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.
- Mutations in BRCA1 and BRCA2 may be responsible for more than 90% of inherited predisposition to ovarian cancer.
- BRCA1 and BRCA2 mutations are associated with a lifetime risk of breast cancer of up to 85% and a 15% to 45% lifetime risk of ovarian cancer.
- The only prospective trial to date found risk-reducing salpingo-oophorectomy (RRSO) was associated with an 85% reduction in ovarian cancer and a 68% reduction in breast cancer.
- Because microscopic cancer may be found in 2% to 4% of RRSO specimens upon careful pathologic review, the ovaries and fallopian tubes should be sectioned in their entirety and examined by an experienced gynecologic pathologist.
When A.M. Liber encountered a family of 5 sisters and their mother with histologically confirmed papillary adenocarcinoma of the ovary, he recommended frequent gynecologic cancer screening for all family members and suggested prophylactic oophorectomy as an option.1 The year was 1950.
Flash forward half a century or so, and prophylactic oophorectomy has gained wider acceptance for the prevention of hereditary ovarian and breast cancer, with the only prospective trial to date confirming its overall efficacy for women with BRCA1 and BRCA2 mutations. These mutations are related to the vast majority of inherited ovarian cancers.
Using the evidence published thus far, including the recently published prospective trial, we discuss surgical technique, post-oophorectomy estrogens, psychosocial impact, insurance reimbursement, and other issues.
Three hereditary syndromes
The single biggest risk factor for ovarian cancer is a family history, although only about 10% of cases are believed to be due to an inherited predisposition. Three syndromes are associated with such a predisposition:
- Hereditary breast-ovarian cancer syndrome, caused by mutations in BRCA1 and BRCA2, is thought to be responsible for more than 90% of inherited predisposition to ovarian cancer.
- Hereditary nonpolyposis colon cancer (HNPCC) syndrome is associated with mutations in the mismatch repair genes and a greatly increased risk of cancers of the colon, endometrium, ovaries, and urinary tract. HNPCC accounts for about 2% of inherited ovarian cancers.
- A syndrome of site-specific ovarian cancer also has been proposed, though we lack conclusive evidence that it exists as a separate entity at the genetic level.
How BRCA mutations lead to cancer
BRCA1 and BRCA2 are tumor suppressor genes that play a role in genomic stability and double-stranded DNA break repair. BRCA1 is located on chromosome 17; BRCA2 on chromosome 13. Both genes function as classic tumor suppressors, as described by Knudson.2 Only a single working copy of each gene is needed for the genes to effectively suppress tumors.
In patients with no inherited mutation in these genes, carcinogenesis caused by dysfunction of this pathway can occur only if both working copies of the gene are lost. In contrast, women with an inherited mutation in BRCA1 or BRCA2 start out with only a single working copy of the gene. If any cell loses this single copy, DNA repair cannot occur via this pathway, and cancer can develop.
These repair pathways seem to be particularly important in dividing breast and ovarian cells. This explains why women with inherited mutations in these genes develop cancers more frequently and at an earlier age.
Quantifying the risk
Specific risks associated with BRCA1 and BRCA2 mutations include:
- a lifetime risk of breast cancer of up to 85%, with half of these cancers occurring prior to age 50
- a 15% to 45% lifetime risk of ovarian cancer3,4
Mutations in these genes can be inherited from a mother or father. In the general population, between 1 in 385 and 1 in 800 individuals carry a deleterious mutation in either BRCA1 or BRCA2.
In certain populations, such as Icelandic, French Canadian, or Eastern European Jewish populations, founder effects can contribute to a greatly increased frequency of mutation. For example, the Eastern European Jewish population, from which approximately 90% of North American Jews are descended, has one of the highest known frequencies of BRCA1 and BRCA2 mutation: 1 in 40 individuals carries a deleterious mutation in 1 of these 2 genes.5,6
Most evidence is historical or retrospective
Liber was not the first to suggest oophorectomy to impact the risk of breast or ovarian cancer: The procedure was initially proposed by Schinziner in 1889 as a treatment for breast cancer.7 However, the earliest evidence that oophorectomy was performed as adjuvant therapy did not appear until 7 years later, in 1896 (reviewed by Love and Philips).8
In 1968, Feinleib9 reported that premenopausal oophorectomy decreased the rate of subsequent breast cancer. Twenty years later, Brinton suggested that prophylactic oophorectomy might reduce breast cancer risk in women with a family history of the disease.10
In the sole prospective trial, salpingo-oophorectomy was associated with a 75% reduction in breast and gynecologic cancer.
Post-oophorectomy cancers identified. Possible limitations to the strategy became apparent in the early 1980s, when Tobacman and colleagues11 reported adenocarcinoma histologically indistinguishable from ovarian cancer after oophorectomy in a series of women with a strong family history.
In 1993, Piver et al12 reported a series of 6 cases of primary peritoneal cancer after prophylactic oophorectomy in 324 women from hereditary ovarian cancer families.
In 1997, the Cancer Genetics Studies Consortium reviewed all available data and concluded: “There is insufficient evidence to recommend for or against prophylactic oophorectomy as a measure for reducing ovarian cancer risk. Women with BRCA1 mutations should be counseled that this is an option available to them. Those considering prophylactic oophorectomy should be counseled that cancer has been documented to occur after the procedure.”13
Although the Cancer Genetics Studies Consortium did not specifically comment on prophylactic oophorectomy in carriers of BRCA2 mutations, most authorities interpreted these recommendations to apply to these women as well.
Predicting life expectancy. After these findings, several groups undertook decision analyses to evaluate the effect of prophylactic oophorectomy on life expectancy in women with BRCA mutations. Schrag et al14 reported that prophylactic oophorectomy in a 30-year-old with a BRCA mutation increased life expectancy by 0.3 to 1.7 years. This compares to 0.9 years for adjuvant chemotherapy in node-negative breast cancer.
A subsequent report by Grann and colleagues15 also suggested that prophylactic oophorectomy was associated with an increased life expectancy of 0.4 to 2.6 years. However, surgery was not cost-effective for quality-adjusted life-years saved.
Investigators cite need for prospective studies. In 1999, Rebbeck and colleagues16 conducted a retrospective case-control study of 43 women with BRCA1 mutations who underwent oophorectomy and 79 age-matched women with BRCA1 mutations who had ovaries in situ. In this series, oophorectomy was associated with a 47% decreased risk of subsequent breast cancer (hazard ratio 0.53). However, several investigators cited the need for prospective studies before incorporating oophorectomy into routine clinical practice for the prevention of cancer.17
The first prospective look at risk-reducing surgery
It was in this setting that our group launched a prospective trial to determine whether salpingo-oophorectomy offers any benefit over surveillance in preventing breast and gynecologic (ovarian, fallopian tube, and peritoneal) cancers in women with BRCA mutations.18
Proportional hazard analysis demonstrated that salpingo-oophorectomy was associated with a 75% reduction in subsequent breast and gynecologic cancer incidence in women with BRCA mutations (hazard ratio 0.25, 95% confidence interval 0.08 to 0.74). When the individual endpoints of breast and gynecologic cancer were observed, risk-reducing salpingo-oophorectomy (RRSO) was associated with an 85% reduction in subsequent ovarian cancer and a 68% reduction in subsequent breast cancer.
Methods. From June 1995 through May 2001, we enrolled 265 women with documented BRCA1 or BRCA2 mutations. Patients were followed by annual questionnaire, telephone contact, and medical-record review. Pathology reports were obtained for all new cancers diagnosed during follow-up.
After excluding women who underwent bilateral salpingo-oophorectomy before genetic testing, who were younger than 35 years at the time of testing, or who did not provide any follow-up information, 173 women with ovaries at risk and a documented BRCA mutation remained. These women participated in formal pre- and post-test genetic counseling and received uniform recommendations for cancer risk reduction, as detailed in the TABLE.
During follow-up, we calculated the incidence of new breast and gynecologic cancers diagnosed in the cohort who elected RRSO and compared it with the incidence of these cancers in women who chose surveillance.
Salpingo-oophorectomy was elected by 101 of the 173 women.
Findings. In 3 of these women, early-stage ovarian or fallopian-tube cancer that had not been detected during preoperative evaluation was found at the time of surgery. In the remaining 98 patients who underwent RRSO, 1 peritoneal cancer and 3 breast cancers were diagnosed during a mean 23 months of follow-up. In the 72 women who chose surveillance, 5 ovarian or peritoneal cancers and 8 breast cancers were diagnosed in a mean 25 months of follow-up.
Kaplan-Meier analysis of time to breast or BRCA-related gynecologic cancer is illustrated in FIGURE 1.
Other studies confirm findings. A second retrospective study by Rebbeck et al19 was released simultaneously with our findings and showed similar benefits. They found a 53% reduction in subsequent breast cancer risk and a 96% reduction in subsequent ovarian cancer risk. In the summer of 2003, a study from Israel by Rutter et al provided further confirmation of the substantially decreased incidence of cancer following risk-reducing surgery.20
Breast and ovarian cancer risk-reduction strategies for women with BRCA1 or BRCA2 mutations
TYPE OF CANCER
ALSO CONSIDER …
Monthly self-examination beginning at age 18
2-4 physician examinations per year, starting at age 25
Salpingo-oophorectomy, after age 35 and completion of childbearing
CA 125 and ultrasound twice yearly, starting at age 35
Source: Adapted from Scheuer et al28
FIGURE 1 Reduction in cancer cases associated with salpingo-oophorectomy
Reprinted with permission from Kauff ND et al.18
Copyright 2002 Massachusetts Medical Society. All rights reserved.
Good technique and pathologic review may prevent post-oophorectomy cancer
There are 3 theories about the origin of primary peritoneal cancer after oophorectomy:
- The cancer represents undetected occult cancer present at the time of risk-reducing surgery.
- It represents cancer arising in an ovarian remnant left behind after risk-reducing surgery.
- The peritoneal cancer arises de novo from the peritoneal surface epithelium.
While surgical technique and detailed pathologic review are unlikely to decrease the incidence of de novo peritoneal cancer, they may play a substantial role in reducing ovarian and related cancers after risk-reducing surgery.
Surgical requirements. Obviously, if a surgery is to be risk-reducing, as much as possible of the tissue at risk should be removed. To do so effectively, the surgeon should be comfortable operating in the retroperitoneum so that the infundibulopelvic ligament can be ligated sufficiently proximal from the ovarian hilum to minimize the possibility of an ovarian remnant. Similarly, if a salpingo-oophorectomy without hysterectomy is to be performed, the fallopian tube should be amputated as close as possible to the uterine cornua (FIGURE 2).
Laparoscopy versus open surgery. RRSO can be performed using either a laparoscopic or open approach. The appropriate choice is best determined by the patient’s history, associated comorbid conditions, need for additional procedures, and experience of the surgeon. At our institution, in the absence of contraindications, we generally offer a laparoscopic approach due to its decreased morbidity.
Concomitant hysterectomy? An area of substantial controversy is whether the uterus should be removed at the time of RRSO. In most studies exploring this issue, hereditary breast-ovarian cancer syndrome does not appear to be associated with an increased risk of uterine cancer.24 However, there is concern that the portion of interstitial fallopian tube left behind after salpingo-oophorectomy may be at risk for malignant transformation.25,26
In our series, almost 90% of risk-reducing procedures were salpingo-oophorectomies without hysterectomy. If there is an additional benefit to concomitant hysterectomy, it has yet to be demonstrated by clinical trials.