Introduction

In the decade since publication of the draft of the human genome sequence, research has led to recommendations about clinical management, screening, and prevention options for those at risk for hereditary gynecologic cancers, particularly ovarian and uterine cancers. Up to 15 % of ovarian cancer is associated with high-penetrance hereditary cancer susceptibility disorders, particularly (i) hereditary breast and ovarian cancer (HBOC) associated with mutations in BRCA1 and BRCA2, and (ii) Lynch syndrome (LS; also referred to as hereditary nonpolyposis colorectal cancer or HNPCC) linked to alterations in mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. In addition to ovarian cancer susceptibility, LS-affected women are at risk for uterine and other cancers, including colorectal cancer (CRC). Specific characteristics of a personal and family medical history are suggestive of hereditary cancer susceptibility, including HBOC and LS (Table 1).

Table 1 Personal and family history characteristics suggestive of hereditary breast and ovarian cancer and Lynch syndrome risk
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Other less common hereditary ovarian cancer-associated susceptibility disorders not covered in this review include: Peutz-Jeghers syndrome, nevoid basal cell carcinoma syndrome; with a small increased risk associated with Li-Fraumeni syndrome. Additionally, Cowden syndrome, a rare inherited condition associated with uterine and other cancer risk, is not discussed here.

Epidemiology

HBOC

Incidence

Estimates of BRCA1/2 mutation frequency vary, ranging from 1/300 to 1/500 in the general population to much higher rates in populations with founder mutations such as those of Ashkenazi Jewish descent and populations from the Netherlands, Iceland, and Sweden [1], as well as in families with early-onset cancers or with multiple cases of breast and/or ovarian cancer [2]. An estimated 3-5 % of breast cancer and 10-15 % of ovarian cancer has been attributed to BRCA1/2 mutations [1, 3].

Cancer risks associated with BRCA1 and BRCA2 mutations

Estimates of penetrance, the occurrence of cancer in individuals with BRCA1/2 mutations vary widely, with greater risk predicted in those with strong family histories, in contrast to HBOC-affected individuals unselected for family history. Among a large pooled analysis of 22 studies of more than 8,000 breast and ovarian cancer patients, including 500 with documented BRCA1/2 mutations, the mean breast cancer risk by age 70 years was 65 % (95 % confidence interval (CI) 44-78 %) for BRCA1 and 45 % (95 % CI 31-56 %) for BRCA2. Mean ovarian cancer risks by age 70 years were 39 % (95 % CI 18-54 %) for BRCA1 and 11 % (95 % CI 2.3-19 %) for BRCA2 [4]. A more recent meta-analysis of ten studies revealed a cumulative breast cancer risk by age 70 years of 57 % (95 % CI 47-66 %) and 49 % (95 % CI 40-57 %), and an ovarian cancer risk of 40 % (95 % CI 35-46 %) and 18 % (95 % CI 13-23 %) for those heterozygous for BRCA1 and BRCA2 mutations, respectively [5]. Mean age at breast cancer diagnosis ranges from 39.9-44.1 years and 42.2-47.3 years for those with BRCA1 and BRCA2 mutations, respectively [6, 7], versus 61 years in the general population. The mean age of ovarian cancer onset also varies, ranging from 49–53 years and 55–58 years for women with BRCA1 and BRCA2 mutations, respectively, versus 63 years in the general population [8].

In addition to cancers of the female breast and ovary, well-established HBOC-component tumors include primary peritoneal and fallopian tube tumors, male breast cancer, cancers of the prostate, pancreas, as well as melanoma (skin and ocular), and possibly others [9]. Without additional intervention, i.e., BSO or tamoxifen, risk for contralateral breast cancer (CBC) is 27.1 % within 5 years, and 43.4 % at 10 years among those with BRCA1 mutations, and 23.5 % and 34.6 % at 5 and 10 years, respectively, for those with BRCA2 mutations. Factors associated with reduced risk for CBC include presence of a BRCA2 mutation versus a BRCA1 mutation (hazard ratio (HR) 0.73; 95 % CI 0.47-1.15), tamoxifen use (HR 0.59; 95 % CI 0.35-1.01), initial diagnosis at age 50 years or older (HR 0.63; 95 % CI 0.36-1.10), and BSO (HR 0.44; 95 % CI 0.21-0.91) [10]. A more recent population-based, nested case control study of CBC risk reported cumulative 5- and 10-year risks of 15.5 % (95 % CI 8.8-27.4) and 28.2 % (95 % CI 16–50) for those heterozygous for BRCA1/2 mutations, diagnosed with initial primary invasive breast cancer before age 30 years, with 5-year and 10-year risks of 9.7 % (95 % CI 8.4-11.2) and 18.4 % (95 % CI 16.0-21.3) for all ages combined (range, 25–55 years) [11]. Long-term CBC risk among those with BRCA1/2 mutations is reported as 47.4 % at 25 years [12].

LS

Incidence

General population risk of LS has been estimated at 1/370 in the United States, based on a 2.8 % incidence of this condition among those with newly diagnosed CRC [13]. Risk of LS increases substantially in families with multiple cases of colorectal, uterine, and other LS-associated cancers, as well as among those with early-onset, syndrome-associated cancers [14]. LS accounts for an estimated 2.3 % of all endometrial cancer cases, 10 % of those diagnosed before age 50 years [15].

Cancer risks associated with MMR gene mutations

Alterations in LS-associated DNA MMR genes MLH1, MSH2, MSH6, and PMS2 are associated with different cancer risks; due to their low prevalence individually, aggregate risk data are usually shown. Studies of families attending high-risk clinics show higher cancer risks than affected individuals ascertained from the general population, reflecting study biases. Cancer risks for those with this condition also appear to vary by gender [16].

Although CRC susceptibility is a major focus of care for women with LS, because those with MMR mutations face a 22-58 % risk of CRC by age 70 years [16], the syndrome’s presence significantly impacts gynecologic care. LS-affected women face an estimated 30-60 % risk of endometrial adenocarcinoma by age 70 years, with risks greatest among those with MSH6 mutations [16, 17]. The mean age at endometrial cancer diagnosis in varied study populations ranges from 48–62 years among those with MLH1 and MSH2 mutations. LS-associated ovarian cancer risk also varies, ranging from 4-12 %, with a mean age of onset of 42.5 years among those with MLH1 and MSH2 mutations [18].

In addition to uterine, ovarian, and CRC, classic LS-associated tumors include cancers of the stomach, urinary tract, hepatobiliary tract, brain (usually glioblastoma), small intestine, and skin (sebaceous cancers). Evidence suggests elevated pancreatic cancer risk as well [18].

Pathogenesis

HBOC

HBOC is an autosomal dominant disorder associated with mutations in BRCA1 and BRCA2. Functioning as tumor suppressor genes and critical to DNA repair, BRCA1 and BRCA2 are localized on chromosome 17q21 and 13q12.3, respectively. Most mutations found in these genes result in protein inactivation, typically from protein truncation. In addition, missense mutations and large gene rearrangements are seen. Mutation type varies by ancestry, i.e., three distinct BRCA1 and BRCA2 mutations result in the majority of HBOC among those of Ashkenazi Jewish decent, including BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT [19].

Carcinogenesis is the result of repeated DNA injury from stressors, including ionizing radiation, oxidative radicals, and certain cytotoxic agents. BRCA1 and BRCA2 serve a central role in the cell’s response to these stressors by their involvement in repair of double-stranded DNA breaks via homologous recombination and other repair mechanisms [20]. BRCA1 plays a broader role in maintaining cellular integrity through its involvement in signaling DNA damage, homologous recombination, nucleotide-excision repair, and nonhomologous end-joining. BRCA2 plays a more specific role in DNA repair through control of RAD51, which is required for homologous recombination, thereby functioning to repair double-stranded DNA breaks and interstrand crosslinks [21]. BRCA deficiency leads to the accumulation of mutations, because it interferes with the cell’s ability to repair DNA damage or undergo apoptosis, ultimately resulting in neoplastic transformation [22].

LS

LS is an autosomal dominant disorder associated with mutations in one of several genes encoding MMR gene complex proteins. Approximately 90 % of LS is associated with mutations in MLH1 and MSH2, with 7-10 % attributed to MSH6 and less than 5 % related to PMS2. Although not a mismatch repair gene, germline deletions in EPCAM silence MSH2 expression in close to 1 % of individuals with LS [18]. MMR proteins function to identify and correct DNA base mispairings occurring as a result of DNA polymerase slippage during the replication of repetitive genomic tracts, i.e., microsatellites. Failure of the MMR system to repair DNA mispairings results in microsatellite instability (MSI), where microsatellites undergo a somatic gain or loss in repeat length. The accumulation of such errors can inactivate genes critical to cellular function, including tumor suppressor genes, ultimately resulting in carcinogenesis. Close to 15 % of CRCs show MSI. Importantly, most MSI-positive tumors are caused by somatic (non-germline) hypermethylation of the MLH1 CpG island promoter region; a smaller portion is caused by LS [23].

Presentation

HBOC

HBOC-risk is suspected based on clinical and family history features, including history of: (i) ovarian cancer; (ii) early-onset breast cancer ≤45 years or ≤50 years with limited family history; (iii) synchronous or metachronous breast and ovarian (fallopian tube, or peritoneal cancers); (iv) bilateral breast cancer with initial diagnosis ≤50 years; (v) male breast cancer; (vi) triple-negative breast cancer ≤ age 60 years; (vii) breast and ovarian cancer in a family; (viii) multiple cases of breast or pancreatic cancer in a family; (ix) population at risk, i.e., Ashkenazi Jewish; or (x) limited family history, i.e., adoption [24]. Probability models determine the pretest likelihood of an individual testing positive for a BRCA1/2 mutation. Each of these models is unique due to the methods and populations used in developing them. The most widely applied models are BRCAPRO, Myriad II, and BOADICEA [25, 26•].

LS

LS-risk assessment is based on established personal and family history criteria, i.e., the Amsterdam II Criteria or the Revised Bethesda Guidelines [27, 28]. These criteria include: (i) young age at CRC onset (before age 50 years); (ii) presence of synchronous or metachronous CRCs or other LS-associated component tumors; (iii) multiple family members of successive generations with LS-associated tumors; and (iv) suggestive CRC pathologic findings, i.e., microsatellite instability or absence of mismatch repair protein expression. Several models, including PREMM1,2,6, MMRpredict, and MMRpro, have been developed to provide a quantitative estimate of an individual testing positive for an MMR gene mutation. These models have been validated in a number of CRC populations [29, 30]. Although they showed a strong ability to distinguish mutation carriers from noncarriers with a high sensitivity and specificity among CRC cases, the discriminative ability of these models is much lower among endometrial cancer cases [30].

Diagnosis

HBOC

In addition to personal and family history, incorporating examination of breast and ovarian cancer pathologic features can assist in identifying HBOC [31–33]. Specifically, compared with sporadic breast cancer, BRCA1-associated tumors often are triple-negative (estrogen receptor [ER], progesterone receptor [PR], and HER-2 negative). Additionally, BRCA1-associated tumors tend to be high grade, exhibit p53 mutations, and stain positive for high-molecular weight epithelial cytokeratins (CKs), CK5/6 and CK14, known as “basal” cytokeratins. In contrast, breast cancers diagnosed in women with BRCA2 mutations, similar to sporadic comparators, often are hormone receptor-positive [3, 34]. Likewise, there appear to be characteristic pathologic features associated with HBOC-associated ovarian cancer. A recent population-based study showed that in comparison with a 14.1 % rate of BRCA mutations among the overall study population of 1001 women with nonmucinous ovarian cancer, 16.6 % of those with serous histology tested positive, whereas 22.6 % of those with high-grade serous tumors tested positive [35••].

LS

Preliminary screening of paraffin-embedded CRC tissue for evidence of defective MMR function can be used to determine an individual’s candidacy for genetic testing. There are two CRC tumor-based screening tests available. First, tumors can be assayed through microsatellite instability (MSI) testing. A high amount of MSI (MSI-high; MSI-H) is found in nearly all LS-associated colorectal tumors. Importantly, MSI-H is also found in about 15 % of all colorectal tumors due to another mechanism, age-related somatic (non-germline) methylation of the MLH1 gene promoter. Therefore, those with tumors lacking the MSI-H phenotype are unlikely to have LS, but MSI-H is not diagnostic of LS.

Immunohistochemistry (IHC) is the second means of screening tumors for evidence of MMR gene alterations. LS-IHC testing determines the expression of mismatch repair enzymes MLH1, MSH2, MSH6, and PMS2 in CRC specimens. Additional tumor tissue testing is warranted (BRAF mutation testing and/or MLH1 hypermethylation analysis) if there is loss of expression of MLH1, because this finding occurs in nearly 75 % of these cases due to somatic MLH1 promoter hypermethylation [36••]. Abnormal IHC for one or more DNA MMR enzyme(s) directs germline mutation testing of the corresponding gene(s). The clinical sensitivity of MSI and IHC testing is estimated at 85 % and 83 %, respectively among those with MLH1 and MSH2 mutations. Estimates of clinical specificity of these two tests among CRC patients are 90.2 % and 88.8 %, respectively [36••]. High amounts of MSI or lack of expression of one or more MMR protein(s), including abnormal expression of the MLH1 protein, not explained by a somatic inactivation of the gene, is highly suggestive of LS.

In 2009, an independent evidence-based review by the Evaluation of Genomic Applications in Practice and Prevention Working Group issued recommendations regarding universal CRC tissue screening (IHC and/or MSI) for evidence of LS [16]. Despite the potential benefits of universal CRC-based LS screening, there is a recognition of: (i) the significant challenges and barriers of this strategy; (ii) the need for education of clinicians, patients, and other stakeholders; and (iii) the need for additional pilot studies to demonstrate evidence of screening efficacy, feasibility, and utility on a broader population-based level [37•].

There has been incomplete study of the clinical utility and validity of tumor-based LS screening among gynecologic cancer patients. Recent data suggest that IHC-based uterine cancer screening for absence of MMR enzyme expression is a feasible and cost-effective way to identify LS-risk, particularly among those with suggestive clinical (i.e., early-onset disease, low BMI), pathological (tumor infiltrating lymphocytes and peritumoral lymphocytes), or family history characteristics. MSI has a lower predictive value in MSH6-associated LS. Because of the higher rate of MSH6 mutations in LS-associated uterine cancer, IHC alone is considered the primary LS screening tool among women with this disease [15].

Genetic counseling

Among those meeting characteristic personal medical, pathological, or family history criteria for risk for HBOC and LS, guidelines recommend referral for genetic counseling by suitably trained health care providers [2, 38•]. Genetic counseling facilitates informed decisions about genetic testing and medical management options, improves knowledge of cancer risk, provides information on available support resources (Table 2), and often reduces anxiety. Elements of genetic counseling include: (i) pedigree analysis; (ii) risk assessment; (iii) recommendations for genetic testing; (iv) genetic test results interpretation; (v) medical management decision making; and (vi) impact of risk for others in the family [2]. In response to growing demands for cancer genetic risk assessment, counseling, and testing, cancer genetic counseling services have recently increased nationally [39]. The National Society of Genetic Counselors provides an up-to-date link to available genetic counseling services across the country (http://www.nsgc.org).

Table 2 Patient and family support resources: hereditary breast and ovarian cancer and Lynch syndrome
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Prognosis

HBOC

Although prognosis is similar between breast cancer-affected women with BRCA mutations and those with presumed noninherited breast cancer [7], women with BRCA-associated ovarian cancer appear to have improved overall survival compared with those with presumed noninherited disease [35••, 40–44]. Consistent with survival data, studies reveal improved response to first-line therapy among ovarian cancer patients with BRCA mutations compared with those with sporadic disease. Furthermore, a recent study comparing HBOC-affected ovarian cancer patients with those with presumed noninherited disease suggests improved response to both non-platin and platin-containing regimens in the treatment of disease-relapse, including those women with early relapses. This study also suggests that somatic (non-germline) BRCA mutations predict treatment responses [35••].

LS

There are limited data regarding the impact of MMR gene mutations on prognosis among women with gynecologic cancers. However, a meta-analysis of 7642 CRC patients from 32 studies, including 1277 MSI-H patients, revealed an improved overall survival among those with MSI-H tumors versus those with microsatellite stable (MSS) tumors (HR 0.65; 95 % CI 0.59-0.71) [45]. Patients with MSI-H CRCs are less prone to have lymph node involvement and systemic metastases [46].

Management

HBOC

Management interventions available to women with or at risk for HBOC include high-risk screening, chemoprevention, and risk-reducing surgery.

Screening

The goal of a screening intervention is to detect disease at an early stage in asymptomatic individuals, when treatment will affect the disease’s natural history. In making breast cancer screening recommendations for women with documented BRCA1/2 mutations, clinicians must consider two unique disease features. First, HBOC-associated breast cancer usually occurs at an earlier age than sporadic breast cancer, when routine mammography is less sensitive due to increased breast density. Second, women with BRCA1/2 mutations have an increased rate of interval cancers (cancers detected between screening exams) [47, 48]. Furthermore, data are limited regarding the safety of early mammograms among those with BRCA mutations. A recent retrospective cohort study of 1993 women with BRCA1/2 mutations showed that compared with no diagnostic radiation, any exposure before age 30 years was associated with increased breast cancer risk (HR 1.9; 95 % CI 1.2-3), with a dose–response seen. This association was not evident among those exposed between ages 30–39 years [49••].

Several large observational studies have evaluated the effectiveness of routine mammography in women with BRCA1/2 mutations. Although studies demonstrated significant variations, the sensitivity of mammography is lower and the percentage of advanced stage cancers is higher among these women compared with the general risk population [50]. Documented limitations of mammograms in HBOC-affected women prompted study of alternative imaging modalities, including MRI. Data indicate that MRI is almost twice as sensitive as mammography in detecting invasive breast cancer in high-risk women (77 % vs. 39 %) [50, 51].

Although the overall sensitivity of MRI for detecting invasive cancers is better than that of mammography, the specificity and corresponding positive predictive value (PPV) of MRI is lower (PPV 63 % for MRI: 95 % CI 43-79 %) versus 77 % for mammography (95 % CI 50-92 %) [52] creating potential for unnecessary follow-up procedures, including biopsies. Other limitations of MRI are high cost, lack of universal availability, and the need for intravenous contrast. However, because of the improved sensitivity of MRI for detecting HBOC-associated breast cancer, national guidelines recommend incorporating it into a surveillance program that also includes ongoing mammograms and close clinical surveillance [24]. The sensitivity of the combined screening approach among high-risk women is 80-100 % [51]. Cost analysis data reveal that MRI screening, when added to mammography, is more cost effective for BRCA1 mutation carriers than for those with BRCA2 mutations, and that the cost-effectiveness of this procedure varies by age [53].

The natural history of preclinical ovarian cancer is incompletely understood. The majority of women with ovarian cancer present with advanced stage disease resulting in high mortality rates. Although a number of studies demonstrate that most women with ovarian cancer experience prediagnosis symptoms [54, 55], these studies fail to identify a consistent symptom pattern that differentiates ovarian cancer from other medical conditions, or early from late-stage disease. To date, ovarian cancer screening among BRCA1/2 mutation carriers has largely focused on serum CA-125 levels and transvaginal ultrasound imaging. Studies examining the impact of each of these methods on stage at diagnosis and mortality have shown them to be largely ineffective [56–59].

Chemoprevention

Chemoprevention for women with known BRCA1/2 mutations includes consideration of agents aimed at breast cancer prevention (i.e., tamoxifen) as well as ovarian cancer prevention. Because this review is focused on gynecologic cancers, we have limited the following discussion to ovarian cancer chemoprevention.

Oral contraceptive (OC) use has been associated with more than a 40 % reduction in ovarian cancer risk and often is recommended for disease prevention for those at known risk. The benefits of OCs have extended to studies of women with BRCA1/2 mutations [60••, 61]. Increased risk of breast cancer has been attributed to OC use in some studies, particularly among women who used them before age 20–30 years and those with BRCA1 mutations [62, 63], whereas other studies fail to show an elevated risk [64, 65].

A randomized clinical trial to assess the impact of OCs on ovarian and/or breast cancer risk is unlikely. The potential reduction in ovarian cancer risk must be weighed against a potential increase in breast cancer risk among women with BRCA1/2 alterations who are considering the use of OCs [8].

Risk-reducing surgery

Given the high cancer risk and known limitations of screening in HBOC-affected women, risk-reducing mastectomy is considered an alternative way to reduce breast cancer risk for mutation carriers. Risk-reducing BSO is recommended between ages 35–40 years, when childbearing is complete, or based on ages at ovarian cancer diagnosis in the family [24]. Studies examining the impact of risk-reducing mastectomy among those with known BRCA mutations are largely limited to observational study design, thereby limiting the generalizability of this work to the care of HBOC-affected women. Despite these limitations, data consistently show an 85-100 % reduction in breast cancer risk among those undergoing risk reducing mastectomy [2]. A meta-analysis of ten studies revealed a HR of 0.21 (95 % CI 0.12-0.39) for ovarian/fallopian tube tumors and a HR of 0.49 (95 % CI 0.37-0.65) for breast cancer among women with BRCA1/2 mutations electing BSO [66]. Although the reduction in risk is remarkably consistent across studies, the benefits of risk-reducing surgery, both mastectomy and BSO, must be weighed against its impact on the woman’s physical, emotional, reproductive, and sexual health. Those electing risk-reducing bilateral mastectomy should be educated regarding reconstruction options and risks.

Emerging therapies

Poly(ADP-ribose) polymerase (PARP) is a novel target for the management of those with HBOC-associated cancers, including ovarian cancer. This enzyme plays a critical role in the repair of single-stranded DNA breaks through the base excision repair pathway. Deficient PARP function results in double-stranded DNA breaks when single-stranded DNA breaks are encountered at the replication fork. Normally, the cell repairs double-stranded DNA breaks through homologous recombination. However, in BRCA deficient cells, homologous recombination repair is defective, resulting in the accumulation of lethal levels of DNA damage. Among those with documented BRCA mutations, PARP-inhibition is unique in its ability to target tumor cells—a process called “synthetic lethality”. Specifically, in HBOC-affected individuals, noncancer cells maintain one functional BRCA allele, supporting ongoing homologous recombination repair. However, PARP inhibition becomes selectively lethal in tumor cells that have lost the normal BRCA allele. As part of the treatment of HBOC-associated tumors, this mechanism of action may improve disease control with limited toxicity [67].

The initial phase I study of an oral PARP inhibitor, olaparib, reported a response rate of 47 %, with manageable adverse toxicities among those with documented BRCA mutations and classic HBOC-associated cancers, including eight patients with ovarian cancer [68••]. A single-stage expansion of this trial examined response to olaparib among 50 previously treated ovarian cancer patients with known or likely BRCA mutations, categorized based on platinum sensitivity. This showed an overall response rate of 46 %, with 6 % of participants experiencing stable disease for 4 months or more. Toxicities were largely low-grade; the most common were nausea (48 %) and fatigue (44 %) [69••]. The overall clinical benefit of olaparib was significantly higher in the platinum-sensitive group (69.2 %) versus the platinum-resistant (45.8 %) and platinum-refractory (23.1 %) groups (p = 0.03) [69••]. Laboratory studies suggest that platinum-insensitive tumors may reacquire BRCA function, thus regaining DNA repair mechanisms facilitating resistance to PARP-inhibition [70].

PARP inhibitors are being investigated in combination with cytotoxic agents for management of HBOC-associated ovarian cancer. Although results of these combined modality studies show promise for improved response, caution has been raised regarding the added toxicity of these combinations. Further study of the role of these agents for the management of HBOC-associated ovarian cancer (as well as other HBOC-associated cancers) is ongoing [67]. Not only are these therapies promising among ovarian cancer-affected women with documented germline BRCA mutations, but somatic BRCA mutations occur in a substantial percentage of sporadic ovarian cancers, particularly high-grade serous ovarian cancers. Furthermore, genetic and epigenetic events can silence other components of the homologous recombination pathway. This suggests a much wider applicability of PARP-inhibition for the management of ovarian cancer with molecular evidence of “BRCAness” [67].

LS

In addition to CRC screening and prevention being important components of care among those with or at risk for LS, women with this condition face significant risk for other cancers, including uterine and ovarian cancers. Management issues reviewed here are limited to the gynecologic care of LS-affected women.

Screening and chemoprevention

There are incomplete data on the efficacy of endometrial cancer screening in women with LS. The clinical utility of transvaginal ultrasound to assess the thickness of the endometrial stripe has been questioned, given that many seeking high-risk care are premenopausal. Previous studies confirmed the limited efficacy of screening transvaginal ultrasound in LS, as well as high false-positive rates [71–73]. In contrast, regular endometrial sampling appears more effective for women with this condition [72, 74]. National Comprehensive Cancer Network guidelines suggest consideration of annual endometrial sampling among LS-affected women [24]. Existing evidence does not support surveillance for ovarian cancer among those with LS.

There are limited data that address the efficacy of chemopreventive agents to reduce gynecologic cancers among those with LS. Nevertheless, oral contraceptives decrease the risk of both endometrial cancer and ovarian cancer in the general population [75, 76].

Risk-reducing surgery

Given the high risk for endometrial cancer and the moderately increased risk for ovarian cancer, women with mismatch repair gene mutations must decide between surveillance and surgical prophylaxis. There are incomplete data regarding the efficacy of risk-reducing gynecologic surgery among Lynch syndrome-affected women [77]. Schmeler et al. reported on a retrospective cohort of 315 women followed for approximately 10 years who had MMR gene mutations. Sixty-one of the 315 women underwent prophylactic surgery. No endometrial or ovarian cancers developed in those who had surgery, whereas 33 % of those without surgery developed endometrial cancer and 5.5 % developed ovarian cancer. National Comprehensive Cancer Network recommendations cite that the risks and benefits of prophylactic hysterectomy and BSO after childbearing should be discussed with LS-affected women [24].

Psychosocial issues

The long-term psychological impact of genetic testing for gynecologic cancer risk is incompletely studied. One 5-year follow-up study of 65 cancer unaffected women who underwent BRCA testing showed that those who tested positive did not differ from those who tested negative on several distress measures. However, anxiety and depression increased in both groups from 1 to 5 years after testing. Higher long-term distress was associated with greater hereditary cancer-related anxiety at the time of genetic testing, having young children, loss of a relative to breast or ovarian cancer, limited test result communication within the family, and changes in relationships with relatives. Although those women with documented BRCA mutations who underwent prophylactic surgery were less satisfied with their body image and noted more changes in sexual relationships than noncarriers, those who elected risk-reducing surgery had reduced fears of developing cancer and noted satisfaction with their surgical decision [78].

Inherent in genetic testing for cancer risk is the burden of making serious medical management decisions. There are few studies that investigate which factors play a role in these decisions. One study reported that age and having children were significant predictors of the choice for risk-reducing mastectomy for cancer unaffected women with BRCA1/2 mutations. Women ages 40–54 years and those with more than a high school education were more likely to opt for prophylactic oophorectomy [79]. In addition to decisions about their own healthcare, younger women that have hereditary cancer syndromes may face difficult decisions about family planning, including the option of preimplantation genetic diagnosis. Although one qualitative study found that the majority of women with documented BRCA mutations preferred not to have a detailed description of preimplantation genetic diagnosis (PGD) at the time of genetic test results disclosure, nearly all agreed that PGD should be addressed during genetic counseling [80].

Both women who test positive, as well as those from HBOC-affected families who test negative (true negative result) experience distress. A qualitative study revealed that those who test negative for the genetic alteration identified in the family report experiencing (i) feelings of isolation, (ii) difficulty with family communication, and (iii) ongoing cancer-related anxiety despite a true negative result [81]. These studies demonstrate the need for ongoing medical and emotional support for those with documented genetic risk, as well as those with true negative results.

Diet and lifestyle

There is incomplete information on the impact of diet and other lifestyle factors on cancer penetrance among those with or at risk for hereditary gynecologic cancers. However, the widely recognized benefits of a healthy diet that is rich in fruits and vegetables, optimum weight control, regular physical activity, and avoidance of known carcinogens, such as cigarettes [82], are considered important for quality of life and longevity. Therefore, it is recommended that HBOC and LS-affected women be advised of the potential benefits of dietary and lifestyle modifications as they relate to overall health and potentially to cancer risk.