Genetics of Breast and Gynecologic Cancers (PDQ®) 7/8 –Health Professional Version - National Cancer Institute

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

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

Management of Male Carriers of BRCA Pathogenic Variants

There are data to suggest that men with BRCA pathogenic variants have an increased risk of various cancers including male breast cancer and prostate cancer (refer to Table 7).[201,235-239] However, clinical guidelines to manage male carriers with BRCA pathogenic variants are based on consensus statements and expert opinions because information is limited.[240,241,33]

There have been suggestions that BRCA2-associated prostate cancers are associated with aggressive disease phenotype.[242-247] Specifically, two recent studies have reported the median survival of male BRCA2 carriers with prostate cancer in the range of 4 to 5 years.[245,246] Furthermore, mortality rate was reported as 60% at 5 years in one of these studies, compared with 2% to 8% reported in the recent European [248] and North American [249] prostate-specific antigen (PSA) screening trials after comparable follow-up. The data have been more limited in BRCA1-associated prostate cancers, however a number of recent studies have suggested an aggressive disease phenotype as well.[242,244,247,250]

The benefits of PSA screening in BRCA carriers are unknown; however, there have been suggestions (based on very small studies) that PSA levels at prostate cancer diagnosis may be higher in carriers than noncarriers.[251,252] These findings suggest that PSA screening may be of potential utility in men with BRCA pathogenic variants, especially in view of the aggressive phenotype. Preliminary results of the IMPACT PSA screening study reported a PPV of 47.6% in 21 BRCA2 carriers undergoing biopsy on the basis of elevated PSA.[253] Because screening these men detected clinically significant prostate cancer, the authors suggest that these findings provide rationale for continued screening in such men; however, a survival benefit from such screening has not been shown. Ultimately, it is possible that information on BRCA pathogenic variant status in men may inform optimal screening and treatment strategies. Furthermore, recent data that the presence of a germline BRCA2 pathogenic variant is an independent prognostic factor for survival in prostate cancer led these authors to conclude that active surveillance may not be the optimal management strategy due to the aggressive disease phenotype.[246]

Screening for male breast cancer in carriers of BRCA pathogenic variants as suggested by the NCCN clinical practice guidelines [33] includes breast self-exam training and education and clinical breast exam every 12 months starting at age 35 years. Furthermore, beginning at age 45 years, NCCN recommends prostate cancer screening for BRCA2 carriers and the consideration of prostate cancer screening for BRCA1 carriers.[33]

Reproductive Considerations in Carriers of BRCA Pathogenic Variants

Refer to the Prenatal diagnosis and preimplantation genetic testing section in the Psychosocial Issues in Inherited Breast and Ovarian Cancer Syndromes section of this summary for more information.

Treatment Strategies

Breast cancer

Prognosis of BRCA1- and BRCA2-related breast cancer

BRCA1-related breast cancer

The distinct features of BRCA1-associated breast tumors are important in prognosis. In addition, there appears to be accelerated growth in BRCA1-associated breast cancer, which is suggested by high-proliferation indices and absence of the expected correlation of tumor size with lymph node status.[254] These pathological features are associated with a worse prognosis in breast cancer, and early studies suggested that carriers of BRCA1 pathogenic variants with breast cancer may have a poorer prognosis compared with sporadic cases.[255-257] These studies particularly noted an increase in ipsilateral and contralateral second primary breast cancers in carriers of BRCA1 and BRCA2 pathogenic variants.[258-262] (Refer to the Contralateral breast cancer in carriers of BRCA pathogenic variants section of this summary for more information.) A retrospective cohort study of 496 Ashkenazi Jewish (AJ) breast cancer patients from two centers compared the relative survival among 56 carriers of BRCA1/BRCA2 pathogenic variants followed up for a median of 116 months. BRCA1 pathogenic variants were independently associated with worse disease-specific survival. The poorer prognosis was not observed in women who received chemotherapy.[263] A large population-based study of incident cases of breast cancer among women in Israel failed to find a difference in OS for carriers of BRCA1 founder pathogenic variants (n = 76) compared with noncarriers (n = 1,189).[264] Similar findings were seen in a European cohort with no differences in disease-free survival in BRCA1-associated breast cancers.[265] A prospective cohort study of 3,220 women from North America and Australia with incident breast cancer (including 93 BRCA1 carriers and 71 BRCA2 carriers) who were followed up for a mean of 7.9 years reported similar outcomes among BRCA1/BRCA2 carriers and those with sporadic disease.[266] However, results were based on chemotherapy regimens used in the late 1990s and did not adjust for surgical approach (lumpectomy vs. mastectomy) and effect of oophorectomy. The Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) study recruited 2,733 women, 12% (n = 338) of whom had a BRCA1/BRCA2 pathogenic variant. Carriers showed no significant difference in outcome from noncarriers.[267] However, the cohort of patients with triple-negative breast cancer (n = 558) had a better overall survival than noncarriers at 2 years (HR, 0.59; P = .47), but not a statistically significant difference at 5 and 10 years.

A group of researchers reported the results of BRCA1/BRCA2 testing in 77 unselected patients with triple-negative breast cancer. Of these, 15 (19.5%) had either a germline BRCA1 (n = 11; 14%) or BRCA2 (n = 3; 4%) pathogenic variant or a somatic BRCA1 (n = 1) mutation. The median age at cancer diagnosis was 45 years in carriers of BRCA1 pathogenic variants and 53 years in noncarriers (P = .005). Interestingly, this study also demonstrated a lower risk of relapse in those with triple-negative breast cancer associated with a BRCA1 pathogenic variant than in non-BRCA1-associated triple-negative breast cancer, although this study was limited by its size.[268] Another study examining clinical outcome in BRCA1-associated versus non–BRCA1-associated triple-negative breast cancer showed no difference, although there was a trend toward more brain metastases in those with BRCA1-associated breast cancer. In both of these studies, all but one carrier of a BRCA1 pathogenic variant received chemotherapy.[269] Subsequently, in a study of 89 BRCA1 carriers and 175 noncarriers with triple-negative breast cancer, BRCA1 pathogenic variant status was not an independent predictor of survival after adjusting for age, oophorectomy, and risk-reducing mastectomy.[270] However, carriers who underwent oophorectomy had a significantly lower rate of breast cancer–related death.

A Polish study of 3,345 patients younger than 50 years with stages I through III breast cancer studied the impact of a BRCA1 pathogenic variant on prognosis. In this cohort, 233 patients (7%) carried one of three Polish BRCA1 founder pathogenic variants (5382insC, C61G, or 4154delA). BRCA1 carriers were younger and more frequently ER-negative and HER2/neu-negative. Ten-year survival was similar (80.9% in BRCA1 carriers and 82.2% in noncarriers). Oophorectomy was associated with improved survival in BRCA1 carriers (HR, 0.30; 95% CI 0.12–0.75).[271]

In summary, BRCA1-associated tumors appear to have a prognosis similar to sporadic tumors despite having clinical, histopathologic, and molecular features that indicate a more aggressive phenotype. Carriers of BRCA1 pathogenic variants who do not receive chemotherapy may have a worse prognosis. However, because most BRCA1-associated breast cancers are triple negative, they are usually treated with adjuvant chemotherapy. Work is ongoing to determine whether BRCA1-associated breast cancers should receive different therapy than do sporadic tumors. (Refer to the Role of BRCA1 and BRCA2 in response to systemic therapy section of this summary for more information.)

BRCA2-related breast cancer

Early studies of the prognosis of BRCA2-associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer.[264,272-274] A small study reported statistically significant higher OS in carriers of BRCA2 pathogenic variants with metastatic breast cancer.[265]

Systemic therapy in breast cancer treatment

Role of BRCA1 and BRCA2 in response to systemic therapy

Chemotherapy alone and BRCA pathogenic variants

Retrospective and prospective studies [275-279] have evaluated the response rate to chemotherapy in carriers of BRCA1 pathogenic variants receiving neoadjuvant chemotherapy for breast cancer, especially when using cisplatin.[277] Several studies detailing the Polish experience with preoperative chemotherapy in carriers of BRCA1 pathogenic variants have been published. The largest report [277] included data on 102 carriers of BRCA1 pathogenic variants (51 of those were also described in two prior studies).[280,275] Women were identified from a registry of 6,903 patients. The study included women with a Polish founder pathogenic variant in BRCA1 (5382insC, C61G, or 4153delA) who had also received preoperative chemotherapy. Of these 102 women, 22% had a pathologic complete response (pCR). Twelve women received cisplatin chemotherapy as part of a clinical trial, ten of whom had a pCR (83%). All other patients were examined retrospectively. Of these, 14 received cyclophosphamide, methotrexate, and fluorouracil with one pCR (7%); 25 received doxorubicin and docetaxel with two pCRs (8%); and 51 received doxorubicin and cyclophosphamide with 11 pCRs (22%). To place this in the context of other available data, several retrospective studies in carriers of BRCA1 and BRCA2 pathogenic variants typically treated with anthracycline-based chemotherapy have demonstrated complete response rates of 46% to 90% after preoperative chemotherapy,[276,278] particularly in carriers of BRCA1 pathogenic variants.[279] A small trial of preoperative cisplatin in patients with triple-negative breast cancer demonstrated a pCR of 22%; however, both carriers of BRCA1 pathogenic variants in the study had a pCR.[281] However, in the GeparSixto trial, carboplatin was added to the neoadjuvant regimen of anthracycline, taxane, and bevacizumab. BRCA status was obtained in a subset of 291 patients. The addition of carboplatin did improve the pCR rate (56.8% vs. 41.4%). There were 50 patients with a BRCA pathogenic variant and the pCR rate in this group was higher at 66.7%, but there was no significant difference between the patients treated with or without carboplatin.[282]

The TNT trial compared docetaxel with carboplatin in 376 patients with metastatic, triple-negative breast cancer. Twenty-nine patients had a pathogenic variant in BRCA1 or BRCA2. There was no difference in the objective response rate (ORR) in the entire cohort between the two arms; however, a difference was noted in the BRCA carriers. The ORR in pathogenic variant carriers who received docetaxel was 33%; the ORR of those patients who received carboplatin was 68% (P = .03).[283]

Targeted therapies with or without chemotherapy

Multiple trials have evaluated the use of poly (ADP-ribose) polymerase (PARP) inhibition with and without chemotherapy. BRCA1 and BRCA2 are active in the repair of double-stranded DNA breaks by homologous recombination; PARP is involved in the repair of single-stranded breaks by base excision repair, as well as by PARP trapping on the DNA strand.

In 2017, two phase III trials explored PARP inhibitors in patients with metastatic breast cancer and a BRCA pathogenic variant. In the OlympiAD trial, 302 patients were randomly assigned to receive olaparib 300 mg orally twice daily or the physician’s choice of chemotherapy (capecitabine, eribulin, or vinorelbine). Progression-free survival (PFS) was improved from a median of 4.2 months to 7.0 months (HR, 0.58; P < .001) in patients treated with olaparib. OS was a secondary endpoint and no statistically significant difference was identified.[284] The EMBRACA trial randomly assigned 431 patients to talazoparib 1 mg orally daily versus the physician’s choice of capecitabine, eribulin, vinorelbine, or gemcitabine.[285] Patients receiving talazoparib had improved PFS by a median of 8.6 months versus 5.6 months (HR, 0.54; P < .001). OS was an alpha-protected endpoint for EMBRACA and, at the time of first report, the data were immature with only 51% of events reported (HR, 0.76; P = .105). On the basis of these results, the U.S. Food and Drug Administration has approved the use of both talazoparib and olaparib for the treatment of patients with inoperable or metastatic breast cancer and who have a germline BRCA pathogenic variant.

Ongoing research is evaluating multiple new strategies with PARP inhibitors to include targeting other germline pathogenic variants and somatic mutations. Trials, both in the early and metastatic settings, are combining PARP inhibitors with other DNA damage repair agents, immunotherapies, and other targeted therapies to improve responses, as well as broaden the patient population who may benefit.

(Refer to the Systemic therapy in ovarian cancer treatment section in the Ovarian cancer section of this summary for more information about treatment strategies for BRCA-associated ovarian cancer.)

Local therapy

Breast conservation therapy for carriers of BRCA1/BRCA2 pathogenic variants

While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early-stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is more complicated. Initial concerns about the potential for therapeutic radiation to induce tumors or cause excess toxicity in carriers of BRCA1/BRCA2 pathogenic variants were unfounded.[286-288] Despite this, an increased rate of second primary breast cancer exists, which could impact treatment decisions.

Because of the established increased risk of second primary breast cancers, which may be up to 60% in younger women with BRCA1 pathogenic variants,[260] some carriers of BRCA1/BRCA2 pathogenic variants choose bilateral mastectomy at the time of their initial cancer diagnosis. (Refer to the Contralateral breast cancer in carriers of BRCA pathogenic variants section of this summary for more information.) However, several studies support the use of breast conservation therapy as a reasonable option to treat the primary tumor.[289-291] The risk of ipsilateral recurrence at 10 years has been estimated to be between 10% to 15% and is similar to that seen in noncarriers.[99,260,289-291] Studies with longer periods of follow-up demonstrate risks of ipsilateral breast events at 15 years to be as high as 24%, largely resulting from ipsilateral second breast cancers (rather than relapse of the primary tumor).[289,291] Although not entirely consistent across studies, radiation therapy, chemotherapy, oophorectomy, and tamoxifen are associated with a decreased risk of ipsilateral events,[99,289-291] as is the case in sporadic breast cancer. The risk of contralateral breast cancer does not appear to differ in women undergoing breast conservation therapy versus unilateral mastectomy, suggesting no added risk of contralateral breast cancer from scattered radiation.[289] This finding is supported by a population-based case-control study of women diagnosed with breast cancer before the age of 55 years.[292] All women were genotyped for BRCA1/BRCA2. Although there was a significant fourfold risk of contralateral breast cancer in carriers compared with noncarriers, carriers who were exposed to radiation therapy for the first primary were not at increased risk of contralateral breast cancer compared with carriers who were not exposed. (Refer to the Mammography section for more information about radiation and breast cancer risk.) Finally, no difference in OS at 15 years has been seen between carriers of BRCA1/BRCA2 pathogenic variants choosing breast conservation therapy and carriers choosing mastectomy.[289]

Level of evidence: 3a

Ovarian cancer

Prognosis of BRCA1- and BRCA2-related ovarian cancer

Despite generally poor prognostic factors, several studies have found an improved survival among ovarian cancer patients with BRCA pathogenic variants.[293-301] A nationwide, population-based, case-control study in Israel found 3-year survival rates to be significantly better for ovarian cancer patients with BRCA founder pathogenic variants, compared with controls.[294] Five-year follow-up in the same cohort showed improved survival for carriers of both BRCA1 and BRCA2 pathogenic variants (54 months) versus noncarriers (38 months), which was most pronounced for women with stages III and IV ovarian cancer and for women with high-grade tumors.[302] In a U.S. study of AJ women with ovarian cancer, those with BRCA pathogenic variants had a longer median time to recurrence and an overall improved survival, compared with both AJ women with ovarian cancer who did not have a BRCA pathogenic variant and two large groups of advanced-stage ovarian cancer clinical trial patients.[298] In a retrospective U.S. hospital-based study, AJ carriers of BRCA pathogenic variants had a better response to platinum-based chemotherapy, as measured by response to primary therapy, disease-free survival, and OS, compared with sporadic cases.[296] Similarly, a significant survival advantage was seen in a case-control study among women with non-AJ BRCA pathogenic variants.[303] A study from the Netherlands also showed a better response to platinum-based primary chemotherapy in 112 BRCA1/BRCA2 carriers than in 220 sporadic ovarian cancer patients.[304] A U.S. population-based study showed improvement in OS in BRCA2, but not in BRCA1, carriers.[305] However, the study included only 12 carriers of BRCA2 pathogenic variants and 20 carriers of BRCA1 pathogenic variants. Significantly better OS and PFS were observed in 29 high-grade serous ovarian cancer cases with a known BRCA2 variant (20 germline, 9 somatic) from The Cancer Genome Atlas study compared with cases negative for a BRCA pathogenic variant. BRCA1 pathogenic variants were not significantly associated with prognosis.[306] Furthermore, a pooled analysis of 26 observational studies that included 1,213 carriers of BRCA pathogenic variants and 2,666 noncarriers with epithelial ovarian cancer showed more favorable survival in carriers of pathogenic variants (BRCA1: HR, 0.73; 95% CI, 0.64–0.84; P < .001; BRCA2: HR, 0.49; 95% CI, 0.39–0.61; P < .001).[307] Thus, 5-year survival in both BRCA1 and BRCA2 carriers with epithelial ovarian cancers was better than that observed in noncarriers, with BRCA2 carriers having the best prognosis. A study in Japanese patients found a survival advantage in stage III BRCA1-associated ovarian cancers treated with cisplatin regimens compared with nonhereditary cancers treated in a similar manner.[297]

In contrast, several studies have not found improved OS among ovarian cancer patients with BRCA pathogenic variants.[256,308-310] The largest of these studies involved a large series of unselected Canadian and U.S. patients who were tested for BRCA1 and BRCA2 pathogenic variants. At 3 years, the presence of a pathogenic variant was associated with a better prognosis, but at 10 years, there was no longer a difference seen in prognosis.[311] Furthermore, one study suggested that there was worse survival in ovarian cancer patients with a family history.[309]

Compelling data suggest a short-term survival advantage in carriers of BRCA pathogenic variants. However, long-term outcomes are yet to be established. Survival in AJ ovarian cancer patients with BRCA1 or BRCA2 founder pathogenic variants does seem to be improved;[306,307] however, further large studies in other populations with appropriate controls are needed to determine whether this survival advantage applies more broadly to all BRCA cancers.

Systemic therapy in ovarian cancer treatment

The molecular mechanisms that explain the improved prognosis in hereditary BRCA-associated ovarian cancer are unknown but may be related to the function of BRCA genes. BRCA genes play an important role in cell-cycle checkpoint activation and in the repair of damaged DNA via homologous recombination.[312,313] In addition to BRCA, other genes maintain homologous recombination, such as ATM, BARD1, PALB2, BRIP1, RAD51, BLM, CHEK2, and NBN. Comprehensive genetic testing of larger numbers of ovarian cancers has shown that approximately 50% of serous ovarian tumors may have somatic mutations or germline variants leading to a defective homologous recombination.[314]

Deficiencies in homologous repair can impair the cells’ ability to repair DNA cross-links that result from certain chemotherapy agents, such as cisplatin. Preclinical data has demonstrated BRCA1 impacts chemosensitivity in breast cancer and ovarian cancer cell lines. Reduced BRCA1 protein expression has been shown to enhance cisplatin chemosensitivity.[315] Patients with BRCA-associated ovarian cancer have shown improved responses to both first-line and subsequent platinum-based chemotherapy compared with patients with sporadic cancers, which may contribute to their better outcome.[296,299] Women with ovarian cancer whose tumors have homologous recombination repair gene deficiency (HRD), resulting from either germline variants or somatic mutations, have improved survival compared with women with an intact homologous recombination. The majority of homologous recombination repair gene variants consist of somatic mutations or germline variants in BRCA1 and BRCA2, with one-third contributed by variants in other homologous repair genes.[316,317]

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

PARP inhibitors

Olaparib

Studies have used PARP inhibitors in ovarian cancer after platinum-based chemotherapy. A phase I study of olaparib, an oral PARP inhibitor, demonstrated tolerability and activity in carriers of BRCA1 and BRCA2 pathogenic variants with ovarian, breast, and prostate cancers.[318] A phase II trial of two different doses of olaparib demonstrated tolerability and efficacy in recurrent ovarian cancer patients with BRCA1 or BRCA2 pathogenic variants.[319] The overall response rate was 33% (11 of 33 patients) in the cohort receiving 400 mg twice daily and 13% (3 of 24 patients) in the cohort receiving 100 mg twice daily (i.e., 16 capsules daily). The most frequent side effects were mild nausea and fatigue.[320] In addition to ovarian cancer patients with germline BRCA1 or BRCA2 pathogenic variants, PARP inhibitors also may be useful in ovarian cancer patients with somatic BRCA1 or BRCA2 mutations or with epigenetic silencing of the genes.[321]

Several phase II treatment studies have explored the efficacy of olaparib in patients with recurrent ovarian cancer, in both platinum-sensitive and platinum-resistant disease. Olaparib at 400 mg twice daily was used in a single-arm study to treat a spectrum of 298 BRCA-associated cancers, including breast, pancreas, prostate, and ovarian. Of the 193 women with ovarian cancer treated with olaparib, 31% had a response, and 40.4% had stable disease that persisted for at least 8 weeks.[322] Among the 154 women previously treated with at least three lines of chemotherapy, a similar overall response rate of 30% was seen, with comparable median durations of response of 8.2 months for platinum-sensitive disease and 8.0 months for platinum-resistant disease.[323] Another study of 173 patients with platinum-sensitive disease were treated with paclitaxel/carboplatin plus olaparib versus paclitaxel/carboplatin alone. The PFS was significantly longer in the olaparib group than the control group (12.2 vs. 9.6 months) (HR, 0.51; 95% CI, 0.34–0.77), especially in the subgroup of patients with BRCA pathogenic variants (HR, 0.21; 95% CI, 0.08–0.55). There were no differences in OS between the olaparib and control groups.[324]

In contrast, other studies found that BRCA status did not predict survival advantage in women with platinum-sensitive ovarian cancer treated with olaparib. A randomized open-label trial assigned 90 women with recurrent platinum-sensitive ovarian cancer to either olaparib or cediranib and olaparib. Median PFS was significantly longer with the combination (17.7 mo vs. 9 mo) (HR, 0.42; 95% CI, 0.23–0.76). Subset analysis showed that combination cediranib and olaparib resulted in significantly longer PFS in the 43 BRCA wild-type/unknown patients than did single agent olaparib (16.5 mo vs. 5.7 mo) (HR, 0.32; P = .008) and a smaller trend toward increased PFS in 47 women with BRCA pathogenic variants (19.4 mo vs. 16.5 mo) (HR, 0.55; P = .16).[325]

In another study, women with BRCA1/BRCA2 pathogenic variants and recurrent ovarian cancer within 12 months of a prior platinum-based regimen were randomly assigned to receive liposomal doxorubicin (Doxil) (n = 33) versus olaparib at 200 mg twice daily (n = 32) versus olaparib at 400 mg twice daily (n = 32). This study did not show a difference in PFS between the groups, which was the primary endpoint.[326] Of interest, the liposomal doxorubicin arm had a higher response rate than anticipated, consistent with other studies demonstrating that BRCA1/BRCA2-associated ovarian cancers may be more sensitive to liposomal doxorubicin than are sporadic ovarian cancers.[327,328] Another study demonstrated significant responses to olaparib in recurrent ovarian cancer patients, including patients with a BRCA1/BRCA2 pathogenic variant (objective response rate [ORR], 41%) and patients without a BRCA1/BRCA2 pathogenic variant (ORR, 24%).[329] This study emphasizes that certain sporadic ovarian cancers, particularly those of high-grade serous histology, may have properties similar to tumors related to a BRCA1/BRCA2 pathogenic variant.

As maintenance treatment, olaparib has shown significantly improved PFS in platinum-sensitive recurrent ovarian cancer. In a randomized controlled study of 265 patients (Study 19), those who received olaparib had a PFS of 8.4 months compared with 4.8 months in those who received the placebo (HR, 0.35; 95% CI, 0.25–0.49).[330] Within the cohort, the 136 patients with BRCA pathogenic variants demonstrated the most benefit with olaparib compared with placebo, with a PFS of 11.2 versus 4.3 months (HR, 0.18; 95% CI, 0.1–0.31).[331] There was no OS difference observed in the entire cohort, or in the carriers of BRCA pathogenic variants. A subsequent post hoc exploratory analysis excluded patients with BRCA pathogenic variants who received a PARP inhibitor at the time of progression to minimize the confounding influence on OS. In this group of 97 patients, an improved OS HR of 0.52 (95% CI, 0.28–0.97) was associated with olaparib, compared with placebo.[332] The more mature Study 19 data, after more than five years of follow-up, showed a trend towards OS benefit but did not meet the a priori significance threshold of P < .0001 with olaparib compared with placebo in the entire cohort (29.8 mo vs. 27.8 mo; HR, 0.73; 95% CI, 0.55–0.96), or among BRCA pathogenic variant carriers treated with olaparib (24.5 mo vs. 26.6 mo; HR, 0.62; 95% CI, 0.41–0.94).[333] Olaparib tablets have been shown to be effective maintenance therapy, compared with placebo, in a similar population of women with recurrent, platinum-sensitive ovarian cancer and BRCA pathogenic variants (SOLO2 trial). Olaparib resulted in a median PFS of 19.1 months versus 5.5 months for placebo (HR, 0.30; 95% CI, 0.22–0.41). Olaparib tablets offer the advantage of a reduced daily pill burden (two tablets twice daily) compared with 16 capsules daily.[334]

Olaparib has demonstrated significant benefit as maintenance treatment in women with newly diagnosed advanced-stage, BRCA-associated ovarian cancer following response to primary treatment. The SOLO-1 trial randomly assigned 391 women with BRCA pathogenic variants to either olaparib 300 mg twice daily (n = 260) or placebo (n = 131) after primary surgery and platinum-based chemotherapy. After a median follow-up of 41 months, women receiving olaparib had a 70% lower risk of disease progression or death compared with women receiving placebo with an estimated improved PFS of approximately 3 years.[335] Within 3 years, disease progression or death occurred in 102 of 260 women (39%) in the olaparib group and 96 of 131 women (73%) in the placebo group. Side effects resulted in a dose reduction in 28% of patients and dose interruptions in more than half of patients. Fatigue and nausea were common side effects and reasons for dose reductions.

Rucaparib

Rucaparib is a small molecule inhibitor of PARP-1, -2, and -3 and was approved in the United States for the treatment of advanced germline BRCA1/BRCA2-associated ovarian cancer in December 2016. A phase II study found that continuous dosing provided better response rates than intermittent dosing in women with pathogenic BRCA-associated breast and ovarian cancer.[336] A subsequent phase I/II dose-finding study selected a dose of 600 mg twice daily on the basis of manageable toxicity and a response rate of 59.5% in 42 women with recurrent, germline BRCA-associated, high-grade serous cancer who had received between two and four prior treatment regimens. Common grade 3 toxicities included fatigue, nausea, and anemia.[337]

The ARIEL-2 phase II study found that rucaparib was effective in the treatment of recurrent, high-grade, platinum-sensitive ovarian cancer in women with BRCA variants, but also in BRCA wild-type women with high genomic loss of heterozygosity (LOH), which is a likely marker of HRD cancers. The study enrolled 206 women, of whom 40 had germline pathogenic variants or somatic mutations in BRCA. An additional 82 were BRCA wild-type, but had high LOH. Median PFS was significantly longer in the BRCA variant subgroup (12.8 mo) (HR, 0.27; 95% CI, 0.16–44), and the high LOH subgroup (5.8 mo) (HR, 0.62; 95% CI, 0.42–0.90), compared with the low LOH subgroup (5.2 mo). The authors concluded that both BRCA variant status and LOH score, as a surrogate for HRD, were molecular predictors of rucaparib sensitivity in women with recurrent, platinum-sensitive, high-grade ovarian cancer.[338]

A phase III trial assessed rucaparib versus placebo in 576 women with recurrent, platinum-sensitive, high-grade ovarian cancer after response to second line, or greater, platinum chemotherapy. The study found that 196 women had BRCA pathogenic variants: 130 germline variants and 56 somatic mutations. Median PFS of women in the rucaparib group was 10.8 versus 5.4 months (HR, 0.35; 95% CI, 0.30–0.45). Median PFS was the most prolonged in BRCA-associated ovarian cancer: 16.6 months in the rucaparib group versus 5.4 months in the placebo group (HR, 0.23; 95% CI, 0.16–0.34). In women with HRD cancers, the median PFS was 13.6 versus 5.4 months (HR, 0.32; 95% CI, 0.24–0.42). On the basis of these data, the authors concluded that platinum sensitivity alone was a sufficient marker to predict benefit from rucaparib in women with advanced high-grade ovarian cancer, without requiring additional HRD or BRCA testing.[339]

Niraparib

Niraparib is a selective inhibitor of PARP-1 and -2. A phase I dose-finding study observed a response rate of 42% with 300 mg daily in women with recurrent, BRCA-associated solid tumors.[340] In a cohort of 500 patients with platinum-sensitive, recurrent ovarian cancer, 234 received niraparib maintenance treatment and 116 received placebo (NOVA trial).[341] Niraparib maintenance resulted in improved PFS in BRCA pathogenic variant carriers (at 21 mo) and in wild-type patients with HRD positivity (at 12 mo) compared with wild-type patients without HRD tumor positivity (at 9 mo). Consistent with prior data, patients with germline BRCA pathogenic variants had the longest PFS of the three groups. Based upon the broad activity of niraparib maintenance in heavily pretreated women with ovarian cancer, regardless of platinum response or variant status, the QUADRA phase II trial studied the antitumor activity of niraparib in 463 women with recurrent, measurable ovarian cancer. Women had received a median of four prior lines of treatment. Twenty-eight percent of women had an overall response with a median duration of 9 months, which was improved in platinum sensitive, HRD-positive women.[342]

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

Level of evidence: 3dii

Available Clinical Practice Guidelines for Hereditary Breast and Ovarian Cancer

Table 13 lists several organizations that have published recommendations for cancer risk assessment and genetic counseling, genetic testing, and/or management for hereditary breast and ovarian cancer.

Table 13. Available Clinical Practice Guidelines for Hereditary Breast and Ovarian Cancer (HBOC)

ENLARGE

Organization	Referral Recommendations	Risk Assessment and Genetic Counseling Recommendations	Genetic Testing Recommendations	Management Recommendations
ACMG/NSGC = American College of Medical Genetics and Genomics/National Society of Genetic Counselors; ACOG = American College of Obstetricians and Gynecologists; ASCO = American Society of Clinical Oncology; ESMO = European Society for Medical Oncology; NAPBC = National Accreditation Program for Breast Centers; NCCN = National Comprehensive Cancer Network; NSGC = National Society of Genetic Counselors; SGO = Society of Gynecologic Oncology; USPSTF = U.S. Preventive Services Task Force.
aThe USPSTF guidelines apply to individuals without a prior cancer diagnosis.
ACMG/NSGC (2015) [343]	Addressed	Risk Assessment: Addressed	Not addressed	Not addressed
		Genetic Counseling: Addressed
ACOG (2017) [344]	Addressed	Risk Assessment: Addressed	Addressed	Addressed
		Genetic Counseling: Addressed
ASCO (2015) [345]	Not addressed	Risk Assessment: General recommendations; not specific to HBOC	General recommendations; not specific to HBOC	Not addressed
		Genetic Counseling: Addressed
ESMO (2016) [346]	Refers to other published guidelines	Risk Assessment: Refers to other published guidelines	Refers to other published guidelines	Addressed
		Genetic Counseling: Addressed
NAPBC (2014) [347]	Refers to other published guidelines	Risk Assessment: Refers to other published guidelines	Indications for testing not addressed; components of pretest and posttest counseling addressed	Not addressed
		Genetic Counseling: Addressed
NSGC (2013) [348]	Addressed	Risk Assessment: Refers to other published guidelines and available models	Addressed	Refers to other published guidelines
		Genetic Counseling: Addressed
NCCN (2019) [33]	Addressed	Risk Assessment: Addressed	Addressed	Addressed
		Genetic Counseling: Addressed
SGO (2015, 2017) [344,349]	Addressed	Risk Assessment: Addressed	Addressed	Addressed
		Genetic Counseling: Addressed
USPSTFa (2019) [350]	Addressed	Risk Assessment: Addressed	Addressed in general terms and other guidelines referenced	Addressed in general terms and other guidelines referenced
		Genetic Counseling: Addressed

References

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95. Gronwald J, Tung N, Foulkes WD, et al.: Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer 118 (9): 2281-4, 2006. [PUBMED Abstract]
96. Phillips KA, Milne RL, Rookus MA, et al.: Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol 31 (25): 3091-9, 2013. [PUBMED Abstract]
97. Vogel VG, Costantino JP, Wickerham DL, et al.: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295 (23): 2727-41, 2006. [PUBMED Abstract]
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100. Vicus D, Rosen B, Lubinski J, et al.: Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers. Gynecol Oncol 115 (1): 135-7, 2009. [PUBMED Abstract]
101. Colditz GA, Rosner BA, Speizer FE: Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group. J Natl Cancer Inst 88 (6): 365-71, 1996. [PUBMED Abstract]
102. Narod S, Lynch H, Conway T, et al.: Increasing incidence of breast cancer in family with BRCA1 mutation. Lancet 341 (8852): 1101-2, 1993. [PUBMED Abstract]
103. Narod SA, Goldgar D, Cannon-Albright L, et al.: Risk modifiers in carriers of BRCA1 mutations. Int J Cancer 64 (6): 394-8, 1995. [PUBMED Abstract]
104. McCredie M, Paul C, Skegg DC, et al.: Family history and risk of breast cancer in New Zealand. Int J Cancer 73 (4): 503-7, 1997. [PUBMED Abstract]
105. Jernström H, Lerman C, Ghadirian P, et al.: Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 354 (9193): 1846-50, 1999. [PUBMED Abstract]
106. Cullinane CA, Lubinski J, Neuhausen SL, et al.: Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers. Int J Cancer 117 (6): 988-91, 2005. [PUBMED Abstract]
107. Friedman E, Kotsopoulos J, Lubinski J, et al.: Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers. Breast Cancer Res 8 (2): R15, 2006. [PUBMED Abstract]
108. Milne RL, Osorio A, Ramón y Cajal T, et al.: Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 119 (1): 221-32, 2010. [PUBMED Abstract]
109. Antoniou AC, Shenton A, Maher ER, et al.: Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 8 (6): R72, 2006. [PUBMED Abstract]
110. Andrieu N, Goldgar DE, Easton DF, et al.: Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J Natl Cancer Inst 98 (8): 535-44, 2006. [PUBMED Abstract]
111. Col: Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360 (9328): 187-95, 2002. [PUBMED Abstract]
112. Jernström H, Lubinski J, Lynch HT, et al.: Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 96 (14): 1094-8, 2004. [PUBMED Abstract]
113. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 347 (9017): 1713-27, 1996. [PUBMED Abstract]
114. Ursin G, Henderson BE, Haile RW, et al.: Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57 (17): 3678-81, 1997. [PUBMED Abstract]
115. Jernström H, Loman N, Johannsson OT, et al.: Impact of teenage oral contraceptive use in a population-based series of early-onset breast cancer cases who have undergone BRCA mutation testing. Eur J Cancer 41 (15): 2312-20, 2005. [PUBMED Abstract]
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247. Gallagher DJ, Gaudet MM, Pal P, et al.: Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 16 (7): 2115-21, 2010. [PUBMED Abstract]
248. Schröder FH, Hugosson J, Roobol MJ, et al.: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 360 (13): 1320-8, 2009. [PUBMED Abstract]
249. Andriole GL, Grubb RL, Buys SS, et al.: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 360 (13): 1310-9, 2009. [PUBMED Abstract]
250. Fiorentino M, Judson G, Penney K, et al.: Immunohistochemical expression of BRCA1 and lethal prostate cancer. Cancer Res 70 (8): 3136-9, 2010. [PUBMED Abstract]
251. Horsburgh S, Matthew A, Bristow R, et al.: Male BRCA1 and BRCA2 mutation carriers: a pilot study investigating medical characteristics of patients participating in a prostate cancer prevention clinic. Prostate 65 (2): 124-9, 2005. [PUBMED Abstract]
252. Hubert A, Peretz T, Manor O, et al.: The Jewish Ashkenazi founder mutations in the BRCA1/BRCA2 genes are not found at an increased frequency in Ashkenazi patients with prostate cancer. Am J Hum Genet 65 (3): 921-4, 1999. [PUBMED Abstract]
253. Mitra AV, Bancroft EK, Barbachano Y, et al.: Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. BJU Int 107 (1): 28-39, 2011. [PUBMED Abstract]
254. Foulkes WD, Metcalfe K, Hanna W, et al.: Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinoma. Cancer 98 (8): 1569-77, 2003. [PUBMED Abstract]
255. Verhoog LC, Brekelmans CT, Seynaeve C, et al.: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351 (9099): 316-21, 1998. [PUBMED Abstract]
256. Jóhannsson OT, Ranstam J, Borg A, et al.: Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol 16 (2): 397-404, 1998. [PUBMED Abstract]
257. Stoppa-Lyonnet D, Ansquer Y, Dreyfus H, et al.: Familial invasive breast cancers: worse outcome related to BRCA1 mutations. J Clin Oncol 18 (24): 4053-9, 2000. [PUBMED Abstract]
258. Haffty BG, Harrold E, Khan AJ, et al.: Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet 359 (9316): 1471-7, 2002. [PUBMED Abstract]
259. Robson M, Levin D, Federici M, et al.: Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations. J Natl Cancer Inst 91 (24): 2112-7, 1999. [PUBMED Abstract]
260. Graeser MK, Engel C, Rhiem K, et al.: Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27 (35): 5887-92, 2009. [PUBMED Abstract]
261. van den Broek AJ, van 't Veer LJ, Hooning MJ, et al.: Impact of Age at Primary Breast Cancer on Contralateral Breast Cancer Risk in BRCA1/2 Mutation Carriers. J Clin Oncol 34 (5): 409-18, 2016. [PUBMED Abstract]
262. Menes TS, Terry MB, Goldgar D, et al.: Second primary breast cancer in BRCA1 and BRCA2 mutation carriers: 10-year cumulative incidence in the Breast Cancer Family Registry. Breast Cancer Res Treat 151 (3): 653-60, 2015. [PUBMED Abstract]
263. Robson ME, Chappuis PO, Satagopan J, et al.: A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res 6 (1): R8-R17, 2004. [PUBMED Abstract]
264. Rennert G, Bisland-Naggan S, Barnett-Griness O, et al.: Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 357 (2): 115-23, 2007. [PUBMED Abstract]
265. Kriege M, Seynaeve C, Meijers-Heijboer H, et al.: Sensitivity to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27 (23): 3764-71, 2009. [PUBMED Abstract]
266. Goodwin PJ, Phillips KA, West DW, et al.: Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study. J Clin Oncol 30 (1): 19-26, 2012. [PUBMED Abstract]
267. Copson ER, Maishman TC, Tapper WJ, et al.: Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol 19 (2): 169-180, 2018. [PUBMED Abstract]
268. Gonzalez-Angulo AM, Timms KM, Liu S, et al.: Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 17 (5): 1082-9, 2011. [PUBMED Abstract]
269. Lee LJ, Alexander B, Schnitt SJ, et al.: Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers. Cancer 117 (14): 3093-100, 2011. [PUBMED Abstract]
270. Tung N, Gaughan E, Hacker MR, et al.: Outcome of triple negative breast cancer: comparison of sporadic and BRCA1-associated cancers. Breast Cancer Res Treat 146 (1): 175-82, 2014. [PUBMED Abstract]
271. Huzarski T, Byrski T, Gronwald J, et al.: Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. J Clin Oncol 31 (26): 3191-6, 2013. [PUBMED Abstract]
272. Verhoog LC, Berns EM, Brekelmans CT, et al.: Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients. J Clin Oncol 18 (21 Suppl): 119S-24S, 2000. [PUBMED Abstract]
273. Brekelmans CT, Tilanus-Linthorst MM, Seynaeve C, et al.: Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer 43 (5): 867-76, 2007. [PUBMED Abstract]
274. Budroni M, Cesaraccio R, Coviello V, et al.: Role of BRCA2 mutation status on overall survival among breast cancer patients from Sardinia. BMC Cancer 9: 62, 2009. [PUBMED Abstract]
275. Byrski T, Huzarski T, Dent R, et al.: Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 115 (2): 359-63, 2009. [PUBMED Abstract]
276. Chappuis PO, Goffin J, Wong N, et al.: A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 39 (8): 608-10, 2002. [PUBMED Abstract]
277. Byrski T, Gronwald J, Huzarski T, et al.: Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 28 (3): 375-9, 2010. [PUBMED Abstract]
278. Fourquet A, Stoppa-Lyonnet D, Kirova YM, et al.: Familial breast cancer: clinical response to induction chemotherapy or radiotherapy related to BRCA1/2 mutations status. Am J Clin Oncol 32 (2): 127-31, 2009. [PUBMED Abstract]
279. Arun B, Bayraktar S, Liu DD, et al.: Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol 29 (28): 3739-46, 2011. [PUBMED Abstract]
280. Byrski T, Gronwald J, Huzarski T, et al.: Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat 108 (2): 289-96, 2008. [PUBMED Abstract]
281. Silver DP, Richardson AL, Eklund AC, et al.: Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 28 (7): 1145-53, 2010. [PUBMED Abstract]
282. Hahnen E, Lederer B, Hauke J, et al.: Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial. JAMA Oncol 3 (10): 1378-1385, 2017. [PUBMED Abstract]
283. Tutt A, Tovey H, Cheang MCU, et al.: Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med 24 (5): 628-637, 2018. [PUBMED Abstract]
284. Robson M, Im SA, Senkus E, et al.: Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 377 (6): 523-533, 2017. [PUBMED Abstract]
285. Litton JK, Rugo HS, Ettl J, et al.: Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 379 (8): 753-763, 2018. [PUBMED Abstract]
286. Leong T, Whitty J, Keilar M, et al.: Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients. Int J Radiat Oncol Biol Phys 48 (4): 959-65, 2000. [PUBMED Abstract]
287. Pierce LJ, Strawderman M, Narod SA, et al.: Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 18 (19): 3360-9, 2000. [PUBMED Abstract]
288. Shanley S, McReynolds K, Ardern-Jones A, et al.: Late toxicity is not increased in BRCA1/BRCA2 mutation carriers undergoing breast radiotherapy in the United Kingdom. Clin Cancer Res 12 (23): 7025-32, 2006. [PUBMED Abstract]
289. Pierce LJ, Phillips KA, Griffith KA, et al.: Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy. Breast Cancer Res Treat 121 (2): 389-98, 2010. [PUBMED Abstract]
290. Kirova YM, Savignoni A, Sigal-Zafrani B, et al.: Is the breast-conserving treatment with radiotherapy appropriate in BRCA1/2 mutation carriers? Long-term results and review of the literature. Breast Cancer Res Treat 120 (1): 119-26, 2010. [PUBMED Abstract]
291. Metcalfe K, Lynch HT, Ghadirian P, et al.: Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 127 (1): 287-96, 2011. [PUBMED Abstract]
292. Bernstein JL, Thomas DC, Shore RE, et al.: Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: a WECARE study report. Eur J Cancer 49 (14): 2979-85, 2013. [PUBMED Abstract]
293. Rubin SC, Benjamin I, Behbakht K, et al.: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335 (19): 1413-6, 1996. [PUBMED Abstract]
294. Ben David Y, Chetrit A, Hirsh-Yechezkel G, et al.: Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20 (2): 463-6, 2002. [PUBMED Abstract]
295. Jazaeri AA, Yee CJ, Sotiriou C, et al.: Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J Natl Cancer Inst 94 (13): 990-1000, 2002. [PUBMED Abstract]
296. Cass I, Baldwin RL, Varkey T, et al.: Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 97 (9): 2187-95, 2003. [PUBMED Abstract]
297. Aida H, Takakuwa K, Nagata H, et al.: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4 (1): 235-40, 1998. [PUBMED Abstract]
298. Boyd J, Sonoda Y, Federici MG, et al.: Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 283 (17): 2260-5, 2000. [PUBMED Abstract]
299. Tan DS, Rothermundt C, Thomas K, et al.: "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 26 (34): 5530-6, 2008. [PUBMED Abstract]
300. Hyman DM, Zhou Q, Iasonos A, et al.: Improved survival for BRCA2-associated serous ovarian cancer compared with both BRCA-negative and BRCA1-associated serous ovarian cancer. Cancer 118 (15): 3703-9, 2012. [PUBMED Abstract]
301. Liu J, Cristea MC, Frankel P, et al.: Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival. Cancer Genet 205 (1-2): 34-41, 2012 Jan-Feb. [PUBMED Abstract]
302. Chetrit A, Hirsh-Yechezkel G, Ben-David Y, et al.: Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol 26 (1): 20-5, 2008. [PUBMED Abstract]
303. Lacour RA, Westin SN, Meyer LA, et al.: Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations. Gynecol Oncol 121 (2): 358-63, 2011. [PUBMED Abstract]
304. Vencken PM, Kriege M, Hoogwerf D, et al.: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22 (6): 1346-52, 2011. [PUBMED Abstract]
305. Pal T, Permuth-Wey J, Kapoor R, et al.: Improved survival in BRCA2 carriers with ovarian cancer. Fam Cancer 6 (1): 113-9, 2007. [PUBMED Abstract]
306. Yang D, Khan S, Sun Y, et al.: Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 306 (14): 1557-65, 2011. [PUBMED Abstract]
307. Bolton KL, Chenevix-Trench G, Goh C, et al.: Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307 (4): 382-90, 2012. [PUBMED Abstract]
308. Zweemer RP, Verheijen RH, Coebergh JW, et al.: Survival analysis in familial ovarian cancer, a case control study. Eur J Obstet Gynecol Reprod Biol 98 (2): 219-23, 2001. [PUBMED Abstract]
309. Pharoah PD, Easton DF, Stockton DL, et al.: Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Res 59 (4): 868-71, 1999. [PUBMED Abstract]
310. Buller RE, Shahin MS, Geisler JP, et al.: Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res 8 (5): 1196-202, 2002. [PUBMED Abstract]
311. McLaughlin JR, Rosen B, Moody J, et al.: Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2. J Natl Cancer Inst 105 (2): 141-8, 2013. [PUBMED Abstract]
312. Yang H, Jeffrey PD, Miller J, et al.: BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297 (5588): 1837-48, 2002. [PUBMED Abstract]
313. Xu X, Weaver Z, Linke SP, et al.: Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3 (3): 389-95, 1999. [PUBMED Abstract]
314. Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature 474 (7353): 609-15, 2011. [PUBMED Abstract]
315. Husain A, He G, Venkatraman ES, et al.: BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res 58 (6): 1120-3, 1998. [PUBMED Abstract]
316. Pennington KP, Walsh T, Harrell MI, et al.: Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 20 (3): 764-75, 2014. [PUBMED Abstract]
317. Norquist BM, Brady MF, Harrell MI, et al.: Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study. Clin Cancer Res 24 (4): 777-783, 2018. [PUBMED Abstract]
318. Fong PC, Boss DS, Yap TA, et al.: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361 (2): 123-34, 2009. [PUBMED Abstract]
319. Audeh MW, Carmichael J, Penson RT, et al.: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376 (9737): 245-51, 2010. [PUBMED Abstract]
320. Fong PC, Yap TA, Boss DS, et al.: Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 28 (15): 2512-9, 2010. [PUBMED Abstract]
321. Hennessy BT, Timms KM, Carey MS, et al.: Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 28 (22): 3570-6, 2010. [PUBMED Abstract]
322. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al.: Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33 (3): 244-50, 2015. [PUBMED Abstract]
323. Domchek SM, Aghajanian C, Shapira-Frommer R, et al.: Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol 140 (2): 199-203, 2016. [PUBMED Abstract]
324. Oza AM, Cibula D, Benzaquen AO, et al.: Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol 16 (1): 87-97, 2015. [PUBMED Abstract]
325. Liu JF, Barry WT, Birrer M, et al.: Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 15 (11): 1207-14, 2014. [PUBMED Abstract]
326. Kaye SB, Lubinski J, Matulonis U, et al.: Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30 (4): 372-9, 2012. [PUBMED Abstract]
327. Adams SF, Marsh EB, Elmasri W, et al.: A high response rate to liposomal doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer. Gynecol Oncol 123 (3): 486-91, 2011. [PUBMED Abstract]
328. Safra T, Borgato L, Nicoletto MO, et al.: BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther 10 (10): 2000-7, 2011. [PUBMED Abstract]
329. Gelmon KA, Tischkowitz M, Mackay H, et al.: Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12 (9): 852-61, 2011. [PUBMED Abstract]
330. Ledermann J, Harter P, Gourley C, et al.: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366 (15): 1382-92, 2012. [PUBMED Abstract]
331. Ledermann J, Harter P, Gourley C, et al.: Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15 (8): 852-61, 2014. [PUBMED Abstract]
332. Matulonis UA, Harter P, Gourley C, et al.: Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy. Cancer 122 (12): 1844-52, 2016. [PUBMED Abstract]
333. Ledermann JA, Harter P, Gourley C, et al.: Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol 17 (11): 1579-1589, 2016. [PUBMED Abstract]
334. Pujade-Lauraine E, Ledermann JA, Selle F, et al.: Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 18 (9): 1274-1284, 2017. [PUBMED Abstract]
335. Moore K, Colombo N, Scambia G, et al.: Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 379 (26): 2495-2505, 2018. [PUBMED Abstract]
336. Drew Y, Ledermann J, Hall G, et al.: Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer 114 (7): 723-30, 2016. [PUBMED Abstract]
337. Kristeleit R, Shapiro GI, Burris HA, et al.: A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors. Clin Cancer Res 23 (15): 4095-4106, 2017. [PUBMED Abstract]
338. Swisher EM, Lin KK, Oza AM, et al.: Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 18 (1): 75-87, 2017. [PUBMED Abstract]
339. Coleman RL, Oza AM, Lorusso D, et al.: Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390 (10106): 1949-1961, 2017. [PUBMED Abstract]
340. Sandhu SK, Schelman WR, Wilding G, et al.: The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol 14 (9): 882-92, 2013. [PUBMED Abstract]
341. Mirza MR, Monk BJ, Herrstedt J, et al.: Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med 375 (22): 2154-2164, 2016. [PUBMED Abstract]
342. Moore KN, Secord AA, Geller MA, et al.: Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 20 (5): 636-648, 2019. [PUBMED Abstract]
343. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
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345. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]
346. Paluch-Shimon S, Cardoso F, Sessa C, et al.: Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol 27 (suppl 5): v103-v110, 2016. [PUBMED Abstract]
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348. Berliner JL, Fay AM, Cummings SA, et al.: NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns 22 (2): 155-63, 2013. [PUBMED Abstract]
349. Lancaster JM, Powell CB, Chen LM, et al.: Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 136 (1): 3-7, 2015. [PUBMED Abstract]
350. Owens DK, Davidson KW, Krist AH, et al.: Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 322 (7): 652-665, 2019. [PUBMED Abstract]

Clinical Management of Other Hereditary Breast and/or Gynecologic Cancer Syndromes

In This Section

• Lynch Syndrome

Lynch Syndrome

As mismatch repair genes were identified as the genetic basis of Lynch syndrome, microsatellite instability was identified as a common molecular marker of mismatch repair deficiency. Approximately 15% of sporadic colorectal cancers show microsatellite instability, while up to 28% of sporadic endometrial cancers have this molecular change.[1,2] Most frequently, sporadic tumors with microsatellite instability have hypermethylation of the MLH1 promoter. In Lynch syndrome–related tumors showing microsatellite instability, there is typically loss of one or more of the proteins associated with the mismatch repair genes.

Certain histopathologic features are also strongly suggestive of a microsatellite instability phenotype, including the presence of tumor infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated carcinomas, and lower uterine segment tumors. Use of clinical criteria is one strategy of selection criteria for tumor testing. Computer models have also been used to predict the probability of a mismatch repair genetic variant and can be used in the absence of microsatellite instability or immunohistochemistry information.[3-6] Overall, however, there is a move towards universal testing of colorectal and endometrial tumors when tumor tissue is available. (Refer to the Universal tumor testing to screen for Lynch syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information.)

References

1. Vilar E, Gruber SB: Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7 (3): 153-62, 2010. [PUBMED Abstract]
2. Nakamura A, Osonoi T, Terauchi Y: Relationship between urinary sodium excretion and pioglitazone-induced edema. J Diabetes Investig 1 (5): 208-11, 2010. [PUBMED Abstract]
3. Balmaña J, Stockwell DH, Steyerberg EW, et al.: Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 296 (12): 1469-78, 2006. [PUBMED Abstract]
4. Barnetson RA, Tenesa A, Farrington SM, et al.: Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 354 (26): 2751-63, 2006. [PUBMED Abstract]
5. Kastrinos F, Allen JI, Stockwell DH, et al.: Development and validation of a colon cancer risk assessment tool for patients undergoing colonoscopy. Am J Gastroenterol 104 (6): 1508-18, 2009. [PUBMED Abstract]
6. Khan O, Blanco A, Conrad P, et al.: Performance of Lynch syndrome predictive models in a multi-center US referral population. Am J Gastroenterol 106 (10): 1822-7; quiz 1828, 2011. [PUBMED Abstract]

Psychosocial Issues in Inherited Breast and Ovarian Cancer Syndromes

In This Section

• Introduction
• Uptake of Genetic Counseling and Genetic Testing
  • Degree of uptake of genetic counseling and genetic testing
  • Factors influencing uptake of genetic counseling and genetic testing
  • Uptake of genetic counseling and genetic testing in diverse populations
  • Factors associated with declining genetic counseling and testing
  • Genetic counseling and testing in children
• What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics
• Genetic Counseling for Hereditary Predisposition to Breast Cancer
• Emotional Outcomes
  • Emotional outcomes in newly diagnosed breast cancer patients
• Family Effects
  • Family communication about genetic testing and hereditary risk
  • Family functioning
  • Partners of high-risk women
  • Children
  • Prenatal diagnosis and preimplantation genetic testing
• Cultural/Community Effects
• Ethical Concerns
• Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer
  • Decision aids for persons considering risk management options for hereditary breast and ovarian cancer
  • Uptake of cancer risk management options
  • Cancer screening and risk-reducing behaviors
• Psychosocial Outcome Studies
  • Risk-reducing mastectomy
  • Risk-reducing salpingo-oophorectomy
• Behavioral Outcomes

Introduction

Psychosocial research in the context of cancer genetic testing helps to define psychological outcomes, interpersonal and familial effects, and cultural and community responses. This type of research also identifies behavioral factors that encourage or impede screening and other health behaviors. It can enhance decision making about risk-reduction interventions, evaluate psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification and genetic testing, provide data to help resolve ethical concerns, and predict the interest in testing of various groups.

This section addresses psychosocial issues in hereditary breast and ovarian cancer syndromes. Psychosocial and screening issues related to gynecologic cancers associated with Lynch syndrome are discussed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section in the PDQ summary on Genetics of Colorectal Cancer.

Uptake of Genetic Counseling and Genetic Testing

Degree of uptake of genetic counseling and genetic testing

Comparison of uptake rates among studies in which counseling and testing were offered is challenging because of differences in methodologies, including the sampling strategy used, the recruitment setting, and testing through a research protocol with high-risk cohorts or kindreds. In a systematic review of 40 studies conducted before 2002 that had assessed genetic testing utilization, uptake rates varied widely and ranged from 25% to 96%, with an average uptake rate of 59%.[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 14 summarizes the uptake of genetic testing in clinical and research cohorts in the United States.

Table 14. Predictors Associated with Uptake of Genetic Testing (GT)

ENLARGE

Study Citation	Study Population	Sample Size (N)	Uptake of GT	Predictors Associated With Uptake of GT	Comments
GC = genetic counseling; HMO = health maintenance organization.
aSelf-report as data source.
bMedical records as data source.
Schwartz et al. (2005) [2]	Newly diagnosed and locally untreated breast cancer patients with ≥10% risk of having a BRCA1/BRCA2 pathogenic variant a	231	177/231 (77%) underwent GT	Having decided on definitive local treatment. Women who were undecided on a definitive local treatment were more likely to be tested.	Testing was offered free of charge.
			34/231 (15%) had baseline interview but declined GT
				Physician recommendation for testing. Women whose physician had recommended GT were more likely to be tested.	38/177 chose to proceed with treatment before receiving test results.
			20/231 declined baseline interview
Kieran et al. (2007) [3]	Women who received GC between 2002 and 2004a	250	88/250 (35%) underwent GT	Ability to pay for GT (entire cost or cost not covered by insurance). Nonuptake was 5.5 times more likely in women who could not afford testing.	450 women received GC for breast and ovarian cancer risk during study period. 250 women were retrospectively identified as eligible and were mailed a study questionnaire.
			36/88 returned surveys
				Ability to recall risk estimates that were provided post-GC. Nonuptake was 15.5 times more likely in women who could not recall their risk estimates.	All women had some form of insurance.
			162/250 (65%) eligible
			65/162 returned surveys
Susswein et al. (2008) [4]	African American women and white women with breast cancerb	768	529/768 (69%) underwent GT	Race/ethnicity. African American women were less likely to be tested than were white women.	Sample obtained from a clinical database. Testing was offered free of charge when it was not covered by insurance. This effect for time of diagnosis was significant in the African American, but not white, subgroup.
			African American women: 77/132 (58%) underwent GT
				Recent diagnosis. African American women who were recently diagnosed were more likely to be tested.
			White women: 452/636 (71%) underwent GT
Olaya et al. (2009) [5]	Patients referred for GT between 2001 and 2008b	213	111/213 (52%) underwent GT	Personal history of breast cancer. Having a personal history was associated with 3 times greater odds of being tested.	Insurance coverage for testing was available for 91.1% (175/213) of patients. Of those who had coverage for GT, 51.4% underwent testing and 48.6% did not. Of those without coverage, 41.2% had GT and 58.9% did not.
			102/213 (48%) declined GT	Higher level of education. Those with a high school education or less had one-third the odds of being tested, compared with those with at least some college.
Levy et al. (2010) [6]	Women aged 20–40 y with newly diagnosed early-onset breast cancer.b	1,474	446/1,474 (30%) underwent GT	Race/ethnicity. Women of Jewish ethnicity were 3 times more likely to be tested than were non-Jewish white women. African American and Hispanic women were significantly less likely to receive testing than were non-Jewish white women.	Sample obtained from a national database of commercially insured individuals.
			Jewish women: 18/32 (56%) underwent GT	Home location. Women living in the south were more likely to be tested than were women living in the northeast.
			African American women: 10/82 (12%) underwent GT	Insurance type. Women with point-of-service plans were more likely to be tested than were women with HMO plans.
				Recent diagnosis. Women diagnosed in 2007 were 3.8 times more likely to be tested than were women diagnosed in 2004.

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/ethnic differences that affect 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 ethnic minority groups including African Americans and Hispanics had more negative views and greater concerns about genetic counseling and testing when compared with whites. African Americans and Hispanics were more likely to believe genetic testing could be used to show their ethnic group was inferior to other groups. Additionally, African Americans and Hispanics 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]

Insurance coverage

Insurance coverage is an important consideration for individuals deciding whether to undergo genetic testing. (Refer to the Insurance coverage section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Uptake of genetic counseling and genetic testing in diverse populations

Degree of uptake of genetic counseling and genetic testing in diverse populations

There are limited data on uptake of genetic counseling and testing among nonwhite populations, and further research will be needed to define factors influencing uptake in these populations.[31] The uptake of BRCA testing appears to vary across some racial/ethnic groups. A few studies have compared uptake rates between African American and white women.[4,32] In a case-control study of women who had been seen in a university-based primary care system, African American women with family histories of breast cancer or ovarian cancer were less likely to undergo BRCA1/BRCA2 testing than were white women who had similar histories.[32] In another study among breast cancer patients who were counseled about BRCA1/BRCA2 risk in a clinical setting, lower uptake was reported among African American women than among white women.[4]

Notably, the racial differences observed in these studies do not appear to be explained by factors related to cost, access to care, risk factors for carrying a BRCA1 or BRCA2 pathogenic variant, or differences in psychosocial factors, including risk perceptions, worry, or attitudes toward testing.

Factors influencing uptake of genetic counseling and genetic testing in diverse populations

Several studies have examined uptake or “acceptance” of BRCA testing among African Americans enrolled in genetic research programs. Among study enrollees from an African American kindred in Utah, 83% underwent BRCA1 testing.[33] Age, perceived risk of being a carrier, and more extensive cancer knowledge predicted testing acceptance. Another study that recruited African American women through physician and community referrals reported a BRCA1/BRCA2 testing acceptance rate of 22%.[34] Predictors of test acceptance included having a higher probability of having a pathogenic variant, being married, and being less certain about one’s cancer risk. Finally, a third study that recruited at-risk African American women from an urban cancer screening clinic found that acceptors of BRCA testing were more knowledgeable about breast cancer genetics and perceived fewer barriers to testing, including negative emotional reactions, stigmatization concerns, and family-related guilt.[35] While these are independent predictors of genetic testing uptake, they do not explain the disparities in testing uptake across different ethnic groups. What may explain these differences are several attitudes and beliefs held about testing by individuals from diverse populations.

Work examining attitudes toward breast cancer genetic testing in Latino and African American populations indicates limited knowledge and awareness about testing but a generally receptive view once they are informed; in comparison with whites, Latino and African American populations have relatively more concerns about testing.

For example, in a qualitative study with 51 Latino individuals unselected for risk status, important findings included the fact that participants were highly interested in genetic testing for inherited cancer susceptibility, despite very limited knowledge about genetics. One important barrier involved secrecy or embarrassment about family discussions of cancer and genetics, which could be addressed in intervention strategies.[36] Another qualitative study with 54 Latina women at risk of hereditary breast cancer showed that knowledge about BRCA1/BRCA2 counseling was low, although the women were interested in learning more about counseling to gain risk information for family members. Barriers to counseling included life demands, cost, and language issues.[37]

A telephone survey of 314 patients from an inner-city network of Pittsburgh, Pennsylvania, health centers, 50% of whom were African American, found that most participants (57%) (both African Americans and whites) felt that genetic testing to evaluate disease risk was a good idea; however, more African Americans than whites thought that genetic testing would lead to racial discrimination (37% vs. 22%, respectively) and that genetics research was unethical and tampered with nature (20% vs. 11%, respectively).[38] Finally, in a study of 222 women in Savannah, Georgia, where most had neither a personal history (70%) nor a family history (60%) of breast cancer, African American women (who comprised 26% of the sample) were less likely to be aware of breast cancer genes and genetic testing. Awareness was also related to higher income, higher education level, and having a family breast cancer history. However, 74% of the entire sample expressed willingness to be tested for breast cancer susceptibility.[39]

In a sample of 146 African American women meeting criteria for BRCA1/BRCA2 pathogenic variant testing, women born outside the United States reported higher levels of anticipated negative emotional reactions (e.g., fear, hopelessness, and lack of confidence that they could emotionally handle testing). Higher levels of breast cancer–specific distress were associated with anticipated negative emotional reactions, confidentiality concerns, and anticipated guilt regarding the family impact of breast cancer genetic testing.[40] A future orientation (e.g., "I often think about how my actions today will affect my health when I am older") was associated with overall perceived benefits of breast cancer genetic testing in this population (n = 140); however, future orientation was also found to be positively associated with family-related cons of testing, including family guilt and worry regarding the impact of testing on the family.[41]

There are racial differences in provider discussion and patient uptake of genetic testing for variants in BRCA1/BRCA2. A study of women aged 18 to 64 years and diagnosed with invasive breast cancer between 2007 and 2009 found that, even after adjusting for pathogenic variant risk, African American women were less likely to report having received a physician recommendation for genetic testing. There was no difference across all races in concerns that BRCA1/BRCA2 testing was too expensive and only minimal differences in testing attitudes or insurance concerns were found, none of which influenced testing uptake.[42] A study of breast or ovarian cancer survivors (N = 50) eligible for BRCA1/BRCA2 genetic testing found that 48% were referred for genetic counseling and testing and/or had undergone genetic testing. Individuals with higher breast cancer genetics knowledge and higher self-efficacy were more likely to have engaged in genetic counseling and testing.[43] In a study of women with invasive breast cancer diagnosed before age 50 years between 2009 and 2012 who were identified through the Florida Cancer Data System state registry and eligible for BRCA1/BRCA2 genetic testing on the basis of existing guidelines, African Americans were less likely to report a discussion with their health care provider and undergo genetic testing.[44] The same study found similar overall testing rates in Hispanic (61%) and non-Hispanic (65%) whites. However, testing rates were lower among Hispanics who spoke primarily Spanish at home (50% Spanish speaking vs. 69% English speaking; P = .0009), and in general, Hispanics were less likely to have been referred for genetic testing.[45] However, this finding is not consistent across all studies. In a study of women aged 20 to 79 years with ductal carcinoma in situ or invasive breast cancer identified through the Surveillance, Epidemiology, and End Results (SEER) registry in Georgia and Los Angeles County, all eligible for BRCA1/BRCA2 genetic testing on the basis of existing guidelines, no ethnic differences were detected in receipt of genetic counseling or physician-directed discussion about genetic testing.[30]

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.[46]

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.[47] Other reasons for declining included having no children and becoming acquainted with breast/ovarian cancer in the family relatively early in their lives.[46,47]

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:

• Their children's health (76%).
• Their life insurance (60%).
• Their own health (56%).
• Loss of their job (5%).
• Receiving less screening if they did not carry a BRCA1/BRCA2 pathogenic variant (62%).

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.[48] In 15% (n = 31) of individuals from 13 hereditary breast and ovarian cancer 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.[49]

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.[50-53]

Studies suggest that persons who have undergone BRCA1/BRCA2 genetic testing or who are adult offspring of persons who have had testing are generally not in favor of testing minors.[54,55] 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.[54] 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.[55]

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.[56-58] 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.[59] 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.

What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics

The emerging literature in this area suggests that risk perceptions, health beliefs, psychological status, and personality characteristics are important factors in decision making about breast/ovarian cancer genetic testing. Many women presenting at academic centers for BRCA1/BRCA2 testing arrive with a strong belief that they have a pathogenic variant, having decided they want genetic testing, but possessing little information about the risks or limitations of testing.[60] Most mean scores of psychological functioning at baseline for subjects in genetic counseling studies were within normal limits.[61] Nonetheless, a subset of subjects in many genetic counseling studies present with elevated anxiety, depression, or cancer worry.[62,63] Identification of these individuals is essential to prevent adverse outcomes. In a study of 205 women pursuing genetic counseling, interactions among cancer worry, breast cancer risk perception, and perceived severity of having a breast cancer genetic variant were found such that those with high worry, high breast cancer risk perception, and low perceived severity were twice as likely to follow through with BRCA1/BRCA2 testing than others.[64]

A general tendency to overestimate inherited risk of breast and ovarian cancer has been noted in at-risk populations,[65-68] in cancer patients,[66,69,70] in spouses of breast and ovarian cancer patients,[71] and among women in the general population.[72-74] but underestimation of breast cancer risk in higher-risk and average-risk women also has been reported.[75] This overestimation may encourage a belief that BRCA1/BRCA2 genetic testing will be more informative than it is currently thought to be. Some evidence exists that even counseling does not dissuade women at low to moderate risk from the belief that BRCA1 testing could be valuable.[31] Overestimation of both breast and ovarian cancer risk has been associated with nonadherence to physician-recommended screening practices.[76,77] A meta-analysis of 12 studies of outcomes of genetic counseling for breast/ovarian cancer showed that counseling improved the accuracy of risk perception.[78]

Women appear to be the prime communicators within families about the family history of breast cancer.[79] Higher numbers of maternal versus paternal transmission cases are reported,[80] likely due to family communication patterns, to the misconception that breast cancer risk can only be transmitted through the mother, and to the greater difficulty in recognizing paternal family histories because of the need to identify more distant relatives with cancer. In an analysis of 2,505 women participating in the Family Healthware Impact Trial,[81] not only was evidence of underreporting of paternal family history identified, but also women reported a lower level of perceived breast cancer risk with a paternal versus maternal breast cancer family history.[82] Physicians and counselors taking a family history are encouraged to elicit paternal and maternal family histories of breast, ovarian, or other associated cancers.[79]

The accuracy of reported family history of breast or ovarian cancer varies; some studies found levels of accuracy above 90%,[83,84] with others finding more errors in the reporting of cancer in second-degree or more distant relatives [85] or in age of onset of cancer.[86] Less accuracy has been found in the reporting of cancers other than breast cancer. Ovarian cancer history was reported with 60% accuracy in one study compared with 83% accuracy in breast cancer history.[87] Providers should be aware that there are a few published cases of Munchausen syndrome in reporting of false family breast cancer history.[88] Much more common is erroneous reporting of family cancer history due to unintentional errors or gaps in knowledge, related in some cases to the early death of potential maternal informants about cancer family history.[79] (Refer to the Taking a Family History section of the Cancer Genetics Risk Assessment and Counseling summary for more information.)

Targeted written,[89,90] video, CD-ROM, interactive computer programs and websites,[91-98] and culturally targeted educational materials [99-101] may be effective and efficient methods of increasing knowledge about the pros and cons of genetic testing. Such supplemental materials may allow more efficient use of the time allotted for pretest education and counseling by genetics and primary care providers and may discourage individuals without appropriate indication of risk from seeking genetic testing.[89]

Genetic Counseling for Hereditary Predisposition to Breast Cancer

Counseling for breast cancer risk typically involves individuals with family histories that are potentially attributable to BRCA1 or BRCA2. It also, however, may include individuals with family histories of Li-Fraumeni syndrome, ataxia-telangiectasia, Cowden syndrome, or Peutz-Jeghers syndrome.[102] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section of this summary for more information.)

Management strategies for carriers may involve decisions about the nature, frequency, and timing of screening and surveillance procedures, chemoprevention, risk-reducing surgery, and use of hormone replacement therapy (HRT). The utilization of breast conservation and radiation as cancer therapy for women who are carriers may be influenced by knowledge of pathogenic variant status. (Refer to the Clinical Management of Carriers of BRCA Pathogenic Variants section of this summary for more information.)

Counseling also includes consideration of related psychosocial concerns and discussion of planned family communication and the responsibility to warn other family members about the possibility of having an increased risk of breast, ovarian, and other cancers. Data suggest that individual responses to being tested as adults are influenced by the results status of other family members.[103,104] Management of anxiety and distress are important not only as quality-of-life factors, but also because high anxiety may interfere with the understanding and integration of complex genetic and medical information and adherence to screening.[105-107] Formal, objective evaluation of these outcomes are well documented. (Refer to the Emotional Outcomes and Behavioral Outcomes sections of this summary for more information.)

Published descriptions of counseling programs for BRCA1 (and subsequently for BRCA2) testing include strategies for gathering a family history, assessing eligibility for testing, communicating the considerable volume of relevant information about breast/ovarian cancer genetics and associated medical and psychosocial risks and benefits, and discussion of specialized ethical considerations about confidentiality and family communication.[108-115] Participant distress, intrusive thoughts about cancer, coping style, and social support were assessed in many prospective testing candidates. The psychosocial outcomes evaluated in these programs have included changes in knowledge about the genetics of breast/ovarian cancer after counseling, risk comprehension, psychological adjustment, family and social functioning, and reproductive and health behaviors.[116] A Dutch study of communication processes and satisfaction levels of counselees going through cancer genetic counseling for inherited cancer syndromes indicated that asking more medical questions (by the counselor), providing more psychosocial information, and longer eye contact by the counselor were associated with lower satisfaction levels. The provision of medical information by the counselor was most highly related to satisfaction and perception that needs have been fulfilled.[117]

Many of the psychosocial outcome studies involve specialized, highly selected research populations, some of which were utilized to map and clone BRCA1 and BRCA2. One such example is K2082, an extensively studied kindred of more than 800 members of a Utah Mormon family in which a BRCA1 pathogenic variant accounts for the observed increased rates of breast and ovarian cancer. A study of the understanding that members of this kindred have about breast/ovarian cancer genetics found that, even in breast cancer research populations, there was incomplete knowledge about associated risks of colon and prostate cancer, the existence of options for RRM and RRSO, and the complexity of existing psychosocial risks.[108] A meta-analysis of 21 studies found that genetic counseling was effective in increasing knowledge and improved the accuracy of perceived risk. Genetic counseling did not have a statistically significant long-term impact on affective outcomes including anxiety, distress, or cancer-specific worry and the behavioral outcome of cancer surveillance activities.[61] These prospective studies, however, were characterized by a heterogeneity of measures of cancer-specific worry and inconsistent findings in effects of change from baseline.[61]

Emotional Outcomes

Although there were initial concerns about the possibility of adverse emotional consequences from BRCA testing, most studies conducted over the years have shown low levels of psychological distress among both carriers and noncarriers, particularly over the longer term.[118-120] In a meta-analysis examining cancer-specific distress over short (0–4 weeks), moderate (5–24 weeks), and long (25–52 weeks) periods of time since the receipt of testing results, carriers were found to demonstrate increased levels of distress shortly after receiving results, with levels returning to baseline within moderate and long periods of time.[118] In contrast, noncarriers and those with inconclusive results showed reduced levels of distress over time.[118,121] Psychological distress patterns were found to vary as a function of several factors, including the cancer history of the individual and the country within which the study was conducted. Carriers with a personal history of cancer experienced small decreases in distress over time, whereas no changes were observed among carriers without a personal history of cancer. Among individuals with inconclusive results, greater decreases in distress were observed among those without a cancer history than among those with a cancer history. Among noncarriers, those in the United States experienced significantly greater decreases in psychological distress than noncarriers from Europe and Australia. A study conducted in Austria noted that certain subgroups of counselees experienced greater distress, including those who were older, had a more recent cancer diagnosis, or those who had received counseling but declined BRCA testing.[122]

Several studies have reported on emotional outcomes over longer follow-up periods (i.e., greater than 12 months after disclosure) than those reported in the meta-analysis described above.[118] In a U.K. study, cancer-related worry did not differ between carriers and noncarriers at 3 years of follow-up.[123] Two U.S.-based studies published since the meta-analytic review [118] have reported similar findings among women who were surveyed more than 3 years after receipt of BRCA test results.[124,125] In a cross-sectional study,[124] 167 women who were surveyed more than 4 years after receiving BRCA test results reported low levels of genetic testing–specific concerns, as measured using the Multidimensional Impact of Cancer Risk Assessment Scale.[126] In multivariate regression models, carriers of pathogenic variants were significantly more likely to experience distress than were noncarriers. In a second study,[125] 464 women were followed prospectively for a median of 5 years (range, 3.4–9.1 y) after testing. Among both affected and unaffected participants, BRCA carriers reported significantly higher levels of distress, uncertainty (affected only), perceived stress (affected only), and lower positive testing experiences (unaffected only) than women who received negative results for a known pathogenic variant in the family.[125] Although both studies [124,125] reported greater distress among BRCA carriers than among noncarriers, the level of distress was not reflective of clinically significant dysfunction.

Although most studies have reported that a positive BRCA test result has a relatively minimal impact on psychological distress, many of these studies were conducted among families with a strong family history of breast or ovarian cancer who underwent extensive pretest genetic counseling. Therefore, emotional responses may not generalize to individuals who test under different contexts. For example, individuals who are tested with population BRCA screening may not have a family history of cancer.[127-129] Although pretest genetic counseling is recommended, this is not always done when genetic testing is ordered by nongenetic providers [130] or directly through commercial companies.[131,132]

For example, in a Canadian study of 2,080 Jewish women who participated in a population-based genetic screening study to test for three BRCA pathogenic variants common in families of Jewish heritage, women were not offered in-person genetic counseling but were given a pamphlet on genetic testing for BRCA1/BRCA2 before they provided a DNA sample. One year after genetic testing, women who were positive for a pathogenic variant (n = 18) showed significant increases in cancer-specific distress, whereas no changes in distress were observed among women who were negative for a pathogenic variant.[128] The mean distress score on the Impact of Event Scale for the 18 women with a known pathogenic variant was 25.3 (range, 2–51); 10 of 18 women (56%) scored within moderate (26–43) (n = 7) or severe (44+) (n = 3) ranges. It is unclear from this study whether the increase in distress observed at 1 year of follow-up was due to the lack of in-person genetic counseling, or whether the lower levels of distress at baseline observed were because the women in the study were low risk but eligible for testing because of their ancestry. A follow-up study with this cohort found that distress decreased between 1 to 2 years after testing and that changes in distress varied by risk-reduction options undertaken by carriers. Specifically, those who had undergone risk-reducing mastectomy or oophorectomy experienced significant decreases in distress compared with those who did not have either surgery.[129] Another smaller qualitative study also supports these findings.[133]

Similarly, the impact of direct-to-consumer (DTC) BRCA testing through commercial companies requires further evaluation. Case studies have reported adverse emotional responses after receipt of a positive BRCA result from DTC genetic testing, suggesting the need for further evaluation of the emotional outcomes of women undergoing genetic testing through commercial companies.[131,132] Only one study, conducted by a commercial company, has attempted to evaluate the impact of BRCA testing in this context.[134] A total of 32 individuals (16 women and 16 men) who tested positive for one of three BRCA founder pathogenic variants common in Ashkenazi Jews completed semi-structured interviews. None of the carriers reported extreme anxiety, although some experienced moderate anxiety (13%) or initial disappointment and anxiety that dissipated over time (28%). These findings should be interpreted with caution given that only 24% (32 of 136) of invited carriers of BRCA pathogenic variants participated in the study, raising concerns about selection bias.

Despite evidence of a short-term increase in distress after the receipt of genetic testing results, any adverse responses to a positive carrier status dissipate within 12 months.[118] Additional research is needed to examine emotional outcomes for those who are not provided genetic counseling before testing.[130]

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 in the Introduction section of this summary for more information.) Although concerns have been raised about the adverse psychological implications of offering rapid genetic counseling and testing between diagnosis and surgery,[135,136] other studies,[137-139] including a randomized trial,[140] have provided evidence indicating no additional adverse psychological effects in newly diagnosed breast cancer patients. 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.[141] However, qualitative research on 20 newly diagnosed breast cancer patients found that some subgroups of these patients may have more difficulty coping with BRCA test results, such as carriers who have no family history of cancer; those who do not have an affected relative with whom they can identify; and higher risk women who receive uninformative negative BRCA results.[135]

Family Effects

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. Gender appears to be an important variable in family communication and psychological outcomes. Studies have documented that female carriers are more likely to disclose their status to other family members (especially sisters and children aged 14–18 y) [142] than are male carriers.[142,143] 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%).[144]

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 second-degree relatives than with more distant family members. Studies have investigated the process and content of communication among sisters about BRCA1/BRCA2 test results.[145,146] Study results suggest that both carriers of pathogenic variants [145] and women with uninformative results [145,146] 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.[146] 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 [145] or had a poor relationship with them.[146] 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.[79,147-150] A study that evaluated communication of test results to FDRs at 4 months postdisclosure found that women aged 40 years or older were more likely to inform their parents of test results compared with younger women. Participants also were more likely to inform brothers of their results if the BRCA pathogenic variant was inherited through the paternal line.[148] Another study found that disclosure was limited mainly to FDRs, and dissemination of information to distant relatives was problematic.[151] Age was a significant factor in informing distant relatives with younger patients being more willing to communicate their genetic test result.[145,147,151] 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.[143] In contrast, a longer time interval since diagnosis was associated with communication to fewer family members.[143]

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 persons, they illustrate the complexity of issues involved in conveying hereditary cancer risk information in families.[152] 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.[152] 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 those persons’ own fears and worries about cancer.[150] 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.[153] The potential importance of persons 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.[150]

A study of 31 mothers with a documented BRCA pathogenic variant explored patterns of dissemination to children.[154] 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.[148,155,156] 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%).[155]

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.[157] 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.[157]

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.[158] 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.[159] 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.[160] 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 hereditary breast and ovarian cancer families 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. Persons 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.[49]

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.[161]

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.[157]

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.[162]

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.[163]

At-risk males

A review of the literature on the experiences of males in families with a known BRCA1 and BRCA2 pathogenic variant reported that while the data are limited, men from variant-positive families are less likely than females to participate in communication regarding genetics at every level, including the counseling and testing process. Men are less likely to be informed of genetic test results received by female relatives, and most men from these families do not pursue their own genetic testing.[164]

A study of Dutch men at increased risk of having inherited a BRCA1 pathogenic variant reported a tendency for the men to deny or minimize the emotional effects of their risk status, and to focus on medical implications for their female relatives. Men in these families, however, also reported considerable distress in relation to their female relatives.[165] In another study of male psychological functioning during breast cancer testing, 28 men belonging to 18 different high-risk families (with a 25% or 50% risk of having inherited a BRCA1/BRCA2 pathogenic variant) participated. The study purpose was to analyze distress in males at risk of carrying a BRCA1/BRCA2 pathogenic variant who applied for genetic testing. Of the men studied, most had low pretest distress; scores were lowest for men who were optimistic or who did not have daughters. Most carriers of pathogenic variants had normal levels of anxiety and depression and reported no guilt, though some anticipated increased distress and feelings of responsibility if their daughters developed breast or ovarian cancer. None of the noncarriers reported feeling guilty.[166] In one study,[160] adherence to recommended screening guidelines after testing was analyzed. In this study, more than half of male carriers of pathogenic variants did not adhere to the screening guidelines recommended after disclosure of genetic test results. These findings are consistent with those for female carriers of BRCA1/BRCA2 pathogenic variants.[160,167]

A multicenter U.K. cohort study examined prospective outcomes of BRCA1/BRCA2 testing in 193 individuals, of which 20% were men aged 28 to 86 years. Men’s distress levels were low, did not differ among carriers and noncarriers, and did not change from baseline (before genetic testing) to the 3-year follow-up. Twenty-two percent of male carriers of pathogenic variants received colorectal cancer screening and 44% received prostate cancer screening;[123] however, it is unclear whether men in this study were following age-appropriate screening guidelines.

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%.[147,148,151,155,168-171] 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.[154] 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.[155]

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,[148,154,155] some parents chose to delay disclosure.[155] 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).[155]

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.[170]

One study looked at the reaction of children to results disclosure or the effect on the parent-child relationship of communicating the results.[155] 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 (BCFH+) compared with those without such family histories had better psychosocial adjustment by maternal report.[172] However, based on a combination of maternal report and direct assessment of girls aged 10 to 13 years, BCFH+ girls 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.[173]

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%).[174]

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.[50-53] 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.[175,176] 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.[175] 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.[56-58] 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.[59] 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 [170] 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 hereditary breast and ovarian cancer (HBOC),[177] perhaps to the extent that some carriers may avoid childbearing.[178,179] These concerns also may prompt women to consider using prenatal testing methods to help reduce the risk of transmission.[177,180] 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).[181,182] Both procedures carry some risk of miscarriage and some evidence suggests fetal defects may result from using these tests.[181,182] 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,[177,183,184] 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.[177,180]

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 persons at increased risk of HBOC.[177,180,185] The first study was a Web-based survey of 283 members,[177] the second included 205 attendees of the 2007 annual FORCE conference,[180] and the third was a Web-based survey of 962 members.[185,186] These studies have documented low levels of awareness, with 20% to 32% of study respondents reporting having heard of PGT before study participation.[180,185] With respect to interest in PGT, the first study [177] 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.[180,185] In the third FORCE-based study (n = 962),[185] 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 persons 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).[187] 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 hereditary breast and ovarian cancer. 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.[188] 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.[189]

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.[190] 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 (PND) 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 PND) and decisions about having children.[191] 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 PND and varied based on personal experience. 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 PND with regard to termination of pregnancy. Decisions regarding the pros and cons of PGT versus PND 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).[192] 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.

Cultural/Community Effects

The recognition that BRCA1/BRCA2 pathogenic variants are prevalent, not only in breast/ovarian cancer families but also in some ethnic groups,[193] has led to considerable discussion of the ethical, psychological, and other implications of having one’s ethnicity be a factor in determination of disease predisposition. Concerns that people will think everything is solely determined by genetic factors and the creation of a genetic underclass [194] have been voiced. Questions about the impact on the group of being singled out as having genetic vulnerability to breast cancer have been raised. There is also confusion about who gives or withholds permission for the group to be involved in studies of their genetic identity. These issues challenge traditional views on informed consent as a function of individual autonomy.[195]

A growing literature on the unique factors influencing a variety of cultural subgroups suggests the importance of developing culturally specific genetic counseling and educational approaches.[99,196-200] The inclusion of members within the community of interest (e.g., breast cancer survivors, advocates, and community leaders) may enhance the development of culturally tailored genetic counseling materials.[100] One study showed that participation in any genetic counseling (culturally mediated or standard approaches) reduced perceived risk of developing breast cancer.[201]

Ethical Concerns

The human implications of the ethical issues raised by the advent of genetic testing for breast/ovarian cancer susceptibility are described in case studies,[202] essays,[203,204] and research reports. Issues about rights and responsibilities in families concerning the spread of information about genetic risk promise to be major ethical and legal dilemmas in the coming decades.

Studies have shown that 62% of studied family members were aware of the family history and that 88% of hereditary breast/ovarian cancer family members surveyed have significant concerns about privacy and confidentiality. Expressed concern about cancer in third-degree relatives, or relatives farther removed, was about the same as that for first- or second-degree relatives of the proband.[205] Only half of surveyed FDRs of women with breast or ovarian cancer felt that written permission should be required to disclose BRCA1/BRCA2 test results to a spouse or immediate family member. Attitudes toward testing varied by ethnicity, previous exposure to genetic information, age, optimism, and information style. Altruism is a factor motivating genetic testing in some people.[206] Many professional groups have made recommendations regarding informed consent.[112,206-209] There is some evidence that not all practitioners are aware of or follow these guidelines.[210] Research shows that many BRCA1/BRCA2 genetic testing consent forms do not fulfill recommendations by professional groups about the 11 areas that should be addressed,[211] and they omit highly relevant points of information.[210] In a study of women with a history of breast or ovarian cancer, the interviews yielded that the women reported feeling inadequately prepared for the ethical dilemmas they encountered when imparting genetic information to family members.[212] These data suggest that more preparation about disclosure to family members before testing reduces the emotional burden of disseminating genetic information to family members. Patients and health care providers would benefit from enhanced consideration of the ethical issues of warning family members about hereditary cancer risk. (Refer to the PDQ summaries Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information about the ethics of cancer genetics and genetic testing.)