sufficiently noninvasive and inexpensive to allow widespread use in the population to be screened. Maintaining high test specificity (i.e., few false-positive results) is essential for a population screening test, because even a low false-positive rate results in many people having to undergo unnecessary and costly diagnostic procedures and psychological stress. It is likely that the use of several such cancer biomarkers in combination will be required for a screening test to be both sensitive and specific.

Furthermore, a clinically useful test must have a high PPV (a parameter derived from sensitivity, specificity, and disease prevalence in the screened population). Practically speaking, a biomarker with a PPV of 10% implies that ten surgical procedures would be required to identify one case of ovarian cancer; the remaining nine surgeries would represent false-positive test findings. In general, the ovarian cancer research community considers biomarkers with a PPV less than 10% to be clinically unacceptable, given the morbidity related to bilateral salpingo-oophorectomy. Finally, it is important to keep in mind that while novel biomarkers may be present in the sera of women with advanced ovarian cancer (who represent most cases analyzed in the early phases of biomarker development), they may or may not be detectable in women with early-stage disease, which is essential if the screening test is to be clinically useful.

It has been suggested that there are five general phases in biomarker development and validation are currently suggested:

Phase 1 — Preclinical exploratory studies

• Identify potentially discriminating biomarkers.
• Usually done by comparing gene over- or underexpression in the tumor compared with normal tissue.
• Because many exploratory analyses in large numbers of genes are performed at this stage, one or more may seem to have good discriminating ability between cancers and normal tissue by random chance alone.

Phase 2 — Clinical assay development for clinical disease

• Develop a clinical assay that can be obtained on noninvasively obtained samples (e.g., a blood specimen).
• Often the test targets the protein product of one of the genes found to be of interest in phase 1.
• The goal is to describe the performance characteristics of the assay for distinguishing between subjects with and without cancer. At this point, the assay should be in its final configuration and remain stable throughout the following phases.
• IMPORTANT: Because the case subjects in a phase 2 study already have cancer, with assay results obtained at the time of disease diagnosis, one cannot determine whether disease can be detected early with a given biomarker.

Phase 3 — Retrospective longitudinal repository studies

• Compare clinical specimens collected from cancer case subjects before their clinical diagnosis with specimens from subjects who have not developed cancer.
• Evaluate, as a function of time before clinical diagnosis, the biomarker’s ability to detect preclinical disease.
• Define the criteria for a positive screening test in preparation for phase 4.
• Explore the influence of other patient characteristics (e.g., age, gender, smoking status, medication use) on the ability of the biomarker to discriminate between those with and without preclinical disease.

Phase 4 — Prospective screening studies

• Determine the operating characteristics of the biomarker-based screening test in a population for which the test is intended.
• Measure the detection rate (number of abnormal tests among all those with the disease) and the false-positive rate (the number of abnormal tests among all those who do not have the disease).
• Evaluate whether the cancers detected by the test are being found at an early stage, a point at which treatment is more likely to be curative.
• Assess whether the test is acceptable in a population of persons for whom it is intended. Will subjects comply with the test schedule and results?

Phase 5 — Cancer control studies

• Ideally, conduct randomized controlled clinical trials in clinically relevant populations, in which one arm is subjected to screening and appropriate intervention if screen-positive, while the other arm is not screened.
• Determine whether the death rate of the cancer being screened for is reduced among those who use the screening test.
• Obtain information about the costs of screening and treatment of screen-detected cancers.

Finally, for a validated biomarker test to be considered appropriate for use in a particular population, it must have been evaluated in that specific population without prior selection of known positives and negatives. In addition, the test must demonstrate clinical utility, that is, a positive net balance of benefits and risks associated with the application of the test. These may include improved health outcomes and net psychosocial and economic benefits.[153]

Ovarian cancer poses a unique challenge relative to the potential impact of false-positive test results. There are no reliable noninvasive diagnostic tests for early-stage disease, and clinically significant early-stage cancer may not be grossly visible at the time of exploratory surgery.[154] Consequently, it is likely that some patients will be reassured that their abnormal test does not indicate the presence of cancer only by having their ovaries and fallopian tubes surgically removed and examined microscopically. High test specificity (i.e., a very low false-positive rate) is required to avoid unnecessary surgery and induction of premature menopause women with in false-positive results.

Variations on CA-125

CA-125 plus an ovarian cancer symptom index

An ovarian cancer symptom index for predicting the presence of cancer was evaluated in 75 cases and 254 high-risk controls (carriers of BRCA pathogenic variants or women with a strong family history of breast and ovarian cancer).[155] Women had a positive symptom index if they reported any of the predefined symptoms (bloating or increase in abdominal size, abdominal or pelvic pain, and difficulty eating or feeling full quickly) more than 12 times per month, occurring only within the prior 12 months. CA-125 values greater than 30 U/mL were considered abnormal. The symptom index independently predicted the presence of ovarian cancer, after controlling for CA-125 levels (P < .05). The combination of an elevated CA-125 and a positive-symptom index correctly identified 89.3% of the cases. The symptom index correlated with the presence of cancer in 50% of the affected women who did not have elevated CA-125 levels, but 11.8% of the high-risk controls without cancer also had a positive-symptom index. The authors suggested that a composite index that included both CA-125 and the symptom index had better performance characteristics than either test used alone, and that this strategy might be used as a first screen in a multistep screening program. Additional test performance validation and determination of clinical utility are required in unselected screening populations.

Level of evidence: 5

Risk of ovarian cancer algorithm

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.[156] 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.[157] 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 normal 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.[158] 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 utilized 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 ends 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 underway) and the Gynecologic Oncology Group Protocol 199 (GOG-0199; enrollment complete; follow-up ended in 2011).[159] Thus, additional data regarding the utility of this currently investigational screening strategy will become available.

Level of evidence: 4

Miscellaneous new markers

A wide array of new candidate ovarian cancer biomarkers has been described during the past decade, e.g., HE4; mesothelin; kallikreins 6, 10, and 11; osteopontin; prostasin; M-CSF; OVX1; lysophosphatidic acid; vascular endothelial growth factor B7-H4; and interleukins 6 and 8.[160-162] These have been singly studied, in combination with CA-125, or in various other permutations. Most of the study populations are relatively small and comprise highly selected, known ovarian cancer cases and healthy controls of the type evaluated in early biomarker development phases 1 and 2. Results have not been consistently replicated in multiple studies; presently, none are considered ready for widespread clinical application.

Level of evidence: 5

Proteomics

Initially, mass spectroscopy of serum proteins was combined with complex analytic algorithms to identify protein patterns that might distinguish between ovarian cancer cases and controls.[163] This approach assumed that pattern recognition alone would be sufficient to permit such discrimination, and that identification of the specific proteins responsible for the patterns identified was not required. This strategy was modified, using similar laboratory tools, to identify finite numbers of specific known serum markers that may be used in place of, or in conjunction with, CA-125 measurements for the early detection of cancer.[164] These studies [162,165] have generally been small case-control studies that are limited by sample size and the number of early-stage cancer cases included. Further evaluation is needed to determine whether any additional markers identified in this fashion have clinical utility for the early detection of ovarian cancer in the unselected clinical population of interest.

Level of evidence: 5

Multiplex biomarker assays for ovarian cancer screening

Because individual biomarkers have not met the criteria for an effective screening test, it has been suggested that it may be necessary to combine multiple ovarian cancer biomarkers to obtain satisfactory screening test results. This strategy was employed to quantitatively analyze six serum biomarkers (leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125), using a multiplex, bead-based platform.[166] A similar assay was available commercially under the trade name OvaSure until its voluntary withdrawal from the market by the manufacturer.[Response to FDA Warning Letter]

The cases in this study were newly diagnosed ovarian cancer patients who had blood collected just before surgery: 36 were stage I and II; 120 were stage III and IV. The controls were healthy age-matched individuals who had not developed ovarian cancer within 6 months of blood draw. Neither cases nor controls in this study were well characterized regarding their familial and/or genetic risk status, but they have been suggested to comprise a high-risk population. First, 181 controls and 113 ovarian cancer cases were tested to determine the initial panel of biomarkers that best discriminated between cases and controls (training set). The resulting panel was applied to an additional 181 controls and 43 ovarian cancer cases (test set). Pooling both early- and late-stage ovarian cancer across the combined training and test sets, performance characteristics were reported as a sensitivity of 95.3% and a specificity of 99.4%, with a PPV of 99.3% and a negative predictive value of 99.2%, using a formula that assumed an ovarian cancer prevalence of about 50%, as seen in the highly selected research population.

To avoid biases that may make test performance appear to be better than it really is, combining training populations and test populations in analyses of this sort is generally not recommended.[167] The most appropriate prevalence to use is the disease prevalence in the unselected population to be screened. The prevalence of ovarian cancer in the general population is 1 in 2,500. In a correction to their manuscript,[166] the authors assumed that the prevalence of ovarian cancer in the screened population was 1 in 2,500 (0.04%) and recalculated the PPV to be only 6.5%. On that basis, the investigators have retracted their claim that this test is suitable for population screening. If this test were used in patients at increased risk of ovarian cancer, the actual prevalence in such a target population is likely to be higher than that observed in the general population, but well below the assumed 50% figure used in the published analysis. This revised PPV of 6.5% indicates that approximately 1 in 15 women with a positive test would in fact have ovarian cancer, and only a fraction of those with ovarian cancer would be stages I or II. The remaining 14 positive tests would represent false-positives, and these women would be at risk of exposure to needless anxiety and potentially morbid diagnostic procedures, including bilateral salpingo-oophorectomy.

Viewed in the context of the criteria previously described,[152] this assay would be classified as phase 2 in its development. While this appears to be a promising avenue of ovarian cancer screening research, additional validation is required, particularly in an unselected population representative of the clinical screening population of interest. A position statementExit Disclaimer by the Society of Gynecologic Oncologists regarding this assay indicated “it is our opinion that additional research is needed to validate the test’s effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an institutional review board.”

Level of evidence: 5

Risk-reducing surgery

RRSO

Numerous studies have found that women with an inherited risk of breast and ovarian cancer have a decreased risk of ovarian cancer after RRSO. A retrospective study of 551 women with BRCA1 or BRCA2 pathogenic variants found a significant reduction in risk of breast cancer (HR, 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR, 0.04; 95% CI, 0.01–0.16) after bilateral oophorectomy.[78] A prospective, single-institution study of 170 women with BRCA1 or BRCA2 pathogenic variants showed a similar trend.[81] With oophorectomy, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective multicenter study of 1,079 women who were followed up for a median 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 BRCA2pathogenic variants; however, the breast cancer risk reduction was more pronounced in BRCA2 carriers (HR, 0.28; 95% CI, 0.08–0.92).[6] In a case-control study in Israel, bilateral oophorectomy was associated with reduced ovarian/peritoneal cancer risks (OR, 0.12; 95% CI, 0.06–0.24).[168] A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in carriers of BRCA1/BRCA2 pathogenic variants confirmed that RRSO was associated with a significant reduction in risk of ovarian or fallopian tube cancer (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).[82] 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).[169] 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 cancer 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] Among studies with 50 or more subjects, prevalence ranged from 2.3% to 11%. Some of the variation in prevalence is likely due to differences in surgical technique, pathologic handling of the tissues, and age at RRSO. In the GOG 199 study of 966 high-risk women, the incidence of occult cancer was highest among carriers of BRCA1 pathogenic variants (4.6%), followed by carriers of BRCA2 pathogenic variants (3.5%), versus only 0.5% of noncarriers. The odds of an occult pathologic finding was fourfold higher among postmenopausal women.[170]

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.[171] This study provides the first evidence to suggest a survival advantage among women undergoing RRSO.

Studies on the degree of risk reduction afforded by RRSO have begun to clarify the spectrum of occult cancers 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 a prevalence of malignant findings among carriers of pathogenic variants undergoing risk-reducing oophorectomy. Among studies with 50 or more subjects, prevalence ranged from 2.3% to 11%.[9,81,172-178] Some of the variation in prevalence probably results from differences in surgical technique, pathologic handling of the tissues, and age at RRSO. In the GOG 199 study of 966 high-risk women, the incidence of occult cancer was highest in carriers of BRCA1 pathogenic variants (4.6%), followed by carriers of BRCA2 pathogenic variants (3.5%), versus only 0.5% of noncarriers. The odds of an occult pathologic finding was fourfold higher among postmenopausal women.[170]

In addition to occult cancers, premalignant lesions have also been described in fallopian tube tissue removed for prophylaxis. In one series of 12 women with BRCA1 pathogenic variants undergoing risk-reducing surgery, 11 had hyperplastic or dysplastic lesions identified in the tubal epithelium. In several of the cases the lesions were multifocal.[179] These pathologic findings are consistent with the identification of germline BRCA1 and BRCA2 pathogenic variants in women affected with both tubal and primary peritoneal cancers.[176,180-185] One study suggests a causal relationship between early tubal carcinoma, or tubal intraepithelial carcinoma, and subsequent invasive serous carcinoma of the fallopian tube, ovary, or peritoneum.[186] (Refer to the Pathology of ovarian cancersection of this summary for more information.)

These findings support the inclusion of fallopian tube cancers, which account for less than 1% of all gynecologic cancers in the general population, as a component of hereditary ovarian cancer syndrome and necessitate removal of the fallopian tubes at the time of risk-reducing surgery. There is clear evidence that RRSO must include routine collection of peritoneal washings and careful adherence to comprehensive pathologic evaluation of the entire adnexa with the use of serial sectioning.[178,187,188]

The peritoneum, however, appears to remain at low risk for the development of a Müllerian-type adenocarcinoma, even after oophorectomy.[189-193] Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomy, 6 (1.8%) subsequently developed primary peritoneal carcinoma. No period of follow-up was specified.[194] Among 238 individuals in the Creighton Registry with BRCA1/BRCA2 pathogenic variants who underwent risk-reducing oophorectomy, 5 subsequently developed intra-abdominal carcinomatosis (2.1%). Of note, all five of these women had BRCA1 pathogenic variants.[195] A study of 1,828 women with a BRCA1 or BRCA2 pathogenic variant found a 4.3% risk of primary peritoneal cancer at 20 years after RRSO.[196]

Data are limited regarding outcomes of carriers of BRCA1 and BRCA2 pathogenic variants who are found to have occult lesions at the time of RRSO. In a multi-institution study of 32 women with either invasive carcinoma (n = 15) or serous tubal intraepithelial carcinoma (STIC) (n = 17), 47% of women with invasive cancer had a recurrence at a median time of 32.5 months, with an OS rate of 73%.[197] For women with intraepithelial lesions, one patient (approximately 6%) had a recurrence at 43 months, suggesting a different disease process between the two entities. Another study confirmed the malignant potential of STIC lesions. While 3 of 243 women (1.2%) with benign pathology at RRSO subsequently developed primary peritoneal carcinoma, 2 of 9 women (22%) with STIC developed high-grade pelvic serous carcinoma after a median follow-up time of 63 months.[198]

Given the current limitations of screening for ovarian cancer and the high risk of the disease in carriers of BRCA1 and BRCA2 pathogenic variants, NCCN GuidelinesExit Disclaimerrecommend RRSO between the ages of 35 and 40 years or upon completion of childbearing, as an effective risk-reduction option. Optimal timing of RRSO must be 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 U.S. BRCA1and BRCA2 families, age-specific cumulative risk of ovarian cancer at age 40 years was 4.7% for carriers of BRCA1 pathogenic variants and 1.9% for carriers of BRCA2 pathogenic variants.[199] In a combined analysis of 22 studies of carriers of BRCA1 and BRCA2pathogenic variants, risk of ovarian cancer for carriers of BRCA1 pathogenic variants increased most sharply from age 40 years to age 50 years, while the risk for carriers of BRCA2 pathogenic variants was low before age 50 years but increased sharply from age 50 years to age 60 years.[200] In a population-based study of BRCA pathogenic variants in ovarian cancer patients, patients with BRCA2 variants had a significantly later age of onset than patients with BRCA1 variants (57.3 years [range, 40–72] vs. 52.6 years [range, 31–78]).[201] In summary, women with BRCA1 pathogenic variants may consider RRSO for ovarian cancer risk reduction at a somewhat earlier age than women with BRCA2 pathogenic variants; however, women with BRCA2 variants may still consider early RRSO for breast cancer risk reduction.

The role of concomitant hysterectomy at the time of RRSO in carriers of BRCA1/BRCA2pathogenic variants is controversial. There is concern that a small portion of the proximal fallopian tube remains when hysterectomy is not performed, thereby resulting in a residual increased risk of fallopian tube cancer. However, several studies that have examined fallopian tube cancers indicate that the vast majority of these cancers occur in the distal or midportion of the fallopian tube, suggesting that the occurrence of proximal fallopian tube cancer would be a very unlikely event. Some reports have suggested an increased incidence of uterine carcinoma in carriers of pathogenic variants,[202] whereas others have not confirmed an elevated risk of serous uterine cancer.[203] 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;[204] this was confirmed by the same group in a later study of 4,456 carriers of BRCA1/BRCA2 pathogenic variants.[205] Even with tamoxifen use, the excess risk of endometrial cancer was small, with a 10-year cumulative risk of 2%.[205] 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. Therefore, on the basis of the current understanding of the risk of uterine cancer in carriers of BRCApathogenic variants, there is not a singularly compelling reason to consider hysterectomy at the time of RRSO to reduce the risk of uterine cancer. Concomitant hysterectomy does offer the advantage of simplifying the hormone replacement regimen for carriers of BRCApathogenic variants who choose to take hormones. After hysterectomy, women can take estrogen alone (which does not increase the risk of breast cancer), without progestins, thereby eliminating the risk of postmenopausal bleeding.

Studies indicate that removal of the uterus is not necessary as a risk-reducing procedure. No increased BRCA pathogenic variant prevalence was seen among 200 Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma.[203,206] However, small studies have reported that uterine papillary serous carcinoma may be part of the BRCA-associated spectrum of disease.[202,207,208] The cumulative risk of endometrial cancer among carriers of BRCA pathogenic variants with ER-positive breast cancer treated with tamoxifen may be an additional factor to consider when counseling this population about risk-reducing hysterectomy.[204,209] Hysterectomy might also be considered in young, unaffected carriers of BRCA pathogenic variants who may want to use HRT but for whom hysterectomy would offer a simplified regimen of estrogen alone. In counseling a carrier of a BRCA pathogenic variant about optimal risk-reducing surgical options, aggregate data suggest that the risk from residual tubal tissue after RRSO is the least compelling reason to suggest hysterectomy. Therefore, in the absence of tamoxifen use or other underlying uterine or cervical problems, hysterectomy is not a routine component of RRSO for BRCA carriers.

For women who are premenopausal at the time of surgery, the symptoms of surgical menopause (e.g., hot flashes, mood swings, weight gain, and genitourinary complaints) can cause a significant impairment in their quality of life. To reduce the impact of these symptoms, providers have often prescribed a time-limited course of systemic HRT after surgery. (Refer to the Hormone replacement therapy in carriers of BRCA1/BRCA2 pathogenic variants section of this summary for more information.)

Studies have examined the effect of RRSO on quality of life (QOL). One study examined 846 high-risk women of whom 44% underwent RRSO and 56% had periodic screening.[210] Of the 368 carriers of BRCA1/BRCA2 pathogenic variants, 72% underwent RRSO. No significant differences were observed in QOL scores (as assessed by the Short Form-36) between those with RRSO or screening or compared with the general population; however, women with RRSO had fewer breast and ovarian cancer worries (P < .001) and more favorable cancer risk perception (P < .05) but more endocrine symptoms (P < .001) and worse sexual functioning (P < .05). Of note, 37% of women used HRT after RRSO, although 62% were either perimenopausal or postmenopausal.[210] Researchers then examined 450 premenopausal high-risk women who had chosen either RRSO (36%) or screening (64%). Of those in the RRSO group, 47% used HRT. HRT users (n = 77) had fewer vasomotor symptoms than did nonusers (n = 87; P < .05), but they had more vasomotor symptoms than did 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 did those in the screening group (P < .01). Therefore, while such symptoms are improved via HRT use, HRT is not completely effective, and additional research is warranted to address these important issues.

The long-term nononcologic effects of RRSO in carriers of BRCA1/BRCA2 pathogenic variants are unknown. In the general population, RRSO has been associated with increased cardiovascular disease, dementia, death from lung cancer, and overall mortality.[211-215] When age at oophorectomy has been analyzed, the most detrimental effect has been seen in women who undergo RRSO before age 45 years and do not take estrogen replacement therapy.[211] Carriers of BRCA1/BRCA2 pathogenic variants undergoing RRSO may have an increased risk of metabolic syndrome.[216] RRSO has also been associated with an improvement in short-term mortality in this population.[171] The benefits related to cancer risk reduction after RRSO are clear, but further data on the long-term nononcologic risks and benefits are needed.