Age

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.[4] Women with pathogenic variants in breast cancer risk genes often develop breast cancer at younger ages than women with sporadic breast cancers.

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.[5-8] A pooled analysis of 38 studies showed that women had increased breast cancer risk when they had at least one FDR with breast cancer (relative risk [RR], 2.1; 95% confidence interval [CI], 2.0–2.2).[9] A large population-based study that used the Swedish Family Cancer Database found that women had a significantly increased risk of breast cancer when they had a mother or a sister with breast cancer.[6,7,9-11]

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.[11] Another study in women with unilateral versus contralateral breast cancer (CBC) evaluated CBC risk among family members.[12] Results indicated that women with at least one affected FDR had an 8.1% chance of developing CBC after 10 years. Participants' risks also increased when relatives were diagnosed with breast cancer before age 40 years (10-year absolute risk [AR], 13.5%; 95% CI, 8.8%–20.8%) or if relatives had CBC (10-year AR, 14.1%; 95% CI, 9.5%–20.7%). These risks were similar to those seen among BRCA carriers (10-year AR, 18.4%; 95% CI, 16.0%–21.3%). These risk estimates remained unchanged when the analysis was restricted to women who tested negative for a pathogenic variant in BRCA1/BRCA2, ATM, CHEK2, or PALB2.

Albright et al. addressed how affected third-degree relatives (TDRs) can contribute to an individual's breast cancer risk.[13] These researchers used the Utah Population Database and the Utah Cancer Registry to estimate RRs for participants to develop breast cancer. They collected family histories with FDRs, SDRs, and TDRs and included both paternal and maternal relatives. They confirmed that individuals with affected FDRs had the highest breast cancer risk, particularly if the FDR was diagnosed with breast cancer early in life. When participants had five or more affected TDRs (and no FDRs/SDRs with breast cancer), they had an RR of 1.32 (95% CI, 1.11–1.57).

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%).[14] If a monozygotic twin had breast cancer, her twin sister had a 28.1% chance of developing breast cancer (95% CI, 23.9%–32.8%), and if a dizygotic twin had breast cancer, her twin sister had a 19.9% chance of developing breast cancer (95% CI, 17%–23.2%). These estimates suggest that monozygotic twins have a 10% higher risk of developing breast cancer than dizygotic twins. However, the high rate of discordance seen, even between monozygotic twins, suggests that environmental factors can also modify breast cancer risk.

Benign breast disease, mammographic density, and background parenchymal enhancement

Benign breast disease (BBD)

Mammographic density

Background parenchymal enhancement (BPE)

Parity, age at first birth, and breastfeeding

Parity

Age at first birth

Breastfeeding

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.

Contraceptives

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.[33]

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.[33] Although the data are not entirely consistent, a meta-analysis of BRCA1/BRCA2 pathogenic variant carriers concluded that breast cancer risk did not significantly increase when participants used OCs.[34] More specifically, the International BRCA1/2 Carrier Cohort Study (IBCCS), the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) Follow-Up Study, and the Breast Cancer Family Registry (BCFR) did not report associations between OC use and increased breast cancer risk in women with BRCA1 pathogenic variants.[35] In fact, OCs are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 pathogenic variant carriers. For more information, see the Oral contraceptives and Risk Factors for Ovarian Cancer sections. However, in the prospective analyses of the IBCCS, kConFab, and BCFR studies mentioned above, women with BRCA2 pathogenic variants had increased breast cancer risk when they took OCs (HR, 1.75; 95% CI, 1.03–2.97). Additionally, a systematic review of the published data concluded that it is unclear if OC use increases breast cancer risk in BRCA1/2 carriers due to inconsistencies across studies.[36]

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).[34] A case-control study of 2,492 matched pairs of women with a BRCA1 pathogenic variant also found that OC use significantly increased breast cancer risk when women began using OCs prior to age 20 years (OR, 1.45; 95% CI, 1.20–1.75).[37]

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).[38]

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.[39,40] A meta-analysis with data from 51 observational studies found a 1.35 RR for breast cancer (95% CI, 1.21–1.49) in women who used HRT for 5 or more years after menopause.[39] The WHI, a randomized, controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined estrogen and progestin or placebo, was halted early because health risks exceeded health benefits.[41,42] Significant increases in both total breast cancer cases (245 in the estrogen-plus-progestin group vs. 185 in the placebo group) and invasive breast cancer cases (199 in the estrogen-plus-progestin group vs. 150 in the placebo group) prompted early closure of the study (RR, 1.24; 95% CI, 1.02–1.5; P < .001). Risks for coronary heart disease, stroke, and pulmonary embolism also increased in the estrogen-plus-progestin group. The WHI study did not stratify data by participants' family histories of breast cancer, and subjects were not systematically tested for BRCA1/BRCA2 pathogenic variants.[42] Similar findings were seen in the estrogen-progestin arm of the prospective, observational Million Women’s Study in the United Kingdom.[43] However, breast cancer risk was not elevated in women randomly assigned to the estrogen-only group when compared with those in the placebo group in the WHI study (RR, 0.77; 95% CI, 0.59–1.01). Hysterectomy was required for women to qualify for the estrogen-only arm of this study; 40% of these patients also had a bilateral oophorectomy, which can potentially decrease breast cancer risk.[44]

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.[45-49,39] A large meta-analysis found that women who used HRT had increased breast cancer risk. However, risk did not differ significantly between subjects with or without family histories of cancer.[49]

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.[50] For example, a prospective, longitudinal cohort study recruited BRCA1 carriers from 80 centers in 17 countries. This study found that HRT use after oophorectomy was not associated with increased breast cancer risk in BRCA1 carriers.[51] The HR was 0.97 (95% CI, 0.62–1.52) for individuals who used HRT when compared with individuals who had never used HRT. However, the effects of estrogen-only HRT and estrogen-plus-progesterone HRT differed. After a 10-year follow-up period, the cumulative breast cancer incidence was 12% in women who used estrogen-only HRT and 22% in women who used estrogen-plus-progesterone HRT. These associations were stronger for women who underwent oophorectomy before age 45 years. The study concluded that using estrogen-only HRT after oophorectomy did not increase risk of BRCA1-associated breast cancers. However, the potential harmful effects of progesterone-containing HRT warrant further study.[52] For more information, see the HRT in Carriers of BRCA1/BRCA2 Pathogenic Variants section in BRCA1 and BRCA2: Cancer Risks and Management.

HRT use may also increase a woman's chance of developing endometrial cancer. For more information, see the Hormones section.

Radiation exposure

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.[53-56] Studies have shown that individuals with germline ATM and TP53 variants also have increased sensitivity to radiation.[57,58]

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.[59]

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.[60-65] A large European study showed a dose-response relationship, in which breast cancer risk increased with total radiation exposure. However, this occurred most often when patients had nonmammographic radiation exposure before age 20 years.[64] A significant association was not observed between prior mammography exposure and breast cancer risk in a prospective study of 1,844 BRCA1 carriers and 502 BRCA2 carriers without breast cancer diagnoses upon study entry. The average follow-up period in this study was 5.3 years.[65]

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).[66] An association was not found between radiation therapy and CBC risk (HR, 0.82; 95% CI, 0.45–1.45). This was also true in patients who were younger than 40 years when they were diagnosed with their primary breast cancers (HR, 1.36; 95% CI, 0.60–3.09). A study examined the impact of radiation therapy on CBC risk in ATM, BRCA1/2, and CHEK2 1100delC carriers. CBC risk was not modified by radiation therapy, even though these women had a higher baseline risk of CBC than women in the general population (BRCA1/2 pathogenic variant carriers without radiation therapy: RR, 3.52; 95% CI, 1.76–7.01; BRCA1/2 pathogenic variant carriers with radiation therapy: RR, 4.46; 95% CI, 2.96–6.71).[67] Thus, it is important to differentiate individuals with increased CBC risk due to pathogenic variants from individuals with increased CBC risk due to radiation therapy. For more information, see the Mammography section in BRCA1 and BRCA2: Cancer Risks and Management.

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.[68,69] Prior studies of BRCA1/BRCA2 pathogenic variant carriers have not found an association between alcohol consumption and increased breast cancer risk.[70-72] The association between cigarette smoking and breast cancer risk in women with BRCA1/2 pathogenic variants is inconclusive.[73,74]

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.[75] This study did not find an association between alcohol consumption and increased breast cancer risk in BRCA1 and BRCA2 carriers. Parous BRCA carriers who smoked for more than 5 years before their first full-term pregnancy had a significantly increased breast cancer risk when compared with parous BRCA carriers who did not smoke. A prospective study evaluating a cohort of women with family histories of breast cancer found that alcohol consumption was associated with an increased number of ER-positive breast cancers in women at the lowest quantile of absolute breast cancer risk (HR, 1.46; 95% CI, 1.07–1.99).[76] Cigarette smoking was also associated with increased breast cancer risk in those at the highest quantile of absolute breast cancer risk.

Physical activity

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).[77] This reduction in breast cancer risk has been seen in women with varying levels of breast cancer susceptibility, including women who have family histories of breast cancer but do not have known BRCA1 or BRCA2 pathogenic variants.[78]

Age

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.[79]

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.[80]

Reproductive history

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.[30] Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.[81,82] Several studies have reported a risk reduction in ovarian cancer after OC use in carriers of BRCA/BRCA2 pathogenic variants;[83-85] a risk reduction has also been shown after tubal ligation in BRCA1 carriers, with a statistically significant decreased risk of 22% to 80% after the procedure.[85,86] Breastfeeding for more than 12 months may also be associated with a reduction in ovarian cancer among carriers of BRCA1/BRCA2 pathogenic variants.[87] On the other hand, evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.[88-91]

Surgical history

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,[81,92,93] including in carriers of BRCA/BRCA2 pathogenic variants.[94] Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 pathogenic variants who chose risk-reducing salpingo-oophorectomy (RRSO). In this same population, risk-reducing oophorectomy also resulted in a nearly 50% reduction in the risk of subsequent breast cancer.[95,96] While some studies have shown more benefit for breast cancer reduction in patients with BRCA2 versus BRCA1 pathogenic variants, others have shown no benefit for BRCA1 carriers. Additionally, many of the studies remain underpowered to demonstrate benefit.[97] (Refer to the Risk-reducing salpingo-oophorectomy for breast cancer risk reduction section in BRCA1 and BRCA2: Cancer Risks and Management for more information about these studies.)

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.[81,98] A majority of, but not all, studies also support OCs being protective among carriers of BRCA/BRCA2 pathogenic variants.[86,99-102] A meta-analysis of 18 studies including 13,627 carriers of BRCA pathogenic variants reported a significantly reduced risk of ovarian cancer (SRR, 0.50; 95% CI, 0.33–0.75) associated with OC use.[34] (Refer to the Chemopreventive agents for reducing ovarian cancer risk section in BRCA1 and BRCA2: Cancer Risks and Management.)

Age

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.[103] Women with Lynch syndrome tend to develop endometrial cancer at an earlier age, with the median age at diagnosis of 48 years.[104]

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,[105] with the main hereditary endometrial cancer syndrome being Lynch syndrome, an autosomal dominant genetic condition with a population prevalence of 1 in 300 to 1 in 1,000 individuals.[106,107] (Refer to the Lynch Syndrome section in Genetics of Colorectal Cancer for more information.)

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.[108] Notably, patients with pathogenic variants in non-Lynch syndrome genes were more likely to have serous tumor histology than were patients without pathogenic variants. Furthermore, although the overall risk of endometrial cancer after RRSO was not increased among carriers of BRCA1 pathogenic variants, these patients seemed to have an increased risk of serous and serous-like endometrial cancer.[109] These findings were supported by a Dutch multicenter cohort study in women with germline BRCA1 and BRCA2 pathogenic variants. This study concluded that participants' AR for endometrial cancer was approximately 3%. Because some serous and p53-aberrant endometrial cancers may harbor germline or somatic BRCA1/BRCA2 variants, poly (ADP-ribose) polymerase (PARP) inhibitor therapy may also be a therapeutic option.[110]

Reproductive history

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.[111,112]

Hormones

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.[113,114] Tamoxifen, a selective estrogen receptor modulator, acts as an estrogen agonist on the endometrium while acting as an estrogen antagonist in breast tissue, and increases the risk of endometrial cancer.[115] In contrast, OCs, the LNG-IUS, and combination estrogen-progesterone HRT all reduce the risk of endometrial cancer through the antiproliferative effect of progesterone acting on the endometrium.[116-119]

Breast cancer risk assessment models

In general, breast cancer risk assessment models are designed for two types of populations: (1) women without pathogenic variants in breast cancer susceptibility genes or strong family histories of breast/ovarian cancer, and (2) women at higher risk because of personal or family histories of breast/ovarian cancer.[137] These two types of models require inputs from both prior literature and model development from large epidemiological studies, which include nongenetic risk factors like reproductive history. Some risk models also include information about prior breast biopsy and mammographic breast density. Only a few models include potentially modifiable factors, like alcohol use and exogenous hormone use.

Models of the first type designed for women (e.g., the Gail model, which is the basis for the Breast Cancer Risk Assessment Tool [BCRAT] [138], and the Colditz and Rosner model [139]) require only limited information about family history (e.g., number of FDRs with breast cancer). Although counting the number of FDRs is simpler to input into a model than the ages of all familial cancer diagnoses, risk may be overestimated in older individuals because the number of FDRs increases with age. Family histories of cancer in older individuals are also less predictive of risk as one ages. Most models of the first type, however, include built-in assumptions about competing risks of other outcomes. These assumptions are particularly important after age 60 years, when risk of other outcomes, like cardiovascular disease, is higher.

Models designed for women at higher risk require more detailed information about personal and family cancer histories of breast and ovarian cancers, including ages at onset of cancer and/or carrier status of specific breast cancer-susceptibility alleles. The genetic factors used by the latter models differ, with some assuming one risk locus (e.g., the Claus model [140]), others assuming two loci (e.g., the International Breast Cancer Intervention Study [IBIS] model [141] and the BRCAPRO model [142]), and still others assuming an additional polygenic component in addition to multiple loci (e.g., the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA]/CanRisk model [143-145]). Prior to formally measuring polygenic risk scores (PRS), the BOADICEA/CanRisk model was the only risk model that captured underlying polygenic risk to explain the variance in risk levels. Now BOADICEA/CanRisk allows direct PRS inputs.[146] However, even with PRS included, as measured by individual single nucleotide polymorphisms (SNPs), there is still a large portion of the polygenic risk component that is not explained by PRS.

The models also differ in whether they include information about nongenetic risk factors. Three models (Gail/BCRAT, Pfeiffer,[133] and IBIS) include nongenetic risk factors but differ in the risk factors they include (e.g., the Pfeiffer model includes alcohol consumption, whereas the Gail/BCRAT does not). The BOADICEA/CanRisk model has also been updated to include nongenetic risk factors.[147] The nongenetic risk factors included in these models include age at menarche and reproductive factors (e.g., age at first birth, parity). Some, but not all, models also include modifiable factors like alcohol consumption. However, cancer risk models do not include social determinants of health or environmental/chemical exposures.

Breast cancer risk models have limited the ability to discriminate between individuals who are affected or unaffected with cancer. A model with high discrimination would be close to 1, and a model with little discrimination would be close to 0.5. Model discrimination is rarely above an AUC of 0.70.[148] Existing models are generally more accurate in prospective studies that have assessed how well they predict future cancers.[137,149-151] Risk models now also include PRS and mammographic density.[146,147,152] For women at higher risk, an analysis comparing the 10-year performance of the BOADICEA/CanRisk, BRCAPRO, BCRAT, and IBIS models demonstrated that models with more detailed pedigree inclusion were superior—specifically, the BOADICEA/CanRisk and IBIS models.[153]

In the United States, the BRCAPRO, Claus,[140,154] and Gail/BCRAT models [138] are still widely used in clinical counseling, although the use of BOADICEA/CanRisk and IBIS models is becoming more common. Risk estimates derived from the models differ for an individual patient. Several other models that include more detailed family history information are also in use and are discussed below.

In addition to statistical and regression-based models, risk-assessment models are being developed based on artificial intelligence (AI), using imaging (primarily from mammography) and other clinical data from the electronic health record. Risk-assessment based on machine learning and AI algorithms (when applied to mammographic images) have produced AUCs in a similar or even higher range than some of the pedigree and regression-based risk models.[152] One such model has been replicated and validated in many different settings and populations (e.g., Mirai model). AI-based models may be advantageous in the future when using a single mammography screening for risk assessment. However, AI-based models cannot yet replace pedigree-based models when determining cancer risk, particularly in younger women and in women without prior mammography imaging.

Ovarian cancer risk assessment models

Model development for prediction of ovarian cancer risk has been similar to that of breast cancer risk models with pedigree-based models and nonpedigree-based models. BOADICEA/CanRisk also can be used to predict ovarian cancer risk over a fixed time interval or an individual's remaining lifetime. The Rosner and Pfeiffer risk models were developed without using pedigrees.[132,133] The Rosner model [132] included age at menopause, age at menarche, oral contraception use, and tubal ligation. The concordance statistic was 0.60 (0.57–0.62). The Pfeiffer model [133] included oral contraceptive use, menopausal HRT use, and family history of breast cancer or ovarian cancer, with a similar discriminatory power of 0.59 (0.56–0.62). Although both models were well calibrated, their modest discriminatory power limited their screening potential. Variations on these regression-based models have included interaction terms to account for modifications menopause can have on several ovarian cancer risk factors, including endometriosis, family history of ovarian cancer in an FDR, and breastfeeding.[168] AI-based models have been used for risk-stratification in ovarian cancer and other gynecological cancers, but they have not been used to predict risk of cancer onset.[169]

Endometrial cancer risk assessment models

Endometrial cancer risk models also can be divided into regression-based models, pedigree-based models, and AI-based models. The Pfeiffer model has been used to predict endometrial cancer risk in the general population.[133] For endometrial cancer, the RR model included BMI, menopausal HRT use, menopausal status, age at menopause, smoking status, and OC use. The discriminatory power of the model was 0.68 (0.66–0.70). It overestimated observed endometrial cancers in most subgroups but underestimated disease in women with the highest BMI category, in premenopausal women, and in women taking menopausal HRT for 10 years or more. The Endometrial Cancer Consortium developed a regression-based model using data from 19 case-control studies and validated it in three cohorts.[170] This analysis found an AUC with a range of 0.62 to 0.67.

Regression-based models differ from pedigree-based models, which require detailed information on the number of relatives with cancer, types of cancer, and ages of cancer diagnoses in family members. MMRpredict, PREMM5 (PREdiction Model for gene Mutations), and MMRpro are three quantitative predictive models used to identify individuals who may potentially have Lynch syndrome.[171-173] MMRpredict incorporates only colorectal cancer patients but does include MSI and immunohistochemistry (IHC) tumor testing results. PREMM5 is an update of PREMM (1,2,6) and includes each of the five genes associated with Lynch syndrome. PREMM5 is a clinical prediction algorithm that estimates the cumulative probability of an individual carrying a germline pathogenic variant in MLH1, MSH2, MSH6, PMS2, or EPCAM genes. It accounts for other Lynch syndrome–associated tumors but does not include tumor testing results.[172] MMRpro incorporates tumor testing and germline testing results, but is more time intensive because it includes affected and unaffected individuals in the risk-quantification process. All three predictive models are comparable to the traditional Amsterdam and Bethesda criteria in identifying individuals with colorectal cancer who carry MMR gene pathogenic variants.[174] However, because these models were developed and validated in colorectal cancer patients, the discriminative abilities of these models to identify Lynch syndrome are lower among individuals with endometrial cancer than among those with colon cancer.[175] In fact, the sensitivity and specificity of MSI and IHC in identifying carriers of pathogenic variants are considerably higher than the prediction models and support the use of molecular tumor testing to screen for Lynch syndrome in women with endometrial cancer.

AI-based models have been used for risk-stratification and prognosis in endometrial cancer cases, but they have not been used to predict risk of endometrial cancer onset.[176]

Indications for hereditary breast and gynecologic cancers genetic testing

Several professional organizations and expert panels—including the American Society of Clinical Oncology,[208] the National Comprehensive Cancer Network (NCCN),[209] the American Society of Human Genetics,[210] the American College of Medical Genetics and Genomics,[211] the National Society of Genetic Counselors,[211] the U.S. Preventive Services Task Force,[212] and the Society of Gynecologic Oncologists [213] —have developed clinical criteria and practice guidelines that can be helpful to health care providers in identifying individuals who may have a BRCA1 or BRCA2 pathogenic variant.

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.[214] This recommendation was based on a study that suggested similar pathogenic variant rates identified through an extended multigene panel in patients with breast cancer who did or did not meet the NCCN guidelines for genetic testing.[215] This study had important methodologic challenges that need to be considered, including exclusion of participants previously tested, uncertain accuracy of the reported risk criteria for study participants, inclusion of genes with uncertain management guidelines, and difference in the specific genes in which pathogenic or likely pathogenic variants were identified across the two groups. For example, there was a statistically significant difference between participants who met and who did not meet NCCN criteria in the detection of BRCA1/BRCA2 variants.

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 [216] and others have found that, if more than one NCCN criterion is met, then the positive predictive value does pass the 10% threshold (e.g., 12% for more than two NCCN criteria).[217]

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.[218] The study assessed the relative performance of NCCN genetic testing criteria as compared with the American Society of Breast Surgeons' recommendation to test all women aged 65 years or younger with breast cancer. The sensitivity of the criteria was defined as the proportion of individuals who met testing criteria and tested positive for a pathogenic or likely pathogenic variant of the total population of pathogenic or likely pathogenic variant carriers in the study, while the specificity was defined as the proportion of individuals who did not meet testing criteria and tested negative for a pathogenic or likely pathogenic variant of the total population of noncarriers in the study. High sensitivity and specificity are both important considerations; however, higher sensitivity leads to lower specificity, so it is important to balance these two factors. Detection of BRCA1/BRCA2 pathogenic or likely pathogenic variants based on NCCN criteria had a sensitivity of 87% with a specificity of 53.5%; when expanded to the nine genes included in the study, sensitivity was 70% and specificity was 53.2%. When including all women diagnosed with breast cancer at age 65 or younger, the sensitivity to detect BRCA1/BRCA2 pathogenic or likely pathogenic variants increased to 98%, while the specificity dropped to 22%. Among those who did not meet NCCN criteria, 0.7% had pathogenic or likely pathogenic BRCA1/BRCA2 variants.

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.[219] The prevalence of pathogenic or likely pathogenic BRCA1/BRCA2 variants among those diagnosed with invasive breast cancer before age 65 years was 2.21%, compared with 1.09% among those diagnosed at age 65 years or older. In comparison, the frequency of pathogenic or likely pathogenic BRCA1/BRCA2 variants was 0.22% in the control group. Current genetic testing criteria detect BRCA pathogenic variants. Although higher sensitivity is always desired, it is at the expense of specificity. Lower specificity leads to higher costs to achieve one positive genetic test.

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.[220,221] Among high-risk patients, the option of genetic testing is an important part of the shared decision-making process regarding cancer treatments at the time of diagnosis. Tools are available to facilitate decision making about genetic testing in this context.[222]

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.[236] In a population of ovarian cancer patients who test negative for BRCA1 and BRCA2 pathogenic variants, multigene panel testing can reveal actionable pathogenic variants.[237-239]

In general, multigene panel testing increases the yield of non-BRCA pathogenic variants across a variety of populations.[221,240-242] In an unselected population of breast cancer patients, the prevalence of BRCA1 and BRCA2 pathogenic variants was 6.1%, while the prevalence of pathogenic variants in other breast/ovarian cancer–predisposing genes was 4.6%.[243] In an unselected population of endometrial cancer patients, the prevalence of Lynch syndrome pathogenic variants (MLH1, MSH2, EPCAM-MSH2, MSH6, and PMS2) was 5.8%; the prevalence of pathogenic variants in other actionable genes was 3.4%.[108] Similarly, in a study of 35,409 women with breast cancer tested with the Myriad 25-gene panel, a pathogenic variant was found in 9.3% of women.[244] Among that 9.3%, 48.5% of the women carried a pathogenic variant in BRCA1 or BRCA2. The majority of other breast cancer genes with pathogenic variants identified included CHEK2 (11.7%), ATM (9.7%), and PALB2 (9.3%). The prevalence of pathogenic variants in the other breast cancer genes on the panel ranged from 0.05% to 0.31%. Pathogenic variants in Lynch syndrome genes accounted for 7.0% of variants identified; 3.7% were found in other genes included in the panel. The rate of pathogenic variants was higher in women with TNBC diagnosed before age 40 years. A similar trend of identifying pathogenic variants in non-BRCA susceptibility genes in male breast cancer patients has also been described.[245] In two studies of women who had previously tested negative for BRCA1/BRCA2, reflex testing with a multigene panel identified pathogenic variants in additional genes among 8% to 11% of cases.[246,247] In a study of 77,085 patients with breast cancer and 6,001 patients with ovarian cancer, 24.1% and 30.9% had genetic testing, respectively. Of those tested, pathogenic or likely pathogenic variants were identified in 7.8% of patients with breast cancer and 14.5% of patients with ovarian cancer. Prevalent non-BRCA pathogenic variants identified in patients with breast cancer included CHEK2 (1.6%), PALB2 (1.0%), ATM (0.7%), and NBN (0.4%). In patients with ovarian cancer, non-BRCA pathogenic variants included CHEK2 (1.4%), BRIP1 (0.9%), MSH2 (0.8%), and ATM (0.6%).[248] The potential utility of genetic testing in patients with ovarian tumors of all histologies was suggested in a study using a 32-gene panel that found 13.2% of 4,439 tumors harbored a pathogenic variant. Rates were highest among those with serous ovarian carcinoma (14.7%), although likely pathogenic variants were also seen in those with other histologies (borderline, germ cell, and sex cord stromal tumors), the significance of which is unclear to clinical management or etiology of disease.[249]

Multi-gene panel testing was conducted as part of two large efforts led by the worldwide Breast Cancer Association Consortium (BCAC) [250] and the United States–based CARRIERS consortium.[251] The BCAC study tested 113,927 women for 34 inherited cancer genes, while the CARRIERS study tested 64,791 women for 28 hereditary cancer genes. In both studies, significant associations were reported between eight genes and breast cancer development (BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2). Associations were only reported between MSH6 and breast cancer development in the BCAC study. Similarly, associations were only reported between CDH1 and breast cancer development in the CARRIERS study. Both TP53 and PTEN (which are established breast cancer risk genes that are linked to early-onset disease) were not significantly associated with breast cancer development in these studies. This is presumably because TP53 and PTEN pathogenic variants are very rare.

NCCN recommends that women diagnosed with TNBC undergo BRCA1/BRCA2, CDH1, PALB2, PTEN, STK11, and TP53 testing to guide treatment decisions at any age.[209] A large study utilizing multigene (panel) testing comprising two separate cohorts reported that, in addition to BRCA1/BRCA2 genes, six other breast cancer susceptibility genes were also related to a higher risk of TNBC. Specifically, pathogenic variants in BARD1, PALB2, and RAD51D, in addition to BRCA1 and BRCA2, were each associated with more than a fivefold increase in breast cancer.[252] Pathogenic variants in three other genes —BRIP1, RAD51C, and TP53— were each associated with an increased TNBC risk of more than twofold. Pathogenic variants in these eight genes were reported in 12% of the TNBC cases (8.3% BRCA1/BRCA2, 3.7% non-BRCA1/BRCA2). The study was conducted in a clinical testing cohort of 140,449 individuals (8,753 TNBC cases) who received genetic testing using a 21-gene panel (sample A). In addition, a second sample (sample B) examined gene frequency rates in a pooled consortium of 2,143 individuals using a 17-gene panel. The overall frequency of pathogenic variants in the 21 genes examined in sample A was 14.4% (8.4% BRCA1/BRCA2, 6.0% non-BRCA1/BRCA2). The two samples had very consistent findings with respect to the risk estimates despite differences in age, race, ethnicity, and family history of cancer with sample A being younger, more racially and ethnically diverse, and more likely to have a family history of cancer. The pathogenic variant frequency detection in these 21 genes was also similar for White individuals (14% overall, 7.8% BRCA1/BRCA2, 6.2% non-BRCA1/BRCA2) and African American individuals (14.6% overall, 9.0% BRCA1/BRCA2, 5.6% non-BRCA1/BRCA2).

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.[253] High ER-negative breast cancer risk was reported in individuals with pathogenic variants in RAD51D (OR, 7.82), while moderate ER-positive breast cancer risk was reported in individuals with pathogenic variants in CHEK2, ATM, ERCC3, and FANCC. Similarly, a case-control study of 3,286 women with African ancestry found significant associations between breast cancer risk and pathogenic variants in the following genes: BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53, NF1, RAD51C, and RAD51D.[254]

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.[239] There is also the possibility of finding a variant of uncertain significance (VUS). Even within a given gene, there may be differential risks on the basis of specific pathogenic variants.[255] A large population-based retrospective study using Surveillance, Epidemiology, and End Results (SEER) program data from Georgia and Los Angeles, California, found that multigene testing led to a twofold increase in the detection of pathogenic variants compared with BRCA-only testing in women with breast cancer.[256] VUS rates, however, were tenfold higher in the multigene panels, especially in African American women (44.5%) and Asian women (50.9%). Many centers now offer a multigene panel test instead of just BRCA1 and BRCA2 testing if there is a concerning family history of syndromes other than hereditary breast and ovarian cancer, or more importantly, to gain as much genetic information as possible with one test, particularly if there may be insurance limitations.

(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 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;[25-28] one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated.[28] However, the largest prospective study to date of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry [29] who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001).[29] The same group subsequently analyzed data on 764 carriers of MMR gene pathogenic variants with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59).[30] A series from the United Kingdom composed of clinically referred Lynch syndrome kindreds, with efforts to correct for ascertainment, showed a twofold increased risk of breast cancer in 157 MLH1 carriers but not in carriers of other MMR variants.[31] Results from a meta-analysis of breast cancer risk in Lynch syndrome among 15 studies with molecular tumor testing results revealed that 62 of 122 breast cancers (51%; 95% CI, 42%–60%) in MMR pathogenic variant carriers were MMR-deficient. In addition, breast cancer risk estimates among a total of 21 studies showed an increased risk of twofold to 18-fold in eight studies that compared MMR variant carriers with noncarriers, while 13 studies did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome.[32]

A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[33-36] although this has not been consistently observed.[37] Through a study of 325 Canadian families with Lynch syndrome, primarily encompassing MLH1 and MSH2 carriers, the lifetime cumulative risk for breast cancer among MSH2 carriers was reported to be 22%.[33] Similarly, breast cancer risks were elevated in a study of 423 women with Lynch syndrome, with substantially higher risks among those with MSH6 and PMS2 pathogenic variants, compared with MLH1 and MSH2 pathogenic variants.[34] In fact, breast cancer risk to age 60 years was 37.7% for PMS2, 31.1% for MSH6, 16.1% for MSH2, and 15.5% for MLH1. These findings are consistent with another study of 528 patients with Lynch syndrome–associated pathogenic variants (including MLH1, MSH2, MSH6, PMS2, and EPCAM) in which PMS2 and MSH6 variants were much more frequent among patients with only breast cancer, compared with those with only colorectal cancer (P = 2.3 x 10-5).[35] Additional data to support an association of MSH6 with breast cancer were provided through a study of over 10,000 cancer patients across the United States who had genetic testing.[36] Findings indicated that MSH6 was associated with breast cancer with an odds ratio (OR) of 2.59 (95% CI, 1.35–5.44). Taken together, these studies highlight how the risk profile among patients with Lynch syndrome is continuing to evolve as more individuals are tested through multigene panel testing, with representation of larger numbers of individuals with PMS2 and MSH6 pathogenic variants compared with prior studies. In the absence of definitive risk estimates, individuals with Lynch syndrome are screened for breast cancer on the basis of family history.[38]

Historical criteria for defining LFS

The term LFS was used for the first time in 1982,[50] and the following criteria, which subsequently became the classical definition of the syndrome, were proposed by Li and Fraumeni in 1988 [51]:

Subsequently in 2001, Chompret et al. [42] systematically developed clinical criteria for recommending TP53 genetic testing, with the narrow LFS tumor spectrum defined as sarcoma, brain tumors, breast cancer, and adrenocortical carcinoma. The criteria were as follows:

These criteria were revised in 2009 [43] based on additional emerging data [41,52] as follows:

*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. [45] revised the criteria based on data from 415 carriers of pathogenic variants, to include the presence of childhood anaplastic rhabdomyosarcoma and breast cancer before age 31 years as an indication for testing, similar to what is recommended for choroid plexus carcinoma and adrenocortical carcinoma. The criteria were revised as follows:

**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.[41] All families with a TP53 pathogenic variant had at least one family member with a sarcoma, breast cancer, brain cancer, or adrenocortical cancer (core cancers). In addition, all eight individuals with a choroid plexus tumor had a TP53 pathogenic variant, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no TP53 variants were found.

Subsequently, a large clinical series of patients from France who were tested primarily based on the 2009 version of the Chompret criteria [43] included 415 carriers of pathogenic variants from 214 families.[45] In this study, 43% of carriers had multiple malignancies, and the mean age at first tumor onset was 24.9 years. The childhood tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas, CNS tumors, and soft tissue sarcomas (present in 23%–30% collectively), whereas the adult tumor spectrum primarily encompassed breast cancer (79% of females) and soft tissue sarcomas (27% of carriers). The TP53 pathogenic variant detection rate was 6% among females younger than 31 years with breast cancer and no additional features suggestive of LFS. Evaluation of genotype-phenotype correlations indicated a gradient of clinical severity, with a significantly lower mean age at onset among those with dominant-negative missense variants (21.3 years), compared with those with all types of loss-of-function variants (28.5 years) or genomic rearrangements (35.8 years). With the exception of adrenocortical carcinoma, affected children mostly harbored dominant-negative missense pathogenic variants. Among 127 female carriers of pathogenic variants with breast cancer, 31% developed contralateral breast cancer (CBC). Receptor status information was available for 40 tumors, which indicated 55% were HER2-positive, and 37% were triple-positive (i.e., ER-positive, PR-positive, and HER2-positive). There was an exceptionally high rate of multiple malignancies (43%) among carriers of pathogenic variants, of which 83% were metachronous. Treatment records were available for 64 carriers who received radiation therapy for treatment of their first tumor; of these, 19 (30%) developed 26 secondary tumors within a radiation field, with a latency of 2 to 26 years (mean, 10.7 y).

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.[53] They reported substantial variations by sex, age, and cancer type. Specifically, cumulative cancer incidence reached 50% by age 31 years in females and age 46 years in males, although male risks were higher in childhood and late adulthood. Cumulative cancer incidence by sex for the top four cancers is included in Table 4. Of those with one cancer, 49% developed at least one additional cancer after a median of 10 years. Age-specific risks for developing first and second cancers were comparable.

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.[54] The clinical significance of finding an isolated TP53 pathogenic variant in an individual or family who does not meet the Chompret criteria is uncertain. Consequently, it remains important to interpret cancer risks and determine optimal management strategies for individuals who are unexpectedly found to have a germline TP53 pathogenic variant, while considering their personal and family histories.

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.[59] In addition, PTEN pathogenic variants have been identified in patients with very diverse clinical phenotypes.[60] The term PHTS refers to any patient with a PTEN pathogenic variant, irrespective of clinical presentation.

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.[61] Pathogenic variants in the 5’ end of PTEN or within the phosphatase core of PTEN tend to affect more organ systems.[62]

Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[63,64] These include major, minor, and pathognomonic criteria that consist of certain mucocutaneous manifestations and adult-onset dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). An updated set of criteria based on a systematic literature review has been suggested [65] and is currently utilized in the National Comprehensive Cancer Network (NCCN) guidelines.[66] Contrary to previous criteria, the authors concluded that there was insufficient evidence for any features to be classified as pathognomonic. Increased genetic testing (especially multigene panels) has identified individuals with germline PTEN pathogenic variants who do not meet diagnostic criteria for PHTS. Diagnostic criteria will need to be reconciled with these recently discovered phenotypes. Hence, it is unclear whether PHTS diagnoses should be based on clinical features or a positive PTEN genetic test result. The American College of Medical Genetics and Genomics (ACMG) suggests that referral for genetics consultation be considered for individuals with a personal history of or a first-degree relative with the following: 1) adult-onset Lhermitte-Duclos disease or 2) any three of the major or minor criteria that have been established for the diagnosis of Cowden syndrome.[67] Detailed recommendations, including diagnostic criteria for Cowden syndrome, can be found in the NCCN and ACMG guidelines.[66,67] Additionally, a predictive model that uses clinical criteria to estimate the probability of a PTEN pathogenic variant is available; a cost-effectiveness analysis suggests that germline PTEN testing is cost effective if the probability of a variant is greater than 10%.[68]

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.[69] Most individuals did not meet the clinical criteria for a diagnosis of Cowden syndrome or BRRS. Of the 3,399 individuals recruited and tested, 295 probands (8.8%) and an additional 73 family members carried a germline PTEN pathogenic variant. The authors concluded that melanoma, kidney cancer, and colorectal cancer should be added to the spectrum of cancers associated with PTEN germline pathogenic variants (in addition to breast cancer, thyroid cancer, and endometrial cancer). This conclusion was based on the high melanoma, kidney, and colorectal cancer lifetime risk estimates found in individuals with PTEN pathogenic variants. A second study of approximately 100 patients with a germline PTEN pathogenic variant confirmed these findings and suggested a cumulative cancer risk of 85% by age 70 years.[70]

PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple GI polyps, both hamartomatous and adenomatous.[79-81] Germline pathogenic variants in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[82-86] GI cancers (including colorectal adenocarcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, and pancreatic adenocarcinoma) are some of the most common malignancies seen in individuals with PJS. PJS also increases the risk of developing cancers in other organs. For example, the cumulative risks have been estimated to be 32% to 54% for breast cancer [87-89] and 21% for ovarian cancer (mainly ovarian sex-cord tumors).[87] The risk of developing pancreatic cancer in individuals with PJS is estimated to be more than 100-fold higher than that of the general population (although these statistics are based on calculations from a small number of individuals with PJS).[87] A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS.[87,90] Table 5 shows the cumulative risk of these tumors.

Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.[91] In addition, females with PJS commonly develop benign ovarian sex-cord tumors with annular tubules, whereas males with PJS are predisposed to development of Sertoli-cell testicular tumors;[92] although neither of these two tumor types is malignant, they can cause symptoms related to increased estrogen production.

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.

PJS is caused by pathogenic variants in the STK11 (also called LKB1) tumor suppressor gene located on chromosome 19p13.[83,84] Unlike the adenomas seen in familial adenomatous polyposis, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (LOH) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene.[95,96] However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency may be sufficient for initial tumor development in PJS.[97] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[98] indeed, compound mutant mice heterozygous for pathogenic variants in STK11 +/- and homozygous for pathogenic variants in TP53 -/- have accelerated development of both hamartomas and cancers.[99]

Germline variants of the STK11 gene represent a spectrum of nonsense, frameshift, and missense variants, and splice-site variants and large deletions.[82,88]

Approximately 85% of variants are localized to regions of the kinase domain of the expressed protein. No strong genotype-phenotype correlations have been identified.[88] Up to 30% of variants are large deletions involving one or more exons of STK11, underscoring the importance of deletion analysis in suspected cases of PJS.[82]

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.[82,90,100] Given the results of these studies, it is unlikely that other major genes cause PJS.

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 6). 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.[7]

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

Variants in some of the FA genes, most notably BRCA1 and BRCA2, but also PALB2, RAD51C, 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.

CHEK2

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.[16-21] One study identified the pathogenic variant in 1.2% of the European controls, 4.2% of the European BRCA1/BRCA2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases.[16] In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC pathogenic variant.[22] In additional European and U.S. (where the pathogenic variant appears to be slightly less common) studies, including a large prospective study,[23] the frequency of CHEK2 pathogenic variants detected in familial breast or ovarian cancer cases has ranged from 0% [24] to 11%; overall, these studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer.[23,25-28] A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among carriers of pathogenic variants.[29] A subsequent meta-analysis based on 29,154 cases and 37,064 controls from 25 case-control studies found a significant association between CHEK2 1100delC heterozygotes and breast cancer risk (OR, 2.75; 95% CI, 2.25–3.36). The ORs and CIs in unselected, familial, and early-onset breast cancer subgroups were 2.33 (1.79–3.05), 3.72 (2.61–5.31), and 2.78 (2.28–3.39), respectively. However, study limitations included pooling of populations without subgroup analysis, using a mix of population-based and hospital-based controls, and basing results on unadjusted estimates (as cases and controls were matched on only a few common factors); therefore, results should be interpreted in the context of these limitations.[30] In a series of male breast cancer patients, the CHEK2 1100delC variant was significantly more frequently identified than in controls, suggesting that this variant is also associated with an increased risk of male breast cancer.[31]

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.[32,33] Furthermore, a meta-analysis of carriers of 1100delC pathogenic variants estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer.[34] Similarly, a Polish study reported that CHEK2 truncating pathogenic variants confer breast cancer risks based on a family history of breast cancer as follows: no family history, 20%; one second-degree relative (SDR), 28%; one first-degree relative (FDR), 34%; and both FDRs and SDRs, 44%.[3] Moreover, a Dutch study suggested that female homozygotes for the CHEK2 1100delC variant have a greater-than-twofold increased breast cancer risk compared with heterozygotes.[35] Although there have been conflicting reports regarding cancers other than breast cancer associated with CHEK2 pathogenic variants, this may be dependent on variant type (i.e., missense vs. truncating) or population studied and is not currently of clinical utility.[21,26,36-41] The contribution of CHEK2 variants to breast cancer may depend on the population studied, with a potentially higher variant prevalence in Poland.[42] Carriers of CHEK2 variants in Poland may be more susceptible to estrogen receptor (ER)–positive breast cancer.[43]

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,[44] although additional studies are needed to further refine these risks.

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

ATM

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.[45] More than 300 variants in the gene have been identified, most of which are truncating variants.[46] ATM proteins have been shown to play a role in cell cycle control.[47-49] In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[50] There is insufficient evidence to recommend against radiation therapy in carriers of a single ATM pathogenic variant (heterozygotes).

Initial, large epidemiological studies demonstrated a statistically increased relative risk (RR) of approximately 2.0 for breast cancer among female ATM heterozygotes.[4,51] Subsequent, large international consortium-based studies have refined risk estimates.[52,53] An international study based on 113,000 females from 25 countries reported an OR of 2.10 (95% CI, 1.71–2.57) for breast cancer in ATM heterozygotes. ATM pathogenic variants were also associated with ER-positive tumors.[52] Domains specifically associated with higher breast cancer risks included the FRAP–ATM–TRRAP (FAT) domain (P = .00019 in all studies) and protein kinase domains (P = .00092 in all studies). Similarly, a United States–based study of 63,000 women reported an OR of 1.82 for breast cancer in ATM heterozygotes (95% CI, 1.46–2.27) and also reported an association between ATM pathogenic variants and ER-positive breast cancers.[53] A similar OR of 2.03 (95% CI, 1.89–2.19) was estimated for invasive ductal breast cancer through a commercial, lab-based study of 4,607 individuals with ATM pathogenic or likely pathogenic variants.[54]

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.[55] Another meta-analysis reported the RR for female breast cancer as 3.0 in ATM carriers (95% CI, 2.1–4.5).[56] A subsequent systematic review and meta-analysis estimated an adjusted OR of 1.67 for breast cancer risk in individuals with ATM pathogenic variants (95% CI, 0.73–3.82) based on seven adjusted case-control studies.[57] The crude OR was 2.27 (95% CI, 1.17–4.40) based on nine unadjusted case-control studies. The RR was estimated as 1.68 (95% CI, 1.17–2.40) based on two cohort studies. Overall, the findings suggested genotype-phenotype correlations, with the ATM c.7271T>G variant (also known as the ATM Val2424Gly variant) as the most predisposing factor and with limited predictive ability for Asp1853Val, Leu546Val, and Ser707Pro ATM variants. Per NCCN guidelines, it is recommended that women who carry an ATM pathogenic variant have annual mammograms starting at age 40 years with consideration of breast magnetic resonance imaging with and without contrast beginning at age 30 to 35 years.[14]

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.[58,59] Specifically, in a commercial laboratory, data-based study of patients referred for hereditary cancer testing with a multi-gene panel (N = 627,742) including 4,607 ATM pathogenic or likely pathogenic variant carriers, risk of invasive ductal breast cancer was higher for the c.7271T>G missense variant (OR, 3.76; 95% CI, 2.76–5.12) than for other missense and truncating ATM variants.[54]

Some studies reported an association between ATM and ovarian cancer, with ovarian cancer lifetime risk approaching ~3%.[60,61] A commercial laboratory, data-based study reported an OR of 1.57 (95% CI, 1.35–1.83) for ovarian cancer in ATM pathogenic variant carriers.[54]

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.[54] Among 130 pancreatic cancer kindreds with a germline ATM pathogenic variant, the cumulative risk of pancreatic cancer was 1.1% (95% CI, 0.8%–1.3%) by age 50 years, 6.3% (95% CI, 3.9%–8.7%) by age 70 years, and 9.5% (95% CI, 5.0%–14.0%) by age 80 years.[62] Overall, the RR of pancreatic cancer was 6.5 (95% CI, 4.5–9.5) in ATM pathogenic variant carriers when compared with noncarriers. The average age at diagnosis was 64 years (range, 31–98 y).

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).[54] For more information, see the ATM section in Genetics of Prostate Cancer.

RAD51

RAD51 and the family of RAD51-related genes, also known as RAD51 paralogs, are thought to encode proteins that are involved in DNA damage repair through homologous recombination and interaction with numerous other DNA repair proteins, including BRCA1 and BRCA2. The 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.[63] Variants in these genes are thought to result in loss of RAD51 focus formation in response to DNA damage.[64]

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%).[65] Another study screened 286 BRCA1/BRCA2-negative patients with breast cancer and/or ovarian cancer and found one likely pathogenic variant in RAD51C-G153D.[66] RAD51C pathogenic variants have also been reported in Australian, British, Finnish, and Spanish non-BRCA1/BRCA2 ovarian cancer–only and breast/ovarian cancer families, and in unselected ovarian cancer cases, with frequencies ranging from 0% to 3% in these populations.[5,67-73] In a sample of 206 high-risk Jewish women (including 79 of Ashkenazi origin) previously tested for the common Jewish pathogenic variants, two previously described and possibly pathogenic missense variants were detected.[74] Four additional studies were unable to confirm an association between the RAD51C gene and hereditary breast cancer or ovarian cancer.[75-78]

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,[6,71,79-83] although the clinical significance of these findings is unknown. In a case-control study of 3,429 ovarian cancer patients, RAD51C and RAD51D pathogenic variants were more commonly found in ovarian cancer cases (0.82%) than in controls (0.11%, P < .001).[84]

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).[85]

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.[86-89] A meta-analysis of nine epidemiologic studies involving 13,241 cases and 13,203 controls of unknown BRCA1/BRCA2 status found that women carrying the CC genotype had an increased risk of breast cancer compared with women with the GG or GC genotype (OR, 1.35; 95% CI, 1.04–1.74). A meta-analysis of 14 case-control studies involving 12,183 cases and 10,183 controls confirmed an increased risk only for women who were known BRCA2 carriers (OR, 4.92; 95% CI, 1.10–21.83).[90] Another meta-analysis of 12 studies included only studies of known BRCA-negative cases and found no association between RAD51 135G→C and breast cancer.[91]

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

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

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

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

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

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.[32] This early attempt at estimating a PRS for breast cancer included 77 SNVs, which collectively conferred lifetime risks of developing breast cancer by age 80 years of 3.5% and 29% for women in the lowest and highest 1% of the PRS, respectively.[32] Since then, PRSs incorporating additional genetic variants and examining other breast cancer–related outcomes including tumor and pathological characteristics, mode of detection, and contralateral breast cancer (CBC) have been estimated.[33-40] In 2019, the PRS with the highest discriminatory ability to date was developed and prospectively validated in the largest GWAS datasets available (79 studies in BCAC and more than 190,000 women in the U.K. Biobank), which incorporates information on 313 genetic variants and is optimized for ER-positive and ER-negative breast cancer.[39] Compared with women in the middle quintile, those in the highest 1% of PRS₃₁₃ had 4.04-, 4.37-, and 2.78-fold risks of developing breast cancer overall, ER-positive disease, and ER-negative disease, respectively.[39] Lifetime absolute risk (AR) of breast cancer by age 80 years for women in the lowest and highest 1% of PRS₃₁₃ ranged from 2% to 31% for ER-positive breast cancer, while for ER-negative disease, the ARs ranged from 0.55% to 4%.[39]

Common genomic variants associated with the development of a first primary breast cancer are also associated with the development of CBC.[40] Women in the highest quartile of the PRS had a 1.6-fold increased risk of developing CBC compared with the lowest quartile.[40] Moreover, PRSs of breast and ovarian cancers have been assessed in women who are carriers of BRCA1 and BRCA2 pathogenic variants, and have been found to be predictive of cancer risk in these women, supporting the hypothesis of a shared polygenic component of cancer risk between the general population and variant carriers.[36] The PRS for ER-negative disease had the strongest association with breast cancer risk in BRCA1 variant carriers, while the strongest association in BRCA2 variant carriers was seen for the overall breast cancer PRS. BRCA1 variant carriers had cumulative lifetime risks of 56% and 75% of developing breast cancer at the 10th and 90th percentile of the PRS, respectively. The ovarian cancer PRS was strongly associated with risk for both BRCA1 and BRCA2 variant carriers. For BRCA2 variant carriers, the ovarian cancer risk was 6% and 19% by age 80 years for those at the 10th and 90th percentile of PRS, respectively. The authors noted that the incorporation of the PRS into risk prediction models may better inform decisions on cancer risk management for this population.[36]

Two large studies have supported that PRSs can improve breast cancer risk stratification.[41,42] PRSs were most important in the breast cancer risk stratification of individuals with CHEK2 and ATM pathogenic variants. After PRSs were incorporated, 30% of individuals with a CHEK2 pathogenic variant and nearly half of the individuals with an ATM pathogenic variant dipped below a 20% lifetime risk of breast cancer. This is significant, since lifetime risk values greater than 20% can prompt more frequent breast cancer screening and other types of clinical management.[41] PRSs were also effective when stratifying breast cancer risk in noncarriers. Gallagher et al. analyzed case-control data from 150,962 women who had multigene hereditary cancer genetic testing. This study examined the impact of a PRS with 86 SNVs on individuals with pathogenic variants in BRCA1, BRCA2, CHEK2, ATM, and PALB2. The PRS was predictive of breast cancer in individuals with pathogenic variants. However, breast cancer risk stratification was more pronounced in noncarriers (OR, 1.47; 95% confidence interval [CI], 1.45–1.49) and CHEK2 pathogenic variant carriers (OR, 1.49; 95% CI, 1.36–1.64) than in carriers of BRCA1 (OR, 1.20; 95% CI, 1.10–1.32) or BRCA2 (OR, 1.23; 95% CI, 1.12–1.34) pathogenic variants. The ORs for ATM (OR, 1.37; 95% CI, 1.21–1.55) and PALB2 (OR, 1.34; 95% CI, 1.16–1.55) pathogenic variant carriers were intermediate when compared with those of BRCA1/2 pathogenic variant carriers, CHEK2 pathogenic variant carriers, and noncarriers. Even though the PRS improved breast cancer risk stratification across all groups, the PRS was most important for individuals with CHEK2 pathogenic variants and for noncarriers.[42] Similarly, Gao et al. analyzed case-control data from 26,798 non-Hispanic White individuals with breast cancer and 26,127 controls using a PRS based on 105 SNVs. More than 95% of BRCA1, BRCA2, and PALB2 pathogenic variant carriers had a 20% lifetime risk of breast cancer. In contrast, 52.5% of ATM pathogenic variant carriers and 69.7% of CHEK2 pathogenic variant carriers without first-degree relatives (FDRs) with breast cancer had a 20% lifetime risk of breast cancer. This was also true in 78.8% of ATM carriers and 89.9% of CHEK2 carriers with an FDR with breast cancer.[41]

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.[43-48] For example, in a study combining PRS₇₇ with clinical models, the AUC for predicting breast cancer before age 50 years improved by more than 20%.[44] Clinical trials, including WISDOM and MyPeBs, are in progress to study the potential clinical utility of the PRS for making screening decisions and understanding outcomes.[49] Because PRSs have been largely developed and validated in populations of European ancestry, the utility and prediction accuracy of these PRSs in non-European populations is unknown.

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.[50]

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%.[1] Results of multivariate analysis found that BRCA1/BRCA2 genetic testing uptake was associated with having a personal or family history of breast or ovarian cancer, and with methodological features of the studies, including sampling strategies, recruitment settings, and how studies defined actual uptake versus the intention to have testing.

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 7 summarizes the uptake of genetic testing in clinical and research cohorts in the United States.

Several studies conducted in non-U.S. settings have examined the uptake of genetic testing.[7-11] In studies examining the uptake of testing among at-risk relatives of carriers of BRCA1/BRCA2 pathogenic variants, uptake rates have averaged below 50% (range, 36%–48%), with higher uptake reported among female relatives than in male relatives. Other factors associated with higher uptake of testing were not consistently reported among studies but have most commonly included being a parent and wanting to learn information about a child’s risk.

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.[1] However, there is evidence that women diagnosed with breast cancer are equally satisfied with genetic counseling (including information received and strength and timing of physician recommendations for counseling), whether they received genetic counseling before or after their definitive surgery for breast cancer.[12] Another review [13] found that uptake of genetic testing for BRCA1/BRCA2 pathogenic variants was related to psychological factors (e.g., anxiety about breast cancer and perceived risk of breast cancer) and demographic and medical factors (e.g., history of breast cancer or ovarian cancer, presence of children, and higher number of affected first-degree relatives [FDRs]). Family members with a known BRCA1/BRCA2 pathogenic variant were more likely to pursue testing; those with more extensive knowledge of BRCA1/BRCA2 testing, heightened risk perceptions, beliefs that mammography would promote health benefit, and high intentions to undergo testing were more likely to follow through with testing.[14]

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.[15] A systematic review found that certain racial and ethnic minority groups, including African American and Hispanic individuals, had more negative views and greater concerns about genetic counseling and testing when compared with White individuals. African American and Hispanic individuals were more likely to believe genetic testing could be used to show their ethnic group was inferior to other groups. Additionally, African American and Hispanic individuals were found to have low awareness and knowledge about the importance of genetics in cancer, BRCA status, and genetic testing.[16]

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.[14,17] Among African American women, the most important reason for testing included motivation to help other relatives decide on genetic testing.[15]

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.[18] However, there is some evidence of referral bias favoring those with a maternal family history of breast cancer or ovarian cancer. In a Canadian retrospective review of 315 patients, those with a maternal family history of breast cancer or ovarian cancer were 4.9 times (95% confidence interval, 3.6–6.7) more likely to be referred for a cancer genetics consultation by their physician than were those with a paternal family history (P < .001).[19] Studies have found that physicians may not adequately assess paternal family history [20] or may underestimate the significance of a paternal family history for genetic risk.[20-22] Other studies have shown that physician referral of patients who meet U.S. Preventive Services Task Force guidelines for BRCA genetic counseling has been suboptimal.[23]

The uptake of BRCA testing to inform surgical treatment decisions when offered appears to be high in research cohorts;[2,24] however, findings from other studies suggest that testing is underutilized in clinical practice to inform breast cancer treatment decisions.[6,25,26] Barriers to the use of BRCA testing to inform surgical treatment decisions, including lack of physician referral of newly diagnosed patients for genetic counseling, type of insurance coverage (such as Medicare or Medicaid), and challenges in the timing and coordination of testing, have been reported.[6,27-30] In a randomized trial that provided proactive rapid genetic counseling (delivery of genetic counseling prior to surgery) compared with usual care for patients with newly diagnosed breast cancer, results suggested that although genetic counseling uptake was higher in the intervention arm, this did not translate into higher rates of genetic testing, receipt of results before surgery, or bilateral mastectomy decisions.[31]

Uptake of genetic counseling and genetic testing in diverse populations

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.[47]

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.[48] Other reasons for declining included having no children and becoming acquainted with breast/ovarian cancer in the family relatively early in their lives.[47,48]

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.[49] In 15% (n = 31) of individuals from 13 hereditary breast and ovarian cancer (HBOC) families who underwent genetic education and counseling and declined testing for a documented pathogenic variant in the family, positive changes in family relationships were reported—specifically, greater expressiveness and cohesion—compared with those who pursued testing.[50]

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.[51-54]

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.[55,56] Although the data are limited, research suggests that males, pathogenic variant noncarriers, and those whose mothers did not have personal histories of breast cancer may be more likely to favor genetic testing in minors in general.[55] Of those who had minor children at the time the study was conducted, only 17% stated a preference for having their own children tested. Concerns regarding testing of minors included psychological risks and insufficient maturity. Potential benefits included the ability to influence health behaviors.[56]

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.[57-59] In one study, 20 children (aged 11–17 y) of a selected group of mothers undergoing genetic testing (80% of whom previously had breast cancer and all of whom had discussed BRCA1/BRCA2 testing with their children) completed self-report questionnaires on their health beliefs and attitudes toward cancer, feelings related to cancer, and behavioral problems.[60] Ninety percent of children thought they would want cancer risk information as adults; half worried about themselves or a family member developing cancer. There was no evidence of emotional distress or behavioral problems.

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.[136,137] However, data from several studies,[138-140] including a large observational study [141] and a randomized trial,[142] provided evidence indicating that there were no adverse psychological effects associated with RGT. For example, an observational study analyzed 1,007 with newly diagnosed breast cancers from four Canadian academic centers. These patients underwent RGT and adverse psychological effects were not noted at one week or one year posttesting.[141] There were no differences in anxiety, distress, or depression between BRCA carriers (6% of the study population) and those with uninformative results in the short-term. However, after one year, BRCA carriers had significantly lower depression scores when compared with patients who had uninformative, negative results. Depression scores were within the normal range for both groups, and these scores did not reach depression levels that were clinically significant. Factors associated with lower levels of psychological functioning included lower educational levels, not having family histories of cancer, and undergoing bilateral mastectomies. Of note, women who had a variant of uncertain significance in the BRCA1/2 genes and a bilateral mastectomy had higher depression scores than BRCA carriers. One randomized controlled trial found that patients undergoing rapid genetic counseling and testing felt more actively involved in treatment decision making than those receiving standard care.[143]

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.[144,145] Female carriers are more likely to disclose their genetic test results to other family members [146] than are male carriers.[146,147] Among males, noncarriers were more likely than carriers to tell their sisters and children the results of their tests. BRCA1/BRCA2 carriers who disclosed their results to sisters had a slight decrease in psychological distress, compared with a slight increase in distress for carriers who chose not to tell their sisters. One study found that men reported greater difficulty disclosing a known pathogenic variant to family members than women (90% vs. 70%).[148]

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.[149,150] Study results suggest that both carriers of pathogenic variants [149] and women with uninformative results [149,150] communicate with sisters to provide them with genetic risk information. Similar findings were reported in women with uninformative results disclosing test results to their daughters.[150]

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 [149] or had a poor relationship with them.[150] Studies found that women with a BRCA pathogenic variant more often shared their results with their mother and adult sisters and daughters than with their father and adult brothers and sons.[80,144,145,151-153]

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.[145] Another study found that disclosure was limited mainly to FDRs, and dissemination of information to distant relatives was problematic.[154] Age was a significant factor in informing distant relatives with younger patients being more willing to communicate their genetic test result.[149,151,154] Additionally, one study found that lower genetic worry, higher interest in genomic information, carrying a BRCA1 or BRCA2 pathogenic variant, or having never been married was associated with communication to more family members.[147] In contrast, a longer time interval since diagnosis was associated with communication to fewer family members.[147]

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.[155] On the basis of 15 interviews conducted with women attending a familial cancer genetics clinic, the authors concluded that while women felt a sense of duty to discuss genetic testing with their relatives, they also experienced conflicting feelings of uncertainty, respect, and isolation. Decisions about whom in the family to inform and how to inform them about hereditary cancer and genetic testing may be influenced by tensions between women's need to fulfill social roles and their responsibilities toward themselves and others.[155] Another qualitative study of 21 women who attended a familial breast and ovarian cancer genetics clinic suggested that some women may find it difficult to communicate about inherited cancer risk with their partners and with certain relatives, especially brothers, because of their own fears and worries about cancer.[153] This study also suggested that how genetic risk information is shared within families may depend on the existing norms for communicating about cancer in general. For example, family members may be generally open to sharing information about cancer with each other, may selectively avoid discussing cancer information with certain family members to protect themselves or other relatives from negative emotional reactions, or may ask a specific relative to act as an intermediary to disclosure of information to other family members.[156] The potential importance of individuals outside the family, such as friends, as both confidantes about inherited cancer risk information and as sources of support for coping with this information was also noted in the study.[153]

A study of 31 mothers with a documented BRCA pathogenic variant explored patterns of dissemination to children.[157] Of those who chose to disclose test results to their children, age of offspring was the most important factor. Fifty percent of the children who were told were aged 20 to 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers. More than 70% of mothers informed their children within a week of learning their test result. Ninety-three percent of mothers who chose not to share their results with their children indicated that it was because their children were too young. These findings were consistent with three other studies showing that children younger than 13 years were less likely to be informed about test results compared with older children.[145,158,159] 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%), talk to prior participants (79%), and support groups (54%).[158]

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.[160] The study found that most couples discussed the decision to undergo testing (98%), most test participants felt their partners were supportive, and most women disclosed test results to their partners (97%, n = 148). Test participants who felt their partners were supportive during pretest discussions experienced less distress after disclosure, and partners who felt more comfortable sharing concerns with test participants pretest experienced less distress after disclosure. Six-month follow-up revealed that 22% of participants felt the need to talk about the testing experience with their partners in the week before the interview. Most participants (72%, n = 107) reported comfort in sharing concerns with their partners, and 5% (n = 7) reported relationship strain as a result of genetic testing. In couples in which the woman had a positive genetic test result, more relationship strain, more protective buffering of their partners, and more discussion of related concerns were reported than in couples in which the woman had a true-negative or uninformative result.[160]

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.[161] Men were less likely to recall receiving the results (P > .001). Of those with recall about receiving the test results, 10.5% of FDRs did not recall the findings. For those with recall of the results, 17.9% of FDRs had an interpretation that was discordant with the correct results. Accuracy of test results recall was greater for informative test results (those that were either true positive or true negative) (P = .029). However, regardless of the test results, FDRs perceived the cancer risk to be higher before they learned of the findings than after (74% and 53% of FDRs reported that they believed their risk for cancer was greater than average before and after hearing test results, respectively).

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.[162] In contrast, a study of 59 men testing positive for a BRCA1/BRCA2 pathogenic variant found that most men participated in family discussions about breast and/or ovarian cancer. However, fewer than half of the men participated in family discussions about risk-reducing surgery. The main reason given for having BRCA testing was concern for their children and a need for certainty about whether they could have transmitted the pathogenic variant to their children. In this study, 79% of participating men had at least one daughter. Most of these men described how their relationships had been strengthened after receipt of BRCA results, helping communication in the family and greater understanding.[163] Men in both studies expressed fears of developing cancer themselves. Irish men especially reported fear of cancer in sexual organs.

Family functioning

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.[50]

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.[164]

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.[160]

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.[165]

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.[166]

Children

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%.[145,151,154,158,171-174] In general, age of offspring was the most important factor in deciding whether to disclose test results. In one study of 31 mothers disclosing their BRCA test results, 50% of the children who were informed of the results were aged 20 to 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers.[157] Similarly, in another study of 42 female carriers of BRCA pathogenic variants, 83% of offspring older than age 18 years were told of the results, while only 21% of offspring aged 13 years or younger were told.[158]

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,[145,157,158] some parents chose to delay disclosure.[158] Reasons for delaying disclosure included waiting for the child to get older, allowing time for the parent to adjust to the information, and waiting until results could be shared in person (in the case of adult children living away from home).[158]

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.[173]

One study looked at the reaction of children to results disclosure or the effect on the parent-child relationship of communicating the results.[158] With regard to offspring’s understanding of the information, almost half of parents from one study reported that their child did not appear to understand the significance of a positive test result, although older children were reported to have a better understanding. This same study also showed that 48% of parents reported at least one negative reaction in their child, ranging from anxiety or concern (22%) to crying and fear (26%). It should be noted, however, that in this study children's level of understanding and reactions to the test result were measured qualitatively and based only on the parents' perception. Also, given the retrospective design of the study, there was a potential for recall bias. There were no significant differences in emotional reaction depending on age or gender of the child. Lastly, 65% of parents reported no change in their relationship with their child, while 5 parents (22%) reported a strengthening of their relationship.

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.[175] However, based on a combination of maternal report and direct assessment of girls aged 10 to 13 years, girls with family histories of breast cancer or familial BRCA1/BRCA2 pathogenic variants experienced greater breast cancer–specific distress and a higher perceived risk of breast cancer than their peers without such family histories. Moreover, higher daughter distress was associated with higher maternal distress. A similarly designed study in older girls, aged 11 to 19 years, found that higher breast cancer–specific distress in daughters was associated with perceived risk and maternal distress. This older age group had higher self-esteem than did their peers without a family history of breast cancer.[176]

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%).[177]

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.[51-54] Surveys of parental interest in testing children for adult-onset hereditary cancers suggest that parents are more eager to test their children than to be tested themselves for a breast cancer gene, suggesting potential conflicts for providers.[178,179] In a general population survey in the United States, 71% of parents said that it was moderately, very, or extremely likely that if they carried a breast-cancer predisposing pathogenic variant, they would test a 13-year-old daughter now to determine her breast cancer gene status.[178] To date, no data exist on the testing of children for BRCA1/BRCA2, though some researchers believe it is necessary to test the validity of assumptions underlying the general prohibition of testing of children for breast/ovarian cancer and other adult-onset disease genes.[57-59] In one study, 20 children (aged 11–17 y) of a selected group of mothers undergoing genetic testing (80% of whom previously had breast cancer and all of whom had discussed BRCA1/BRCA2 testing with their children) completed self-report questionnaires on their health beliefs and attitudes toward cancer, feelings related to cancer, and behavioral problems.[60] Ninety percent of children thought they would want cancer risk information as adults; half worried about themselves or a family member developing cancer. There was no evidence of emotional distress or behavioral problems. Another study by this group [173] found that 1 month after disclosure of BRCA1/BRCA2 genetic test results, 53% of 42 enrolled mothers of children aged 8 to 17 years had discussed their result with one or more of their children. Age of the child rather than pathogenic variant status of the mother influenced whether they were told, as did family health communication style.

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,[180] perhaps to the extent that some carriers may avoid childbearing.[181,182] These concerns also may prompt women to consider using prenatal testing methods to help reduce the risk of transmission.[180,183] Prenatal diagnosis is an encompassing term used to refer to any medical procedure conducted to assess the presence of a genetic disorder in a fetus. Methods include amniocentesis and chorionic villous sampling (CVS).[184,185] Both procedures carry some risk of miscarriage and some evidence suggests fetal defects may result from using these tests.[184,185] Moreover, discovering the fetus is a carrier for a genetic defect may impose a difficult decision for couples regarding pregnancy continuation or termination. An alternative to these tests is preimplantation genetic testing (PGT), a procedure used to test fertilized embryos for genetic disorders before uterine implantation,[180,186,187] thereby avoiding the potential dangers associated with amniocentesis and CVS and the decision to terminate a pregnancy. Using the information obtained from the genetic testing, potential parents can decide whether or not to implant. PGT can be used to detect pathogenic variants in hereditary cancer predisposing genes, including BRCA.[180,183]

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.[180,183,188] The first study was a web-based survey of 283 members,[180] the second included 205 attendees of the 2007 annual FORCE conference,[183] and the third was a web-based survey of 962 members.[188,189] These studies have documented low levels of awareness, with 20% to 32% of study respondents reporting having heard of PGT before study participation.[183,188] With respect to interest in PGT, the first study [180] found only 13% of women would be likely to use PGT, whereas, 33% of respondents in the subsequent FORCE studies reported that they would consider using PGT.[183,188] In the third FORCE-based study (n = 962),[188] multivariable analysis revealed PGT interest was associated with the desire to have more children, having previously had any prenatal genetic test, and previous awareness of PGT. Attitudinal predictors of interest in PGT included agreement that others at risk of HBOC should be offered PGT; the belief that PGT is acceptable for individuals at risk of HBOC; the belief that PGT information should be given to individuals at risk of HBOC; and endorsement of PGT benefits of having children without genetic variants and eliminating genetic diseases. Conversely, those who indicated that PGT was “too much like playing God” and reported that they considered PGT in the context of religion, had less interest in PGT.

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).[190] Of those who indicated that their families were not complete, 41% of BRCA carriers reported that their carrier status impacted their decision about future biological children. This study also revealed that 21.5% of unpartnered BRCA carriers felt more pressure to get married.

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.[191] In a study of 77 individuals undergoing BRCA testing as part of a multicenter cohort study in Spain, 61% of respondents reported they would consider PGT. Factors associated with PGT interest were age 40 years and older and had a prior cancer diagnosis.[192]

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.[193] Upon qualitative analysis of written comments provided by some respondents, the primary impact was related to accelerating the timing of pregnancy, feelings of guilt about possibly passing on the pathogenic variant to offspring, and having future children. In response to a hypothetical scenario in which PGT was readily available, 33% of participants reported that they would undergo PGT. Factors associated with this intention were having no future reproductive plans at the time of the survey, feeling pregnancy termination was an acceptable option in the context of identifying a BRCA pathogenic variant, and having fewer cases of breast and/or ovarian cancer in the family. When presented with questions about expectations about delivery of PGT or prenatal diagnosis information, 85% of respondents felt it should be provided along with BRCA test results; 45% felt that it should be provided when carriers decide to have children. Respondents stated that they would expect this information to be delivered by cancer geneticists (92%), obstetrician/gynecologists (76%), and general practitioners (48%).

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.[194] In this study, the decision to undergo BRCA testing was primarily motivated by the desire to manage one’s personal cancer risk, rather than a desire to inform future reproductive decisions. The perceived severity of HBOC influenced concerns about passing on a BRCA pathogenic variant to children and also influenced willingness to consider PGT or prenatal diagnosis. Decisions about PGT and prenatal diagnosis also varied based on the participant's personal experiences. Most did not believe that a known BRCA pathogenic variant was a reason to terminate a pregnancy. As observed in prior studies, knowledge of reproductive options varied; however, there was a tendency among participants to view PGT as more acceptable than prenatal diagnosis with regard to termination of pregnancy. Decisions regarding the pros and cons of PGT versus prenatal diagnosis with termination of pregnancy were driven primarily by personal preferences and experiences, rather than by morality judgments. For example, women were deterred from PGT based on the need to undergo in vitro fertilization and to take hormones that might increase cancer risk and based on the observed experiences of others who underwent this procedure.

One study has examined these issues among high-risk men recruited from FORCE and Craigslist (a bulletin board website) (N = 228).[195] Similar to the previous studies of women, only 20% of men were aware of PGT before survey participation. In a multivariate analysis, those who selected the “other” option for possible benefits of PGT compared with those who selected from several predetermined options (e.g., having children without genetic variants) and those who considered PGT in the context of religion (as opposed to health and safety) were less likely to report that they would ever consider using PGT.

Decision aids for individuals considering risk management options for hereditary breast and gynecologic cancers

A systematic review of decision aids for BRCA1/BRCA2 carriers suggested that these tools are beneficial during the decision-making process.[216] BRCA1/BRCA2 carriers who used decision aids had lower decisional conflict (regarding treatment decisions), were more likely to reach risk-management decisions, and were more satisfied with their decisions than those who did not use decision aids. There were mixed or null findings regarding information-related outcomes like participant knowledge and whether there were consistent differences in actual risk-management choices.

A telephone-based intervention study used integrated motivational interviewing techniques and was led by genetic counselors.[217] This study found no differences in rates of RRSO among BRCA1/BRCA2 carriers in the intervention arm and the control arm after 1 year. However, women in the intervention arm had significantly lower decisional conflict and higher knowledge scores after 1 year. Two years after the intervention, 53.9% of women in the intervention arm had undergone RRSO, while 32.6% of women in the control arm had undergone RRSO.

Uptake of cancer risk management options

Several studies have examined uptake and adherence to cancer risk management options in individuals who have had genetic counseling and testing for BRCA1 and BRCA2 pathogenic variants. Outcomes vary across studies and include the following: 1) uptake/adherence to screening options (mammography, magnetic resonance imaging [MRI]) and 2) selection of risk-reducing options (i.e., risk-reducing mastectomy [RRM] and/or RRSO).

Most studies reported outcomes by pathogenic variant carrier status. Follow-up time after participants received their genetic test results also varied across studies, ranging from 12 months to several years. The Hereditary Breast Cancer Clinical Study Group assessed uptake of cancer risk management options in 6,223 women with a BRCA1/BRCA2 pathogenic variant.[218] These women were 25 to 80 years old and lived in 10 different countries (including the United States). Data from this study revealed the following:

Mammography

MRI

Risk-reducing mastectomy (RRM)

Risk-reducing bilateral salpingo-oophorectomy (RRSO)

Chemoprevention

In summary, breast cancer screening with mammogram in BRCA1/BRCA2 carriers may be suboptimal and can diminish over time.[218] A portion of this decline is associated with an increase in breast MRI use, and a corresponding decrease in mammography screening, in certain countries. However, the uptake of breast MRI in BRCA1/BRCA2 carriers was also suboptimal.

Women were more likely to undergo RRM when testing from 2009 and onward (30.3%) when compared with those who tested prior to 2009 (26.9%; P = .04).[218] Decisions about RRM may be influenced by personal factors, such as young patient age. When compared with women aged 30 to 39 years, women aged 50 to 59 years had lower rates of RRM (statistically significant) at 2, 5, and 10 years post–genetic testing.[219] Other factors that may influence decisions about RRM include the following: a family history of breast cancer, psychosocial factors (such as a desire to reduce cancer-related distress), recommendation from a health care provider, cultural/health care system–related factors, intact ovaries, and a recent diagnosis of breast/ovarian cancer.[220,221] An individual’s choice to have RRM also appears to be influenced by pretreatment genetic education and counseling, regardless of the patient's genetic test results.[222] Additionally, when those diagnosed with breast cancer had BRCA1/BRCA2 genetic test results at the time of surgical decision-making, this resulted in increased uptake of bilateral mastectomy (OR, 8.23; 95% CI, 2.55–26.59; P < .001).[223]

Uptake of RRSO was associated with increasing age, White race, having children, a family history of ovarian cancer, a personal history of mastectomy, higher perceived risk of ovarian cancer, and higher perceived benefit of RRSO.[224,225] The decision to have RRSO also varied based on pathogenic variant carrier status, with carriers of BRCA1 pathogenic variants (N = 226) undergoing RRSO more frequently than those with BRCA2 pathogenic variants (N = 188; P = .01).[219] In this study, a small proportion of women who were previously healthy developed breast cancer and chose to have RRSO after their cancer diagnoses (N = 14/60; 23.3%).

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.[222,226,227] Predictors of contralateral RRM before genetic counseling and testing included younger age at breast cancer diagnosis, more time since diagnosis, having at least one affected FDR, and not being employed full-time. In the year after disclosure of test results, 18% of women who tested positive for a BRCA1/BRCA2 pathogenic variant and 2% of those whose test results were uninformative underwent contralateral RRM. Predictors of contralateral RRM after genetic testing included younger age at breast cancer diagnosis, higher cancer-specific distress before genetic counseling, and having a positive BRCA1/BRCA2 test result. In this study, contralateral RRM was not associated with distress at 1 year after disclosure of genetic test results. A retrospective chart review evaluated uptake of bilateral mastectomies in 110 women who underwent BRCA1/BRCA2 genetic testing before making surgical decisions about the treatment of newly diagnosed breast cancer. Carriers of BRCA pathogenic variants were more likely to undergo bilateral mastectomies than were women in whom no variant was detected (83% vs. 37%; P = .046).[228] The only predictor of contralateral RRM in women without a pathogenic variant was being married (P = .03). Age, race, parity, disease stage and biomarkers, increased mammographic breast density, and breast MRI did not influence contralateral RRM decisions at the time of primary surgical treatment.

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.[227] Within 1 year after diagnosis, 87% of the sample underwent BRCA testing. The rate increased from 77% of newly diagnosed women tested in 2006 to 95% of women tested in 2013. Among women who tested positive for a pathogenic BRCA variant and stated that testing affected their surgery decisions (n = 88), 86% underwent bilateral mastectomy compared with 51% of noncarriers (P < .001). Among untested women, about one-third reported that they were not told by a health care provider that they were candidates for BRCA testing; yet, according to national guidelines, all were eligible for testing solely on the basis of their age at diagnosis.

A systematic review of risk-reducing salpingectomy with delayed oophorectomy (RRDSO) found that the avoidance of surgical menopause, preservation of fertility, concerns about sexual functioning, a family history of breast cancer, and an interest to avoid HRT were all related to being more likely to accept this option.[229] Those concerned with surgical timing, complications, and ongoing cancer risk were less likely to opt for RRDSO. In a small cohort of premenopausal BRCA1/BRCA2 carriers (n = 43), 44% chose to pursue RRDSO, 28% chose to pursue RRSO, and 28% chose to pursue only screening.[230] One year after surgery, cancer worry had decreased among all of those who elected to have surgery. Surgical complications were not reported.

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.[231]

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.[232]

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.[233]

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.[234]

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 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.[235] Interestingly, women opting for RRM had lower pretest satisfaction with their breasts and general body image than carriers who opted for surveillance or noncarriers of BRCA1/BRCA2 pathogenic variants. Of the women who had an RRM, all but one did not regret the decision at 1 year posttest disclosure, but many had difficulties with body image, sexual interest and functioning, and self-esteem. The perception that doctors had inadequately informed them about the consequences of RRM was associated with regret.[235] At the 5-year follow-up, women who had undergone RRM had less favorable body image and changes in sexual relationships, but also had a significant reduction in the fear of developing cancer.[236] In a study of 78 women who underwent risk-reducing surgery (including BRCA1/BRCA2 carriers and women who were from high-risk families with no detectable BRCA1/BRCA2 pathogenic variant), cancer-specific and general distress were assessed 2 weeks before surgery and at 6 and 12 months postsurgery.[237] The sample included women who had RRM and RRSO alone and women who had both surgeries. There was no observable increase in distress over the 1-year period.

Mixed psychosocial outcomes were reported in a follow-up study (mean, 14 y) 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.[238]

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.[239]

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.[24,222] One of these studies found that genetic testing at the time of diagnosis significantly altered surgical decision making, with more pathogenic variant carriers than noncarriers opting for bilateral mastectomy. Bilateral RRM was chosen by 48% of women with a known pathogenic variant [222] and by 100% of women with a known pathogenic variant in a smaller series [24] of women undergoing testing at the time of diagnosis. Of women in whom no pathogenic variant was found, 24% also opted for bilateral RRM. Four percent of the test decliners also underwent bilateral RRM. Among carriers of pathogenic variants, predictors of bilateral RRM included whether patients reported that their physicians had recommended BRCA1/BRCA2 testing and bilateral RRM before testing, and whether they received a positive test result.[222] Data are lacking on quality-of-life outcomes for women who undergo RRM after genetic testing that is performed at the time of 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.[240]

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.[241] The mean time of follow-up was 10.3 years after risk-reducing surgery. Overall, 83% of all participants stated they were satisfied or very satisfied, 8% were neutral, and 9% were dissatisfied with contralateral RRM. Most women also reported favorable effects or no change in their self-esteem, level of stress, and emotional stability after surgery (88%, 83%, and 88%, respectively). Despite the high levels of overall satisfaction, 33% reported negative body image, 26% reported a reduced sense of femininity, and 23% reported a negative effect on sexual relationships. The type of surgical procedure also affected levels of satisfaction. The authors attributed this difference to the high rate of unanticipated reoperations in the group of women having subcutaneous mastectomy (43%) versus the group having simple mastectomy (15%) (P < .0001). Limitations to this study are mostly related to the time period during which participants had their surgery (i.e., availability of surgical reconstructive option).[241,242] None of these women had genetic testing for pathogenic variants in the BRCA1/BRCA2 genes. Nevertheless, this study shows that while most women in this group were satisfied with contralateral RRM, all women reported at least one adverse outcome.

A retrospective survey of 137 BRCA carriers examined the psychosocial impact of preserving the nipple-areolar complex (NAC) in women with bilateral RRM.[243] The study found that body image and sexual well-being differed significantly based on the type of RRM the women underwent. Women with NAC preservation were more satisfied with their breasts (72% vs. 61%), were more satisfied with the surgical outcome (85% vs. 74%) and had greater sexual well-being (68% vs. 52%) than women without NAC preservation. No differences in cancer-related distress, anxiety, depression, or risk perceptions were observed between the two groups. Oncological outcomes of nipple-sparing mastectomy in BRCA carriers have not been inferior to RRM without NAC preservation.[244] (Refer to the Risk-reducing strategies for breast cancer section in BRCA1 and BRCA2: Cancer Risks and Management for more information.)

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.[245]

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.[246] The study utilized questions designed to elicit yes versus no responses and found that the surgery was well-tolerated with 83% of participants reporting that the results of their reconstructive surgery were as they expected, 90% reporting that they had received adequate preoperative information, none reporting that they regretted the surgery, and all reporting that they would choose the same route if they had to do it again. Satisfaction with the results ranged from 74% satisfied with the shape of their breasts to 89% satisfied with the appearance of the scarring. Comparison of this group to normative samples on quality-of-life indicators (Short Form 36 Health Survey Questionnaire; Hospital Anxiety and Depression Scale questionnaire scores) indicated no reductions in quality of life in these women.

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.[247]

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.[248] A majority of women (59%) also had reconstructive surgery. Interestingly, based on a Likert scale, 85% of women reported that they were satisfied or very satisfied with their decision to have an RRM. However, in qualitative interviews, many women went on to describe dissatisfaction or negative psychosocial outcomes associated with surgery. The authors coded the responses as negative when women reported still being anxious about their breast cancer risk and/or reported negative feelings about their body image, pain, and sexuality. Seventy-nine percent of the women providing negative comments and 84% of those making mixed comments (mixture of satisfaction and dissatisfaction) responded that they were either satisfied or very satisfied with their decision. Twice as many women with bilateral mastectomy made negative and mixed comments than did women with contralateral mastectomy. The areas of most concern were body image, problems with breast implants, pain after surgery, and sexuality. The authors proposed that those who had undergone contralateral procedures had already been treated for cancer, while those who had undergone bilateral procedures had not been treated previously, and this may partially account for the differences in satisfaction between the two groups. These findings suggest that women's satisfaction with RRM may be tempered by their complex reactions over time.

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.[249]

Psychosocial outcomes associated with risk-reducing salpingo-oophorectomy (RRSO)

Prior studies on the impact of RRSO suggest some variability in outcomes based on menopausal status: