Noah D. Kauff

Meta-analysis of Risk Reduction Estimates Associated With Risk-Reducing Salpingo-oophorectomy in BRCA1 or BRCA2 Mutation Carriers

Background Risk-reducing salpingo-oophorectomy (RRSO) is widely used by carriers of BRCA1 or BRCA2 (BRCA1/2) mutations to reduce their risks of breast and ovarian cancer. To guide women and their clinicians in optimizing cancer prevention strategies, we summarized the magnitude of the risk reductions in women with BRCA1/2 mutations who have undergone RRSO compared with those who have not. Methods All reports of RRSO and breast and/or ovarian or fallopian tube cancer in BRCA1/2 mutation carriers published between 1999 and 2007 were obtained from a PubMed search. Hazard ratio (HR) estimates were identified directly from the original articles. Pooled results were computed from nonoverlapping studies by fixed-effects meta-analysis. Results Ten studies investigated breast or gynecologic cancer outcomes in BRCA1/2 mutation carriers who had undergone RRSO. Breast cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers, four of BRCA1 mutation carriers, and three of BRCA2 mutation carriers. Gynecologic cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers and one of BRCA1 mutation carriers. RRSO was associated with a statistically significant reduction in risk of breast cancer in BRCA1/2 mutation carriers (HR = 0.49; 95% confidence interval [CI] = 0.37 to 0.65). Similar risk reductions were observed in BRCA1 mutation carriers (HR = 0.47; 95% CI = 0.35 to 0.64) and in BRCA2 mutation carriers (HR = 0.47; 95% CI = 0.26 to 0.84). RRSO was also associated with a statistically significant reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer (HR = 0.21; 95% CI = 0.12 to 0.39). Data were insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with RRSO in BRCA1 or BRCA2 mutation carriers. Conclusion The summary estimates presented here indicate that RRSO is strongly associated with reductions in the risk of breast, ovarian, and fallopian tube cancers and should provide guidance to women in planning cancer risk reduction strategies.

Outcome of Preventive Surgery and Screening for Breast and Ovarian Cancer in BRCA Mutation Carriers

PURPOSE To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer. PATIENTS AND METHODS Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians. RESULTS Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker-based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing. CONCLUSION This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.

PURPOSE Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers. PATIENTS AND METHODS A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model. RESULTS During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance. CONCLUSION The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated.

Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study

BACKGROUND Several of the known risk factors for ovarian cancer are thought to act through their effects on ovulation and the menstrual cycle, such as parity, breastfeeding, and use of oral contraceptives. We aimed to assess the effect of these three risk factors, and of tubal ligation, on the risk of ovarian cancer in women who carry a mutation in the BRCA1 or BRCA2 genes. METHODS We did a matched case-control study in women who were found to carry a pathogenetic mutation in BRCA1 or BRCA2. Participants were derived from a population-based study of ovarian cancer in Ontario, Canada, and from an international registry of mutation carriers based in Toronto, ON, Canada. All participants completed a written questionnaire that detailed their reproductive history. Women with invasive ovarian cancer and controls were matched on year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of breast cancer. The odds ratios and 95% CI for ovarian cancer were estimated with respect to use of oral contraceptives, parity, breastfeeding, and tubal ligation. FINDINGS Questionnaires were completed by 799 women with a history of invasive ovarian cancer (670 with BRCA1 mutations, 128 with BRCA2 mutations, and one with a mutation in both genes), and controls were 2424 women without ovarian cancer (2043 with BRCA1 mutations, 380 with BRCA2 mutations, and one with a mutation in both genes). Use of oral contraceptives reduced the risk of ovarian cancer in carriers of BRCA1 mutations (odds ratio 0.56 [95% CI 0.45-0.71]; p<0.0001) and carriers of BRCA2 mutations (0.39 [0.23-0.66]; p=0.0004). Parity was associated with a reduced risk for carriers of BRCA1 mutations (0.67 [0.46-0.96]; p=0.03), but with an increased risk for those with BRCA2 mutations (2.74 [1.18-6.41]; p=0.02). Breastfeeding was associated with a reduced risk for carriers of BRCA1 mutations (0.74 [0.56-0.97]; p=0.03). An effect of similar magnitude was seen for carriers of BRCA2 mutations (0.72 [0.41-1.29]; p=0.27), but this was not statistically significant. The association with tubal ligation was not significant for carriers of BRCA1 mutations (0.80 [0.59-1.08]; p=0.15), or for carriers of BRCA2 mutations (0.63 [0.34-1.15]; p=0.13). INTERPRETATION Oral contraceptives could be used as a means to prevent ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The possible adverse effect of parity on ovarian-cancer risk in women with a BRCA2 mutation needs further study.

BRCA Mutations and Risk of Prostate Cancer in Ashkenazi Jews

Purpose: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study. Experimental Design: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age. Results: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64–7.06; P = 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87–12.25; P = 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased. Conclusions: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.

Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities.

Women with hereditary nonpolyposis colorectal cancer (HNPCC) have a high risk for endometrial cancer (EC) and frequently present with a gynecologic cancer as their first or sentinel malignancy. Identification of these patients is important given their personal and family risk for synchronous and metachronous tumors. The revised Bethesda Guidelines provide screening criteria for HNPCC in colorectal cancers. However, there are currently no such screening recommendations for women with endometrial carcinoma. We applied some of the colorectal cancer screening criteria, including age and tumor morphology, to endometrial endometrioid carcinoma. The purpose of this study was to describe patient and tumor characteristics and to assess the ability of these criteria to enhance detection of mismatch repair (MMR) deficiency, and hence HNPCC in EC. Immunohistochemistry (IHC) for DNA mismatch repair (IHC-MMR) proteins was performed in a defined subset of patients with EC. This included women younger than 50 years of age and women ≥50 years whose tumors showed morphologic features suggestive of MMR deficiency (TM-MMR). The extent of IHC-MMR in the older patient group was compared with that in a comparison group of EC ≥50 years that was previously analyzed for microsatellite instability status. Seventy-one patients met the selection criteria for IHC testing; 32 (45%) showed abnormal results. The rate of IHC abnormality in the younger group was approximately 30% with a nearly equal distribution of MLH1/PMS2 and MSH2/MSH6 abnormalities. In the older age group, TM-MMR triggered IHC analysis in 31 of 34 cases. Of these, 18 cases showed loss of IHC-MMR (58% of cases), 7 with loss of MSH2/MSH6. In contrast, the rate of microsatellite instability in the comparison group was only 21%. The IHC abnormal group showed more frequent tumor infiltrating lymphocytes, dedifferentiated EC, more tumors centered in the lower uterine segment, and more frequent synchronous clear cell carcinomas of the ovary than tumors with a normal immunophenotype. Although many of the patients with loss of IHC-MMR showed personal and/or family history (13 of 32) of HNPCC-associated tumors, most did not. Tumor morphology (TM-MMR) along with IHC-MMR enhances the detection of EC patients at risk of HNPCC.

Risk-Reducing Salpingo-Oophorectomy in Patients With Germline Mutations in BRCA1 or BRCA2

Women with mutations in BRCA1 or BRCA2 are at tremendously increased lifetime risk of both breast and BRCA-associated gynecologic (ovarian, fallopian tube, and primary peritoneal) cancer. Because of limitations in the efficacy of available screening and chemopreventive approaches for women with a mutation in one of these genes, surgical risk reduction, particularly risk-reducing salpingo-oophorectomy (RRSO), has become an important component of the management options in hereditary breast-ovarian cancer syndrome. This article will review the rationale and efficacy of RRSO for prevention of breast and BRCA-associated gynecologic cancer. Surgical technique and methods of pathologic evaluation will be presented. Controversies regarding uterine preservation and post-RRSO hormone replacement therapy will be addressed. Considerations that may impact the appropriate timing of the procedure will be reviewed, and the potential role of RRSO in BRCA-negative hereditary breast cancer families will also be discussed.

Early Detection and Prognosis of Ovarian Cancer Using Serum YKL-40

PURPOSE YKL-40 is a secreted glycoprotein (chitinase family). We compared YKL-40 with two ovarian cancer serum markers, CA125 and CA15-3, for the detection of early-stage ovarian cancer. MATERIALS AND METHODS Serum YKL-40 levels were assayed by enzyme-linked immunosorbent assay for 46 healthy subjects, 61 high-risk individuals, 33 patients with benign gynecologic processes, and 50 preoperative patients subsequently diagnosed with predominantly early-stage ovarian cancer. Serum CA125 and CA15-3 values were obtained. RESULTS Median YKL-40 level was 28 ng/mL (range, 15 to 166 ng/mL) for healthy subjects, 36 ng/mL (range, 9 to 69 ng/mL) for high-risk individuals without prior cancer, 44.5 ng/mL (range, 5 to 133 ng/mL) for high-risk patients with prior breast cancer, and 38 ng/mL (range, 5 to 67 ng/mL) for individuals with benign gynecologic processes (P = NS). Median preoperative YKL-40 level for ovarian cancer patients was 94 ng/mL (range, 17 to 517 ng/mL; P <.0001 compared with normal and high-risk). YKL-40 was elevated (>/= 62 ng/mL) in 36 (72%) of 50 patients compared with 23 (46%) of 50 and 13 (26%) of 50 patients for CA125 and CA15-3 (P <.008). Twenty (65%) of 31 early-stage patients had elevated serum YKL-40 levels compared with 11 (35%) of 31 and four (13%) of 31 patients for CA125 and CA15-3 (P =.039). YKL-40 levels increased with stage (P <.005), regardless of grade, histology, or patient age. Patients with early-stage tumors with YKL-40 values more than 80 ng/mL had a worse prognosis (71% recurrence v no recurrence [P =.034]). CONCLUSION YKL-40 may represent a novel marker for the detection of early-stage ovarian cancer. YKL-40 levels in early-stage patients may also predict disease recurrence and survival. The utility of YKL-40 in detection of early-stage ovarian cancer deserves further investigation.

SGO White Paper on Ovarian Cancer: Etiology, Screening and Surveillance☆

Ovarian cancer is a heterogeneous, rapidly progressive, highly lethal disease of low prevalence. The etiology remains poorly understood. Numerous risk factors have been identified, the most prominent involving an inherited predisposition in 10% of cases. Women with germline mutations associated with Hereditary Breast/Ovarian Cancer and Lynch syndromes have dramatically elevated risks (up to 46% and 12%, respectively). Risk-reducing salpingo-oophorectomy is the best method to prevent ovarian cancer in these high-risk women. Significant risk reduction is also seen in the general population who use oral contraceptives. Since up to 89% patients with early-stage disease have symptoms prior to diagnosis, increased awareness of the medical community may facilitate further workup in patients who otherwise would have had a delay. Despite enormous effort, there is no proof that routine screening for ovarian cancer in either the high-risk or general populations with serum markers, sonograms, or pelvic examinations decreases mortality. Further evaluation is needed to determine whether any novel biomarkers, or panels of markers, have clinical utility in early detection. Prospective clinical trials have to be designed and completed prior to offering of any of these new diagnostic tests. CA125 is currently the only biomarker recommended for monitoring of therapy as well as detection of recurrence. This commentary provides an overview on the background, screening and surveillance of ovarian cancer.

Genome-Wide Association Studies of Cancer

Knowledge of the inherited risk for cancer is an important component of preventive oncology. In addition to well-established syndromes of cancer predisposition, much remains to be discovered about the genetic variation underlying susceptibility to common malignancies. Increased knowledge about the human genome and advances in genotyping technology have made possible genome-wide association studies (GWAS) of human diseases. These studies have identified many important regions of genetic variation associated with an increased risk for human traits and diseases including cancer. Understanding the principles, major findings, and limitations of GWAS is becoming increasingly important for oncologists as dissemination of genomic risk tests directly to consumers is already occurring through commercial companies. GWAS have contributed to our understanding of the genetic basis of cancer and will shed light on biologic pathways and possible new strategies for targeted prevention. To date, however, the clinical utility of GWAS-derived risk markers remains limited.