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Hereditary Gynecologic Cancer

A hereditary gynecologic cancer syndrome is an inherited cancer-susceptibility syndrome that predisposes women to a higher than usual risk of developing gynecologic cancer and other malignancies, such as breast and colon cancer.  The hallmarks of a hereditary gynecologic cancer syndrome include multiple affected members from the same side of the family (either maternal or paternal), early age of cancer onset (in the 20’s, 30’s, or 40s), and the development of multiple and/or bilateral cancers in the same individual.  Although these clinical features of a hereditary gynecologic cancer syndrome have long been recognized, a syndrome can be diagnosed—rather than just suspected—with genetic testing (via a blood or saliva test).  Genetic testing makes it possible to identify the specific harmful genetic changes (or mutations) that are responsible for hereditary gynecologic cancer syndromes.

The most common hereditary gynecologic cancer syndrome is Hereditary Breast and Ovarian Cancer Syndrome, or HBOC.  It accounts for 15% of ovarian cancers and 5-10% of female breast cancers in the U.S. Another gynecologic cancer syndrome is Lynch Syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer Syndrome, or HNPCC. It accounts for 2-3% of endometrial (uterine) cancers and 3% of all colorectal cancers (and 8% of those diagnosed under age 50).

HBOC predisposes women to ovarian and breast cancer (and ductal carcinoma in situ, or DCIS), as well as to fallopian tube and peritoneal cancer.  It is the consequence of inheriting a mutated, or defective, BRCA1 or BRCA2 gene from one of her parents.  BRCA1 and BRCA2 are genes that help fix damaged DNA, and if they don’t function properly because of harmful mutations, unrepaired DNA damage in cells might lead to cancer.  The BRCA1 and BRCA2 gene mutations are located in the germline, that is, in the DNA that is present in every cell of the body, including the female egg and male sperm.  A germline mutation is passed on from either the mother or the father to female or male offspring.

Lynch Syndrome predisposes women to endometrial (uterine) and colorectal cancer. It also predisposes them to ovarian, stomach, kidney, small intestine, liver, sebaceous skin, and some types of breast and brain cancer.  It is the consequence of a woman’s inheritance of a mutated MLH1, MSH2, MSH6, PMS2, or EPCAM gene.  These genes normally protect an individual from developing these cancers, but as in the case of HBOC, if they don’t function properly because of mutations, a cancer may develop. These gene mutations are also germline type and can be passed down from either parent.

If a woman develops epithelial-type ovarian cancer at any age, she qualifies for genetic testing for HBOC even if she has no family history of either ovarian or breast cancer. If a woman develops breast cancer or DCIS, she may qualify for genetic testing for HBOC if she meets certain criteria related to her age of diagnosis, type of breast cancer, the presence of cancer in both breasts, ancestry, and family health history. If a woman develops endometrial or colorectal cancer under the age of 50, she may qualify for genetic testing for Lynch Syndrome on that basis alone or based on the finding of certain molecular features of the cancer tissue.

The importance of identifying HBOC or Lynch Syndrome in an affected woman lies in that it commonly helps determine the choice of her cancer therapy and it should trigger genetic testing in family members in case they also have the mutation and are able to prevent the hereditary cancer. If a woman has HBOC, her children have a 50% chance of carrying a BRCA mutation. If a woman has Lynch Syndrome, her parents, children, and siblings have a 50% chance of having Lynch Syndrome genetic mutation.

If a woman is unaffected by cancer but has a family health history that is suspect for a hereditary gynecologic cancer syndrome, she should be offered genetic counseling before undertaking genetic testing. In the case of HBOC, some clues in the family health history include: having one or more relative with ovarian cancer, breast and ovarian cancer in multiple generations on the same side of the family, early diagnosis of a breast cancer (under age 50), and both breast and ovarian cancer or two breast cancers in the same family member. For Lynch Syndrome, clues include: having a first-degree relative (parent, sibling, or child) with endometrial or colorectal cancer under the age of 50, a first-degree relative with colorectal or endometrial cancer at any age plus another Lynch Syndrome-related cancer, and three or more relatives with Lynch Syndrome-relate cancers at any age. The genetic counselor will determine whether an unaffected woman is likely enough to have a mutation that is worth getting tested for, and if so, discuss the possible outcomes of the testing—specifically addressing the issues of positive, negative, and uninformative test results. Possible psychological and familial implications of test results are also discussed before genetic testing is ordered.

Sometimes, however, features of a woman’s family health history are striking enough to justify expedited genetic testing in a doctor’s office before extensive genetic counseling is conducted. It is important to “capture” these women who may have an inherited gynecologic cancer syndrome because the cancers can be prevented. Ideally, the unaffected woman’s relative with the cancer should be genetically tested first to see if the gene mutation is even present.  If that isn’t possible, then the unaffected woman should be tested. Certainly, if a woman has a relative that has been proven to have HBOC or Lynch Syndrome, prompt genetic testing should be strongly recommended.

If a woman inherits a BRCA genetic mutation, her risks for ovarian and breast cancer (especially before the age of 50) are much higher than average.  The average lifetime risk for ovarian cancer in the general population in the U.S. is 1.3%.  In comparison, with a BRCA1 mutation, the risk for ovarian cancer is 39-46% by age 70, and with a BRCA2 mutation, it is 12-20%.  The average risk for breast cancer in the U.S. is 13%.   In contrast, for a woman with either a BRCA1 or BRCA 2 mutation, the estimated risk for breast cancer is 65-85%.

If a woman inherits one of the Lynch Syndrome-associated genetic mutations, her lifetime risks for endometrial, ovarian, colorectal cancer, and for of all the other associated cancers increase. The average risk for endometrial cancer in the U.S. is 3%, but for women with Lynch Syndrome genetic mutations, the risk ranges from 15-54%. The increased risk of ovarian cancer is considerably higher than the 1.3% average; it ranges from 4-24%. The average risk for colorectal cancer is 4%, but with Lynch Syndrome mutations, it’s 25-50%. The average risks that have been quantified for the other Lynch Syndrome-associated cancers are: Stomach cancer: 13%, small intestine cancer : 12%, and kidney cancer: 25%.

With regard to HBOC Syndrome, it is estimated that approximately 1 in 300 to 1 in 800 individuals (women and men) in the general population carry a mutation in the BRCA1 or BRCA2 gene.  In certain populations founded by a small ancestral group, specific BRCA1 or BRCA2 mutations may occur more frequently, and they are known as founder mutations. Founder mutations have been identified in Ashkenazi Jews, French Canadians, and Icelanders, among other groups.  It is estimated that 1 in 40 Ashkenazi Jews carries a founder mutation in BRCA1 or BRCA2.

With Lynch Syndrome, it is estimated that as many as 1 in every 300 individuals in the general population carry a mutation in one of the associated genes.

Clinical and radiologic surveillance for early detection of HBOC- and Lynch Syndrome-related cancers and chemoprevention and prophylactic surgery for cancer prevention are strategies available in the management of women diagnosed with either syndrome.

For early detection of HBOC-related ovarian cancer, current radiologic modalities unfortunately fall short in being able to find ovarian cancer at an early, more curable stage.  Nevertheless, ovarian cancer screening recommendations for women with HBOC remain, and they are: periodic screening (every 6-12 months) with transvaginal pelvic ultrasound and the serum CA-125 ovarian cancer tumor marker test.  Pelvic sonograms should begin between the ages of 30-35 years or 5-10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family. For early detection of HBOC-related breast cancer, recommended screening includes: clinical breast examination every 6 months and staggered annual mammography and breast MRI beginning at age 25 or sooner based on the earliest age of breast cancer onset in the family.

Chemoprevention is the prevention of disease using a medication. Using oral contraceptives (birth control pills) significantly decreases the risk of developing ovarian cancer for BRCA mutation carriers and average risk women alike. Use of the oral estrogen modulator tamoxifen has been shown to treat and prevent breast cancer, but data are conflicting in the setting of HBOC-related breast cancer prevention.

Surgery offers the most definitive risk management for HBOC-related ovarian cancer. Risk-reducing salpingo-oophorectomy (RRSO), which is the complete removal of the ovaries and fallopian tubes, usually done laparoscopically, should be recommended by age 40 or after the completion of childbearing. RRSO has been shown to reduce the risk of HBOC-related ovarian cancer and fallopian tube cancer by about 85-90%. Of note, for premenopausal women with HBOC, removing the ovaries also reduces the risk of breast cancer by 40-70%.

The most invasive risk-reducing surgical option in HBOC-related cancer prevention is bilateral mastectomy for the reduction of breast cancer risk. Bilateral total mastectomy reduces the risk of breast cancer by 95%. Opposite side preventive mastectomy is worth considering for women with HBOC who have already been diagnosed with breast cancer since there is a 30% risk of developing a breast cancer recurrence in the opposite breast within 10 years following the initial diagnosis.

Screening for endometrial cancer in women with Lynch Syndrome consists of an office endometrial biopsy every 1-2 years starting at age 30-35 years.  Escalated evaluation is recommended in women with Lynch syndrome who have a change in their usual menstrual bleeding pattern.  Colorectal cancer screening consists of colonoscopy every 1-2 years, beginning at age 20-25 or 2-5 years before the earliest cancer diagnosis in the family, whichever is earlier.

Specific data are lacking on the efficacy of Lynch Syndrome-related endometrial cancer chemoprevention in the form of oral contraceptives or progestin hormone therapy. Limited data, however, do support the use of progestin-based contraception, including oral contraceptives, to prevent endometrial cancer in these women.

Prophylactic total hysterectomy and removal of both tubes and ovaries in their early to mid-40s is a very effective endometrial cancer risk-reduction option for women with Lynch Syndrome.  The surgery can be preferably performed vaginally or via a minimally invasive approach (laparoscopically or robotically).  Before hysterectomy, colonoscopy should be up-to-date.

Prior to making the serious decision to undergo any surgery, a thorough discussion must be had to address the menopausal and psychosocial issues and the risks and benefits related to all of these risk-reducing surgical procedures.

We at Adaptive Gynecology have a key role as part of a multi-disciplinary team dedicated to the identification, surveillance, and management of women diagnosed with hereditary gynecologic cancer syndrome in the effort to avoid preventable cancers. Genetic testing is available in our office for BRCA and Lynch syndrome mutations as well as the many other mutations available on genetic panels.

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