This executive summary reviews the topics covered in this PDQ summary on the genetics of breast and gynecologic cancers.
Factors suggestive of a genetic contribution to both breast cancer and gynecologic cancer include 1) an increased incidence of these cancers among individuals with a family history of these cancers; 2) multiple family members affected with these and other cancers; and 3) a pattern of cancers compatible with autosomal dominant inheritance. Both males and females can inherit and transmit an autosomal dominant cancer predisposition gene.
Additional factors coupled with family history can influence an individual's risk of developing cancer—such as reproductive history, contraceptive and hormone replacement use, radiation exposure early in life, alcohol consumption and smoking, and physical activity.
Risk assessment models have been developed to clarify an individual's 1) lifetime risk of developing breast and/or gynecologic cancer; 2) likelihood of having a pathogenic variant in BRCA1 or BRCA2; and 3) likelihood of having a pathogenic variant in one of the mismatch repair genes associated with Lynch syndrome.
Breast and ovarian cancer are present in several autosomal dominant cancer syndromes, although they are most strongly associated with highly penetrant germline pathogenic variants in BRCA1 and BRCA2. Other genes, such as PALB2, TP53 (associated with Li-Fraumeni syndrome), PTEN (associated with PTEN hamartoma tumor syndromes, including Cowden syndrome), CDH1 (associated with diffuse gastric and lobular breast cancer syndrome), and STK11 (associated with Peutz-Jeghers syndrome), confer a risk to either or both of these cancers with relatively high penetrance.
Inherited endometrial cancer is most commonly associated with Lynch syndrome, a condition caused by inherited pathogenic variants in the highly penetrant mismatch repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM. Colorectal cancer (and, to a lesser extent, ovarian cancer and stomach cancer) is also associated with Lynch syndrome.
Additional genes, such as CHEK2, BRIP1, RAD51, and ATM, are associated with breast and/or gynecologic cancers with moderate penetrance. Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including breast and gynecologic cancers, but the clinical utility of these findings remains uncertain.
Breast cancer screening strategies, including breast magnetic resonance imaging and mammography, are commonly performed in carriers of BRCA pathogenic variants and in individuals at increased risk of breast cancer. Initiation of screening is generally recommended at earlier ages and at more frequent intervals in individuals with an increased risk due to genetics and family history than in the general population. There is evidence to demonstrate that these strategies have utility in early detection of cancer. In contrast, there is currently no evidence to demonstrate that ovarian cancer screening using cancer antigen–125 testing and transvaginal ultrasound leads to early detection of cancer.
Risk-reducing surgeries, including risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), have been shown to significantly reduce the risk of developing breast and/or ovarian cancer and improve overall survival in carriers of BRCA1 and BRCA2 pathogenic variants. Chemoprevention strategies for breast cancer and chemoprevention strategies for ovarian cancer have been examined in this population. For example, tamoxifen use has been shown to reduce the risk of contralateral breast cancer among carriers of BRCA1 and BRCA2 pathogenic variants after treatment for breast cancer, but there are limited data in the primary cancer prevention setting to suggest that it reduces the risk of breast cancer among healthy female carriers of BRCA2 pathogenic variants. The use of OCs also has been associated with a protective effect on the risk of developing ovarian cancer, including in carriers of BRCA1 and BRCA2 pathogenic variants, with no association of increased risk of breast cancer when using formulations developed after 1975.
Psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Uptake of genetic testing varies widely across studies. Psychological factors that have been associated with testing uptake include cancer-specific distress and perceived risk of developing breast or ovarian cancer. Studies have shown low levels of distress after genetic testing for both carriers and noncarriers, particularly in the longer term. Uptake of RRM and RRSO also varies across studies and may be influenced by factors such as cancer history, age, family history, recommendations of the health care provider, and pretreatment genetic education and counseling. Patients' communication with their family members about an inherited risk of breast and gynecologic cancer is complex; gender, age, and the degree of relatedness are some elements that affect disclosure of this information. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.
Among women in the United States, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and it is the second leading cause of cancer deaths after lung cancer. In 2022, an estimated 290,560 new cases of breast cancer (including 2,710 cases in men) will be diagnosed, and 43,780 deaths (including 530 deaths in men) will occur.[
A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (refer to the Risk Factors for Breast Cancer, Risk Factors for Ovarian Cancer, and Risk Factors for Endometrial Cancer sections below for more information), and by the observation of some families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with an inheritance of autosomal dominant cancer susceptibility. Formal studies of families (linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many families. (Refer to the PDQ summary Cancer Genetics Overview for more information about linkage analysis.) Pathogenic variants in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.
Risk Factors for Breast Cancer
This section discusses factors that can modify an individual's risk of developing breast cancer. These risk factors can affect women in the general population, women who have a family histories of breast cancer, and women who carry pathogenic variants in breast cancer risk genes. For more information on breast cancer risk factors in the general population, see Breast Cancer Prevention, and for more information on risks associated with BRCA1/2 pathogenic variants, see the Cancer Risks, Spectrum, and Characteristics section in BRCA1 and BRCA2: Cancer Risks and Management.
The following breast cancer risk factors are discussed in this section:
These factors can increase or decrease breast cancer risk in all women. However, they may affect breast cancer risk differently in women with increased breast cancer susceptibility (i.e., women who have high-risk family histories and/or pathogenic variants in hereditary breast cancer genes). Factors that increase breast cancer risk in the general population may lower breast cancer risk, increase breast cancer risk more than expected, or have no effect on breast cancer risk in women with high breast cancer susceptibility. In some cases, these risk factors may affect high-risk women in the same way that they affect average-risk women. Furthermore, modifying risk factors has a greater effect on the absolute breast cancer risk in women with high breast cancer susceptibility than in women with low breast cancer susceptibility.[
Like other cancer types, breast cancer's cumulative risk increases with age. As individuals age, they encounter more environmental exposures and accumulate genomic changes. Hence, most breast cancers occur after age 50 years.[
Family history of breast cancer
A family history of breast cancer is a well-established, consistent risk factor for breast cancer. Approximately 5% to 10% of women with breast cancer also had a mother or sister with breast cancer in cross-sectional studies. About 10% to 20% of women had a first-degree relative (FDR) or a second-degree relative (SDR) with breast cancer.[
The following factors can increase a woman's breast cancer risk:
Furthermore, women with family histories of multiple breast cancers had higher hazard ratios (HRs) (HR, 2.7; 95% CI, 2.6–2.9) than women who had a single breast cancer in their families (HR, 1.8; 95% CI, 1.8–1.9). When women had multiple breast cancers in their families (with one breast cancer occurring before age 40 years), the HR was 3.8 (95% CI, 3.1–4.8). However, breast cancer risk also significantly increased when a relative was diagnosed with breast cancer at 60 years or older, suggesting that having a relative with breast cancer at any age can increase risk.[
Albright et al. addressed how affected third-degree relatives (TDRs) can contribute to an individual's breast cancer risk.[
One of the largest studies of twins ever conducted examined 80,309 monozygotic twins and 123,382 dizygotic twins. This study had a heritability estimate of 31% for breast cancer (95% CI, 11%–51%).[
Benign breast disease, mammographic density, and background parenchymal enhancement
Benign breast disease (BBD)
Background parenchymal enhancement (BPE)
Parity, age at first birth, and breastfeeding
Age at first birth
Reproductive history can also affect a woman's risk for ovarian cancer and endometrial cancer. For more information, see the Risk Factors for Ovarian Cancer and Risk Factors for Endometrial Cancer sections.
Breast cancer risk is one of the factors to consider when prescribing contraceptives, which assist with pregnancy control, abnormal bleeding, and other gynecological symptoms. Oral contraceptives (OCs) may slightly increase breast cancer risk in long-term users, but this appears to be a short-term effect.[
Some studies show that OC use does not further increase breast cancer risk in women with high breast cancer susceptibility. For example, a meta-analysis with data from 54 studies showed that women with family histories of breast cancer did not have increased breast cancer risk from OC use.[
Some studies also suggest that the year an OC was made and a woman's age when beginning OC use may matter. For example, OCs made before 1975 are associated with increased breast cancer risk in BRCA1/2 carriers (summary relative risk [SRR], 1.47; 95% CI, 1.06–2.04).[
Other contraceptive methods have not been studied in women with pathogenic variants in breast cancer risk genes. However, studies have investigated associations between intrauterine devices and breast cancer risk in the general population. A meta-analysis and systematic review of seven studies examined the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) on breast cancer risk. The meta-analysis included studies that controlled for family history of breast cancer, but associations were not separately evaluated or stratified by family history of breast cancer. In LNG-IUS users, breast cancer risk increased in all women (OR, 1.16; 95% CI, 1.06–1.28), in women younger than 50 years (OR, 1.12; 95% CI, 1.02–1.22), and in women 50 years and older (OR, 1.52; 95% CI, 1.34–1.72).[
Hormone replacement therapy
Both observational studies and randomized clinical trials have examined the association between postmenopausal HRT and breast cancer. Short-term use of HRT for treatment of postmenopausal symptoms appears to confer little or no breast cancer risk.[
Among women with family histories of breast cancer, the associations between HRT and breast cancer risk have not been consistent. Some studies suggested risk was particularly elevated among women with family histories of breast cancer, while others did not report an interaction between these factors.[
The effect of HRT on breast cancer risk among carriers of BRCA1 and BRCA2 pathogenic variants has been studied in the context of bilateral risk-reducing oophorectomy. Short-term HRT use does not seem to alter an oophorectomy's protective effect on breast cancer risk.[
HRT use may also increase a woman's chance of developing endometrial cancer. For more information, see the Hormones section.
Radiation exposure can increase an individual's breast cancer risk. This is demonstrated by the survivors of the atomic bombings in Hiroshima and Nagasaki and by women who have received therapeutic radiation treatments to the chest and upper body. However, it is unclear how much radiation exposure affects breast cancer risk in women with high breast cancer susceptibility.
Early data suggested that carriers of BRCA1 and BRCA2 pathogenic variants may have increased sensitivity to radiation, which may contribute to cancer susceptibility.[
It is possible that radiation exposure from diagnostic procedures, including mammography, poses a greater risk to women with high breast cancer susceptibility than to women who are at average risk of developing breast cancer. Therapeutic radiation could also increase cancer risk in women with high breast cancer susceptibility. However, a cohort study of BRCA1 and BRCA2 pathogenic variant carriers treated with breast-conserving therapy did not show evidence of increased radiation sensitivity in participants. Sequelae were not observed in the breasts, lungs, or bone marrow of BRCA carriers.[
Conversely, tumors in women with pathogenic variants in breast cancer risk genes may be more responsive to radiation treatment than tumors in women at average breast cancer risk. Studies examining the impact of radiation exposure in carriers of BRCA1 and BRCA2 pathogenic variants have had conflicting results.[
A retrospective cohort study estimated the effect of adjuvant radiation therapy (for primary breast cancer) on CBC risk in BRCA1 and BRCA2 carriers (N, 691; median follow-up period, 8.6 y).[
Alcohol and smoking
The risk of breast cancer increases by approximately 10% for each 10 g of daily alcohol intake (approximately one drink or less) in the general population.[
Recent studies have evaluated the association between alcohol consumption, tobacco smoking, and breast cancer risk in individuals with BRCA1/2 pathogenic variants or family histories of breast cancer. One study evaluated if tobacco smoking and alcohol consumption are associated with increased breast cancer risk in BRCA1 and BRCA2 carriers using pooled data from an international cohort.[
Increased physical activity has been associated with reduced breast cancer risk in most epidemiological studies. This risk reduction has also been seen in studies of female BRCA1 or BRCA2 pathogenic variant carriers. For example, one study reported a 38% reduction in premenopausal breast cancer risk from moderate physical activity (OR for the top quartile of physical activity compared with the lowest level, 0.62; 95% CI, 0.40–0.96).[
Risk Factors for Ovarian Cancer
Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancers Prevention for information about risk factors for ovarian cancer in the general population.
Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote, even in hereditary cancer families.[
Family history including inherited cancer genes
Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an OR of 3.1 for the risk of ovarian cancer associated with at least one FDR with ovarian cancer.[
Nulliparity is consistently associated with an increased risk of ovarian cancer, including among carriers of BRCA/BRCA2 pathogenic variants, yet a meta-analysis identified a risk reduction only in women with four or more live births.[
Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,[
Oral contraceptives (OCs)
Use of OCs for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.[
Risk Factors for Endometrial Cancer
Refer to the PDQ summary on Endometrial Cancer Prevention for information about risk factors for endometrial cancer in the general population.
Age is an important risk factor for endometrial cancer. Most women with endometrial cancer are diagnosed after menopause. Only 15% of women are diagnosed with endometrial cancer before age 50 years, and fewer than 5% are diagnosed before age 40 years.[
Family history including inherited cancer genes
Although the hyperestrogenic state is the most common predisposing factor for endometrial cancer, family history also plays a significant role in a woman's risk for disease. Approximately 3% to 5% of uterine cancer cases are attributable to a hereditary cause,[
Non-Lynch syndrome genes may also contribute to endometrial cancer risk. In an unselected endometrial cancer cohort undergoing multigene panel testing, approximately 3% of patients tested positive for a germline pathogenic variant in non-Lynch syndrome genes, including CHEK2, APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, NBN, PTEN, and RAD51C.[
Reproductive factors such as multiparity, late menarche, and early menopause decrease the risk of endometrial cancer because of the lower cumulative exposure to estrogen and the higher relative exposure to progesterone.[
Hormonal factors that increase the risk of type I endometrial cancer are better understood. All endometrial cancers share a predominance of estrogen relative to progesterone. Prolonged exposure to estrogen or unopposed estrogen increases the risk of endometrial cancer. Endogenous exposure to estrogen can result from obesity, polycystic ovary syndrome, and nulliparity, while exogenous estrogen can result from taking unopposed estrogen or tamoxifen. Unopposed estrogen increases the risk of developing endometrial cancer by twofold to twentyfold, proportional to the duration of use.[
Autosomal Dominant Inheritance of Breast and Gynecologic Cancer Predisposition
Autosomal dominant inheritance of breast and gynecologic cancers is characterized by transmission of cancer predisposition from generation to generation, through either the mother's or the father's side of the family, with the following characteristics:
Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the syndromes associated with BRCA1 or BRCA2 pathogenic variants. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 pathogenic variants and of PTEN hamartoma tumor syndromes (including Cowden syndrome) due to PTEN pathogenic variants.[
Germline pathogenic variants in the genes responsible for these autosomal dominant cancer syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.
The family characteristics that suggest hereditary cancer predisposition include the following:
Figure 1 and Figure 2 depict some of the classic inheritance features of a BRCA1 and BRCA2 pathogenic variant, respectively. Figure 3 depicts a classic family with Lynch syndrome. (Refer to the Standard Pedigree Nomenclature figure in Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.)
Figure 1. BRCA1 pedigree. This pedigree shows some of the classic features of a family with a BRCA1 pathogenic variant across three generations, including affected family members with breast cancer or ovarian cancer and a young age at onset. BRCA1 families may exhibit some or all of these features. As an autosomal dominant syndrome, a BRCA1 pathogenic variant can be transmitted through maternal or paternal lineages, as depicted in the figure.
Figure 2. BRCA2 pedigree. This pedigree shows some of the classic features of a family with a BRCA2 pathogenic variant across three generations, including affected family members with breast (including male breast cancer), ovarian, pancreatic, or prostate cancers and a relatively young age at onset. BRCA2 families may exhibit some or all of these features. As an autosomal dominant syndrome, a BRCA2 pathogenic variant can be transmitted through maternal or paternal lineages, as depicted in the figure.
Figure 3. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer, a young age at onset in some individuals, and incomplete penetrance. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure. Because the cancer risk is not 100%, individuals who have Lynch syndrome may not develop cancer, such as the mother of the female with colon cancer diagnosed at age 37 years in this pedigree (called incomplete penetrance).
There are no pathognomonic features distinguishing breast and ovarian cancers occurring in carriers of BRCA1 or BRCA2 pathogenic variants from those occurring in noncarriers. Breast cancers occurring in carriers of BRCA1 pathogenic variants are more likely to be ER-negative, progesterone receptor (PR)–negative, human epidermal growth factor receptor two (HER2/neu)–negative (i.e., triple-negative breast cancers [TNBC]), and have a basal phenotype. BRCA1-associated ovarian cancers are more likely to be high-grade and of serous histopathology. (Refer to the BRCA1/2-associated breast cancer pathology and Pathologies of BRCA1/2-associated ovarian, fallopian tube, and primary peritoneal cancers sections in BRCA1 and BRCA2: Cancer Risks and Management for more information.)
Some pathologic features distinguish carriers of Lynch syndrome–associated pathogenic variants from noncarriers. The hallmark feature of endometrial cancers occurring in Lynch syndrome is mismatch repair (MMR) deficiencies, including the presence of microsatellite instability (MSI), and the absence of specific MMR proteins. In addition to these molecular changes, there are also histologic changes including tumor-infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated tumor histology, lower uterine segment origin, and synchronous tumors.
Considerations in Risk Assessment and in Identifying a Family History of Breast and Ovarian Cancer Risk
The accuracy and completeness of family histories must be considered when they are used to assess risk. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than does breast or ovarian cancer on the maternal side, so information may be more difficult to obtain. When self-reported information is compared with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.[
Models for Prediction of Breast and Gynecologic Cancer Risk
Models to predict an individual's lifetime risk of developing breast and/or gynecologic cancer are available.[
Breast cancer risk assessment models
In general, breast cancer risk assessment models are designed for two types of populations: 1) women without a pathogenic variant or strong family history of breast or ovarian cancer; and 2) women at higher risk because of a personal or family history of breast cancer or ovarian cancer.[
In the United States, BRCAPRO, the Claus model,[
Additional considerations for clinical use of breast cancer risk assessment models
The Gail model is the basis for the BCRAT, a computer program available from the National Cancer Institute by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). This version of the Gail model estimates only the risk of invasive breast cancer. The Gail/BCRAT model has been found to be reasonably accurate at predicting breast cancer risk in large groups of White women who undergo annual screening mammography; however, reliability varies depending on the cohort studied.[
The Gail/BCRAT model is valid for women aged 35 years and older. The model was primarily developed for White women.[
Generally, the Gail/BCRAT model should not be the sole model used for families with one or more of the following characteristics:
Commonly used models that incorporate family history include the IBIS, BOADICEA, and BRCAPRO models. The IBIS/Tyrer-Cuzick model incorporates both genetic and nongenetic factors.[
In addition, readily available models that provide information about an individual woman's risk in relation to the population-level risk depending on her risk factors may be useful in a clinical setting (e.g., Your Disease Risk). Although this tool was developed using information about average-risk women and does not calculate AR estimates, it still may be useful when counseling women about cancer prevention. Risk assessment models are being developed and validated in large cohorts to integrate genetic and nongenetic data, breast density, and other biomarkers.
Although most breast cancer risk models have been shown to be well calibrated overall, model performance can be different for subgroups of women. In particular, independent, prospective validation of risk models for women who tested negative for BRCA1 or BRCA2 pathogenic variants supported that the most commonly used clinical risk models underpredicted risk for this group of women.[
Ovarian cancer risk assessment models
Two risk prediction models have been developed for ovarian cancer.[
Endometrial cancer risk assessment models
The Pfeiffer model has been used to predict endometrial cancer risk in the general population.[
In contrast, MMRpredict, PREMM5 (PREdiction Model for gene Mutations), and MMRpro are three quantitative predictive models used to identify individuals who may potentially have Lynch syndrome.[
Table 1 summarizes salient aspects of breast and gynecologic cancer risk assessment models that are commonly used in the clinical setting. These models differ by the extent of family history included, whether nongenetic risk factors are included, and whether carrier status and polygenic risk are included (inputs to the models). The models also differ in the type of risk estimates that are generated (outputs of the models). These factors may be relevant in choosing the model that best applies to a particular individual.
|Model||Family History (input)||Pathogenic Variants (input)||Risk Factors (input)||Risk Estimate Generated (output)|
|BCRAT = Breast Cancer Risk Assessment Tool; BOADICEA = Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm; IBIS = International Breast Cancer Intervention Study; PREMM = PREdiction Model for gene Mutations.|
|a High risk is defined as those with a personal or family history of the designated cancer type.|
|b Takes into account polygenes as an underlying assumption of the model.|
|Breast Cancer Risk Assessment Models|
|Models for Average-Risk Women|
|Gail/BCRAT||First-degree relatives (breast cancer)||No||Yes||Breast cancer|
||First-degree relatives (breast, ovarian cancers)||No||Yes||Breast cancer|
|Colditz and Rosner[
|Models for High-Risk Womena|
||Multigenerational (breast cancer)||No||No||Breast cancer|
|BRCAPRO||Multigenerational (breast, ovarian cancers)||BRCA1/BRCA2||No||Breast cancer; % risk of carryingBRCA1/BRCA2pathogenic variant|
|IBIS||Multigenerational (ovarian cancer)||BRCA1/BRCA2||Yes||Breast cancer; % risk of carryingBRCA1/BRCA2pathogenic variant|
|BOADICEAb||Multigenerational (pancreatic, breast, ovarian cancers)||BRCA1/BRCA2||No||Breast and ovarian cancer; % risk of carryingBRCA1/BRCA2pathogenic variant|
|Ovarian Cancer Risk Assessment Models|
|Models for Average-Risk Women|
||First-degree relatives (breast, ovarian cancers)||No||Yes||Breast cancer|
|Models for High-Risk Womena|
|BOADICEAb||Multigenerational (pancreatic, breast, ovarian cancers)||BRCA1/BRCA2||No||Breast and ovarian cancer; % risk of carryingBRCA1/BRCA2pathogenic variant|
|Endometrial Cancer Risk Assessment Models|
|Models for Average-Risk Women|
|Models for High-Risk Womena|
|PREMM5||Multigenerational (colon, endometrial and other Lynch syndrome–associated cancers and polyps)||No||No||% risk of carryingMLH1,MSH2,MSH6pathogenic variant|
|MMRpro||Multigenerational (colon, endometrial cancers)||No||No||% risk of carryingMLH1,MSH2,MSH6pathogenic variant|
||Multigenerational (colon, endometrial cancers)||No||No||% risk of carryingMLH1,MSH2,MSH6pathogenic variant|
Models for Predicting the Likelihood of aBRCA1/BRCA2Pathogenic Variant
Many models have been developed to predict the probability of identifying germline BRCA1/BRCA2 pathogenic variants in individuals or families. These models include those using logistic regression,[
In addition to BOADICEA, BRCAPRO is commonly used for genetic counseling in the clinical setting. BRCAPRO and BOADICEA predict the probability of being a carrier and produce estimates of breast cancer risk (refer to Table 2). The discrimination and accuracy (factors used to evaluate the performance of prediction models) of these models are much higher for their ability to report on carrier status than for their ability to predict fixed or remaining lifetime risk.
BOADICEA is a polygenetic model that uses complex segregation analysis to examine both breast cancer risk and the probability of having a BRCA1 or BRCA2 pathogenic variant.[
The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families.[
The power of several of the models has been compared in different studies.[
|||Myriad Prevalence Tables[
|AJ = Ashkenazi Jewish; BOADICEA = Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm; FDR = first-degree relatives; SDR = second-degree relatives.|
|Method||Empiric data from Myriad Genetics based on personal and family history reported on requisition forms||Statistical model, assumes autosomal dominant inheritance||Statistical model, assumes polygenic risk||Statistical model, assumes autosomal dominant inheritance|
|Features of the model||Probandmay or may not have breast or ovarian cancer||Proband may or may not have breast or ovarian cancer||Proband may or may not have breast or ovarian cancer||Proband must beunaffected|
|Considers age of breast cancer diagnosis as <50 y, >50 y||Considers exact age at breast and ovarian cancer diagnosis||Considers exact age at breast and ovarian cancer diagnosis||Also includes reproductive factors and body mass index to estimate breast cancer risk|
|Considers breast cancer in ≥1 affected relative only if diagnosed <50 y||Considers prior genetic testing in family (i.e.,BRCA1/BRCA2 pathogenic variant–negative relatives)||Includes allFDRandSDRwith and without cancer|
|Considers ovarian cancer in ≥1 relative at any age||Considers oophorectomy status||Includes AJ ancestry|
|Includes AJ ancestry||Includes all FDR and SDR with and without cancer|
|Very easy to use||Includes AJ ancestry|
|Limitations||Simplified/limited consideration of family structure||Requires computer software and time-consuming data entry||Requires computer software and time-consuming data entry||Designed for individuals unaffected with breast cancer|
|Incorporates only FDR and SDR; may need to change proband to best capture risk and to account for disease in the paternal lineage|
|May overestimate risk in bilateral breast cancer[
|Early age of breast cancer onset||May perform better in White populations than in racial and ethnic minority populations[
||Incorporates only FDR and SDR; may need to change proband to best capture risk|
|May underestimate risk ofBRCApathogenic variant in high-grade serous ovarian cancers but overestimate the risk for other histologies[
Genetic testing for BRCA1 and BRCA2 pathogenic variants has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This, in turn, gives providers better data to estimate an individual patient's risk of carrying a pathogenic variant, but risk assessment continues to be an art. There are factors that might limit the ability to provide an accurate risk assessment (i.e., small family size, paucity of women, or ethnicity) including the specific circumstances of the individual patient (such as history of disease or risk-reducing surgeries).
Considerations When Conducting Genetic Testing
Indications for hereditary breast and gynecologic cancers genetic testing
Several professional organizations and expert panels—including the American Society of Clinical Oncology,[
In 2019, the American Society of Breast Surgeons published a recommendation to make genetic testing for "BRCA1/BRCA2, and PALB2, with other genes as appropriate for the clinical scenario and family history" available to all breast cancer patients.[
Other studies have also found that the NCCN criteria have good sensitivity when predicting BRCA1/BRCA2 variants; however, less is known about many other genes. For example, one study showed that the NCCN criteria were able to detect 88.9% of the BRCA1/BRCA2 pathogenic variant carriers [
As the cost of genetic testing continues to decrease, there is a need for unbiased evidence to guide indications for testing, including the cost-benefit impact on screening, prevention, and treatment. Efforts to generate less biased evidence include a single institution study of 3,907 unselected women with breast cancer tested for nine breast cancer genes, including BRCA1/BRCA2, ATM, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53.[
Another study to assess frequency of pathogenic or likely pathogenic variants among breast cancer patients included a nested case-control study conducted through the WHI cohort among women with (cases) and without (controls) invasive breast cancer. Participants were tested for pathogenic or likely pathogenic variants in ten breast cancer–associated genes, including BRCA1/BRCA2.[
Benefits of offering genetic testing at the time of cancer diagnosis
At the time of a new cancer diagnosis, genetic testing for inherited cancer predisposition may guide patient care including decisions about surgery, chemotherapy and other biologics, and radiation treatment.[
Breast cancer diagnosis
Benefits of offering genetic testing at the time of breast cancer diagnosis include, but are not limited to, the following:
Ovarian cancer diagnosis
Benefits of offering genetic testing at the time of ovarian cancer diagnosis include, but are not limited to, the following:
Endometrial cancer diagnosis
Benefits of offering genetic testing at the time of endometrial cancer diagnosis include, but are not limited to, the following:
Multigene (panel) testing
Since the availability of next-generation sequencing and the Supreme Court of the United States ruling that human genes cannot be patented, several clinical laboratories now offer genetic testing through multigene panels at a cost comparable to that of single-gene testing. Even testing for BRCA1 and BRCA2 is a limited panel test of two genes. Approximately 25% of all ovarian/fallopian tube/peritoneal cancers are caused by a heritable genetic condition. Of these, about one-quarter (6% of all ovarian/fallopian tube/peritoneal cancers) are caused by genes other than BRCA1 and BRCA2, including many genes associated with the Fanconi anemia pathway or otherwise involved with homologous recombination.[
In general, multigene panel testing increases the yield of non-BRCA pathogenic variants across a variety of populations.[
Multi-gene panel testing was conducted as part of two large efforts led by the worldwide Breast Cancer Association Consortium (BCAC) [
NCCN recommends that women diagnosed with TNBC undergo BRCA1/BRCA2, CDH1, PALB2, PTEN, and TP53 testing to guide treatment decisions at any age.[
Multi-gene panel testing studies were conducted in women from the United States who had African ancestry, and results showed that certain genes were associated with increased breast cancer risk in this population. These genes were similar to the breast cancer risk genes found in individuals from the United States with European ancestry. A case-control study of 10,047 women with African ancestry found a pathogenic variant frequency of 10.3% in those with ER-negative breast cancer, 5.2% in those with ER-positive breast cancer, and 2.3% in those without breast cancer. BRCA1 (OR, 47), BRCA2 (OR, 7.25) and PALB2 (OR, 8.54) were associated with the highest breast cancer risks.[
There are caveats of multigene testing. Genes identified as part of multigene panel testing can be associated with varied breast cancer risk or confer no known risk.[
(Refer to the Multigene [panel] testing section in Cancer Genetics Risk Assessment and Counseling for more information about multigene testing, including genetic education and counseling considerations and research examining the use of multigene testing.)
The proportion of individuals carrying a pathogenic variant who will manifest a certain disease is referred to as penetrance. In general, common genetic variants that are associated with cancer susceptibility have a lower penetrance than rare genetic variants. This is depicted in Figure 4. For adult-onset diseases, penetrance is usually described by the individual carrier's age, sex, and organ site. For example, the penetrance for breast cancer in female carriers of BRCA1 pathogenic variants is often quoted by age 50 years and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual carrier's risk of cancer involves some level of imprecision.
Figure 4. Genetic architecture of cancer risk. This graph depicts the general finding of a low relative risk associated with common, low-penetrance genetic variants, such as single-nucleotide polymorphisms identified in genome-wide association studies, and a higher relative risk associated with rare, high-penetrance genetic variants, such as pathogenic variants in the BRCA1/BRCA2 genes associated with hereditary breast and ovarian cancer and the mismatch repair genes associated with Lynch syndrome.
Throughout this summary, we discuss studies that report on relative and absolute risks (ARs). These are two important but different concepts. Relative risk (RR) refers to an estimate of risk relative to another group (e.g., risk of an outcome like breast cancer for women who are exposed to a risk factor relative to the risk of breast cancer for women who are unexposed to the same risk factor). RR measures that are greater than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is higher than the risk for those captured in the denominator (i.e., the unexposed). RR measures that are less than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is lower than the risk for those captured in the denominator (i.e., the unexposed). Measures with similar relative interpretations include the odds ratio (OR), hazard ratio, and risk ratio.
AR measures consider the number of people who have a particular outcome, the number of people in a population who could have the outcome, and person-time (the period of time during which an individual was at risk of having the outcome). AR measures also reflect the absolute burden of an outcome in a population. Absolute measures include risks and rates and can be expressed over a specific time frame (e.g., 1 year, 5 years) or overall lifetime. Cumulative risk is a measure of risk that occurs over a defined time period. For example, overall lifetime risk is a type of cumulative risk that is usually calculated on the basis of a given life expectancy (e.g., 80 or 90 years). Cumulative risk can also be presented over other time frames (e.g., up to age 50 years).
Large RR measures do not mean that there will be large effects in the actual number of individuals at a population level because the disease outcome may be quite rare. For example, the RR for smoking is much higher for lung cancer than for heart disease, but the absolute difference between smokers and nonsmokers is greater for heart disease, the more-common outcome, than for lung cancer, the more-rare outcome.
Therefore, in evaluating the effect of exposures and biological markers on disease prevention across the continuum, it is important to recognize the differences between relative and absolute effects in weighing the overall impact of a given risk factor. For example, the magnitude is in the range of 30% (e.g., ORs or RRs of 1.3) for many breast cancer risk factors, which means that women with a risk factor (e.g., alcohol consumption, late age at first birth, oral contraceptive use, postmenopausal body size) have a 30% relative increase in breast cancer in comparison with what they would have if they did not have that risk factor. But the absolute increase in risk is based on the underlying AR of disease. Figure 5 and Table 3 show the impact of a RR factor in the range of 1.3 on AR. (Refer to the Standard Pedigree Nomenclature figure in Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.) As shown, women with a family history of breast cancer have a much higher benefit from risk factor reduction on an absolute scale.[
Figure 5. These five pedigrees depict probands with varying degrees of family history. Table 3 accompanies this figure.
|Family History||Lifetime Risk (%)||Lifetime Risk After Risk Factor Modification (%)||Absolute Risk Difference (%)||Relative Risk|
|a Refer to Figure 5, which accompanies this table.|
|Low (Family 1)||10.9||8.4||2.50||1.29 (29% increased risk)|
|Moderate (Family 2)||21.6||16.8||4.80||1.28 (28% increased risk)|
|Moderate/high (Family 3)||27.1||21.3||5.80||1.27 (27% increased risk)|
|High (Family 4)||32.0||25.3||6.70||1.26 (26% increased risk)|
|BRCA1pathogenic variant (Family 5)||53.7||44.2||9.50||1.21 (21% increased risk)|
With the increasing use of multigene panel tests, a framework for cancer risk management among individuals with pathogenic variants detected in novel genes has been described [
Several genes are found to be associated with the development of breast and/or gynecologic cancers. These genes are categorized as high-penetrance, moderate-penetrance, and low-penetrance in this summary. The high- and moderate-penetrance genes are summarized in Table 4. Low-penetrance genes and loci primarily include polymorphisms that have been associated with cancer susceptibility. (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes, Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancer, and Single Nucleotide Variant–Associated Cancer Risks sections of this summary for more information.)
|Cancer Susceptibilitya||Moderate-Penetrance Genesb||High-Penetrance Genes|
|a Other cancers may be associated with the genes in this table.|
|b Other genes discussed in the Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancersection of this summary but for which penetrance is unknown includeCASP8,TGFB1,Abraxas,RECQL, andSMARCA4.|
For more information about BRCA1 and BRCA2 pathogenic variants and BRCA-associated cancer risks, see BRCA1 and BRCA2: Cancer Risks and Management.
Lynch syndrome is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer.[
After colorectal cancer, endometrial cancer is the second hallmark cancer of a family with Lynch syndrome. Even in the original Family G, described by Dr. Aldred Scott Warthin, numerous family members were noted to have extracolonic cancers including endometrial cancer. Although the first version of the Amsterdam criteria did not include endometrial cancer,[
The lifetime risk of ovarian carcinoma in females with Lynch syndrome is estimated to be as high as 12%, and the reported relative risk (RR) of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected Lynch syndrome.[
The issue of breast cancer risk in Lynch syndrome has been controversial.
Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome;[
A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[
Refer to the Lynch Syndrome section of the Clinical Management of Other Hereditary Breast and/or Gynecologic Cancer Syndromes section of this summary for information about clinical management of Lynch syndrome.
Li-Fraumeni Syndrome (LFS)
Breast cancer is also a component of the rare LFS, in which germline variants of the TP53 gene on chromosome 17p have been documented. Located on chromosome 17p, TP53 encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. It is also an active component of programmed cell death.[
LFS is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[
Germline variants in TP53 are thought to account for fewer than 1% of breast cancer cases.[
Historical criteria for defining LFS
The term LFS was used for the first time in 1982,[
Subsequently in 2001, Chompret et al. [
These criteria were revised in 2009 [
*The 2009 Chompret criteria defined the LFS tumor spectrum as including the following cancers: soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, and lung bronchoalveolar cancer.
In 2015, Bougeard et al. [
**The 2015 Chompret criteria defined the LFS tumor spectrum as including the following cancers: premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, and adrenocortical carcinoma.
Clinical characteristics of LFS
Germline TP53 pathogenic variants were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical TP53 testing.[
Subsequently, a large clinical series of patients from France who were tested primarily based on the 2009 version of the Chompret criteria [
Similarly, results of 286 TP53 pathogenic variant–positive individuals in the National Cancer Institute's LFS Study indicated a cumulative cancer incidence of almost 100% by age 70 years for both males and females.[
|||Cumulative Cancer Risk by Age 70 Years|
| a Adapted from Mai et al.[
| b Other cancers, such as adrenocortical carcinoma, leukemia, and lung bronchoalveolar cancer, have been considered part of the LFS cancer spectrum.[
|Cancer Type||Females (%)||Males (%)|
|Soft tissue sarcoma||15||22|
With the increasing use of multigene (panel) tests, it is important to recognize that pathogenic variants in TP53 are unexpectedly being identified in individuals without a family history characteristic of LFS.[
One cohort study evaluated 116 individuals with a germline TP53 pathogenic variant yearly at the National Institutes of Health Clinical Center using multimodality screening with and without gadolinium. Baseline screening identified a cancer in eight patients (6.9%) with a false-positive rate of 34.5% for MRI (n = 40).[
PTENHamartoma Tumor Syndromes (Including Cowden Syndrome)
Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes (PHTS). Approximately 85% of patients diagnosed with Cowden syndrome, and approximately 60% of patients with BRRS have an identifiable PTEN pathogenic variant.[
PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, serine, and threonine. PTEN pathogenic variants are diverse and can present as nonsense, missense, frameshift, or splice-site variants. Approximately 40% of variants are found in exon 5, which encodes the phosphatase core motif; several recurrent pathogenic variants have been observed at this location.[
Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[
Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for PTEN testing in the United States, Europe, and Asia.[
Although PTEN pathogenic variants, which are estimated to occur in 1 in 200,000 individuals,[
Diffuse Gastric and Lobular Breast Cancer Syndrome
The E-cadherin gene CDH1 was first described in 1998 in three Maori families with multiple cases of diffuse gastric cancer (DGC), leading to the designation of hereditary diffuse gastric cancer (HDGC). There have been multiple subsequent reports of an excess of lobular breast cancer in HDGC families.[
HDGC is an autosomal dominant syndrome associated with poorly differentiated invasive adenocarcinoma of the stomach presenting as linitis plastica. It is a highly penetrant and highly fatal syndrome, with a risk of clinical DGC ranging from 40% to 83%.[
Peutz-Jeghers Syndrome (PJS)
PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[
Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.[
Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in overestimates of these risks should be considered.
|Site||Age (y)||Cumulative Risk (%)b||Reference(s)|
|GI = gastrointestinal.|
| a Reprinted with permission from Macmillan Publishers Ltd: Gastroenterology[
|b All cumulative risks were increased compared with the general population (P< .05), with the exception of cervix and testes.|
|c GI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.|
| d Westerman et al.: GI cancer does not include pancreatic cancer.[
|e Did not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.|
PJS is caused by pathogenic variants in the STK11 (also called LKB1) tumor suppressor gene located on chromosome 19p13.[
Germline variants of the STK11 gene represent a spectrum of nonsense, frameshift, and missense variants, and splice-site variants and large deletions.[
Approximately 85% of variants are localized to regions of the kinase domain of the expressed protein. No strong genotype-phenotype correlations have been identified.[
STK11 has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% pathogenic variant detection rate in STK11, studies adding techniques to detect large deletions have found pathogenic variants in up to 94% of individuals meeting clinical criteria for PJS.[
The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS) in the PDQ summary on Genetics of Colorectal Cancer.
PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double-stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic pathogenic variants in PALB2 have also been shown to cause Fanconi anemia.[
PALB2 pathogenic variants have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations.[
Data based on 154 families with loss-of-function PALB2 variants suggest that this gene may be an important cause of hereditary breast cancer, with risks that overlap with BRCA2.[
In a later Polish study of more than 12,529 unselected women with breast cancer and 4,702 controls, PALB2 pathogenic variants were detected in 116 cases (0.93%; 95% CI, 0.76%–1.09%) and 10 controls (0.21%; 95% CI, 0.08%–0.34%), with an OR for breast cancer of 4.39 (95% CI, 2.30–8.37).[
A similar case-control study from China enrolled 16,501 unselected patients with breast cancer and 5,890 controls. These patients were screened for PALB2, BRCA1, and BRCA2 pathogenic variants. The prevalence of PALB2 pathogenic variants was 0.97% in the cases and 0.19% in the controls. The OR for breast cancer for carriers was 5.23 (95% CI, 2.84–9.65; P > .0001). PALB2 carriers were more likely to be age 30 years or younger (6.88% vs. 3.56%; P = .04). PALB2 carriers were also more likely to have TNBCs (22.83% vs. 13.56%; P = .004), larger tumors (tumor size ≥2 cm, 55.93% vs. 45.93%; P = .04), node-positive tumors (49.60% vs. 38.80%; P = .018), and CBCs (6.29% vs. 2.01%; P = .003). Additionally, PALB2 carriers were more likely to have a family history of breast and/or ovarian cancers (20.63% vs. 7.96%; P < .0001).[
In the largest study to date, 524 families with pathogenic variants in PALB2 recruited through an international effort, the RR of breast cancer in women was reported to be 7.18 (95% CI, 5.82–8.85), with a 53% risk (95% CI, 44%–63%) of breast cancer to age 80 years.[
Male breast cancer has been observed in PALB2 pathogenic variant–positive breast cancer families.[
After the identification of PALB2 pathogenic variants in pancreatic tumors and the detection of germline pathogenic variants in 3% of 96 familial pancreatic patients,[
Overall, the observed prevalence of PALB2 pathogenic variants in familial breast cancer varied depending on ascertainment relative to personal and family history of pancreatic and ovarian cancers, but in all studies, the observed pathogenic variant rate was lower than 4%. Data suggest that the RR of breast cancer may overlap with that of BRCA2, particularly in those with a strong family history; thus, it remains important to refine cancer risk estimates in larger studies. Furthermore, the risk of other cancers (e.g., pancreatic) is poorly defined. Given the low PALB2 pathogenic variant prevalence in the population, additional data are needed to define best candidates for testing and appropriate management.
De Novo Pathogenic Variant Rate
Until the 1990s, the diagnosis of genetically inherited breast and ovarian cancer syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous pathogenic variant rate (de novo pathogenic variant rate) in these populations. Interestingly, PJS, PTEN hamartoma syndromes, and LFS are all thought to have high rates of spontaneous pathogenic variants, in the 10% to 30% range,[
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.[
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 7). 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, FANCC accounts for approximately 14%, and the remaining genes each account for 3% or fewer.[
|a Refer to the BRCA1 and BRCA2summary for information about the cumulative risk of breast cancer incarriersofBRCA1andBRCA2pathogenic variants.|
|b Refer to thePALB2section for information about the cumulative risk of breast cancer in carriers ofPALB2pathogenic variants.|
|c Moderate risk is defined as a statistically significant, twofold or lower increased risk estimate.|
|Moderate-Risk Genes c|
|Genes With Uncertain or No Significantly Increased Risk|
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.[
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 (also known as BACH1) encodes a helicase that interacts with the BRCA1 C-terminal 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,[
Monoallelic pathogenic variants in BRIP1 have emerged as having a significant association with increased ovarian cancer risk. Nine-tenths to two and half percent of women with ovarian cancer carry a pathogenic variant in BRIP1.[
With respect to breast cancer risk, several studies consistently report ORs less than 2.0. A meta-analysis of 148 studies found an OR for breast cancer of 1.62 in individuals with BRIP1 pathogenic variants (95% confidence interval [CI], 1.20–2.20).[
CHEK2 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.[
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.[
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,[
(Refer to the CHEK2 section in Genetics of Colorectal Cancer for more information.)
Ataxia telangiectasia (AT) 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.[
Initial, large epidemiological studies demonstrated a statistically increased relative risk (RR) of approximately 2.0 for breast cancer among female ATM heterozygotes.[
Age-specific cumulative breast cancer risks modeled through a meta-analysis were reported to be 6.02% by age 50 years and 32.83% by age 80 years.[
While multiple studies have reported that most ATM pathogenic variants impart moderate risks for breast cancer, the c.7271T>G missense variant has been shown to predispose individuals to higher breast cancer risks.[
Some studies reported an association between ATM and ovarian cancer, with ovarian cancer lifetime risk approaching ~3%.[
Pancreatic cancer has also been associated with ATM pathogenic variants, with an OR of 4.21 (95% CI, 3.24–5.47) reported through a commercial lab–based study.[
The association between ATM pathogenic variants and prostate cancer risk have been inconclusive, with a commercial lab–based study reporting an OR of 2.58 (95% CI, 1.93–3.44).[
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.[
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%).[
In addition to carriers of RAD51C pathogenic variants, there are other RAD51 paralogs, including RAD51B, RAD51D, RAD51L1, XRCC2, and XRCC3, that may be associated with breast and/or ovarian cancer risk,[
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 SNV (hazard ratio, 1.17; 95% CI, 0.91–1.51).[
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.[
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.
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.[
Despite only approximately 300 cases in the literature, three separate research groups showed SCCOHT to be associated with germline pathogenic variants and somatic mutations 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.[
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.[
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.[
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.[
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 SNVs that are chosen to capture a large portion of common variation within the genome based on the HapMap and the 1000 Genomes Project.[
Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases,[
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 SNVs and epidemiologic risk factors for breast cancer have been identified.[
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.[
Polygenic risk scores for breast and ovarian cancer
The collective influence of many genetic variants has more recently been evaluated using an aggregate score. In 2015, a polygenic risk score (PRS) comprising all of the known breast cancer risk genetic variants or SNVs was estimated in women of European ancestry using 41 studies in the BCAC, including more than 33,000 breast cancer cases and 33,000 controls.[
Common genomic variants associated with the development of a first primary breast cancer are also associated with the development of CBC.[
Two large studies have supported that PRSs can improve breast cancer risk stratification.[
Several studies have also examined the extent to which clinical breast cancer risk prediction models can be improved by including information on known susceptibility SNVs, and reporting improved discriminatory accuracy after inclusion of the PRS.[
A large study examined whether known reproductive and lifestyle risk factors interact with PRSs to increase breast cancer risk and did not find a multiplicative interaction with established risk factors.[
Whole-Genome and Whole-Exome Sequencing
In addition to GWAS interrogating common genetic variants, sequencing-based studies involving whole-genome or whole-exome sequencing [
For more information, see the Management of Cancer Risks in BRCA1/2 Carriers section in BRCA1 and BRCA2: Cancer Risks and Management.
As mismatch repair genes were identified as the genetic basis of Lynch syndrome, microsatellite instability was identified as a common molecular marker of mismatch repair deficiency. Approximately 15% of sporadic colorectal cancers show microsatellite instability, while up to 28% of sporadic endometrial cancers have this molecular change.[
Certain histopathologic features are also strongly suggestive of a microsatellite instability phenotype, including the presence of tumor infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated carcinomas, and lower uterine segment tumors. Use of clinical criteria is one strategy of selection criteria for tumor testing. Computer models have also been used to predict the probability of a mismatch repair genetic variant and can be used in the absence of microsatellite instability or immunohistochemistry information.[
Psychosocial research in the context of cancer genetic testing helps to define psychological outcomes, interpersonal and familial effects, and cultural and community responses. This type of research also identifies behavioral factors that encourage or impede screening and other health behaviors. It can enhance decision making about risk-reduction interventions, evaluate psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification and genetic testing, provide data to help resolve ethical concerns, and predict the interest in testing of various groups.
Psychosocial and screening issues related to gynecologic cancers associated with Lynch syndrome are discussed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section in Genetics of Colorectal Cancer.
Uptake of Genetic Counseling and Genetic Testing
Degree of uptake of genetic counseling and genetic testing
Comparison of uptake rates among studies in which counseling and testing were offered is challenging because of differences in methodologies, including the sampling strategy used, the recruitment setting, and testing through a research protocol with high-risk cohorts or kindreds. In a systematic review of 40 studies conducted before 2002 that had assessed genetic testing utilization, uptake rates varied widely and ranged from 25% to 96%, with an average uptake rate of 59%.[
Other factors have been positively correlated with uptake of BRCA1/BRCA2 genetic testing, although these findings are not consistent across all studies. Psychological factors that have been positively correlated with testing uptake include greater cancer-specific distress and greater perceived risk of developing breast or ovarian cancer. Having more cancer-affected relatives also has been correlated with greater testing uptake.
Table 8 summarizes the uptake of genetic testing in clinical and research cohorts in the United States.
|Study Citation||Study Population||Sample Size (N)||Uptake of GT||Predictors Associated With Uptake of GT||Comments|
|GC =genetic counseling; HMO = health maintenance organization.|
|a Self-report as data source.|
|b Medical records as data source.|
|Schwartz et al. (2005)[
||Newly diagnosed and locally untreated breast cancer patients with ≥10% risk of having aBRCA1/BRCA2 pathogenic variant a||231||177/231 (77%) underwent GT||Having decided on definitive local treatment. Women who were undecided on a definitive local treatment were more likely to be tested||Testing was offered free of charge|
|34/231 (15%) had baseline interview but declined GT|
|Physician recommendation for testing. Women whose physician had recommended GT were more likely to be tested||38/177 chose to proceed with treatment before receiving test results|
|20/231 declined baseline interview|
|Kieran et al. (2007)[
||Women who received GC between 2002 and 2004a||250||88/250 (35%) underwent GT||Ability to pay for GT (entire cost or cost not covered by insurance). Nonuptake was 5.5 times more likely in women who could not afford testing||450 women received GC for breast and ovarian cancer risk during study period. 250 women were retrospectively identified as eligible and were mailed a study questionnaire|
|36/88 returned surveys|
|Ability to recall risk estimates that were provided post-GC. Nonuptake was 15.5 times more likely in women who could not recall their risk estimates||All women had some form of insurance|
|162/250 (65%) eligible|
|65/162 returned surveys|
|Susswein et al. (2008)[
||African American women and White women with breast cancerb||768||529/768 (69%) underwent GT||Race and ethnicity. African American women were less likely to be tested than White women||Sample obtained from a clinical database. Testing was offered free of charge when it was not covered by insurance. This effect for time of diagnosis was significant in the African American subgroup but not in the White subgroup|
|African American women: 77/132 (58%) underwent GT|
|Recent diagnosis. African American women who were recently diagnosed were more likely to be tested|
|White women: 452/636 (71%) underwent GT|
|Olaya et al. (2009)[
||Patients referred for GT between 2001 and 2008b||213||111/213 (52%) underwent GT||Personal history of breast cancer. Having a personal history was associated with 3 times greater odds of being tested||Insurance coverage for testing was available for 91.1% (175/213) of patients. Of those who had coverage for GT, 51.4% underwent testing and 48.6% did not. Of those without coverage, 41.2% had GT and 58.9% did not|
|102/213 (48%) declined GT||Higher level of education. Those with a high school education or less had one-third the odds of being tested, compared with those with at least some college|
|Levy et al. (2010)[
||Women aged 20–40 y with newly diagnosed early-onset breast cancer.b||1,474||446/1,474 (30%) underwent GT||Race and ethnicity. Women of Jewish ethnicity were 3 times more likely to be tested than non-Jewish White women. African American and Hispanic women were significantly less likely to receive testing than non-Jewish White women||Sample obtained from a national database of commercially insured individuals|
|Jewish women: 18/32 (56%) underwent GT||Home location. Women living in the south were more likely to be tested than women living in the northeast|
|African American women: 10/82 (12%) underwent GT||Insurance type. Women with point-of-service plans were more likely to be tested than women with HMO plans|
|Recent diagnosis. Women diagnosed in 2007 were 3.8 times more likely to be tested than women diagnosed in 2004|
Several studies conducted in non-U.S. settings have examined the uptake of genetic testing.[
Factors influencing uptake of genetic counseling and genetic testing
In reviews that have examined the cumulative evidence concerning the predictors of uptake of BRCA1/BRCA2 genetic testing, important predictors of testing uptake include older age, Ashkenazi Jewish (AJ) heritage, unmarried status, a personal history of breast cancer, and a family history of breast cancer. Studies recruiting participants in hospital settings had significantly higher recruitment rates than did studies recruiting participants in community settings. Studies that required an immediate decision to test, rather than allowing delayed decision making, tended to report higher uptake rates.[
In a review of racial and ethnic differences that affect the uptake of BRCA1/BRCA2 testing, intention to undergo genetic testing in African American women was related to having at least one FDR with breast cancer or ovarian cancer, higher perceived risk of being a carrier, and less anticipatory guilt about the possibility of being a gene carrier.[
Reasons cited for following through with testing included a desire to learn about a child's risk, to feel relief from uncertainty, to inform screening or risk-reducing surgery decisions, and to inform important life decisions such as marriage and childbearing.[
Physician recommendation may be another motivator for testing. In a retrospective study of 335 women considering genetic testing, 77% reported that they wanted the opinion of a genetics physician about whether they should be tested, and 49% wanted the opinion of their primary care provider.[
The uptake of BRCA testing to inform surgical treatment decisions when offered appears to be high in research cohorts;[
Insurance coverage is an important consideration for individuals deciding whether to undergo genetic testing. (Refer to the Insurance coverage section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Uptake of genetic counseling and genetic testing in diverse populations
Degree of uptake of genetic counseling and genetic testing in diverse populations
There are limited data on uptake of genetic counseling and testing among non-White populations, and further research will be needed to define factors influencing uptake in these populations.[
Notably, the racial differences observed in these studies do not appear to be explained by factors related to cost, access to care, risk factors for carrying a BRCA1 or BRCA2 pathogenic variant, or differences in psychosocial factors, including risk perceptions, worry, or attitudes toward testing.
Factors influencing uptake of genetic counseling and genetic testing in diverse populations
Several studies have examined uptake or "acceptance" of BRCA testing among African American individuals enrolled in genetic research programs. Among study enrollees from an African American kindred in Utah, 83% underwent BRCA1 testing.[
Work examining attitudes toward breast cancer genetic testing in Latino and African American populations indicates limited knowledge and awareness about testing but a generally receptive view once they are informed; in comparison with White populations, Latino and African American populations have relatively more concerns about testing.
For example, in a qualitative study with 51 Latino individuals unselected for risk status, important findings included the fact that participants were highly interested in genetic testing for inherited cancer susceptibility, despite very limited knowledge about genetics. One important barrier involved secrecy or embarrassment about family discussions of cancer and genetics, which could be addressed in intervention strategies.[
A telephone survey of 314 patients from an inner-city network of Pittsburgh, Pennsylvania, health centers, 50% of whom were African American, found that most participants (57%) (both African American and White participants) felt that genetic testing to evaluate disease risk was a good idea; however, more African American participants than White participants thought that genetic testing would lead to racial discrimination (37% vs. 22%, respectively) and that genetics research was unethical and tampered with nature (20% vs. 11%, respectively).[
In a sample of 146 African American women meeting criteria for BRCA1/BRCA2 pathogenic variant testing, women born outside the United States reported higher levels of anticipated negative emotional reactions (e.g., fear, hopelessness, and lack of confidence that they could emotionally handle testing). Higher levels of breast cancer–specific distress were associated with anticipated negative emotional reactions, confidentiality concerns, and anticipated guilt regarding the family impact of breast cancer genetic testing.[
There are racial differences in provider discussion and patient uptake of genetic testing for variants in BRCA1/BRCA2. A study of women aged 18 to 64 years and diagnosed with invasive breast cancer between 2007 and 2009 found that, even after adjusting for pathogenic variant risk, African American women were less likely to report having received a physician recommendation for genetic testing. There was no difference across all races in concerns that BRCA1/BRCA2 testing was too expensive and only minimal differences in testing attitudes or insurance concerns were found, none of which influenced testing uptake.[
Factors associated with declining genetic counseling and testing
There is evidence that primary reasons for declining testing involves being childless, which reduces any family motivations for testing; and concerns about the negative ramifications of testing, including difficulty retaining insurance or concerns about personal health.
Limited data are available about the characteristics of at-risk individuals who decline to be tested or have never been tested. It is difficult to access samples of test decliners because they may be reluctant to participate in research studies. Studies of genetic testing uptake are difficult to compare because people may decline at different points and with different amounts of pretest education and counseling. One study found that 43% of affected and unaffected individuals from hereditary breast/ovarian cancer families who completed a baseline interview regarding testing declined to be tested. Most individuals who declined testing chose not to participate in educational sessions. Decliners were more likely to be male and be unmarried and have fewer relatives with breast cancer. Decliners who had high levels of cancer-related stress had higher levels of depression. Decliners lost to follow-up were significantly more likely to be affected with cancer.[
Another study looked at a small number (n = 13) of women decliners who carried a 25% to 50% probability of harboring a BRCA pathogenic variant; these nontested women were more likely to be childless and to have higher levels of education. This study showed that most women decided not to undergo the test after serious deliberation about the risks and benefits. Satisfaction with frequent surveillance was given as one reason for nontesting by most of these women.[
A third study evaluated characteristics of 34 individuals who declined BRCA1/BRCA2 testing in a large multicenter study in the United Kingdom. Decliners were younger than a national sample of test acceptors, and female decliners had lower mean scores on a measure of cancer worry. Although 78% of test decliners/deferrers felt that their health was at risk, they reported that learning about their BRCA1/BRCA2 pathogenic variant status would cause them to worry about the following:
Apprehension about the impact of the test result was a more important factor in the decision to decline testing than were concrete burdens such as time required to travel to a genetics clinic and time spent away from work, family, and social obligations.[
Genetic counseling and testing in children
Testing for BRCA1/BRCA2 pathogenic variants has been almost universally limited to adults older than 18 years. The risks of testing children for adult-onset disorders, such as breast and ovarian cancers, as inferred from developmental data on children's medical understanding and ability to provide informed consent, have been outlined in several reports.[
Studies suggest that individuals who have undergone BRCA1/BRCA2 genetic testing or who are adult offspring of individuals who have had testing are generally not in favor of testing minors.[
No data exist on the testing of children for BRCA1/BRCA2 pathogenic variants, although some researchers believe it is necessary to test the validity of assumptions underlying the general prohibition of testing children for genetic variants associated with breast and ovarian cancers and other adult-onset diseases.[
What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics
The emerging literature in this area suggests that risk perceptions, health beliefs, psychological status, and personality characteristics are important factors in decision making about breast/ovarian cancer genetic testing. Many women presenting at academic centers for BRCA1/BRCA2 testing arrive with a strong belief that they have a pathogenic variant, having decided they want genetic testing, but possessing little information about the risks or limitations of testing.[
A general tendency to overestimate inherited risk of breast and ovarian cancer has been noted in at-risk populations,[
Women appear to be the prime communicators within families about the family history of breast cancer.[
The accuracy of reported family history of breast or ovarian cancer varies; some studies found levels of accuracy above 90%,[
Genetic Counseling for Hereditary Predisposition to Breast Cancer
Counseling for breast cancer risk typically involves individuals with family histories that are potentially attributable to BRCA1 or BRCA2. It also, however, may include individuals with family histories of Li-Fraumeni syndrome, ataxia-telangiectasia, Cowden syndrome, or Peutz-Jeghers syndrome.[
Management strategies for carriers may involve decisions about the nature, frequency, and timing of screening and surveillance procedures, chemoprevention, risk-reducing surgery, and use of hormone replacement therapy (HRT). The utilization of breast conservation and radiation as cancer therapy for women who are carriers may be influenced by knowledge of pathogenic variant status. (Refer to the Management of Cancer Risks in BRCA1/2 Carriers section in BRCA1 and BRCA2: Cancer Risks and Management for more information.)
Counseling also includes consideration of related psychosocial concerns and discussion of planned family communication and the responsibility to warn other family members about the possibility of having an increased risk of breast, ovarian, and other cancers. Data suggest that individual responses to being tested as adults are influenced by the results status of other family members.[
Published descriptions of counseling programs for BRCA1 (and subsequently for BRCA2) testing include strategies for gathering a family history, assessing eligibility for testing, communicating the considerable volume of relevant information about breast/ovarian cancer genetics and associated medical and psychosocial risks and benefits, and discussion of specialized ethical considerations about confidentiality and family communication.[
Many of the psychosocial outcome studies involve specialized, highly selected research populations, some of which were utilized to map and clone BRCA1 and BRCA2. One such example is K2082, an extensively studied kindred of more than 800 members of a Utah Mormon family in which a BRCA1 pathogenic variant accounts for the observed increased rates of breast and ovarian cancer. A study of the understanding that members of this kindred have about breast/ovarian cancer genetics found that, even in breast cancer research populations, there was incomplete knowledge about associated risks of colon and prostate cancer, the existence of options for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), and the complexity of existing psychosocial risks.[
Although there were initial concerns about the possibility of adverse emotional consequences from BRCA testing, most studies conducted over the years have shown low levels of psychological distress among both carriers and noncarriers, particularly over the longer term.[
Several studies have reported on emotional outcomes over longer follow-up periods (i.e., greater than 12 months after disclosure) than those reported in the meta-analysis described above.[
Although most studies have reported that a positive BRCA test result has a relatively minimal impact on psychological distress, many of these studies were conducted among families with a strong family history of breast or ovarian cancer who underwent extensive pretest genetic counseling. Therefore, emotional responses may not generalize to individuals who test under different contexts. For example, individuals who are tested with population BRCA screening may not have a family history of cancer.[
For example, in a Canadian study of 2,080 Jewish women who participated in a population-based genetic screening study to test for three BRCA pathogenic variants common in families of Jewish heritage, women were not offered in-person genetic counseling but were given a pamphlet on genetic testing for BRCA1/BRCA2 before they provided a DNA sample. One year after genetic testing, women who were positive for a pathogenic variant (n = 18) showed significant increases in cancer-specific distress, whereas no changes in distress were observed among women who were negative for a pathogenic variant.[
Similarly, the impact of direct-to-consumer (DTC) BRCA testing through commercial companies requires further evaluation. Case studies have reported adverse emotional responses after receipt of a positive BRCA result from DTC genetic testing, suggesting the need for further evaluation of the emotional outcomes of women undergoing genetic testing through commercial companies.[
Despite evidence of a short-term increase in distress after the receipt of genetic testing results, any adverse responses to a positive carrier status dissipate within 12 months.[
Emotional outcomes in newly diagnosed breast cancer patients
It is increasingly common for women with breast cancer to pursue genetic counseling and testing at the time of diagnosis to assist with treatment decision making. (Refer to the Benefits of offering genetic testing at the time of cancer diagnosis section for more information.) Given that women with new breast cancer diagnoses are likely to experience some distress, concerns have been raised about the potential for additional adverse psychological implications of rapid genetic counseling and testing (RGT) between diagnosis and surgery.[
Family communication about genetic testing and hereditary risk
Family communication about genetic testing for cancer susceptibility, and specifically about the results of BRCA1/BRCA2 genetic testing, is complex. Age and gender appear to be important variables in the disclosure of genetic test results. Studies have documented that older women were more likely to disclose genetic test results (especially to their daughters) than younger women.[
Family communication of BRCA1/BRCA2 test results to relatives is another factor affecting participation in testing. There have been more studies of communication with FDRs and SDRs than with more distant family members. Studies have investigated the process and content of communication among sisters about BRCA1/BRCA2 test results.[
Among relatives with whom genetic test results were not discussed, the most important reason given was that the affected women were not close to their relatives [
A study that evaluated communication of test results to FDRs at 4 months postdisclosure found that participants were more likely to inform brothers of their results if the BRCA pathogenic variant was inherited through the paternal line.[
A few in-depth qualitative studies have looked at issues associated with family communication about genetic testing. Although the findings from these studies may not be generalizable to the larger population of at-risk individuals, they illustrate the complexity of issues involved in conveying hereditary cancer risk information in families.[
A study of 31 mothers with a documented BRCA pathogenic variant explored patterns of dissemination to children.[
A longitudinal study of 153 women self-referred for genetic testing for BRCA1 and BRCA2 pathogenic variants and 118 of their partners evaluated communication about genetic testing and distress before testing and at 6 months posttesting.[
A study of 561 FDRs of women who had undergone BRCA1/BRCA2 genetic testing found that 22% of FDRs did not recall being informed of the genetic test results despite the women reporting that the results had been shared.[
There is a small but growing body of literature regarding psychological effects in men who have a family history of breast cancer and who are considering or have had BRCA testing. A qualitative study of 22 men from 16 high-risk families in Ireland revealed that more men in the study with daughters were tested than men without daughters. These men reported little communication with relatives about the illness, with some men reporting being excluded from discussion about cancer among female family members. Some men in the study also reported actively avoiding open discussion with daughters and other relatives.[
One study assessed 212 individuals from 13 families with HBOC who received genetic counseling and were offered BRCA1/BRCA2 testing for documented pathogenic variants in the family. Individuals who were not tested were found 6 to 9 months later to have significantly greater increases in family expressiveness and cohesiveness compared with those who were tested. Individuals who were randomly assigned to a client-centered versus problem-solving genetic counseling intervention had a significantly greater reduction in conflict, regardless of the test decision.[
Partners of high-risk women
Many studies have looked at the psychological effects in women of having a high risk of developing cancer, either on the basis of carrying a BRCA1/BRCA2 pathogenic variant or having a strong family history of cancer. Some studies have also examined the effects on the partners of such women.
A Canadian study assessed 59 spouses of women found to have a BRCA1/BRCA2 pathogenic variant. All were supportive of their spouses' decision to undergo genetic testing and 17% wished they had been more involved in the genetic testing process. Spouses who reported that genetic testing had no impact on their relationship had long-term relationships (mean duration 27 years). Forty-six percent of spouses reported that their major concern was of their partner dying of cancer. Nineteen percent were concerned their spouse would develop cancer and 14% were concerned their children would also be carriers of BRCA1/BRCA2 pathogenic variants.[
In a U.S. study, 118 partners of women who underwent genetic testing for pathogenic variants in BRCA1 and BRCA2 completed a survey before testing and then again 6 months after result disclosure. At 6 months, only 10 partners reported that they had not been told of the test result. Ninety-one percent reported that the testing had not caused strain on their relationship. Partners who were comfortable sharing concerns before testing experienced less distress after testing. Protective buffering was not found to impact distress levels of partners.[
An Australian study of 95 unaffected women at high risk of developing breast and/or ovarian cancer (13 carriers of pathogenic variants and 82 with unknown variant status) and their partners showed that although the majority of male partners had distress levels comparable to a normative population sample, 10% had significant levels of distress that indicated the need for further clinical intervention. Men with a high monitoring coping style and greater perceived breast cancer risk for their wives reported higher levels of distress. Open communication between the men and their partners and the occurrence of a cancer-related event in the wife's family in the last year were associated with lower distress levels. When men were asked what kind of information and support they would like for themselves and their partners, 57.9% reported that they would like more information about breast and ovarian cancer, and 32.6% said they would like more support in dealing with their partner's risk. Twenty-five percent of men had suggestions on how to improve services for partners of high-risk women, including strategies on how to best support their partner, greater encouragement from health care professionals to attend appointments, and meeting with other partners.[
A review of this literature reported that the BRCA testing process may be distressing for male partners, particularly for those with spouses identified as carriers. Male partner distress appears to be associated with their beliefs about the woman's breast cancer risk, lack of couple communication, and feelings of alienation from the testing process.[
A review of the literature on the experiences of males in families with a known BRCA1 and BRCA2 pathogenic variant reported that while the data are limited, men from variant-positive families are less likely than females to participate in communication regarding genetics at every level, including the counseling and testing process. Men are less likely to be informed of genetic test results received by female relatives, and most men from these families do not pursue their own genetic testing.[
A study of Dutch men at increased risk of having inherited a BRCA1 pathogenic variant reported a tendency for the men to deny or minimize the emotional effects of their risk status, and to focus on medical implications for their female relatives. Men in these families, however, also reported considerable distress in relation to their female relatives.[
A multicenter U.K. cohort study examined prospective outcomes of BRCA1/BRCA2 testing in 193 individuals, of which 20% were men aged 28 to 86 years. Men's distress levels were low, did not differ among carriers and noncarriers, and did not change from baseline (before genetic testing) to the 3-year follow-up. Twenty-two percent of male carriers of pathogenic variants received colorectal cancer screening and 44% received prostate cancer screening;[
Several studies have explored communication of BRCA test results to at-risk children. Across all studies, the rate of disclosure to children ranging in age from 4 to 25 years is approximately 50%.[
Several studies have also looked at the timing of disclosure to children after parents receive their test results. Although the majority of children were told within a week to several months after results disclosure,[
In one study, participants who told children younger than 13 years about their carrier status had increased distress, and those who did not tell their young children experienced a slight decrease in distress. Communication with young children was found to be influenced by developmental variables such as age and style of parent/child communication.[
One study looked at the reaction of children to results disclosure or the effect on the parent-child relationship of communicating the results.[
Interestingly, a large multicenter study of 869 mother-daughter pairs (the daughters were aged 6 to 13 y) found that girls with a family history of breast cancer or a familial BRCA1/BRCA2 pathogenic variant compared with those without such family histories had better psychosocial adjustment by maternal report.[
Another study of 187 mothers undergoing BRCA1/BRCA2 testing evaluated their need for resources to prepare for a facilitated conversation about sharing their BRCA1/BRCA2 testing results with their children. Seventy-eight percent of mothers were interested in three or more resources, including literature (93%), family counseling (86%), talking to prior participants (79%), and support groups (54%).[
Testing for BRCA1/BRCA2 has been almost universally limited to adults older than 18 years. The risks of testing children for adult-onset disorders (such as breast and ovarian cancer), as inferred from developmental data on children's medical understanding and ability to provide informed consent, have been outlined in several reports.[
Prenatal diagnosis and preimplantation genetic testing
The possibility of transmitting a pathogenic variant to a child may pose a concern to families affected by HBOC,[
In the United States, a series of studies has evaluated awareness, interest (e.g., would consider using PGT), and attitudes related to PGT among members of Facing Our Risk of Cancer Empowered (FORCE), an advocacy organization focused on individuals at increased risk of HBOC.[
It is unknown whether the attitudes of FORCE members toward PGT are representative of the majority of BRCA carriers. A cross-sectional study of 1,081 BRCA carriers, 65% of whom were recruited through FORCE and the remainder by the University of Pennsylvania, revealed that a majority of carriers were in favor of offering PGT and prenatal diagnosis to carriers (59% for PGT and 55.5% for prenatal diagnosis).[
The U.K. Human Fertilization and Embryology authority has approved the use of PGT for HBOC. In a sample of 102 women with a BRCA pathogenic variant, most were supportive of PGT but only 38% of the women who had completed their families would consider it for themselves had PGT been available, and only 14% of women who were contemplating a future pregnancy would consider PGT.[
In France, couples who obtain authorization from a multidisciplinary prenatal diagnosis team may access PGT free of charge as a benefit of their national health care system. However, no BRCA carriers have been authorized to use PGT. In a national study of 490 unaffected carriers of BRCA pathogenic variants of childbearing age (women aged 18–49 y; men aged 18–69 y), 16% stated that BRCA test results had altered their ongoing plans for childbearing.[
A small (N = 25) qualitative study of women of reproductive age positive for a BRCA pathogenic variant who underwent genetic testing before having children evaluated how their BRCA status influenced their attitudes about reproductive genetic testing (both PGT and prenatal diagnosis) and decisions about having children.[
One study has examined these issues among high-risk men recruited from FORCE and Craigslist (a bulletin board website) (N = 228).[
The recognition that BRCA1/BRCA2 pathogenic variants are prevalent, not only in breast/ovarian cancer families but also in some ethnic groups,[
A growing literature on the unique factors influencing a variety of cultural subgroups suggests the importance of developing culturally specific genetic counseling and educational approaches.[
The human implications of the ethical issues raised by the advent of genetic testing for breast/ovarian cancer susceptibility are described in case studies,[
Studies have shown that 62% of studied family members were aware of the family history and that 88% of hereditary breast/ovarian cancer family members surveyed have significant concerns about privacy and confidentiality. Concern about cancer in third-degree relatives, or relatives further removed, did not differ from concern about cancer in the proband's FDRs or SDRs.[
Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Gynecologic Cancers
Decision aids for individuals considering risk management options for hereditary breast and gynecologic cancers
There is a small but growing body of literature on the use of decision aids as an adjunct to standard genetic counseling to assist patients in making informed decisions about cancer risk management.[
Uptake of cancer risk management options
An increasing number of studies have examined uptake and adherence to cancer risk management options among individuals who have undergone genetic counseling and testing for BRCA1 and BRCA2 pathogenic variants. Findings from these studies are reported in Table 9 and Table 10. Outcomes vary across studies and include uptake or adherence to screening (mammography, magnetic resonance imaging [MRI], cancer antigen–125 [CA-125], transvaginal ultrasound [TVUS]) and selection of RRM and RRSO. Studies generally report outcomes by pathogenic variant carrier or testing status (e.g., positive for pathogenic variants, negative for pathogenic variants, or declined genetic testing). Follow-up time after notification of genetic risk status also varied across studies, ranging from 12 months up to several years.
Findings from these studies suggest that breast screening often improves after notification of BRCA1/BRCA2 pathogenic variant carrier status; nonetheless, screening remains suboptimal. Fewer studies have examined adoption of MRI as a screening modality, probably due to the recent availability of efficacy data. Screening for ovarian cancer varied widely across studies, and also varied based on type of screening test (i.e., CA-125 serum testing vs. TVUS screening). However, ovarian cancer screening does not appear to be widely adopted by carriers of BRCA1/BRCA2 pathogenic variants. Uptake of RRM varied widely across studies and may be influenced by personal factors (such as younger age or having a family history of breast cancer), psychosocial factors (such as a desire for reduction of cancer-related distress), recommendations of the health care provider, and cultural or health care system factors. An individual's choice to have a bilateral mastectomy also appears to be influenced by pretreatment genetic education and counseling regardless of the genetic test results.[
|Study Citation||Study Population||Uptake of RRM||Uptake of Breast Screening Mammography and/or Breast MRI||Length of Follow-up||Comments|
|MRI = magnetic resonance imaging; RRSO = risk-reducing salpingo-oophorectomy.|
|a Self-report as data source.|
|b Medical records as data source.|
|Botkin et al. (2003)[
||Carriers (n = 37)a||Carriers 0%||Mammography||24 mo|
|– Carriers 57%|
|Noncarriers (n = 92)a||Noncarriers 0%||– Noncarriers 49%|
|– Declined test 20%|
|Declined testing (n = 15)a||MRI|
|– Not evaluated|
|Beattie et al. (2009)[
||Carriers (n = 237)b||Carriers 23%||Not applicable||Mean, 3.7 y||Women opting for RRM were younger than 60 y, had a prior diagnosis of breast cancer, and also underwent RRSO|
|Median time to RRM: 124 days from receiving results|
|O'Neill et al. (2010)[
||Carriers (n = 146)a||Carriers 13%||Not applicable||12 mo||Intentions at test result disclosure predicted RRM decisions|
|Schwartz et al. (2012)[
||Carriers (n = 108)a||Carriers 37%||Mammography||Mean, 5.3 y||Predictors of RRM were younger age, higher precounseling cancer distress, more recent diagnosis of breast or ovarian cancer, and intact ovaries|
|– Carriers affected 92%|
|– Carriers unaffected 82%|
|Noncarriers (n = 60)a||Noncarriers 0%||– Noncarriers 66%|
|– Uninformative affected 89%|
|Uninformative (n = 206)a||Uninformative 6.8%||– Carriers affected 51%|
|– Carriers unaffected 46%|
|– Noncarriers 11%|
|– Uninformative 27%|
|Garcia et al. (2013)[
||Carriers (n = 250)b||Carriers 44%||Excluding women post RRM:||41 months; range, 26–66 mo||Breast surveillance decreased significantly from y 1–5 of follow-up: Mammography 43% to 7%; MRI 35% to 3%|
|– Carriers 43%|
|– Carriers 35%|
|Singh et al. (2013)[
||Carriers (n = 136)b||Carriers 42%||Not applicable||Range, 1–11 y||Predictors of RRM were first- or second-degree relative diseased from breast cancer, having had at least one childbirth, and having undergone testing after 2005|
|Phillips et al. (2006)[
||Carriers (n = 70)a||Carriers 11%||Mammography||3 y|
|– Carriers 89%|
|– Not evaluated|
|Metcalfe et al. (2008)[
||Carriers (N = 2,677)a||Carriers 18% (unaffected)||Mammography||3.9 y; range, 1.5–10.3 y||Large differences in uptake of risk management options by country|
|– Carriers 87%|
|MRI||1,294 participants had a personal history of breast cancer|
|– Carriers 31%|
|Julian-Reynier et al. (2011)[
||Carriers (n = 101)a||Carriers 6.9%||Mammography||5 y||Noncarriers often continued screening|
|– Carriers 59%|
|– Noncarriers aged 30–39 y 53%|
|Noncarriers (n = 145)a||Noncarriers 0%||MRI|
|– Carriers 31%|
|– Noncarriers 4.8%|
|Study Citation||Study Population||Uptake of RRSO||Uptake of Gynecologic Screening||Length of Follow-up||Comments|
|CA-125 = cancer antigen 125; RRM = risk-reducing mastectomy; TVUS = transvaginal ultrasound.|
|a Self-report as data source.|
|b Medical records as data source.|
|c Data source not specified.|
|Scheuer et al. (2002)[
||Carriers (n = 179)a||Carriers 50.3%||CA-125||Mean, 24.8 mo; range, 1.6–66.0 mo||Women undergoing RRSO were older and more likely to have a personal history of breast cancer|
|– Carriers 67.6%|
|– Carriers 72.9%|
|Beattie et al. (2009)[
||Carriers (n = 240)b||Carriers 51%||Not applicable||Mean, 3.7 y||Women opting for RRSO <60 y had a prior diagnosis of breast cancer and also underwent RRM|
|Median time to RRSO: 123 days from receiving results|
|O'Neill et al. (2010)[
||Carriers (n = 146)a||Carriers 32%||Not applicable||12 mo|
|Schwartz et al. (2012)[
||Carriers (n = 100)a||Carriers 65%||CA-125||Mean, 5.3 y||Predictors of RRSO were being ≥40 y and having received a diagnosis of breast cancer more than 10 y ago|
|Noncarriers (n = 52)a||Noncarriers 1.9%||– Carriers 56%|
|– Noncarriers 12%|
|– Uninformative 33%|
|Uninformative (n = 203)a||Uninformative 13.3%||TVUS|
|– Carriers 42%|
|– Noncarriers 20%|
|– Uninformative 26%|
|Garcia et al. (2013)[
||Carriers (n = 305)b||Carriers 74%||Excluding women post-RRSO:||41 mo; range, 26–66 mo||Ovarian surveillance decreased significantly from years 1–5 of follow-up; CA-125: 47% to 2%; TVUS: 45% to 2.3%|
|– Carriers 47%|
|– Carriers 45%|
|Mannis et al. (2013)[
||Carriers (n = 201)a||Carriers 69.6%||CA-125||Median, 3.7 y||Predictors of RRSO and screening included being a carrier of aBRCApathogenic variant, age 40–49 y, having a higher income, ≥2 children, a personal history of breast cancer, and a first-degree relative with ovarian cancer|
|Noncarriers (n = 103)a||Noncarriers 2.0%||Not reported|
|Uninformative (n = 773)a; 59/773 with avariant of uncertain significance||Uninformative 12.3%||CA-125|
|Singh et al. (2013)[
||Carriers (n = 136)b||Carriers 52%||Not applicable||Range, 1–11 y||Predictors of RRSO were first- or second-degree relative with breast cancer, a mother lost to pelvic cancer, having had ≥1 childbirths, age ≥50 y, and having undergone testing after 2005|
|Phillips et al. (2006)[
||Carriers (n = 70)a||Carriers 29%||CA-125||3 y|
|– Carriers 0%|
|– Carriers 67%|
|Friebel et al. (2007)[
||Carriers (N = 537)c||Carriers 55%||Not applicable||Minimum 6 mo; median 36 mo||RRSO greatest in parous women >40 y|
|Madalinska et al. (2007)[
||Carriers (n = 160)a, b||Carriers 74%||Carriers 26%||12 mo||Women who underwent RRSO had lower education levels, viewed ovarian cancer as incurable, and believed strongly in the benefits of RRSO|
|Specific method(s) of gynecological screening not reported|
|Metcalfe et al. (2008)[
||Carriers (N = 2,677)a||Carriers 57%||Not applicable||3.9 y; range, 1.5–10.3 y||Large differences in uptake of risk management options by country|
|Julian-Reynier et al. (2011)[
||Carriers (n = 101)a||Carriers 42.6%||TVUS||5 y||RRSO uptake increased with age. Having undergone RRSO did not alter breast cancer risk perception. Noncarriers often continued screening|
|Noncarriers (n = 145)a||Noncarriers 2%||– Noncarriers 43.2%|
|Rhiem et al. (2011)[
||Carriers (N = 306)b||Carriers 57%||Not evaluated||Mean, 47.8 mo post-oophorectomy||Median age at time of RRSO = 47 y. One occult fallopian tube cancer was detected at the time of RRSO. One peritoneal carcinoma was diagnosed 26 mo post-RRSO|
|Sidon et al. (2012)[
||Carriers (N = 700)a; 386/700 with personal history of breast cancer||BRCA1carriers:||Not evaluated||Affected with breast cancer||Uptake of RRSO was lower in women >60 y (22% uptake at 5 y). None of the women >70 y had a RRSO performed|
|BRCA2 carriers:||–BRCA1: Mean, 2.29; range, 0.1–11.45 y|
|All carriers with no personal history of breast cancer||–BRCA2: Mean, 1.77; range, 0.1–11.1 y|
|Not affected with breast cancer|
|All carriers with personal history of breast cancer||–BRCA1: Mean, 1.63; range, 0.1–11.28 y|
|– 43.2%||–BRCA2:Mean, 1.75; range, 0.1–8.98 y|
On the other hand, many women found to be pathogenic variant carriers express interest in RRM in hopes of minimizing their risk of breast cancer. In one study of a number of unaffected women with no previous risk-reducing surgery who received results of BRCA1 testing after genetic counseling, 17% of carriers (2 of 12) intended to have mastectomies and 33% (4 of 12) intended to have oophorectomies.[
Initial interest does not always translate into the decision for surgery. Two different studies found low rates of RRM among carriers of pathogenic variants in the year after result disclosure, one showing 3% (1 of 29) of carriers and the other 9% (3 of 34) of carriers having had this surgery.[
A number of women choose to undergo RRM and RRSO without genetic testing because of the following:
Among FDRs of breast cancer patients attending a surveillance clinic, women who expressed an interest in RRM and/or had undergone surgery were found to have significantly more breast cancer biopsies (P < .05) and higher subjective 10-year breast cancer risk estimates (P < .05) than women not interested in RRM. Cancer worry at the time of entry into the clinic was highest among women who subsequently underwent RRM compared with women who expressed interest but had not yet had surgery and women who did not intend to have surgery (P < .001).[
BRCA testing, when offered to women newly diagnosed with breast cancer, has been shown to influence surgical decision making in that carriers are more likely to opt for bilateral mastectomy compared with noncarriers.[
A study conducted from 2006 to 2014 in 11 U.S. academic and community centers of 897 women, aged 40 years and younger at breast cancer diagnosis, found that rates of BRCA genetic testing have increased over time.[
Dutch women (N = 114) who had undergone unilateral or bilateral RRM with breast reconstruction between 1994 and 2002 were retrospectively surveyed to determine their satisfaction with the procedure.[
Ninety Swedish women who had undergone RRM between 1997 and 2005 were surveyed before surgery, 6 months after surgery, and 1 year after surgery to evaluate changes in health-related quality of life, depression, anxiety, sexuality, and body image. There were no significant changes in health-related quality of life or depression at the three time points; anxiety decreased over time (P = .0004). More than 80% of women reported having an intimate relationship at all three time points. Women who reported being sexually active were asked to respond to questions about sexual pleasure, discomfort, habit, and frequency of activity. There were no statistically significant differences related to frequency, habit, or discomfort. However, pleasure significantly decreased between baseline and 1 year after surgery (P = .005). At 1 year after surgery, 48% of women reported feeling less attractive, 48% reported feeling self-conscious, and 44% reported dissatisfaction with surgical scars.[
Discussion of risk-reducing surgical options may not consistently occur during pretest genetic counseling. In one multi-institutional study, only one-half of genetics specialists discussed RRM and RRSO in consultations with women from high-risk breast cancer families,[
Given the increased risk of ovarian cancer faced by women with a BRCA1 or BRCA2 pathogenic variant, those who do receive information about RRSO show wide variations in surgery uptake (27%–72%).[
Cancer screening and risk-reducing behaviors
Data are now emerging regarding uptake and adherence to cancer risk management recommendations such as screening and risk-reducing interventions. Cancer screening adherence and risk-reduction behaviors as defined by the National Comprehensive Cancer Network Guidelines were assessed in a cross-sectional study of 214 women with a personal history (n = 134) or family history (n = 80) of breast or ovarian cancer. Among unaffected women older than 40 years, 10% had not had a mammogram or clinical breast examination (CBE) in the previous year and 46% did not practice breast self-examination (BSE). Among women previously affected with breast or ovarian cancer, 21% had not had a mammogram, 32% had not had a CBE, and 39% did not practice BSE.[
Three hundred and twelve women who were counseled and tested for BRCA pathogenic variants between 1997 and 2005 responded to a survey regarding their perception of genetic testing for HBOC. The survey included questions on risk reduction options, including screening and risk-reducing surgeries. Two hundred and seventeen (70%) of the women had been diagnosed with breast cancer, and 86 (28%) tested positive for a pathogenic variant in either the BRCA1 or BRCA2 gene. None of the BRCA-positive women agreed that mammograms are difficult procedures because of the discomfort, while 11 (5.4%) of the BRCA-negative women did agree with this statement. Both groups (BRCA-positive and BRCA-negative) agreed that risk-reducing surgeries provide the best means for lowering cancer risk and worry, and most patients in both groups expressed the belief that RRM is not too drastic, too scary, or too disfiguring.[
A prospective study from the United Kingdom examined the psychological impact of mammographic screening in 1,286 women aged 35 to 49 years who have a family history of breast cancer and were participants in a multicenter screening program. Mammographic abnormalities that required additional evaluation were detected in 112 women. These women, however, did not show a statistically significant increase in cancer worry or negative psychological consequences as a result of these findings. The 1,174 women who had no mammographic abnormality detected experienced a decrease in cancer worry and a decrease in negative psychological consequences compared with baseline after receipt of their results. At 6 months, the entire cohort had experienced a decrease in measures of cancer worry and psychological consequences of breast screening.[
A qualitative study explored health care professionals' views regarding the provision of information about health protective behaviors (e.g., exercise and diet). Seven medical specialists and ten genetic counselors were interviewed during a focus group or individually. The study reported wide variation in the content and extent of information provided about health-protective behaviors and in general, participants did not consider it their role to promote such behaviors in the context of a genetic counseling session. There was agreement, however, about the need to form consensus about provision of such information both within and across risk assessment clinics.[
Not all studies specify whether screening uptake rates fall within recommended guidelines for the targeted population or the specific clinical scenario, nor do they report on other variables that may influence cancer screening recommendations. For example, women who have a history of atypical ductal hyperplasia would be advised to follow screening recommendations that may differ from those of the general population.
Psychosocial Outcome Studies
Psychosocial outcomes associated with risk-reducing mastectomy (RRM)
A prospective study conducted in the Netherlands found that among 26 carriers of BRCA1/BRCA2 pathogenic variants, the 14 women who chose mastectomy had higher distress both before test result disclosure and 6 and 12 months later, compared with the 12 carriers who chose surveillance and compared with 53 women negative for a pathogenic variant. Overall, however, anxiety declined in women undergoing RRM; at 1 year, their anxiety scores were closer to those of women choosing surveillance and to the scores of women negative for a pathogenic variant.[
Mixed psychosocial outcomes were reported in a follow-up study (mean 14 years) of 609 women who received RRM at the Mayo Clinic. Seventy percent were satisfied with RRM, 11% were neutral, and 19% were dissatisfied. Eighteen percent believed that if they had the choice to make again, they probably or definitely would not have an RRM. About three-quarters said their worry about cancer was diminished by surgery. One-half reported no change in their satisfaction with body image; 16% reported improved body image after surgery. Thirty-six percent said they were dissatisfied with their body image after RRM. About one-quarter of the women reported adverse impact of RRM on their sexual relationships and sense of femininity, and 18% had diminished self-esteem. Factors most strongly associated with satisfaction with RRM were postsurgical satisfaction with appearance, reduced stress, no reconstruction or lack of problems with implants, and no change or improvement in sexual relationships. Women who cited physician advice as the primary reason for choosing RRM tended to be dissatisfied after RRM.[
A study of 60 healthy women who underwent RRM measured levels of satisfaction, body image, sexual functioning, intrusion and avoidance, and current psychological status at a mean of 4 years and 4 months postsurgery. Of this group, 76.7% had either a strong family history (21.7%) or carried a BRCA1 or BRCA2 pathogenic variant (55%). Overall, 97% of the women surveyed were either satisfied (17%) or extremely satisfied (80%) with their decision to have RRM, and all but one participant would recommend this procedure to other women. Most women (66.7%) reported that surgery had no impact on their sexual life, although 31.7% reported a worsening sexual life, and 76.6% reported either no change in body image or an improvement in body image, regardless of whether reconstruction was performed. Worsening self-image was reported by 23.3% of women after surgery. Women's mean distress levels after surgery were only slightly above normal levels, although those women who continued to perceive their postsurgery breast cancer risk as high had higher mean levels of global and cancer-related distress than those who perceived their risk as low. Additionally, carriers of BRCA1 and BRCA2 pathogenic variants and women with a strong family history of breast and/or ovarian cancer had higher mean levels of cancer-related distress than women with a limited family history.[
Very little is known about how the results of genetic testing affect treatment decisions at the time of cancer diagnosis. Two studies explored genetic counseling and BRCA1/BRCA2 genetic testing at the time of breast cancer diagnosis.[
A prospective study from the Netherlands evaluated long-term psychological outcomes of offering women with breast cancer genetic counseling and, if indicated, genetic testing at the onset of breast radiation for treatment of their primary breast cancer. Of those who were approached for counseling, some underwent genetic testing and chose to receive their result (n = 58), some were approached but did not fulfill referral criteria (n = 118), and some declined the option of counseling/testing (n = 44). Another subset of women undergoing radiation therapy was not approached for counseling (n = 182) but was followed using the same measures. Psychological distress was measured at baseline and at 4, 11, 27, and 43 weeks after initial consultation for radiation therapy. No differences were detected in general anxiety, depression or breast cancer–specific distress across all four groups.[
A retrospective questionnaire study of 583 women with a personal and family history of breast cancer and who underwent contralateral RRM between 1960 and 1993 measured overall satisfaction after mastectomy and factors influencing satisfaction and dissatisfaction with this procedure.[
A retrospective survey of 137 BRCA carriers examined the psychosocial impact of preserving the nipple-areolar complex (NAC) in women with bilateral RRM.[
Another study compared long-term quality-of-life outcomes in 195 women after bilateral RRM performed between 1979 and 1999 versus 117 women at high risk of breast cancer opting for screening. No statistically significant differences were detected between the groups for psychosocial outcomes. Eighty-four percent of those opting for surgery reported satisfaction with their decision. Sixty-one percent of women from both the surgery and screening groups reported being very much or quite a bit contented with their quality of life.[
In a study of psychosocial outcomes associated with RRM and immediate reconstruction, 61 high-risk women (27 carriers of pathogenic variants, others with high-risk family history), 31 of whom had a prior history of breast cancer, were evaluated on average 3 to 4 years after surgery.[
A qualitative study examining material on the FORCE website posted by 21 high-risk women (BRCA1/BRCA2-positive) undergoing RRM showed that these women anticipated and received negative reactions from friends and family regarding the surgery, and that they managed disclosure in ways to maintain emotional support and self-protection for their decision. Many of the women expressed a relief from intrusive breast cancer thoughts and worry, and were satisfied with the cosmetic result of their surgery.[
In contrast, another study examined long-term psychosocial outcomes in 684 women who had had bilateral or contralateral RRM on average 9 years before assessment.[
In a qualitative study of 108 women who underwent or were considering RRM, more than half of those who had RRM felt that presurgical consultation with a psychologist was advisable; nearly two-thirds thought that postsurgical consultation was also appropriate. All of the women who were considering RRM believed that psychological consultation before surgery would facilitate decision-making.[
Psychosocial outcomes associated with risk-reducing salpingo-oophorectomy (RRSO)
A retrospective self-administered survey of 40 women aged 35 to 74 years at time of RRSO (57.5% were younger than 50 y), who had undergone the procedure through the Ontario Ministry of Health due to a family history of ovarian cancer, found that RRSO resulted in a significant reduction in perceived ovarian cancer risk. Fifty-seven percent identified a decrease in perceived risk as a benefit of RRSO (35% did not comment on RRSO benefits) and 49% reported that they would repeat RRSO to decrease cancer risk. The overall quality-of-life scores were consistent with those published for women who are menopausal or participating in hormone studies.[
A Canadian prospective study examined the impact of RRSO on menopausal symptoms and sexual functioning before surgery and then 1 year later in a sample of 114 women with known BRCA1/BRCA2 pathogenic variants.[
Additional work reported by this group found that the majority of the 127 women who had undergone RRSO 1 year previously (75 with BRCA1 pathogenic variants; 52 with BRCA2 pathogenic variants) felt that RRSO reduced their risk of both breast and ovarian cancer.[
A larger study assessed quality of life in women at high risk of ovarian cancer who opted for periodic gynecologic screening (GS) versus those who underwent RRSO. Eight hundred forty-six high-risk women, 44% of whom underwent RRSO and 56% of whom chose GS, completed questionnaires evaluating quality of life, cancer-specific distress, endocrine symptoms, and sexual functioning.[
Women (N = 182) at risk of HBOC referred for genetic counseling were surveyed concerning their satisfaction with their choice of either RRSO or periodic screening (PS) (biannual pelvic examination with TVUS and CA-125 determination) to manage their ovarian cancer risk.[
A retrospective study assessed 98 carriers of BRCA pathogenic variants who underwent RRSO about their preoperative counseling regarding symptoms to expect after surgery.[
A study [
While motivations cited for pursuing genetic testing often include the expectation that carriers of pathogenic variants will be more compliant with breast and/or ovarian screening recommendations,[
This is a critical issue not only for women testing positive, but also for adherence to screening for those testing negative and those who have received indeterminate results or choose not to receive their results. It is possible that adherence actually diminishes with a decrease in the perceived risk that may result from a negative genetic test result.
In addition, while there is still some question regarding the link between cancer-related worry and breast cancer screening behavior, accumulating evidence appears to support a linear rather than a curvilinear relationship. That is, for some time, the data were not consistent; some data supported the hypothesis that mild-to-moderate worry may increase adherence, while excessive worry may actually decrease the utilization of recommended screening practices. Other reports support the notion that a linear relationship is more likely; that is, more worry increases adherence to screening recommendations. Few studies, however, have followed women to assess their health behaviors after genetic testing. Thus, a negative test result leading to decreased worry could theoretically result in decreased screening adherence. A large study found that patient compliance with screening practices was not related to general or screening-specific anxiety—with the exception of BSE, for which compliance is negatively associated with procedure-specific anxiety.[
Further complicating this area of research are issues such as the baseline rate of mammography adherence among women older than 40 or 50 years before genetic testing. More specifically, the ability to note a significant difference in adherence on this measure may be affected by the high adherence rate to this screening behavior before genetic testing by women undergoing such testing. It may be easier to find significant changes in mammography use among women with a family history of breast cancer who test positive. Finally, adherence over time will likely be affected by how women undergoing genetic testing and their caregivers perceive the efficacy of many of the screening options in question, such as mammography for younger women, BSE, and ovarian cancer screening (periodic vaginal ultrasound and serum CA-125 measurements), along with the value of preventive interventions.
The issue of screening decision-making and adherence among women undergoing genetic testing for breast and ovarian cancer is the subject of several ongoing trials, and an area of much needed ongoing study.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was extensively revised.
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and gynecologic cancers. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Genetics of Breast and Gynecologic Cancers are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Breast and Gynecologic Cancers. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389210]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2023-03-10
This information does not replace the advice of a doctor. Healthwise, Incorporated, disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the
Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.
Individual and family medical and dental insurance plans are insured by Cigna Health and Life Insurance Company (CHLIC), Cigna HealthCare of Arizona, Inc., Cigna HealthCare of Illinois, Inc., Cigna HealthCare of Georgia, Inc., Cigna HealthCare of North Carolina, Inc., Cigna HealthCare of South Carolina, Inc., and Cigna HealthCare of Texas, Inc. Group health insurance and health benefit plans are insured or administered by CHLIC, Connecticut General Life Insurance Company (CGLIC), or their affiliates (see
All insurance policies and group benefit plans contain exclusions and limitations. For availability, costs and complete details of coverage, contact a licensed agent or Cigna sales representative. This website is not intended for residents of New Mexico.