Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version
Chemoprevention
Tamoxifen
Tamoxifen (a synthetic antiestrogen) increases breast-cell growth inhibitory factors and concomitantly reduces breast-cell growth stimulatory factors. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP-P-1), a prospective, randomized, double-blind trial, compared tamoxifen (20 mg/day) with placebo for 5 years. Tamoxifen was shown to reduce the risk of invasive breast cancer by 49%. The protective effect was largely confined to ER-positive breast cancer, which was reduced by 69%. The incidence of ER-negative cancer was not significantly reduced.[88] Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted both among women with a family history of breast cancer and in those without a family history. An increased incidence of endometrial cancers and thrombotic events occurred among women older than 50 years. Interim data from two European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months [89] or 70 months,[90] respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used hormone replacement therapy (HRT).[89] These trials varied considerably in study design and populations. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
Subsequently, the International Breast Cancer Intervention Study 1 (IBIS-1) breast cancer prevention trial randomly assigned 7,154 women between the ages of 35 and 70 years to receive tamoxifen or placebo for 5 years. Eligibility for the trial was based on family history or abnormal benign breast disease. At a median follow-up of 16 years, there was a 29% reduction in risk of breast cancer in the tamoxifen arm (HR, 0.71; 95% CI, 0.60–0.83). There was a 43% reduction in risk for invasive ER-positive breast cancer (HR, 0.66; 95% CI, 0.54–0.81) and a 35% reduction in risk for DCIS (HR, 0.65; 95% CI 0.43–1.00). There was no reduction in risk of invasive ER-negative breast cancer.[91] These findings confirm those of the Breast Cancer Prevention Trial (P-1).[88]
A substudy of the NSABP-P-1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in carriers of BRCA1/BRCA2 pathogenic variants older than 35 years. BRCA2-positive women benefited from tamoxifen to the same extent as BRCA1/BRCA2 pathogenic variant–negative participants; however, tamoxifen use among healthy women with BRCA1pathogenic variants did not appear to reduce breast cancer incidence. These data must be viewed with caution in view of the small number of carriers of pathogenic variants in the sample (8 BRCA1 carriers and 11 BRCA2 carriers).[92]
In contrast to the very limited data on primary prevention in carriers of BRCA1 and BRCA2pathogenic variants with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of contralateral breast cancer.[93-95] In one study involving approximately 600 carriers of BRCA1/BRCA2 pathogenic variants, tamoxifen use was associated with a 51% reduction in contralateral breast cancer.[93] An update to this report examined 285 carriers of BRCA1/BRCA2 pathogenic variants with bilateral breast cancer and 751 carriers of BRCA1/BRCA2 pathogenic variants with unilateral breast cancer (40% of these patients were included in their initial study). Tamoxifen was associated with a 50% reduction in contralateral breast cancer risk in carriers of BRCA1 pathogenic variants and a 58% reduction in carriers of BRCA2 pathogenic variants. Tamoxifen did not appear to confer benefit in women who had undergone an oophorectomy, although the numbers in this subgroup were quite small.[95] Another study that involved 160 carriers of BRCA1/BRCA2pathogenic variants demonstrated that tamoxifen use after the treatment of breast cancer with lumpectomy and radiation was associated with a 69% reduction in the risk of contralateral breast cancer.[94] In another study, 2,464 carriers of BRCA1/BRCA2 pathogenic variants with a personal history of breast cancer were identified from three family cohorts. Using both retrospective and prospective data, researchers found a significant decrease in the risk of contralateral breast cancer among women who received adjuvant tamoxifen therapy after their diagnosis. This association persisted after researchers adjusted for age at diagnosis and the ER status of the first cancer. A major limitation of this study is the lack of information on ER status of the first breast cancer in 56% of the women.[96] These studies are limited by their retrospective, case-control designs and the absence of information regarding ER status in the primary tumor.
The STAR trial (NSABP-P-2) included more than 19,000 women and compared 5 years of raloxifene versus tamoxifen in reducing the risk of invasive breast cancer.[97] There was no difference in incidence of invasive breast cancer at a mean follow-up of 3.9 years; however, there were fewer noninvasive cancers in the tamoxifen group. The incidence of thromboembolic events and hysterectomy was significantly lower in the raloxifene group. Detailed quality-of-life data demonstrate slight differences between the two arms.[98] Data regarding efficacy in carriers of BRCA1 or BRCA2 pathogenic variants are not available. (Refer to the PDQ summary on Breast Cancer Prevention for more information about the use of selective ER modulators and aromatase inhibitors in the general population, including postmenopausal women.)
Another case-control study of carriers of pathogenic variants and noncarriers identified through ascertainment of women with bilateral breast cancer found that systemic adjuvant chemotherapy reduced CBC risk among carriers of pathogenic variants (RR, 0.5; 95% CI, 0.2–1.0). Tamoxifen was associated with a nonsignificant risk reduction (RR, 0.7; 95% CI, 0.3–1.8). Similar risk reduction was seen in noncarriers; however, given the higher absolute CBC risk in carriers, there is potentially a greater impact of adjuvant treatment in risk reduction.[99]
The effect of tamoxifen on ovarian cancer risk was studied in 714 carriers of BRCA1pathogenic variants. All subjects had a prior history of breast cancer; use of tamoxifen was not associated with an increased risk of subsequent ovarian cancer (odds ratio [OR], 0.78; 95% CI, 0.46–1.33).[100]
Reproductive factors
In the general population, breast cancer risk increases with early menarche and late menopause, and is reduced at early first full-term pregnancy. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) In the Nurses’ Health Study, these were risk factors among women who did not have a mother or sister with breast cancer.[101] Among women with a family history of breast cancer, pregnancy at any age appeared to be associated with an increase in risk of breast cancer, persisting to age 70 years.
One study evaluated risk modifiers among 333 female carriers of a BRCA1 high-risk pathogenic variant. In women with known pathogenic variants of the BRCA1 gene, early age at first live birth and parity of three or more have been associated with a lowered risk of breast cancer. A RR of 0.85 was estimated for each additional birth, up to five or more; however, increasing parity appeared to be associated with an increased risk of ovarian cancer.[102,103] In a case-control study from New Zealand, investigators noted no difference in the impact of parity on the risk of breast cancer between women with a family history of breast cancer and those without a family history.[104]
Studies of the effect of pregnancy on breast cancer risk have revealed complex results and the relationship with parity has been inconsistent and may vary between carriers of BRCA1and BRCA2 pathogenic variants.[105-107] Parity has more consistently been associated with a reduced risk of breast cancer in carriers of BRCA1 pathogenic variants.[105-109] Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.[107,110]
In the general population, breastfeeding has been associated with a slight reduction in breast cancer risk in a few studies, including a large collaborative reanalysis of multiple epidemiologic studies,[111] and at least one study suggests that it may be protective in carriers of BRCA1 pathogenic variants. In a multicenter, case-control study of 685 carriers of BRCA1 pathogenic variants with breast cancer and 280 carriers of BRCA2 pathogenic variants with breast cancer and 965 carriers without breast cancer drawn from multiple-case families, among carriers of BRCA1 pathogenic variants, breastfeeding for 1 year or more was associated with approximately a 45% reduced risk of breast cancer.[112] No such reduced risk was observed among carriers of BRCA2 pathogenic variants. A second study failed to confirm this association.[110]
Oral contraceptives
There is no consistent evidence that the use of oral contraceptives (OCs) increases the risk of breast cancer in the general population.[113] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
Although several smaller studies have reported a slightly increased risk of breast cancer with OC use in carriers of BRCA1/BRCA2 pathogenic variants,[114,115] a meta-analysis concluded that the associated risk is not significant with more recent OC formulations.[116] However, OCs formulated before 1975 were associated with an increased risk of breast cancer.[116] A large proportion of patients on whom this meta-analysis was based were drawn from three large studies summarized in Table 12.[117-119]
When patients are counseled about contraceptive options and preventive actions, the potential impact of OC use on the risk of breast cancer and ovarian cancer and other health-related effects of OCs need to be considered. A number of important issues remain unresolved, including the potential differences between carriers of BRCA1 or BRCA2pathogenic variants, effect of age and duration of exposure, and effect of OCs on families with highly penetrant early-onset breast cancer.
(Refer to the Oral contraceptives section in the Chemoprevention section of this summary for a discussion of OC use and ovarian cancer in this population.)
Hormone replacement therapy (HRT)
Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with HRT in the general population.[121-124] The Women’s Health Initiative (WHI) was a randomized controlled trial of approximately 160,000 postmenopausal women that investigated the risks and benefits of dietary interventions and hormone therapy to reduce the incidence of heart disease, breast cancer, colorectal cancer, and fractures. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits.[123,124] One of the adverse outcomes prompting closure was a significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150) breast cancers (RR, 1.24; 95% CI, 1.02–1.50; P < .001) in women randomly assigned to receive estrogen and progestin.[124] Results of a follow-up study suggest that the recent reduction in breast cancer incidence, especially among women aged 50 to 69 years, is predominantly related to decrease in use of combined estrogen plus progestin HRT.[125] HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.[124]
Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [126-128] or unaffected by a family history of breast cancer;[102,129,130] risk did not vary by family history in the meta-analysis.[113] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 pathogenic variants.[124] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.[131]
HRT in carriers of BRCA1/BRCA2 pathogenic variants
The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 pathogenic variant has been examined in two studies. In a prospective study of 462 carriers of BRCA1and BRCA2 pathogenic variants, bilateral RRSO (n = 155) was significantly associated with breast cancer risk-reduction overall (HR, 0.40; 95% CI, 0.18–0.92). When carriers of pathogenic variants without bilateral RRSO or HRT were used as the comparison group, HRT use (n = 93) did not significantly alter the reduction in breast cancer risk associated with bilateral RRSO (HR, 0.37; 95% CI, 0.14–0.96).[132] In a matched case-control study of 472 postmenopausal women with BRCA1 pathogenic variants, HRT use was associated with an overall reduction in breast cancer risk (OR, 0.58; 95% CI, 0.35–0.96; P = .03). A nonsignificant reduction in risk was observed both in women who had undergone bilateral oophorectomy and in those who had not. Women taking estrogen alone had an OR of 0.51 (95% CI, 0.27–0.98; P = .04), while the association with estrogen and progesterone was not statistically significant (OR, 0.66; 95% CI, 0.34–1.27; P = .21).[133] A case-control study of 432 matched pairs of postmenopausal women with a BRCA1 pathogenic variant who had a personal history of cancer were compared with unaffected BRCA1 carriers. The use of HRT was not associated with an increased risk of developing breast cancer (OR, 0.80; P = .24).[134] Especially given the differences in estimated risk associated with HRT between observational studies and the WHI, these findings should be confirmed in randomized prospective studies,[135] but they suggest that HRT in carriers of BRCA1/BRCA2 pathogenic variants neither increases breast cancer risk nor negates the protective effect of oophorectomy.
Ovarian cancer
Screening/surveillance
Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening for information on screening in the general population and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information about levels of evidence related to screening and prevention. The latter also outlines the five requirements that must be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice.
Clinical examination
In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early ovarian cancer. No data exist regarding the benefit of clinical examination of the ovaries (bimanual pelvic examination) in women at inherited risk of ovarian cancer.
Level of evidence: None assigned
Transvaginal ultrasound
In the general population, transvaginal ultrasound (TVUS) appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries (e.g., transient corpus luteum cysts) that can cause difficulty in interpretation. The randomized prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO-1) found no reduction in mortality with the annual use of combined TVUS and cancer antigen 125 (CA-125) in screening asymptomatic postmenopausal women at general-population risk of ovarian cancer.[136]
Data are limited regarding the potential benefit of TVUS in screening women at inherited risk of ovarian cancer. A number of retrospective studies have reported experience with ovarian cancer screening in high-risk women using TVUS with or without CA-125.[9,137-147] However, there is little uniformity in the definition of high-risk criteria and compliance with screening, and in whether cancers detected were incident or prevalent. One of the largest reported studies included 888 carriers of BRCA1/BRCA2 pathogenic variants who were screened annually with TVUS and CA-125. Ten women developed ovarian cancer; five of the ten developed interval cancers after normal screening results within 3 to 10 months before diagnosis. Five of the ten ovarian cancers were screen-detected incident cases, which had normal screening results within 6 to 14 months before diagnosis. Of these five cases, four were stage IIIB or IV.[137]
A similar study reported the results of annual TVUS and CA-125 in a cohort of 312 high-risk women (152 carriers of BRCA1/BRCA2 pathogenic variants).[139] Of the four cancers that were detected due to abnormal TVUS and CA-125, all four patients were symptomatic, and three had advanced-stage disease. Annual screening of carriers of BRCA1/BRCA2pathogenic variants with pelvic ultrasound, TVUS, and CA-125 failed to detect early-stage ovarian cancer among 241 carriers of BRCA1/BRCA2 pathogenic variants in a study from the Netherlands.[148] Three cancers were detected over the course of the study, all advanced stage IIIC disease.[148] Finally, a study of 1,100 moderate- and high-risk women who underwent annual TVUS and CA-125 reported that ten of 13 ovarian tumors were detected due to screening. Only five of ten were stage I or II.[138] There are limited data related to the efficacy of semiannual screening with TVUS and CA-125.[9,146]
In the United Kingdom Familial Ovarian Cancer Screening Study, 3,563 women with an estimated 10% or higher lifetime risk of ovarian cancer were screened with annual ultrasound and serum CA-125 measurements for a mean of 3.2 years. Four of 13 screen-detected cancers were stage I or II. Women screened within the previous year were less likely to have higher than stage IIIC disease; there was also a trend towards better rates of optimal cytoreduction and improved OS. Furthermore, most of the cancers occurred in women with known ovarian cancer susceptibility genes, identifying a cohort at highest cancer risk for consideration of screening.[149] Phase II of this study increased the frequency of screening to every 4 months; the impact of this is not yet available.
The first prospective study of TVUS and CA-125 with survival as the primary outcome was completed in 2009. Of the 3,532 high-risk women screened, 981 were carriers of BRCApathogenic variants, 49 of whom developed ovarian cancer. The 5- and 10-year survival was 58.6% (95% CI, 50.9%–66.3%) and 36% (95% CI, 27–45), respectively, and there was no difference in survival between carriers and noncarriers. A major limitation of the study was the absence of a control group. Despite limitations, this study suggests that annual surveillance by TVUS and CA-125 level appear to be ineffective in detecting tumors at an early stage to substantially influence survival.[150]
Serum CA-125
Serum CA-125 screening for ovarian cancer in high-risk women has been evaluated in combination with TVUS in a number of retrospective studies, as described in the previous section.[9,137-146]
The National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA-125. (Refer to the Prostate, Lung, Colorectal and Ovarian [PLCO] Cancer Screening Trial: Single-threshold CA-125 levels and TVU section in the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening for more information.) The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA-125 screening every 6 to 12 months, beginning at age 35 years.[151] The Cancer Genetics Studies Consortium task force has recommended that female carriers of a BRCA1 pathogenic variant undergo annual or semiannual screening using TVUS and serum CA-125 levels, beginning at age 25 to 35 years.[11] Both recommendations are based solely on expert opinion and best clinical judgment.
Other candidate ovarian cancer biomarkers
The need for effective ovarian cancer screening is particularly important for women carrying BRCA1 and BRCA2 pathogenic variants, and the mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, PMS2), disorders in which the risk of ovarian cancer is high. There is a special sense of urgency for carriers of BRCA1 pathogenic variants, in whom cumulative lifetime risks of ovarian cancer may exceed 40%.
Thus, it is expected that many new ovarian cancer biomarkers (either singly or in combination) will be proposed as ovarian cancer screening strategies during the next 5 to 10 years. While this is an active area of research with a number of promising new biomarkers in early development, at present, none of these biomarkers alone or in combination have been sufficiently well studied to justify their routine clinical use for screening purposes, either in the general population or in women at increased genetic risk.
Before information related to emerging ovarian cancer biomarkers is addressed, it is important to consider the several steps that are required to develop and, more importantly, validate a new biomarker. One useful framework is that published by the National Cancer Institute Early Detection Research Network investigators.[152] They indicated that the goal of a cancer-screening program is to detect tumors at an early stage so that treatment is likely to be successful. The gold standard by which such programs are judged is whether the death rate from the cancer for which screening is performed is reduced among those being screened. In addition, the screening test must be sufficiently noninvasive and inexpensive to allow widespread use in the population to be screened. Maintaining high test specificity (i.e., few false-positive results) is essential for a population screening test, because even a low false-positive rate results in many people having to undergo unnecessary and costly diagnostic procedures and psychological stress. It is likely that the use of several such cancer biomarkers in combination will be required for a screening test to be both sensitive and specific.
Furthermore, a clinically useful test must have a high PPV (a parameter derived from sensitivity, specificity, and disease prevalence in the screened population). Practically speaking, a biomarker with a PPV of 10% implies that ten surgical procedures would be required to identify one case of ovarian cancer; the remaining nine surgeries would represent false-positive test findings. In general, the ovarian cancer research community considers biomarkers with a PPV less than 10% to be clinically unacceptable, given the morbidity related to bilateral salpingo-oophorectomy. Finally, it is important to keep in mind that while novel biomarkers may be present in the sera of women with advanced ovarian cancer (who represent most cases analyzed in the early phases of biomarker development), they may or may not be detectable in women with early-stage disease, which is essential if the screening test is to be clinically useful.
It has been suggested that there are five general phases in biomarker development and validation are currently suggested:
Phase 1 — Preclinical exploratory studies
- Identify potentially discriminating biomarkers.
- Usually done by comparing gene over- or underexpression in the tumor compared with normal tissue.
- Because many exploratory analyses in large numbers of genes are performed at this stage, one or more may seem to have good discriminating ability between cancers and normal tissue by random chance alone.
Phase 2 — Clinical assay development for clinical disease
- Develop a clinical assay that can be obtained on noninvasively obtained samples (e.g., a blood specimen).
- Often the test targets the protein product of one of the genes found to be of interest in phase 1.
- The goal is to describe the performance characteristics of the assay for distinguishing between subjects with and without cancer. At this point, the assay should be in its final configuration and remain stable throughout the following phases.
- IMPORTANT: Because the case subjects in a phase 2 study already have cancer, with assay results obtained at the time of disease diagnosis, one cannot determine whether disease can be detected early with a given biomarker.
Phase 3 — Retrospective longitudinal repository studies
- Compare clinical specimens collected from cancer case subjects before their clinical diagnosis with specimens from subjects who have not developed cancer.
- Evaluate, as a function of time before clinical diagnosis, the biomarker’s ability to detect preclinical disease.
- Define the criteria for a positive screening test in preparation for phase 4.
- Explore the influence of other patient characteristics (e.g., age, gender, smoking status, medication use) on the ability of the biomarker to discriminate between those with and without preclinical disease.
Phase 4 — Prospective screening studies
- Determine the operating characteristics of the biomarker-based screening test in a population for which the test is intended.
- Measure the detection rate (number of abnormal tests among all those with the disease) and the false-positive rate (the number of abnormal tests among all those who do not have the disease).
- Evaluate whether the cancers detected by the test are being found at an early stage, a point at which treatment is more likely to be curative.
- Assess whether the test is acceptable in a population of persons for whom it is intended. Will subjects comply with the test schedule and results?
Phase 5 — Cancer control studies
- Ideally, conduct randomized controlled clinical trials in clinically relevant populations, in which one arm is subjected to screening and appropriate intervention if screen-positive, while the other arm is not screened.
- Determine whether the death rate of the cancer being screened for is reduced among those who use the screening test.
- Obtain information about the costs of screening and treatment of screen-detected cancers.
Finally, for a validated biomarker test to be considered appropriate for use in a particular population, it must have been evaluated in that specific population without prior selection of known positives and negatives. In addition, the test must demonstrate clinical utility, that is, a positive net balance of benefits and risks associated with the application of the test. These may include improved health outcomes and net psychosocial and economic benefits.[153]
Ovarian cancer poses a unique challenge relative to the potential impact of false-positive test results. There are no reliable noninvasive diagnostic tests for early-stage disease, and clinically significant early-stage cancer may not be grossly visible at the time of exploratory surgery.[154] Consequently, it is likely that some patients will be reassured that their abnormal test does not indicate the presence of cancer only by having their ovaries and fallopian tubes surgically removed and examined microscopically. High test specificity (i.e., a very low false-positive rate) is required to avoid unnecessary surgery and induction of premature menopause women with in false-positive results.
Variations on CA-125
CA-125 plus an ovarian cancer symptom index
An ovarian cancer symptom index for predicting the presence of cancer was evaluated in 75 cases and 254 high-risk controls (carriers of BRCA pathogenic variants or women with a strong family history of breast and ovarian cancer).[155] Women had a positive symptom index if they reported any of the predefined symptoms (bloating or increase in abdominal size, abdominal or pelvic pain, and difficulty eating or feeling full quickly) more than 12 times per month, occurring only within the prior 12 months. CA-125 values greater than 30 U/mL were considered abnormal. The symptom index independently predicted the presence of ovarian cancer, after controlling for CA-125 levels (P < .05). The combination of an elevated CA-125 and a positive-symptom index correctly identified 89.3% of the cases. The symptom index correlated with the presence of cancer in 50% of the affected women who did not have elevated CA-125 levels, but 11.8% of the high-risk controls without cancer also had a positive-symptom index. The authors suggested that a composite index that included both CA-125 and the symptom index had better performance characteristics than either test used alone, and that this strategy might be used as a first screen in a multistep screening program. Additional test performance validation and determination of clinical utility are required in unselected screening populations.
Risk of ovarian cancer algorithm
A novel modification of CA-125 screening is based on the hypothesis that rising CA-125 levels over time may provide better ovarian cancer screening performance characteristics than simply classifying CA-125 as normal or abnormal based on an arbitrary cut-off value. This has been implemented in the form of the risk of ovarian cancer algorithm (ROCA), an investigational statistical model that incorporates serial CA-125 test results and other covariates into a computation that produces an estimate of the likelihood that ovarian cancer is present in the screened subject. The first report of this strategy, based on reanalysis of 5,550 average-risk women from the Stockholm Ovarian Cancer screening trial, suggested that ovarian cancer cases and controls could be distinguished with 99.7% sensitivity, 83% specificity, and a PPV of 16%. That PPV represents an eightfold increase over the 2% PPV reported with a single measure of CA-125.[156] This report was followed by applying the ROCA to 33,621 serial CA-125 values obtained from the 9,233 average-risk postmenopausal women in a prospective British ovarian cancer screening trial.[157] The area under the receiver operator curve increased from 84% to 93% (P = .01) for ROCA compared with a fixed CA-125 cutoff. These observations represented the first evidence that preclinical detection of ovarian cancer might be improved using this screening strategy. A prospective study of 13,000 normal volunteers aged 50 years and older in England used serial CA-125 values and the ROCA to stratify participants into low, intermediate, and elevated risk subgroups.[158] Each had its own prescribed management strategy, including TVUS and repeat CA-125 either annually (low risk) or at 3 months (intermediate risk). Using this protocol, ROCA was found to have a specificity of 99.8% and a PPV of 19%.
Two prospective trials in England utilized the ROCA. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) randomly assigned normal-risk women to either (1) no screening, (2) annual ultrasound, or (3) multimodal screening (N = 202,638; accrual completed; follow-up ends in 2014), and the U.K. Familial Ovarian Cancer Screening Study (UKFOCSS) targeted high-risk women (accrual completed). There are also two high-risk cohorts using the ROCA under evaluation in the United States: the Cancer Genetics Network ROCA Study (N = 2,500; follow-up complete; analysis underway) and the Gynecologic Oncology Group Protocol 199 (GOG-0199; enrollment complete; follow-up ended in 2011).[159] Thus, additional data regarding the utility of this currently investigational screening strategy will become available.
Miscellaneous new markers
A wide array of new candidate ovarian cancer biomarkers has been described during the past decade, e.g., HE4; mesothelin; kallikreins 6, 10, and 11; osteopontin; prostasin; M-CSF; OVX1; lysophosphatidic acid; vascular endothelial growth factor B7-H4; and interleukins 6 and 8.[160-162] These have been singly studied, in combination with CA-125, or in various other permutations. Most of the study populations are relatively small and comprise highly selected, known ovarian cancer cases and healthy controls of the type evaluated in early biomarker development phases 1 and 2. Results have not been consistently replicated in multiple studies; presently, none are considered ready for widespread clinical application.
Proteomics
Initially, mass spectroscopy of serum proteins was combined with complex analytic algorithms to identify protein patterns that might distinguish between ovarian cancer cases and controls.[163] This approach assumed that pattern recognition alone would be sufficient to permit such discrimination, and that identification of the specific proteins responsible for the patterns identified was not required. This strategy was modified, using similar laboratory tools, to identify finite numbers of specific known serum markers that may be used in place of, or in conjunction with, CA-125 measurements for the early detection of cancer.[164] These studies [162,165] have generally been small case-control studies that are limited by sample size and the number of early-stage cancer cases included. Further evaluation is needed to determine whether any additional markers identified in this fashion have clinical utility for the early detection of ovarian cancer in the unselected clinical population of interest.
Multiplex biomarker assays for ovarian cancer screening
Because individual biomarkers have not met the criteria for an effective screening test, it has been suggested that it may be necessary to combine multiple ovarian cancer biomarkers to obtain satisfactory screening test results. This strategy was employed to quantitatively analyze six serum biomarkers (leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125), using a multiplex, bead-based platform.[166] A similar assay was available commercially under the trade name OvaSure until its voluntary withdrawal from the market by the manufacturer.[Response to FDA Warning Letter]
The cases in this study were newly diagnosed ovarian cancer patients who had blood collected just before surgery: 36 were stage I and II; 120 were stage III and IV. The controls were healthy age-matched individuals who had not developed ovarian cancer within 6 months of blood draw. Neither cases nor controls in this study were well characterized regarding their familial and/or genetic risk status, but they have been suggested to comprise a high-risk population. First, 181 controls and 113 ovarian cancer cases were tested to determine the initial panel of biomarkers that best discriminated between cases and controls (training set). The resulting panel was applied to an additional 181 controls and 43 ovarian cancer cases (test set). Pooling both early- and late-stage ovarian cancer across the combined training and test sets, performance characteristics were reported as a sensitivity of 95.3% and a specificity of 99.4%, with a PPV of 99.3% and a negative predictive value of 99.2%, using a formula that assumed an ovarian cancer prevalence of about 50%, as seen in the highly selected research population.
To avoid biases that may make test performance appear to be better than it really is, combining training populations and test populations in analyses of this sort is generally not recommended.[167] The most appropriate prevalence to use is the disease prevalence in the unselected population to be screened. The prevalence of ovarian cancer in the general population is 1 in 2,500. In a correction to their manuscript,[166] the authors assumed that the prevalence of ovarian cancer in the screened population was 1 in 2,500 (0.04%) and recalculated the PPV to be only 6.5%. On that basis, the investigators have retracted their claim that this test is suitable for population screening. If this test were used in patients at increased risk of ovarian cancer, the actual prevalence in such a target population is likely to be higher than that observed in the general population, but well below the assumed 50% figure used in the published analysis. This revised PPV of 6.5% indicates that approximately 1 in 15 women with a positive test would in fact have ovarian cancer, and only a fraction of those with ovarian cancer would be stages I or II. The remaining 14 positive tests would represent false-positives, and these women would be at risk of exposure to needless anxiety and potentially morbid diagnostic procedures, including bilateral salpingo-oophorectomy.
Viewed in the context of the criteria previously described,[152] this assay would be classified as phase 2 in its development. While this appears to be a promising avenue of ovarian cancer screening research, additional validation is required, particularly in an unselected population representative of the clinical screening population of interest. A position statement by the Society of Gynecologic Oncologists regarding this assay indicated “it is our opinion that additional research is needed to validate the test’s effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an institutional review board.”
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 Guidelinesrecommend 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]
(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.)
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