Genetics of Breast and Gynecologic Cancers (PDQ®) 7/10 —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

Risk-reducing surgery

RRSO

Numerous studies have found that women with an inherited risk of breast and ovarian cancer have a decreased risk of ovarian cancer after RRSO. A retrospective study of 551 women with BRCA1 or BRCA2 pathogenic variants found a significant reduction in risk of breast cancer (HR, 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR, 0.04; 95% CI, 0.01–0.16) after bilateral oophorectomy.[78] A prospective, single-institution study of 170 women with BRCA1 or BRCA2 pathogenic variants showed a similar trend.[81] With oophorectomy, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective multicenter study of 1,079 women who were followed up for a median of 30 to 35 months found that RRSO is highly effective in reducing ovarian cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants. This study also showed that RRSO was associated with reductions in breast cancer risk in both carriers of BRCA1 and BRCA2pathogenic variants; however, the breast cancer risk reduction was more pronounced in BRCA2 carriers (HR, 0.28; 95% CI, 0.08–0.92).[6] In a case-control study in Israel, bilateral oophorectomy was associated with reduced ovarian/peritoneal cancer risks (OR, 0.12; 95% CI, 0.06–0.24).[168] A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in carriers of BRCA1/BRCA2 pathogenic variants confirmed that RRSO was associated with a significant reduction in risk of ovarian or fallopian tube cancer (HR, 0.21; 95% CI, 0.12–0.39). The study also found a significant reduction in risk of breast cancer (overall: HR, 0.49; 95% CI, 0.37–0.65; BRCA1: HR, 0.47; 95% CI, 0.35–0.64; BRCA2: HR, 0.47; 95% CI, 0.26–0.84).[82] Subsequently, a matched case-control study of 2,854 pairs of women with a BRCA1 or BRCA2 pathogenic variant with or without breast cancer showed a greater breast cancer risk reduction with surgical menopause (OR, 0.52; 95% CI, 0.40–0.66) than with natural menopause (OR, 0.81; 95% CI, 0.62–1.07). This study also reported a highly significant reduction in breast cancer risk among women who had an oophorectomy after natural menopause (OR, 0.13; 95% CI, 0.02–0.54; P = .006).[169] Another study of 5,783 women with BRCA1 or BRCA2 pathogenic variants who were followed up for an average of 5.6 years reported that 68 of 186 women who developed either ovarian, fallopian, or peritoneal cancer had died. The HR for these cancers with bilateral oophorectomy was 0.20 (95% CI, 0.13–0.30; P = .001). In carriers of BRCA pathogenic variants without a history of cancer, the HR for all-cause mortality to age 70 years associated with oophorectomy was 0.23 (95% CI, 0.13–0.39; P < .001).[7] Among studies with 50 or more subjects, prevalence ranged from 2.3% to 11%. Some of the variation in prevalence is likely due to differences in surgical technique, pathologic handling of the tissues, and age at RRSO. In the GOG 199 study of 966 high-risk women, the incidence of occult cancer was highest among carriers of BRCA1 pathogenic variants (4.6%), followed by carriers of BRCA2 pathogenic variants (3.5%), versus only 0.5% of noncarriers. The odds of an occult pathologic finding was fourfold higher among postmenopausal women.[170]

In addition to a reduction in risk of ovarian and breast cancer, RRSO may also significantly improve OS and breast and ovarian cancer–specific survival. A prospective cohort study of 666 women with germline pathogenic variants in BRCA1 and BRCA2 found an HR for overall mortality of 0.24 (95% CI, 0.08–0.71) in women who had RRSO compared with women who did not.[171] This study provides the first evidence to suggest a survival advantage among women undergoing RRSO.

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

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

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

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

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

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

The role of concomitant hysterectomy at the time of RRSO in carriers of BRCA1/BRCA2pathogenic variants is controversial. There is concern that a small portion of the proximal fallopian tube remains when hysterectomy is not performed, thereby resulting in a residual increased risk of fallopian tube cancer. However, several studies that have examined fallopian tube cancers indicate that the vast majority of these cancers occur in the distal or midportion of the fallopian tube, suggesting that the occurrence of proximal fallopian tube cancer would be a very unlikely event. Some reports have suggested an increased incidence of uterine carcinoma in carriers of pathogenic variants,[202] whereas others have not confirmed an elevated risk of serous uterine cancer.[203] A prospective study of 857 women suggested that any increased incidence of uterine cancer appeared to be among carriers of BRCA1 pathogenic variants who used tamoxifen;[204] this was confirmed by the same group in a later study of 4,456 carriers of BRCA1/BRCA2 pathogenic variants.[205] Even with tamoxifen use, the excess risk of endometrial cancer was small, with a 10-year cumulative risk of 2%.[205] In addition, the use of tamoxifen can now be minimized, given the options of raloxifene (which does not increase the risk of uterine cancer) and aromatase inhibitors for breast cancer prevention in postmenopausal women. Therefore, on the basis of the current understanding of the risk of uterine cancer in carriers of BRCApathogenic variants, there is not a singularly compelling reason to consider hysterectomy at the time of RRSO to reduce the risk of uterine cancer. Concomitant hysterectomy does offer the advantage of simplifying the hormone replacement regimen for carriers of BRCApathogenic variants who choose to take hormones. After hysterectomy, women can take estrogen alone (which does not increase the risk of breast cancer), without progestins, thereby eliminating the risk of postmenopausal bleeding.

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

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

Studies have examined the effect of RRSO on quality of life (QOL). One study examined 846 high-risk women of whom 44% underwent RRSO and 56% had periodic screening.[210] Of the 368 carriers of BRCA1/BRCA2 pathogenic variants, 72% underwent RRSO. No significant differences were observed in QOL scores (as assessed by the Short Form-36) between those with RRSO or screening or compared with the general population; however, women with RRSO had fewer breast and ovarian cancer worries (P < .001) and more favorable cancer risk perception (P < .05) but more endocrine symptoms (P < .001) and worse sexual functioning (P < .05). Of note, 37% of women used HRT after RRSO, although 62% were either perimenopausal or postmenopausal.[210] Researchers then examined 450 premenopausal high-risk women who had chosen either RRSO (36%) or screening (64%). Of those in the RRSO group, 47% used HRT. HRT users (n = 77) had fewer vasomotor symptoms than did nonusers (n = 87; P < .05), but they had more vasomotor symptoms than did women in the screening group (n = 286). Likewise, women who underwent RRSO and used HRT had more sexual discomfort due to vaginal dryness and dyspareunia than did those in the screening group (P < .01). Therefore, while such symptoms are improved via HRT use, HRT is not completely effective, and additional research is warranted to address these important issues.

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

Bilateral salpingectomy

Bilateral salpingectomy has been suggested as an interim procedure to reduce risk in carriers of BRCA pathogenic variants.[217,218] There are no data available on the efficacy of salpingectomy as a risk-reducing procedure. The procedure preserves ovarian function and spares the premenopausal patient the adverse effects of a premature menopause. The procedure can be performed using a minimally invasive approach, and a subsequent bilateral oophorectomy could be deferred until the patient approaches menopause. While the data make a compelling argument that some pelvic serous cancers in carriers of BRCApathogenic variants originate in the fallopian tube, some cancers clearly arise in the ovary. Furthermore, bilateral salpingectomy could give patients a false sense of security that they have eliminated their cancer risk as completely as if they had undergone a bilateral salpingo-oophorectomy. A small study of 14 young carriers of BRCA pathogenic variants documented the procedure as feasible.[219] However, efficacy and impact on ovarian function was not assessed in this study. Future prospective trials are needed to establish the validity of the procedure as a risk-reducing intervention.

In a statistical Markov model using Monte Carlo simulation, risk-reducing salpingectomy with delayed oophorectomy was a cost-effective strategy considering quality-adjusted life expectancy for women with pathogenic variants in BRCA1/BRCA2.[220] Another study modeling ovarian cancer risk and effects of RRSO and salpingectomy found that the difference in estimated ovarian cancer risk is small when salpingectomy is performed on women of childbearing age and oophorectomy is performed 5 to 10 years later.[221]

Chemoprevention

Oral contraceptives

OCs have been shown to have a protective effect against ovarian cancer in the general population.[222] Several studies, including a large, multicenter, case-control study, showed a protective effect,[121,223-226] while one population-based study from Israel failed to demonstrate a protective effect.[227]

There has been great interest in determining whether a similar benefit extends to women who are at increased genetic risk of ovarian cancer. A multicenter study of 799 ovarian cancer patients with BRCA1 or BRCA2 pathogenic variants, and 2,424 control patients without ovarian cancer but with a BRCA1 or BRCA2 pathogenic variant, showed a significant reduction in ovarian cancer risk with use of OCs (OR, 0.56; 95% CI, 0.45–0.71). Compared with never-use of OCs, duration up to 1 year was associated with an OR of 0.67 (95% CI, 0.50–0.89). The OR for each year of OC use was 0.95 (95% CI, 0.92–0.97), with a maximum observed protection at 3 years to 5 years of use.[226] This study included women from a prior study by the same authors and confirmed the results of that prior study.[121] A population-based case-control study of ovarian cancer did not find a protective benefit of OC use in carriers of BRCA1 or BRCA2 pathogenic variants (OR, 1.07 for ≥5 years of use), although they were protective, as expected, among noncarriers (OR, 0.53 for ≥5 years of use).[227] A small, population-based, case-control study of 36 carriers of BRCA1 pathogenic variants, however, observed a similar protective effect in both carriers of pathogenic variants and noncarriers (OR, approximately 0.5).[225] A larger case-control study of women with pathogenic variants in BRCA1 demonstrated maximum benefit after 5 years of OC use, while women with pathogenic variants in BRCA2 seemed to reach maximum benefit after 3 years of OC use.[228] A multicenter study of subjects drawn from numerous registries observed a protective effect of OCs among the 147 carriers of BRCA1 or BRCA2pathogenic variants, with ovarian cancer compared with the 304 matched carriers of pathogenic variants without cancer (OR, 0.62 for ≥6 years of use).[224] Finally, a meta-analysis of 18 studies that included 13,627 carriers of BRCA pathogenic variants, 2,855 of whom had breast cancer and 1,503 of whom had ovarian cancer, reported a significantly reduced risk of ovarian cancer (summary RR, 0.50; 95% CI, 0.33–0.75) associated with OC use. The authors also reported significantly higher risk reductions with longer duration of OC use (36% reduction in risk for each additional 10 years of OC use). There was no association with breast cancer risk and use of OC pills formulated after 1975.[116]

Level of evidence: 3aii

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

Reproductive factors

It has been suggested that incessant ovulation, with repetitive trauma and repair to the ovarian epithelium, increases the risk of ovarian cancer. In epidemiologic studies in the general population, physiologic states that prevent ovulation have been associated with decreased risk of ovarian cancer. It has also been suggested that chronic overstimulation of the ovaries by luteinizing hormone plays a role in ovarian cancer pathogenesis.[229] Most of these data derive from studies in the general population, but some information suggests the same is true in women at high risk due to genetic predisposition.

Pregnancy

Among the general population, parity decreases the risk of ovarian cancer by 45% compared with nulliparity. Subsequent pregnancies appear to decrease ovarian cancer risk by 15%.[230] Earlier studies of women with BRCA1/BRCA2 pathogenic variants showed that parity decreases the risk of ovarian cancer.[227,231] In a large case-control study, parity was associated with a significant reduction in ovarian cancer risk in women with BRCA1pathogenic variants, OR 0.67 (CI, 0.46–0.96).[226] For each birth, carriers of BRCA1pathogenic variants had an OR of 0.87 (CI, 0.79–0.95). In this same study, parity was associated with an increase in ovarian cancer risk in carriers of BRCA2 pathogenic variants; however, there was no significant trend for each birth, OR 1.08 (CI, 0.90–1.29). Further studies are necessary to define the association of parity and risk of ovarian cancer in carriers of BRCA2 pathogenic variants, but for BRCA1 carriers, each live birth significantly decreases risk of ovarian cancer, as it does in sporadic ovarian cancer.

Lactation and tubal ligation

In the general population, breastfeeding is associated with a decrease in ovarian cancer risk.[232] In carriers of BRCA pathogenic variants, data are limited. One study found no protective effect with breastfeeding.[231] A case-control study among women with BRCA1or BRCA2 pathogenic variants demonstrates a significant reduction in risk of ovarian cancer (OR, 0.39) for women who have had a tubal ligation. This protective effect was confined to those women with pathogenic variants in BRCA1 and persists after controlling for OC use, parity, history of breast cancer, and ethnicity.[223] A case-control study of ovarian cancer in Israel found a 40% to 50% reduced risk of ovarian cancer among women undergoing gynecologic surgeries (tubal ligation, hysterectomy, unilateral oophorectomy, ovarian cystectomy, excluding bilateral oophorectomy).[168] The mechanism of protection is uncertain. Proposed mechanisms of action include decreased blood flow to the ovary, resulting in interruption of ovulation and/or ovarian hormone production; occlusion of the fallopian tube, thus blocking a pathway for potential carcinogens; or a reduction in the concentration of uterine growth factors that reach the ovary.[233] (Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention for information relevant to the general population.)

Oral contraceptives

Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.

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).[201,234-238] However, clinical guidelines to manage male carriers with BRCA pathogenic variants are based on consensus statements and expert opinions because information is limited.[239,240,33]

There have been suggestions that BRCA2-associated prostate cancers are associated with aggressive disease phenotype.[241-246] Specifically, two recent studies have reported the median survival of male BRCA2 carriers with prostate cancer in the range of 4 to 5 years.[244,245] 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 [247] and North American [248] 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.[241,243,246,249]

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.[250,251] 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.[252] 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.[245]

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 diagnosis 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.[253] These pathological features are associated with a worse prognosis in breast cancer, and early studies suggested that carriers of BRCA1pathogenic variants with breast cancer may have a poorer prognosis compared with sporadic cases.[254-256] These studies particularly noted an increase in ipsilateral and contralateral second primary breast cancers in carriers of BRCA1 and BRCA2 pathogenic variants.[257-261] (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.[262] 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).[263] Similar findings were seen in a European cohort with no differences in disease-free survival in BRCA1-associated breast cancers.[264] 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.[265] 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.[266] 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) pathogenic variant. The median age at cancer diagnosis was 45 years in carriers of BRCA1pathogenic 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.[267] 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 BRCA1pathogenic variant received chemotherapy.[268] Subsequently, in a study of 89 BRCA1carriers 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.[269] 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).[270]

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.[263,271-273] A small study reported statistically significant higher OS in carriers of BRCA2 pathogenic variants with metastatic breast cancer.[264]

Systemic therapy in breast cancer treatment

Role of BRCA1 and BRCA2 in response to systemic therapy

A growing body of preclinical and clinical literature suggests a differential response of BRCA-related breast cancers to systemic chemotherapy. This is based on the emerging understanding of the functions of these genes in response to DNA damage and mitotic spindle machinery control. As several chemotherapeutic agents target either DNA or mitotic spindle structural integrity, the lack of BRCA functions could alter response to these agents. Intact BRCA1 and BRCA2 are important in DNA repair by homologous recombination. Preclinical studies of BRCA1- and BRCA2-deficient cell lines have suggested increased sensitivity to drugs that cause DNA damage that is repaired by homologous recombination, such as cisplatin, carboplatin and mitomycin C.[274,275] Conversely, intact BRCA1 may be important for spindle poisons, such as taxanes, to be effective.[276,277] Preclinical models suggest decreased sensitivity to these drugs in mutated cell lines.[278,279]

Evidence of the role of BRCA1/BRCA2 pathogenic variants in humans is evolving. A number of small studies have suggested increased clinical response rates, particularly in carriers of BRCA1 pathogenic variants, but design limitations make it difficult to use these studies to guide clinical recommendations.

Retrospective and prospective studies [280-284] have suggested a higher-than-expected response rate to chemotherapy in carriers of BRCA1 pathogenic variants receiving neoadjuvant chemotherapy for breast cancer, especially when using cisplatin.[282] Several studies regarding the Polish experience on the use of preoperative chemotherapy in carriers of BRCA1 pathogenic variants have been published. The largest report [282] includes data on 102 carriers of BRCA1 pathogenic variants of which 51 were described in two prior studies.[285,280] Women were identified from a registry of 6,903 patients. Those with a Polish founder pathogenic variant in BRCA1 (5382insC, C61G, or 4153delA) who had also received preoperative chemotherapy were included. 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 BRCA2pathogenic variants typically treated with anthracycline-based chemotherapy have demonstrated clinical complete response rates of 46% to 90% after preoperative chemotherapy,[281,283] particularly in carriers of BRCA1 pathogenic variants.[284] A trial of preoperative cisplatin in triple-negative breast cancer patients demonstrated a pCR of 22%; however, both carriers of BRCA1 pathogenic variants in the study had a pCR.[286]

A small study reported a statistically significant higher sensitivity to first-line treatment in carriers of BRCA2 pathogenic variants with metastatic breast cancer than in those with sporadic metastatic cancer; conversely, no statistically significant differences were observed for BRCA1 carriers with metastatic breast cancer.[264] No data directly compare different types of chemotherapy in BRCA1 and carriers of BRCA2 pathogenic variants. However, in a small study of 20 carriers of BRCA1 pathogenic variants with metastatic breast cancer, there was an overall response rate of 80% to cisplatin therapy.[287] Further studies are evaluating the role of platinums in BRCA1- and BRCA2-associated metastatic cancer.

Thus, the preclinical and clinical data suggesting improved chemotherapy response rates in BRCA1-associated breast cancer are consistent with the emerging understanding of BRCA1 function in DNA-damage response and cell-cycle regulation. While these findings raise the possibility that germline status may influence treatment choices, there is insufficient evidence at this time to support treating carriers of pathogenic variants with different regimens in the adjuvant and neoadjuvant setting.

Another specific process to exploit in BRCA1/BRCA2-deficient tumors is the poly (ADP-ribose) polymerase (PARP) pathway. Whereas 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. It was hypothesized that inhibiting base excision repair in BRCA1- or BRCA2-deficient cells would lead to enhanced cell death as two separate repair mechanisms would be compromised—the concept of synthetic lethality. In vitro studies have shown that PARP inhibition kills BRCA variant cells with high specificity.[288,289]

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.[290] The EMBRACA trial randomly assigned 431 patients to talazoparib 1 mg orally daily versus the physician’s choice of capecitabine, eribulin, vinorelbine, or gemcitabine.[291] 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). Given these results, PARP inhibitors are considered a standard option for patients with metastatic breast cancer and a BRCApathogenic variant.

Ongoing research is evaluating multiple new combinations with PARP inhibitors to include other DNA damage repair agents, immunotherapies, and targeted therapies, as well as their use in early-stage breast cancer. In addition, emerging studies are exploring the activity of other classes of drugs which target the DNA repair process. A phase II study demonstrated that treatment with lurbinectedin, a trabectedin analog, which selectively inhibits the active transcription of protein-coding genes and irreversibly stalls the elongation of RNA polymerase II on the DNA template degrading the ubiquitin/proteasome machinery, resulted in a significant improvement in PFS and a trend toward improvements in OS in patients with BRCA1/BRCA2-mutated metastatic breast cancer.[292]

(Refer to the Systemic therapy in ovarian cancer treatment section in the Ovarian cancersection 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.[293-295] 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,[259] 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.[296-298] 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.[99,259,296-298] 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).[296,298] Although not entirely consistent across studies, radiation therapy, chemotherapy, oophorectomy, and tamoxifen are associated with a decreased risk of ipsilateral events,[99,296-298] 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.[296] This finding is supported by a population-based case-control study of women diagnosed with breast cancer before the age of 55 years.[299] 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.[296]

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.[300-308] 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.[301] 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.[309] 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.[305] In a retrospective U.S. hospital-based study, AJ carriers of BRCApathogenic 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.[303] Similarly, a significant survival advantage was seen in a case-control study among women with non-AJ BRCA pathogenic variants.[310] 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.[311] A U.S. population-based study showed improvement in OS in BRCA2, but not in BRCA1, carriers.[312] However, the study included only 12 carriers of BRCA2 pathogenic variants and 20 carriers of BRCA1pathogenic variants. Significantly better OS and progression-free survival (PFS) were observed in 29 high-grade serous ovarian cancer cases with a known BRCA2 pathogenic 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.[313] 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).[314] 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.[304]

In contrast, several studies have not found improved OS among ovarian cancer patients with BRCA pathogenic variants.[255,315-317] The largest of these studies involved a large series of unselected Canadian and U.S. patients who were tested for BRCA1 and BRCA2pathogenic 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.[318] Furthermore, one study suggested that there was worse survival in ovarian cancer patients with a family history.[316]

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;[313,314] 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.[319,320] 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.[275] 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.[303,306]

PARP pathway inhibitors are currently being 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.

A phase I study of olaparib, an oral PARP inhibitor, demonstrated tolerability (with minimal side effects) and activity in carriers of BRCA1 and BRCA2 pathogenic variants with ovarian, breast, and prostate cancers.[321] 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.[322] 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. The most frequent side effects were mild nausea and fatigue. [323] 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 BRCA2pathogenic variants or with epigenetic silencing of the genes.[324]

Studies have used PARP inhibitors in ovarian cancer, as both treatment and maintenance, after platinum-based chemotherapy. 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.[325] 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.[326] 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 BRCApathogenic variants (HR, 0.21; 95% CI, 0.08–0.55). There were no differences in OS between the olaparib and control groups.[327]

In contrast, another study observed a survival advantage among BRCA wild-type patients. 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 months vs. 9 months) (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 months vs. 5.7 months) (HR, 0.32; P =.008) and a smaller trend toward increased PFS in 47 women with BRCA pathogenic variants (19.4 vs. 16.5 months) (HR, 0.55; P = 0.16).[328]

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.[329] 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.[330,331] 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%).[332] 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 256 patients, 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).[333] 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).[334] 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 BRCApathogenic 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.[335] More mature data are necessary to determine whether platinum sensitivity is a marker of response to PARP inhibitors in women with pathogenic BRCA variants, and the optimal timing of PARP inhibitors as treatment or as maintenance therapy.

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) [336]	Addressed	Risk Assessment:Addressed	Not addressed	Not addressed
		Genetic Counseling:Addressed
ACOG (2017) [337]	Addressed	Risk Assessment:Addressed	Addressed	Addressed
		Genetic Counseling:Addressed
ASCO (2015) [338]	Not addressed	Risk Assessment:General recommendations; not specific to HBOC	General recommendations; not specific to HBOC	Not addressed
		Genetic Counseling:Addressed
ESMO (2016) [339]	Refers to other published guidelines	Risk Assessment: Refers to other published guidelines	Refers to other published guidelines	Addressed
		Genetic Counseling:Addressed
NAPBC (2014) [340]	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) [341]	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) [337,342]	Addressed	Risk Assessment:Addressed	Addressed	Addressed
		Genetic Counseling:Addressed
USPSTFa(2014) [343]	Addressed	Risk Assessment:Addressed	Addressed in general terms and other guidelines referenced	Addressed in general terms and other guidelines referenced
		Genetic Counseling:Addressed

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