Current and future role of genetic screening in gynecologic malignancies

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Current and future role of genetic screening in gynecologic malignancies Kari L. Ring, MD; Christine Garcia, MD; Martha H. Thomas, MS; Susan C. Modesitt, MD

The world of hereditary cancers has seen exponential growth in recent years. While hereditary breast and ovarian cancer and Lynch syndrome account for the majority of mutations encountered by gynecologists, newly identified deleterious genetic mutations continue to be unearthed with their associated risks of malignancies. However, these advances in genetic cancer predispositions then force practitioners and their patients to confront the uncertainties of these less commonly identified mutations and the fact that there is limited evidence to guide them in expected cancer risk and appropriate riskreduction strategies. Given the speed of information, it is imperative to involve cancer genetics experts when counseling these patients. In addition, coordination of screening and care in conjunction with specialty high-risk clinics, if available, allows for patients to have centralized management for multiple cancer risks under the guidance of physicians with experience counseling these patients. The objective of this review is to present the current literature regarding genetic mutations associated with gynecologic malignancies as well to propose screening and risk-reduction options for these high-risk patients. Key words: BRCA, cervical cancer, endometrial cancer, hereditary cancer, high risk, Lynch syndrome, ovarian cancer, risk reduction, screening

Introduction The world of hereditary cancers has seen exponential growth in recent years with the identification of new genes associated with gynecologic malignancies as well as a better understanding of the spectrum of potential cancers associated with previously described mutations. The advent of next-generation sequencing, development of hereditary cancer panels, and decreased costs of testing helped to rapidly move the field forward. However, these advances have the potential to provide patients and

From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology (Drs Ring, Garcia, and Modesitt), and Division of Cancer Genetics (Dr Thomas), University of Virginia Health System, Charlottesville, VA. Received Feb. 15, 2016; revised March 28, 2017; accepted April 4, 2017. The authors report no conflict of interest. Corresponding author: Kari L. Ring, MD. [email protected] 0002-9378/$36.00 ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2017.04.011

practitioners with results that have limited evidence to guide them in expected cancer risk and appropriate riskreduction strategies. The objective of this review is to present the current literature regarding genetic mutations associated with gynecologic malignancies as well as to examine screening and risk-reduction options for these high-risk patients.

Spectrum of mutations Ovarian cancer Ovarian cancer remains the leading cause of death among gynecologic malignancies and up to 24% of the 22,280 new cases diagnosed each year are due to an underlying inherited predisposition.1,2 While mutations in BRCA1 or BRCA2 account for the majority of hereditary ovarian cancers, Lynch syndrome and other genes in the DNA double-strand repair pathway are responsible for a significant proportion of hereditary ovarian cancers.3-6 Although all of these genes carry a significantly increased lifetime risk of developing ovarian cancer, their risks are not equivalent. Clinicians must take the gene, the personal history, and the family history into consideration when

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designing a personalized screening and risk-reduction strategy for each individual patient.7-9 Mutations in BRCA1 and BRCA2 make up 75% of all hereditary ovarian cancers and are inherited in an autosomal dominant manner.1 Women with BRCA1 or BRCA2 mutations are at most increased risk of developing breast and/or ovarian cancers but these two genes also carry an increased risk for other cancers including pancreatic cancer, melanoma, and possibly uterine cancer.10-12 Women who carry a BRCA1 mutation have a lifetime risk for developing ovarian cancer of 39-46%, while women who carry a BRCA2 mutation have a lower lifetime risk of 11-27%.13-15 In addition, women with BRCA2 mutations tend to present with both ovarian and breast cancer about a decade later compared to BRCA1 mutation carriers.15 In October 2014, the Society of Gynecologic Oncology (SGO) released a clinical practice statement recommending that all women with newly diagnosed epithelial ovarian, tubal, and peritoneal cancers be offered genetic testing for germline BRCA1 and BRCA2 mutations.16 This recommendation has also been endorsed by the National Comprehensive Cancer Network (NCCN).17 Lynch syndrome is inherited in an autosomal dominant manner and caused by a mutation in 1 of the 4 mismatch repair genes (MMR; MLH1, MSH2, MSH6, and PMS2) or the epithelial cell ashesion molecule (EPCAM), which is a regulator of MSH2, and Lynch accounts for up to 15% of all hereditary ovarian cancers (Table 1). Lynch-associated ovarian cancers tend to be either endometrioid or clear cell histology18,19 and individuals with Lynch syndrome are also at increased risk of developing colorectal cancer, endometrial cancer, gastric cancer, small bowel cancer, transitional cell carcinoma of the genitourinary tract, pancreatic cancer, sebaceous

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TABLE 1

Outline of current hereditary gynecologic malignancies with surveillance and risk-reduction strategies Genetic syndrome

Gene

Gynecologic cancer

Cancer risk, %

Surveillance strategy (age to start)7,17,31,32,37

Risk-reduction strategy (age to consider)7,17,a

HBOC

BRCA1

Ovary

39e46

Consider Q6 mo/annual TVUS and serum CA-125

RRSO (35e40 y)

HBOC

BRCA2

Ovary

10e27

Consider Q6 mo/annual TVUS and serum CA-125

RRSO (40e45 y)

Lynch

MLH1

Ovary Uterus

4e24 25e60

Consider annual TVUS and/or office endometrial sampling

RRSO when childbearing complete (35e40 y) Risk-reducing hysterectomy when childbearing complete

Lynch

MSH2/EPCAM

Ovary Uterus

4e24 25e60

Consider annual TVUS and/or office endometrial sampling

RRSO when childbearing complete (35e40 y) Risk-reducing hysterectomy when childbearing complete

Lynch

MSH6

Ovary Uterus

1e11 16e26

Consider annual TVUS and/or office endometrial sampling

RRSO when childbearing complete (35e40 y) Risk-reducing hysterectomy when childbearing complete

Lynch

PMS2

Ovary Uterus

6b 15

Consider annual TVUS and/or office endometrial sampling

RRSO when childbearing complete (35e40 y) Risk-reducing hysterectomy when childbearing complete

HOC

BRIP1

Ovary

10e15

No current recommendations

Consider RRSO (45e50 y)

HOC

RAD51C

Ovary

10e15

No current recommendations

Consider RRSO (45e50 y)

HOC

RAD51D

Ovary

10e15

No current recommendations

Consider RRSO (45e50 y)

PeutzJeghers

STK11

Ovary (SCTAT) Uterus Cervix (adenoma malignum)

18e21 9 10

Annual pelvic exam and Pap smear (18e20 y) Consider annual TVUS

No current recommendations

Cowden

PTEN

Uterus

19e28

Consider annual TVUS and office endometrial sampling (30e35 y)

Discuss hysterectomy upon completion of childbearing

Li-Fraumeni

TP53

Ovary1 Uterus83

Elevatedc Elevatedc

No current recommendations

No current recommendations

PPAP

POLD1

Uterus

Elevatedc

No current recommendations

No current recommendations

HBOC, hereditary breast and ovarian cancer syndrome; HOC, hereditary ovarian cancer; PPAP, polymerase proofreading-associated polyposis; Q, every; RRSO, risk-reducing salpingo-oophorectomy; SCTAT, sex cord stromal tumor with annular tubules; TVUS, transvaginal ultrasound. a

Age may be adjusted based on age of first diagnosis in family; b Combined risk of renal pelvis, stomach, ovary, small bowel, ureter, and brain; c Mutations carry increased risk, but specific range unknown.

Ring. Role of genetic evaluation in gynecologic malignancies. Am J Obstet Gynecol 2017.

adenomas, and glioblastoma multiforme (Table 2).7,20 Mutations in other genes within the DNA double-strand repair pathway also confer an increased risk of developing ovarian cancer. In particular, mutations in RAD51C, RAD51D, and BRIP1 have been shown to have an increased risk of ovarian cancer as high as 10% (Table 1).3,4,5 Other genes in the DNA double-strand repair pathway, including PALB2 and BARD1, have been investigated for an increased risk of ovarian cancer but none have reached the point of firm recommendations for changing

ovarian cancer risk management to date. Mutations in genes within the DNA double-strand repair pathway are inherited in an autosomal dominant manner; however, many of these genes are also associated with Fanconi anemia, which occurs when an individual is homozygous for mutations. Rare syndromes such as Peutz-Jeghers syndrome (PJS) (STK-11 mutation), DICER1 syndrome (DICER1 mutation), and Li-Fraumeni syndrome (LFS) (TP53 mutation) also carry increased risks of developing ovarian cancers. PJS carries an increased risk of developing a

particular stromal tumor called sex cord tumors with annular tubules of the ovary, DICER1 syndrome carries an increased risk of developing SertoliLeydig ovarian tumors, and LFS carries an increased risk for many cancers that can include ovarian.1,21-25 Up to 50% of women with Sertoli-Leydig ovarian tumors will have a germline DICER1 mutation and genetic testing should be considered in all women who present with these tumors.26 All of these syndromes are inherited in an autosomal dominant manner but can also be caused by de novo mutations. Given the

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TABLE 2

Outline of current hereditary nongynecologic malignancies with surveillance and risk-reduction strategies Genetic syndrome

Gene

Nongynecologic Cancer cancer risk, %

Surveillance strategy (age to start)7,17,25,37

HBOC

BRCA1

Breast

65e85

Breast awareness (18 y) Clinical breast exam Q6e12 mo (25 y) Annual breast MRI (25e29 y) Annual mammogram (30 y)

HBOC

BRCA2

Breast Pancreas Melanoma

45e85 Breast awareness (18 y) Elevatedb Clinical breast exam Q6e12 mo (25 y) Elevatedb Annual breast MRI (25e29 y) Annual mammogram (30 y) No clear evidence for pancreatic cancer screening

Lynch

MLH1

Colon Gastric Hepatobiliary tract Small bowel Urothelial CNS Pancreatic Sebaceous neoplasms

52e82 6e13 1e4 3e6 1e7 1e3 1e6 1e9

Colonoscopy Q1e2 y (20e25 y or 2e5 y prior to earliest colon cancer if <25 y) Consider EGD with duodenoscopy Q3e5 y (30e35 y) Consider annual urinalysis (30e35 y) Consider annual physical/neurologic exam (25e30 y)

Discuss aspirin therapy

Lynch

MSH2/EPCAM Colon Gastric Hepatobiliary tract Small bowel Urothelial CNS Pancreatic Sebaceous neoplasms

52e82 6e13 1e4 3e6 1e7 1e3 1e6 1e6

Colonoscopy Q1e2 y (20e25 y or 2e5 y prior to earliest colon cancer if <25 y) Consider EGD with duodenoscopy Q3e5 y (30e35 y) Consider annual urinalysis (30e35 y) Consider annual physical/neurologic exam (25e30 y) No clear evidence for pancreatic cancer screening

Discuss aspirin therapy

Lynch

MSH6

Colon Gastric Hepatobiliary tract Small bowel Urothelial CNS Pancreatic Sebaceous neoplasms

10e22 3 NR NR <1 NR NR NR

Colonoscopy Q1e2 y (20e25 y or 2e5 y prior to earliest colon cancer if <25 y) Consider EGD with duodenoscopy Q3e5 y (30e35 y) Consider annual urinalysis (30e35 y) Consider annual physical/neurologic exam (25e30 y) No clear evidence for pancreatic cancer screening

Discuss aspirin therapy

Lynch

PMS2

Colon Gastric Hepatobiliary tract Small bowel Urothelial CNS Pancreatic Sebaceous neoplasms

15e20 6c 6c 6c 6c 6c NR NR

Colonoscopy Q1e2 y (20e25 y or 2e5 y prior to earliest colon cancer if <25 y) Consider EGD with duodenoscopy Q3e5 y (30e35 y) Consider annual urinalysis (30e35 y) Consider annual physical/neurologic exam (25e30 y) No clear evidence for pancreatic cancer screening

Discuss aspirin therapy

HOC

BRIP1

No known

No current recommendations

No current recommendations

HOC

RAD51C

No known

No current recommendations

No current recommendations

HOC

RAD51D

No known

No current recommendations

No current recommendations

Ring. Role of genetic evaluation in gynecologic malignancies. Am J Obstet Gynecol 2017.

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Risk-reduction strategy7,17 Discuss risk-reducing mastectomy Consider risk-reducing agenta

Discuss risk-reducing mastectomy Consider risk-reducing agenta

(continued)

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TABLE 2

Outline of current hereditary nongynecologic malignancies with surveillance and risk-reduction strategies (continued) Genetic syndrome

Gene

Nongynecologic Cancer cancer risk, %

Surveillance strategy (age to start)7,17,25,37

Risk-reduction strategy7,17

Peutz-Jeghers STK11

Breast Colon Gastric Small intestine Pancreas Testes Lung

45e50 39 29 13 11e36 Elevated 15e17

Discuss risk-reducing mastectomy Clinical breast exam Q6 mo (25 y) Annual breast MRI (25 y) Annual mammogram (25 y) Colonoscopy Q2e3 y (late teens) Upper endoscopy Q2e3 y (late teens) CT or MRI enterography (8e10 y) MRCP or endoscopic US Q1e2 y (30e35 y) Annual testicular exam (10 y)

Cowden

PTEN

Breast Follicular thyroid Renal cell Colon

25e50 3e38 2e5 9

Annual comprehensive physical exam (18 y) Discuss risk-reducing mastectomy Breast awareness (18 y) Clinical breast exam Q6e12 mo (25 y) Annual breast MRI (30e35 y) Annual mammogram (30e35 y) Annual thyroid US (at diagnosis) Colonoscopy Q5 y (35 y) Consider renal US Q1e2 y (40 y) Consider dermatologic exam Consider psychomotor assessment in children and brain MRI if symptoms

Li-Fraumeni

TP53

Breast CNS Soft-tissue sarcoma Bone sarcoma Adrenocortical Carcinoma Leukemia

Elevatedd Elevatedd Elevatedd Elevatedd Elevatedd Elevatedd

Breast awareness (18 y) Discuss risk-reducing mastectomy Clinical breast exam Q6e12 mo (20e25 y) Annual breast MRI (20e25 y) Annual mammogram (20e25 y) Physical assessment Q6 mo (18 y) Annual brain MRI (18 y) Annual whole-body MRI (18 y) Abdominal and pelvic US Q6 mo (18 y) Annual dermatologic exam Colonoscopy Q2e5 y (25 y) Upper endoscopy Q2 y (25 y) Blood work Q6 mo (18 y)e

PPAP

POLD1

Colon

Elevatedb Colonoscopy Q1e2 y (20e25 y) Upper endoscopy Q3 y (20e25 y)

No current recommendations

CNS, central nervous system; CT, computed tomography; EGD, esophagogastroduodenoscopy; HBOC, hereditary breast and ovarian cancer syndrome; HOC, hereditary ovarian cancer; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; NR, not reported; PPAP, polymerase proofreading-associated polyposis; Q, every; US, ultrasound. a

Tamoxifen, raloxifene, aromatase inhibitors; b Mutations carry increased risk, but specific range unknown; c Combined risk of renal pelvis, stomach, ovary, small bowel, ureter, and brain; d Lifetime risk of any cancer 90% by age 70 y; e Complete blood cell count, comprehensive metabolic panel, erythrocyte sedimentation rate, lactate dehydrogenase, adrenal function, tumor markers.

Ring. Role of genetic evaluation in gynecologic malignancies. Am J Obstet Gynecol 2017.

increasing evidence for ovarian cancer risk associated with genes other than Lynch, BRCA1, and BRCA2, there should be consideration for the utilization of hereditary cancer panels rather than single-gene testing for patients with newly diagnosed epithelial ovarian cancer.27 Endometrial cancer Inherited endometrial cancer predisposition syndromes account for up to 6% of all endometrial cancers and Lynch syndrome accounts for the majority of these

cases.28-31 Like ovarian cancer, not all genes confer the same risks for endometrial cancer, so it is again important to take the gene along with a woman’s personal and family histories into consideration when determining individual risk of developing endometrial cancer and what strategies to recommend. Lynch syndrome accounts for approximately 2-6% of endometrial cancers and >50% of women with Lynch syndrome will initially present with a gynecologic cancer, typically endometrial but potentially also ovarian cancer

(Table 1).32,33 The five Lynch syndrome genes all carry different lifetime endometrial cancer risks, with MLH1 and MSH2/EPCAM conferring the highest risk and PMS2 conferring the lowest.33 Lynch syndromeeassociated endometrial cancers are typically microsatellite unstable and often show loss of protein expression of mismatch repair proteins on immunohistochemistry. In March 2014, SGO released a clinical practice statement that recommends systematic screening for Lynch syndrome in all newly diagnosed endometrial cancers.34

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Expert Reviews Mutations in the phosphatase and tensin homolog (PTEN) gene, more commonly known as Cowden syndrome, carry up to a 28% lifetime risk of endometrial cancer (Table 1).30 Cowden syndrome is part of a larger genetic syndrome known as PTEN hamartomatous tumor syndrome that includes syndromes such as Bannayan-Riley-Ruvalcaba syndrome and PTEN-associated Proteus syndrome. Cowden syndrome also has increased risk of other cancers such as but not limited to: breast cancers, thyroid cancer (typically follicular), and renal cell cancers (Table 2). Cowden syndrome has hallmark physical characteristics such as macrocephaly (head circumference >58 cm in women) and Lhermitte-Duclos disease, as well as other benign findings such as multinodular goiters, trichilemmomas, and gastrointestinal hamartomas. Cowden syndrome is inherited in an autosomal dominant pattern and can display reduced penetrance and variable expressivity even within a family. POLD1 and POLE are genes that work in conjunction with the Lynch syndrome complex. Mutations in POLE or POLD1 cause a syndrome that is currently being called “polymerase proofreadingassociated polyposis” as these genes primarily cause colonic polyps (both tubular adenomas and hyperplastic polyps) and subsequently colorectal cancers (Table 2).35,36 Mutations in POLD1 have been shown to carry an increased risk of endometrial cancer although the exact risk has not been quantified to date (Table 1).31 Cancers caused by germline POLD1 or POLE mutations (both colorectal and endometrial) can show features similar to Lynch syndrome cancers such as microsatellite instability and loss of MMR protein staining on immunohistochemistry. Mutation analysis of these 2 genes should be included when there is a suspicion of Lynch syndrome. POLD1 and POLE mutations are inherited in an autosomal dominant pattern. Cervical cancer While the overwhelming majority of cervical cancers are caused by the human papillomavirus, there are some inherited syndromes that put women at increased

ajog.org risk of developing specific subtypes of cervical cancer. Women with PJS have up to a 30% lifetime risk of developing minimal deviation adenocarcinoma, also known as adenoma malignum of the cervix.37 Women with DICER1 mutations are at increased risk of developing a rare form of rhabdomyosarcoma, uterine cervix embryonal rhabdomyosarcoma, which typically develops in the teen years.38 Tomiak and colleagues39 suggest that any woman diagnosed with a cervix embryonal rhabdomyosarcoma consider germline DICER1 mutation analysis.

Screening strategies Despite advances in the identification of high-risk women with germline mutations, several questions remain regarding appropriate and optimal gynecologic cancer screening for these women (Table 1). Ovarian cancer screening Pelvic ultrasound and serum CA-125 levels have well-documented inadequacies when applied to ovarian cancer screening and are not recommended for ovarian cancer screening in the general population; however, we await the results of 2 trials regarding its potential effectiveness in the high-risk population.40,41 While pelvic ultrasound does have excellent sensitivity for pelvic masses, the large majority of masses identified are benign, and may lead to unnecessary surgeries that carry risks inherent to operative procedures as well as to loss of ovarian function.42 Similarly, serum CA-125 levels may be elevated due to many benign factors including age, benign gynecologic conditions, history of breast cancer, smoking, liver issues, and the use of hormone replacement therapy.43,44 Previous studies have evaluated screening in the general population as well as women at high risk of developing ovarian cancer based on family history or germline BRCA1/2 mutation and have been unable to show a stage shift, meaning that cancers were not identified at an earlier stage, and had no effect on ovarian cancer mortality.45,46 The NCCN recently updated guidelines for

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the management of BRCA-related breast and ovarian cancer syndrome. In these guidelines, transvaginal ultrasound and CA-125 are not deemed sensitive or specific enough to warrant a positive recommendation, however they may be “considered” at the physician’s discretion starting at age 30-35 years if a patient decides not to proceed with riskreducing surgery and inclusion into clinical screening trials is encouraged.17 Given the shortcomings of traditional serum CA-125 testing in the detection of ovarian cancer, there have been attempts to improve on this technique. The Risk of Ovarian Cancer Algorithm (ROCA) evaluates the rate of change of serum CA-125 levels over time in the individual patient, rather than using a single data point with defined normal cut-off values.47,48 Recently, Jacobs and colleagues reported on the preliminary results of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). This was a large randomized trial that assigned 202,638 average-risk postmenopausal women to 1 of 3 arms: multimodal screening with CA-125 levels using ROCA, annual pelvic ultrasound, or no screening. While the results did show that cancers were more likely to be identified with lowvolume disease and there was a lower rate of death as a result of multimodal screening, the overall average mortality reduction was not significant.49,50 Two studies, one by the same group that completed the UKCTOCS study as well as the Gynecologic Oncology Group (GOG), evaluated screening in the highrisk population specifically. Rosenthal and colleagues51 reported the phase I results of the United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS), a prospective observational study that evaluated annual transvaginal ultrasound and serum CA125 screening in women with at least a 10% estimated lifetime risk of ovarian cancer. Screening had an 81% sensitivity for incident cancers, however there was no stage shift with 85% of incident cancers diagnosed stage >I.51 The results of phase II of UKFOCSS were recently reported. While this was a large study that enrolled >4000 women, only 19

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ajog.org patients were diagnosed with an invasive ovarian cancer within 1 year of screening; 13 of these were detected on screening and another 6 were occult cancers that were only identified after risk-reducing salpingo-oophorectomy. Five of the 13 screen-detected cancers were diagnosed at an early stage, however, a significant proportion of screendetected cancers still presented with advanced disease. In addition, it is still unknown if screening has any impact on survival.52 A separate trial, GOG 199, has also completed accrual in the high-risk population in the United States. This was a prospective, nonrandomized cohort study in which patients chose to undergo risk-reducing salpingo-oophorectomy or to be followed up with screening. GOG 199 also utilized ROCA triage method as in the UKCTOCS trial.53 The results of this study were analyzed in conjunction with a similar prospective trial by the Cancer Genetics Network. A total of 3692 women were screened with 6 incident cancers identified and 9 occult cancers found at risk-reducing salpingooophorectomy. Screening with ROCA every 3 months did show a stage shift with 50% of incident cancers diagnosed as early stage and ROCA did identify patients for further evaluation before CA-125 levels reached the normal cutoff value of 35. While the results from UKFOCSS as well as the combined US studies show an incremental improvement in screening, it is clear that the data do not currently support screening as an alternative to risk-reducing surgery and should be utilized only until the patient has reached the appropriate age for consideration of surgery and is willing to proceed.54 Despite the literature to date, many physicians still choose to screen patients with BRCA1 and BRCA2 mutations with pelvic ultrasound and serum CA-125 levels every 6 months. It is important to note that all of the studies to date in high-risk women include both women with a family history of ovarian cancer and those with known BRCA and Lynch mutations. These studies did not evaluate enrolled women for presence of other genes now known to be associated

with hereditary ovarian cancer including RAD51C, RAD51D, and BRIP1. It is currently unknown if screening has any benefit for these patients but given that screening has not yet been proven effective in the highest risk patients, it is hard to recommend for the lower prevalence genes. There are even fewer data to support screening for ovarian cancer in Lynch syndrome. As opposed to the BRCAassociated ovarian cancers, Lynchassociated ovarian cancers present at an earlier age and early stage, and are more likely to be nonserous histology.55 Similar to hereditary breast and ovarian cancer syndrome, NCCN does not support screening for ovarian cancer in Lynch syndrome, but acknowledges that this may be left to the physician’s discretion.7 In addition, NCCN recommends consideration of annual pelvic ultrasound for patients with PJS, given increased risk for sex cord tumors with annular tubules.7 There are no clear recommendations for ovarian cancer screening in patients with LFS outside of consideration of whole body magnetic resonance imaging, however several institutions include ovarian cancer screening as part of their comprehensive protocol.17 Endometrial cancer screening Screening options for women at high risk of endometrial cancer, including Lynch syndrome and Cowden syndrome, include either pelvic ultrasound or in-office endometrial sampling, but given the relative early onset of the hallmark symptom of abnormal bleeding, most do not recommend it. Using pelvic ultrasound to measure the endometrial stripe and evaluate for intrauterine masses is an attractive option for screening as it noninvasive and relatively cost-effective. However, this modality simply cannot be effectively utilized to exclude cancer in premenopausal women, the patient population in which screening for endometrial cancer would be most important. There have been several studies of screening ultrasound in Lynch syndrome, which have thus far shown ultrasound to be ineffective in the identification of

cancers.56,57 Dove-Edwin and colleagues58 evaluated 269 women with Lynch syndrome and followed them up with annual pelvic ultrasound. Two cancers were found in the study population, neither of which were identified by ultrasound.58 As ultrasound is unreliable for screening in Lynch syndrome, several groups have evaluated the use of inoffice endometrial biopsy as a screening option in this patient population. While endometrial biopsy did identify patients with hyperplasia or cancer, there was no difference in stage at diagnosis or overall survival for patients screened with annual endometrial biopsy compared to patients who had no screening.56,57 This is likely due to the fact that the majority of patients with endometrial cancer, whether sporadic or familial, present with early-stage disease and abnormal bleeding as an indicator of disease. The NCCN again does not recommend annual endometrial biopsy for patients with Lynch syndrome, but does note that it is an option.7 Cervical cancer screening The only recommendation for cervical cancer screening that differs from recommendations for the general population as outlined by the American Society for Colposcopy and Cervical Pathology is for patients with PJS. The NCCN recommends annual pelvic exam with Pap smear for these patients starting at age 18-20 years.7 Nongynecologic cancer screening While the focus of the current review is hereditary gynecologic malignancies, hereditary cancer syndromes span multiple tumor types, and gynecologists should be aware of the spectrum of malignancies associated with these mutations. In addition, most gynecologists take responsibility for breast cancer screening as part of well-woman care. Hereditary breast and ovarian cancer, LFS, PJS, and Cowden syndrome all place women at a substantially increased lifetime risk of breast cancer. Some studies also propose an association of Lynch syndrome with increased breast cancer risk and Lynch families should be evaluated

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Expert Reviews individually for their potential breast cancer risk.59 In 2007, the American Cancer Society published guidelines for the incorporation of annual breast magnetic resonance imaging in addition to mammography for breast cancer screening in patients with at least a 2025% lifetime risk of breast cancer or an inherited predisposition to breast cancer.60 A review of nongynecologic cancer risks as well as screening and riskreduction strategies are summarized in Table 2.

Risk-reduction strategies Chemoprevention for gynecologic cancers Oral contraceptives. Oral contraceptive pills (OCP) have been shown to decrease both ovarian and endometrial cancer risk in the general population. Risk reduction is correlated with duration of use, with an up to 50% reduction in ovarian cancer seen with 15 years of OCP use and a 24% reduction seen in endometrial cancer for every 5 years of use.61,62 This risk reduction has been further confirmed specifically in BRCA carriers by multiple studies and the degree of risk reduction with 1 year of use has been estimated at 33-80% for BRCA1 and 58-63% for BRCA2 carriers.63 Use should be considered for all women at increased risk of epithelial ovarian cancer including those with Lynch syndrome BRIP1, RAD51C, or RAD51D mutations. While long-term risk reduction for endometrial cancer has not been evaluated in the Lynch population specifically, Lu and colleagues64 evaluated intermediate biomarker changes in women aged 25-50 years with Lynch syndrome treated with OCP or Depo-Provera. Treatment with both OCP and medroxyprogesterone resulted in decreased endometrial proliferation.64 While there have been no studies to date regarding endometrial cancer risk reduction with progesteronecontaining intrauterine devices, these devices should offer similar risk reduction for endometrial cancer, however, the effect on ovarian cancer risk remains unknown.

ajog.org Surgical risk-reduction options Salpingo-oophorectomy. Bilateral salpingooophorectomy is the gold standard for ovarian cancer risk reduction in those with a hereditary predisposition for ovarian cancer. While the benefits of the procedure have been most extensively reported for BRCA carriers, the NCCN recently expanded the list of mutation carriers who should be offered this procedure. It is recommended for women with a BRCA1 mutation between 35-40 years of age; for women with a BRCA2 mutation between 40-45 years; and for women with RAD51C, RAD51D, or BRIP1 mutations by 45-50 years. The procedure should also be offered to women with Lynch syndrome who have completed childbearing, usually starting at age 35-40 years.17 Multiple prospective studies have demonstrated both an 80-90% decreased risk of ovarian cancer and a 60-75% reduction in all-cause mortality for BRCA carriers who undergo risk-reducing bilateral salpingo-oophorectomy (RRSO).65-69 There is also evidence that salpingooophorectomy may decrease breast cancer risk by as much as 50% when performed in premenopausal women, however, other studies have not confirmed these findings, specifically in BRCA1 mutation carriers, who are more likely to present with triple-negative breast disease.66,70,71 In Lynch syndrome, support for RRSO comes from a case-control study by Schmeler and colleagues72 that demonstrated no cases of ovarian cancer in 47 women who underwent RRSO compared with a 5% rate of cancer in 223 age-matched women with Lynch syndrome who did not undergo surgery. A decision tree analysis also described an overall survival benefit for RRSO in women with Lynch syndrome compared with screening or annual pelvic exam.73 The benefits seen in these patients have been extrapolated to carriers of RAD51C, RAD51D, and BRIP1 mutations, as there are no prospective studies examining RRSO in these populations. Salpingectomy. Given the evolving understanding that a large percentage of serous ovarian cancers are believed to

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originate in the fallopian tube, salpingectomy as means of ovarian cancer prevention is an active area of study. A decision analysis in BRCA carriers suggested that while salpingooophorectomy prevents the most ovarian cancers, salpingectomy with delayed oophorectomy has a higher quality-adjusted life expectancy.74 This strategy has been reported to be acceptable to women with a BRCA mutation, with a survey reporting that up to 33% would be interested in pursuing this approach.75 However, RRSO remains the standard of care, and those interested in pursuing salpingectomy with delayed oophorectomy should only do so as part of one of the ongoing clinical trials or with a clear understanding of the potential risks and unknowns (NCT02321228, NCT01608074, NCT01907789, NCT02760849).76 Hysterectomy. Hysterectomy has been shown to decrease the risk of endometrial cancer in women with Lynch syndrome. There were no cases of endometrial cancer in 61 women with Lynch syndrome who underwent prophylactic hysterectomy, compared to a 33% rate of uterine cancer in agematched controls who did not have surgery.72 The NCCN recommends that hysterectomy should be considered as an option for women with Lynch syndrome at the completion of childbearing.7 The SGO and the American Congress of Obstetricians and Gynecologists encourage discussion of surgical risk reduction by a woman’s early to mid40s.77 Although there has been some evidence of an increased risk of uterine papillary serous cancer in BRCA carriers, the absolute risk is small and the role of hysterectomy for BRCA carriers remains controversial.78,79 While one benefit of hysterectomy at the time of RRSO is simplification of hormone therapy, there remains to be definitive evidence that it is useful in preventing uterine cancers.80 Risks and benefits of hysterectomy should be discussed and the surgical decision individualized. Hysterectomy should also be considered for women with Cowden syndrome

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TABLE 3

Outline of personal or family history of malignancies that may warrant referral to genetics expert Cancer (patient or first-degree relative) Breast

CRC

EC

Ovarian

Syndrome to consider

When to refer81,82 Breast cancer dx 50 y Triple-negative breast cancer dx 60 y 2 Primary breast cancers in same person Ashkenazi Jewish ancestry and breast cancer at any age 3 Cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer in close relatives Single case of male breast cancer Breast cancer and 1 additional LFS tumor, 1 dx 45 y Breast cancer and 1 PJ polyp in same person Breast cancer and 2 additional Cowden syndrome criteria in same person

HBOC

CRC dx <50 y CRC 50 y if first-degree relative with CRC or EC at any age Synchronous or metachronous CRC or EC in same person CRC with MMR deficiency on tumor screening CRC and 2 additional LS-associated cancers CRC and 2 additional Cowden syndrome criteria in same person CRC and 1 additional LFS tumor in same person or in 2 relatives, 1 dx 45 y

LS

EC dx <50 y EC dx 50 y if there is first-degree relative with CRC or EC at any age Synchronous or metachronous CRC or EC in same person EC with MMR deficiency on tumor screening EC and 2 additional LS-associated cancers Epithelial EC and 2 additional Cowden syndrome criteria in same person

LS

Single case present in patient or first-degree relative

HBOC, HOC

LFS PJS Cowden

Cowden LFS

Cowden

CRC, colorectal cancer; dx, diagnosed; EC, endometrial cancer; HBOC, hereditary breast and ovarian cancer syndrome; HOC, hereditary ovarian cancer; LFS, Li-Fraumeni syndrome; LS, Lynch syndrome; PJS, Peutz-Jeghers syndrome. Ring. Role of genetic evaluation in gynecologic malignancies. Am J Obstet Gynecol 2017.

at completion of childbearing, although no prospective evidence exists comparing this management strategy to surveillance alone.17 Hysterectomy to decrease uterine or cervical cancer risk has not been advocated for women with PJS. Mastectomy. The NCCN recommends discussion of risk-reducing mastectomy for patients with hereditary breast and ovarian cancer syndrome, LFS, PJS, and Cowden syndrome (Table 2). However, when to perform risk-reducing mastectomy should be individualized based on personal and family history.7,17

Conclusions Cancer genetics knowledge continues to rapidly evolve as new information arises about previously identified genes as well as new genes associated with gynecologic cancers. As a result, guidelines for screening and risk reduction must be

constantly reassessed for these high-risk patients and consultation with genetics experts or high-risk clinics should be considered when counseling these patients about their risks and medical/surgical management options. Gynecologists play an important role in the identification of patients who may benefit from a cancer predisposition assessment. It is important that a woman’s personal and family history be updated at each visit and that consideration for referral to a genetics expert be considered when patients present with a history that may raise suspicion for a hereditary cancer predisposition. The SGO, the American College of Medical Genetics and Genomics, and the National Society of Genetic Counselors proposed guidelines for when to refer patients for further evaluation (Table 3).81,82 In addition to these guidelines, if there is a question as to whether a patient would benefit from further

evaluation, or if a provider does not feel comfortable counseling a patient regarding their potential risk, then referral is appropriate. Regardless of where highrisk patients are treated, coordination of screening and risk-reduction measures must occur under the guidance of physicians with experience counseling these patients regarding the risks and benefits to ensure optimal management of the associated cancer risks. REFERENCES 1. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci 2011;108:18032-7. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30. 3. Loveday C, Turnbull C, Ruark E, et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet 2012;44: 475-6.

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