COVER ARTICLE OBGMANAGEMENT BY NOAH D. KAUFF, MD, DEBORAH GOLDFRANK, MD, and RICHARD R. BARAKAT, MD When BRCA1 and BRCA2 mutations are present, only a single working copy of the gene is available to protect against cancer. Salpingo-oophorectomy adds protection, provided the fallopian tube is amputated as close to the uterine cornua as possible. Preventing BRCA-related cancers The case for oophorectomy The team that conducted the recent prospective trial of risk-reducing surgery versus surveillance reviews the evidence, plus surgical technique, psychosocial factors, use of estrogen after surgery, and insurance issues. hen A.M. Liber encountered a fam- ovarian and breast cancer, with the only ily of 5 sisters and their mother with prospective trial to date confirming its overall Whistologically confirmed papillary efficacy for women with BRCA1 and BRCA2 adenocarcinoma of the ovary, he recommended mutations. These mutations are related to the frequent gynecologic cancer screening for all vast majority of inherited ovarian cancers. family members and suggested prophylactic Using the evidence published thus far, oophorectomy as an option.1 The year was 1950. including the recently published prospective Flash forward half a century or so, and trial, we discuss surgical technique, post- prophylactic oophorectomy has gained wider oophorectomy estrogens, psychosocial impact, acceptance for the prevention of hereditary insurance reimbursement, and other issues. 56 OBG MANAGEMENT • April 2004 Three hereditary syndromes These repair pathways seem to be partic- he single biggest risk factor for ovarian ularly important in dividing breast and ovar- Tcancer is a family history, although only ian cells. This explains why women with about 10% of cases are believed to be due to inherited mutations in these genes develop an inherited predisposition. Three syndromes cancers more frequently and at an earlier age. are associated with such a predisposition: • Hereditary breast-ovarian cancer syndrome, Quantifying the risk caused by mutations in BRCA1 and BRCA2, is pecific risks associated with BRCA1 and thought to be responsible for more than 90% of SBRCA2 mutations include: inherited predisposition to ovarian cancer. • a lifetime risk of breast cancer of up to 85%, • Hereditary nonpolyposis colon cancer with half of these cancers occurring prior to (HNPCC) syndrome is associated with age 50 mutations in the mismatch repair genes and • a 15% to 45% lifetime risk of ovarian cancer3,4 a greatly increased risk of cancers of the Mutations in these genes can be inherit- colon, endometrium, ovaries, and urinary ed from a mother or father. In the general tract. HNPCC accounts for about 2% of population, between 1 in 385 and 1 in 800 inherited ovarian cancers. individuals carry a deleterious mutation in • A syndrome of site-specific ovarian either BRCA1 or BRCA2. cancer also has been proposed, though we In certain populations, such as Icelandic, lack conclusive evidence that it exists as a French Canadian, or Eastern European separate entity at the genetic level. Jewish populations, founder effects can con- tribute to a greatly increased frequency of How BRCA mutations lead to cancer mutation. For example, the Eastern RCA1 and BRCA2 are tumor suppressor European Jewish population, from which Bgenes that play a role in genomic stabili- approximately 90% of North American Jews ty and double-stranded DNA break repair. are descended, has one of the highest known BRCA1 is located on chromosome 17; frequencies of BRCA1 and BRCA2 muta- BRCA2 on chromosome 13. Both genes tion: 1 in 40 individuals carries a deleterious 5,6 function as classic tumor suppressors, as mutation in 1 of these 2 genes. CONTINUED described by Knudson.2 Only a single work- ing copy of each gene is needed for the genes KEY POINTS to effectively suppress tumors. In patients with no inherited mutation ■ Mutations in BRCA1 and BRCA2 may be in these genes, carcinogenesis caused by responsible for more than 90% of inherited predis- dysfunction of this pathway can occur only position to ovarian cancer. if both working copies of the gene are lost. ■ BRCA1 and BRCA2 mutations are associated with In contrast, women with an inherited muta- a lifetime risk of breast cancer of up to 85% and a tion in BRCA1 or BRCA2 start out with 15% to 45% lifetime risk of ovarian cancer. only a single working copy of the gene. If any cell loses this single copy, DNA repair ■ The only prospective trial to date found risk- cannot occur via this pathway, and cancer reducing salpingo-oophorectomy (RRSO) was can develop. associated with an 85% reduction in ovarian cancer and a 68% reduction in breast cancer. ■ Dr. Kauff is clinical assistant physician on the gynecology and clinical genetics services, Dr. Goldfrank is a fellow in clinical ■ Because microscopic cancer may be found in 2% genetics, and Dr. Barakat is chief of the gynecology service, to 4% of RRSO specimens upon careful pathologic Memorial Sloan-Kettering Cancer Center, New York City. review, the ovaries and fallopian tubes should be sectioned in their entirety and examined by an April 2004 • OBG MANAGEMENT 57 experienced gynecologic pathologist. Preventing BRCA-related cancers: The case for oophorectomy Most evidence is historical prophylactic oophorectomy in carriers of or retrospective BRCA2 mutations, most authorities inter- iber was not the first to suggest oophorec- preted these recommendations to apply to Ltomy to impact the risk of breast or ovarian these women as well. cancer: The procedure was initially proposed Predicting life expectancy. After these by Schinziner in 1889 as a treatment for breast findings, several groups undertook decision cancer.7 However, the earliest evidence that analyses to evaluate the effect of prophylactic oophorectomy was performed as adjuvant oophorectomy on life expectancy in women therapy did not appear until 7 years later, in with BRCA mutations. Schrag et al14 reported 1896 (reviewed by Love and Philips).8 that prophylactic oophorectomy in a 30-year- In 1968, Feinleib9 reported that pre- old with a BRCA mutation increased life menopausal oophorectomy decreased the rate expectancy by 0.3 to 1.7 years. This compares of subsequent breast cancer. Twenty years later, to 0.9 years for adjuvant chemotherapy in Brinton suggested that prophylactic oophorec- node-negative breast cancer. tomy might reduce breast cancer risk in A subsequent report by Grann and col- women with a family history of the disease.10 leagues15 also suggested that prophylactic oophorectomy was associated with an In the sole prospective trial, salpingo- increased life expectancy of 0.4 to 2.6 years. However, surgery was not cost-effective for oophorectomy was associated with a 75% quality-adjusted life-years saved. reduction in breast and gynecologic cancer. Investigators cite need for prospective studies. In 1999, Rebbeck and colleagues16 Post-oophorectomy cancers identified. conducted a retrospective case-control study of Possible limitations to the strategy became 43 women with BRCA1 mutations who apparent in the early 1980s, when Tobacman underwent oophorectomy and 79 age-matched and colleagues11 reported adenocarcinoma women with BRCA1 mutations who had histologically indistinguishable from ovarian ovaries in situ. In this series, oophorectomy cancer after oophorectomy in a series of was associated with a 47% decreased risk of women with a strong family history. subsequent breast cancer (hazard ratio 0.53). In 1993, Piver et al12 reported a series of 6 However, several investigators cited the need cases of primary peritoneal cancer after pro- for prospective studies before incorporating phylactic oophorectomy in 324 women from oophorectomy into routine clinical practice for hereditary ovarian cancer families. the prevention of cancer.17 In 1997, the Cancer Genetics Studies Consortium reviewed all available data and The first prospective look concluded: “There is insufficient evidence to at risk-reducing surgery recommend for or against prophylactic t was in this setting that our group launched oophorectomy as a measure for reducing Ia prospective trial to determine whether salp- ovarian cancer risk. Women with BRCA1 ingo-oophorectomy offers any benefit over sur- mutations should be counseled that this is an veillance in preventing breast and gynecologic option available to them. Those considering (ovarian, fallopian tube, and peritoneal) can- prophylactic oophorectomy should be coun- cers in women with BRCA mutations.18 seled that cancer has been documented to Proportional hazard analysis demonstrat- occur after the procedure.”13 ed that salpingo-oophorectomy was associated Although the Cancer Genetics Studies with a 75% reduction in subsequent breast and Consortium did not specifically comment on gynecologic cancer incidence in women with 58 OBG MANAGEMENT • April 2004 Preventing BRCA-related cancers: The case for oophorectomy TABLE Breast and ovarian cancer risk-reduction strategies for women with BRCA1 or BRCA2 mutations TYPE OF CANCER STRATEGY ALSO CONSIDER ... Breast Monthly self-examination Imaging beginning at age 18 Breast ultrasound or magnetic resonance imaging 2-4 physician examinations Risk–reducing surgery per year, starting at age 25 Mastectomy, no earlier than mid-20s Annual mammography Salpingo-oophorectomy, after age 35 and completion beginning at age 25 of childbearing Chemoprevention Tamoxifen. Need to discuss conflicting reports on efficacy Ovarian CA 125 and ultrasound Salpingo-oophorectomy twice yearly, starting at age