Hereditary Syndromes Part 2

Hereditary Syndromes
Written By Sydney Oesch

Episode Notes

  1. General management considerations

    1. If desiring future fertility > refer to fertility specialist for consideration of IVF, consideration of preimplantation genetic testing (PGT) of embryos.

  2. Ovarian Cancer hereditary Syndromes

    1. High penetrance syndromes: BRCA 1, BRCA2

      1. Lifetime Gynecologic Cancer risks: 

        1. BRCA1: Ovarian cancer 39-46% (risk increase starting at age 35-40)

        2. BRCA2: Ovarian cancer 13-27% (risk increase starting at age 45)

      2. Surgical risk reduction > 80% lifetime risk reduction (small residual risk of primary peritoneal cancer, <1% 10-year risk)

        1. 1% chance of identifying occult malignancy at time of surgical risk reduction, 4-12% risk of identifying occult neoplasia including serous tubal intraepithelial neoplasia/carcinoma (STIN/STIC) 

        2. Increased risk of developing carcinoma after surgical risk reduction if a STIN/STIC is identified at time of surgical risk reduction

          1. 10-year risk of developing primary peritoneal carcinoma has been reported at 5-27% in this setting

      3. Management beyond ovarian cancer

        1. Refer to breast surgeon to coordinate advance breast imaging and/or surgical risk reduction

          1. 80% lifetime breast cancer risk

        2. Female patients: Increased risk of pancreatic, gastric cancer, melanoma (BRCA2): NCCN has guidelines for screening for pancreatic cancer. Can refer to GI prevention clinics.

    2. Low to Moderate penetrance syndromes: RAD51C, RAD51D, BRIP1, PALB2

      1. These proteins are all involved in DNA repair > mutation increases susceptibility to cancer

      2. Recommendations for management based on data from BRCA1 and 2 patients.

      3. Surgical risk reduction decisions are made on an individual basis including patients goals of care. Some providers use a ~10% lifetime risk as a guideline for when surgical risk reduction is specifically recommended.

      4. Lifetime gynecologic cancer risks

        1. RAD51C,D: 15-20% lifetime risk of ovarian cancer. Risk-reducing BSO recommended at age 45-50

        2. BRIP1: 15% lifetime risk of ovarian cancer. Risk-reducing BSO recommended at age 45-50.

        3. PALB2: ~5% lifetime risk of ovarian cancer.  Risk-reducing BSO can be “considered” starting at age 45-50, not specifically recommended by the NCCN

        4. STK11, ATM mutations: slight increased risk of ovarian cancer. Risk-reducing BSO not routinely recommended. Incorporation of family history can guide counseling.

    3. Lynch Syndrome: mismatch repair gene mutation (MLH1, MSH2, PMS2, MSH6)

      1. Lifetime risk of ovarian cancer is increased with MLH1/MSH2 mutations: up to 24%.

      2. Lifetime risk of ovarian cancer increased with MSH6 mutation: up to 16%

      3. PMS2 not associated with increased ovarian cancer risk.

      4. Risk reducing BSO can be considered in patients with MLH1, MSH2, MSH6 mutations as part of Lynch management (more below). Not recommended as risk-reducing intervention in the setting of a PMS2 mutation.

    4. Patients with a family history of ovarian cancer with negative genetic testing

      1. Lifetime risk of ovarian cancer: with one first degree relative with ovarian cancer, lifetime risk is 4-5%. With two first degree relatives, lifetime risk may be closer to 8-10%.

      2. No specific guidelines for BSO in this setting; reasonable to discuss based on estimated risk for family history. 

    5. Surgical considerations/technique

      1. Preop: CA-125, TVUS (evaluate for occult malignancy, surgical planning)

      2. BSO:

        1. Intraop: goal to minimize risk of leaving behind residual ovarian tissue and risk of missing an occult neoplasia/malignancy

          1. Pelvic washings

          2. Complete abdominal survey

          3. Peritoneal biopsies

          4. Gonadal vessels transected ~2cm proximal to the end of visible ovarian tissue

        2. BRCA 1: Surgical risk reduction: BSO recommended between age 35-40

        3. BRCA 2: Surgical risk reduction: BSO recommended between ages 40-45

      3. Salpingectomy:

        1. Data: No data on oncologic safety in BRCA patients. In non BRCA/nonhereditary patients, salpingectomy reduces risk of ovarian cancer by ~50%

          1. Ongoing trials

            1. SOROCK: noninferiority trial of bilateral salpingectomy with delayed oophorectomy vs. bilateral salpingo-oophorectomy. Study completion expected 2037

            2. TUBA-WISP II: Building off of results from TUBA and WISP trials. Open, recruiting. Noninferiority design to evaluate risk of cancer between patients undergoing BSO vs. salpingectomy w/ delayed oophorectomy. Results expected 2037. 

              1. TUBA: Netherlands. Risk-reducing salpingectomy with delayed oophorectomy vs. risk-reducing BSO (primary outcomy menopause-related QOL)

                1. Results: even with hormone replacement after BSO, patients with salpingectomy followed by delayed oophorectomy have improved menopause-related QOL

              2. WISP: United States, ongoing. Similar structure, primary outcome changes in female sexual function. Includes comparison of rates of ovary/fallopian tube/peritoneal cancers by arm as a secondary objective.

          2. For now, salpingectomy w/ delayed oophorectomy is not proven to be noninferior to BSO for cancer prevention in patients with hereditary ovarian cancer syndromes. Salpingectomy should be done only in the context of a clinical trial until data is mature. Enroll interested patients in clinical trials!

      4. Hysterectomy:

        1. Uterine cancer risk

          1. BRCA1/2: some data that there is a slightly high risk of serous uterine cancer in patients with BRCA1 mutations, and perhaps with BRCA2, but data is conflicting.

            1. Dutch study (De Jonge, 2021):  observed a 2-3 fold increase risk of endometrial cancer, mainly serous or p-53 mutated

            2. Systematic review/meta-analysis (Matanes et al, 2021: no difference in the risk of endometrial, including serous, cancers with BRCA 1 or 2 carriers

          2. History of tamoxifen use may alter uterine cancer risk in these patients outside of genetic risk

        2. Hysterectomy not recommended for cancer reduction purposes. If hysterectomy is added for other indications, this simplifies administration of postoperative HRT. 

      5. Pathology: Sectioning and Extensively Examining the Fimbriated end of the tubes (SEE-FIM) technique should be employed (microsectioning)

      6. Postop

        1. If STIN/STIC identified > refer to gyn onc to discuss

          1. No standard management recommended. Options include: observation w/ or w/o CA-125 and ultrasound surveillance, full surgical staging, consideration of chemotherapy administration to reduce the risk of peritoneal carcinomatosis

            1. Practices may vary by institution

        2. If carcinoma identified > full staging > appropriate adjuvant treatment (see ovarian cancer episodes for details)

        3. Premenopausal patients: hormone replacement therapy is indicated! HRT reduces the risk of all-cause mortality, improves bone/cardiac/brain function in patients with premenopausal BSO. 

    6. Nonsurgical risk reduction

      1. Oral contraceptives: significant reduction in ovarian cancer risk in BRCA 1 and 2 carriers, increased protection with increased duration of use

      2. LNG-IUD also associated with reduced ovarian cancer risk in the average risk population (not yet studied in BRCA 1 and 2 carriers)

    7. Screening/surveillance

      1. CA-125 and pelvic ultrasound: has not been shown to decrease mortality of ovarian cancer. Increases the use of surgical intervention, imaging and labs without an improvement in ovarian cancer mortality. May allow identification of cancers at an earlier stage.

        1. Use of this strategy not routinely recommended; use is controversial

  3. Endometrial Cancer Hereditary Syndromes

    1. High penetrance syndromes: Lynch

      1. Lifetime Gynecologic Cancer risks: 

        1. MLH1/MSH2: lifetime endometrial cancer risk up to 55%

          1. Ovarian cancer risk up to 24% as mentioned above

        2. MSH6: lifetime endometrial cancer risk up to 70%

          1. Ovarian cancer risk up to 16% as mentioned above

        3. PMS2: lifetime risk of endometrial cancer ~15%

          1. No increased risk of ovarian cancer

      2. Endometrial cancer in Lynch more common presents in the lower uterine segment, more commonly diagnosed at an early stage

      3. Surgical risk reduction 

        1. Hysterectomy: has not been shown to decrease mortality from endometrial cancer in patients with Lynch, given overall good prognosis in this patient population

          1. Can be considered starting at age 40

        2. BSO: can consider, as above, for ovarian cancer risk reduction, in patietns with MLH1, MSH2, MSH6 mutations. Not indicated with PMS2 mutation before the natural age of menopause. 

      4. Nonsurgical risk reduction: 

        1. Symptom education! AUB, pelvic pain/bloating, abnormal discharge > these symptoms should trigger an evaluation

        2. Annual endometrial biopsy: has not demonstrated improved mortality from Lynch, but can help with early detection. Is an option while awaiting/if not performing surgical risk reduction

      5. Management beyond endometrial cancer

        1. Colorectal cancer risk: lifetime risk ranges from 20% (PMS2 mutation) to 80% (MLH1/MSH2)

          1. Refer to GI prevention clinic (gastric and colon cancer risks) 

        2. Refer to genetic counseling and other cancer prevention clinics depending on specific mutation

          1. Patients with Lynch syndrome also have increased risk of pancreatic, gastric, urinary tract, prostate, brain, and skin cancer

    2. Moderate penetrance syndromes: Cowden

      1. Cowden syndrome: PTEN mutation

        1. Endometrial, colon, breast cancer, other benign neoplasms

          1. Endometrial cancer: lifetime risk ~20%

        2. Screening: annual comprehensive physical exam starting at age 18 or 5 years before the youngest age of diagnosis of cancer of a family member

        3. Surgical risk reduction: no specific recommendations for hysterectomy. Symptom education is paramount. Can consider risk-reducing hysterectomy without oophorectomy after completion of childbearing.

        4. Consider endometrial biopsy screening every 1-2 years

References

1.    Narod SA, Risch H, Moslehi R, et al. Oral Contraceptives and the Risk of Hereditary Ovarian Cancer. New England Journal of Medicine. 1998;339(7):424-428. doi:10.1056/NEJM199808133390702/ASSET/5CDF2BA1-D35E-423D-BF3C-1F4FBEE72A07/ASSETS/IMAGES/LARGE/NEJM199808133390702_T2.JPG

2.    Xia YY, Kotsopoulos J. Beyond the pill: contraception and the prevention of hereditary ovarian cancer. Hered Cancer Clin Pract. 2022;20(1):21. doi:10.1186/S13053-022-00227-Z

3.    Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009;101(2):80-87. doi:10.1093/JNCI/DJN442,

4.    Finch APM, Lubinski J, Møller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32(15):1547-1553. doi:10.1200/JCO.2013.53.2820

5.    Steenbeek MP, Van Bommel MHD, Bulten J, et al. Risk of Peritoneal Carcinomatosis after Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis. Journal of Clinical Oncology. 2022;40(17):1879-1891. doi:10.1200/JCO.21.02016,

6.    Powell CB, Swisher EM, Cass I, et al. Long term follow up of BRCA1 and BRCA2 mutation carriers with unsuspected neoplasia identified at risk reducing salpingo-oophorectomy. Gynecol Oncol. 2013;129(2):364-371. doi:10.1016/j.ygyno.2013.01.029

7.    Steenbeek MP, van Bommel MHD, intHout J, et al. TUBectomy with delayed oophorectomy as an alternative to risk-reducing salpingo-oophorectomy in high-risk women to assess the safety of prevention: The TUBA-WISP II study protocol. International Journal of Gynecological Cancer. 2023;33(6):982-987. doi:10.1136/IJGC-2023-004377,

8.    Study Details | A Study to Compare Two Surgical Procedures in Individuals With BRCA1 Mutations to Assess Reduced Risk of Ovarian Cancer | ClinicalTrials.gov. Accessed May 5, 2025. https://clinicaltrials.gov/study/NCT04251052

9.    De Jonge MM, De Kroon CD, Jenner DJ, et al. Endometrial Cancer Risk in Women With Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study. J Natl Cancer Inst. 2021;113(9):1203-1211. doi:10.1093/JNCI/DJAB036,

10.  Matanes E, Volodarsky-Perel A, Eisenberg N, et al. Endometrial Cancer in Germline BRCA Mutation Carriers: A Systematic Review and Meta-analysis. J Minim Invasive Gynecol. 2021;28(5):947-956. doi:10.1016/j.jmig.2020.11.023

Sydney Oesch
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