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© 2003 American Society for Clinical Oncology Fallopian Tube and Primary Peritoneal Carcinomas Associated With BRCA Mutations
From the Departments of Surgery, Medicine, and Pathology, Memorial Sloan-Kettering Cancer Center; and the Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Science, Mount Sinai School of Medicine, New York, NY. Address reprint requests to Jeff Boyd, PhD, Department of Surgery, Box 201, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: boydj{at}mskcc.org.
Purpose: The aims of this study were to determine the incidence of BRCA mutations among Ashkenazi Jewish patients with fallopian tube carcinoma (FTC) or primary peritoneal carcinoma (PPC), to study the clinicopathologic features of these cancers, and to estimate the risks of these cancers in association with a BRCA mutation. Patients and Methods: A retrospective review at two institutions identified 29 Jewish patients with FTC and 22 Jewish patients with PPC. These patients were genotyped for the three Ashkenazi Jewish BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). Surgical and pathologic information, family history, and survival data were obtained from hospital records. All statistical tests were two sided. Results: Germline BRCA mutations were identified in five of 29 patients with FTC (17%) and nine of 22 patients with PPC (41%). Mutation carriers had a younger mean age at diagnosis than patients without a mutation (60 v 70 years; P = .002). The overall median survival was 148 months for mutation carriers and 41 months for patients without a mutation (P = .04). For BRCA mutation carriers, the lifetime risks of FTC and PPC were 0.6% and 1.3%, respectively. Conclusion: Substantial proportions of Ashkenazi Jewish patients with FTC or PPC are BRCA mutation carriers. Patients with BRCA-associated FTC or PPC are younger at diagnosis and have improved survival compared with patients without a BRCA mutation. Although the lifetime risks of FTC or PPC for patients with BRCA heterozygotes are greater than those for the general population, the absolute risks seem relatively low.
THE LIFETIME risks of breast cancer and epithelial ovarian carcinoma (EOC) are substantially increased for women with deleterious germline mutations in the BRCA1 or BRCA2 genes; current penetrance estimates range from 30% to 60% for breast cancer and 15% to 40% for EOC, depending on the gene and population studied.1–7 Lower but significant risks for other cancers, most prominently male breast cancer, pancreatic, prostate, and stomach cancers, have also been associated with germline mutations in BRCA1 and BRCA2.8–10 Among gynecologic cancers other than EOC, the risk of uterine cancer is controversial, but the majority of data indicate no increased risk.8–12 With respect to fallopian tube carcinoma (FTC) and primary peritoneal carcinoma (PPC), there is molecular evidence that both tumors may be causally linked to germline BRCA mutations,13–16 and population-based evidence that both tumors should be considered components of the BRCA-related breast and ovarian cancer syndrome.17,18 The clinicopathologic similarities of FTC, PPC, and EOC support the probability of a common molecular pathogenesis. The prevalence of founder mutations in BRCA1 and BRCA2 among Ashkenazi Jews is approximately 2.5%, markedly higher than that found in the general population.19–22 For Ashkenazi patients with EOC, the likelihood of carrying a BRCA mutation is approximately 40%.4,23–25 Although FTC and PPC are likely to be under-reported as a result of the strict diagnostic criteria required to verify origin in these sites, they probably combine to account for less than 2% of all gynecologic cancers.26–28 Thus, there are few data bearing on the proportion of cases attributable to BRCA mutation in either the Ashkenazi or general populations. Two recent reports suggest that BRCA mutations account for 16% of FTCs in an unselected population17 and 28% of PPCs in the Jewish population.18 However, in contrast to BRCA-linked EOC,29 little is known about the clinicopathologic characteristics or lifetime risks of FTC and PPC associated with BRCA mutation in any population. The purpose of this study was to investigate these aspects of BRCA-linked FTC and PPC in a hospital-based retrospective cohort of Ashkenazi Jewish patients.
Study Population A retrospective review using institutional databases was conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) and Mount Sinai Medical Center (MSMC) to identify patients with FTC or PPC over a 20-year period, from 1981 to 2001. From MSKCC, 81 cases of FTC and 66 cases of PPC were identified. From MSMC, 24 cases of FTC were identified; no PPC cases were provided by MSMC. All tumors were invasive epithelial carcinomas. Self-identification of Jewish religion was used as a surrogate for Ashkenazi Jewish ancestry of patients selected for study. After excluding non-Jewish patients and cases with insufficient archival tissues or with diagnoses altered on the basis of pathology review, 51 tumors, 29 FTCs, and 22 PPCs were included in the study (Fig 1  ).
Archival pathologic tissue specimens were accessioned from hospital tissue banks. Eighty percent of the specimens were available for comprehensive review by a gynecologic pathologist. Six primary specimens (three FTC and three PPC) were unavailable for review, and four of the PPC patients had a previous oophorectomy not available for review, so that an ovarian primary could not be excluded with certainty. Criteria recommended by the Gynecologic Oncology Group were used to confirm patients with PPC,30 and FTCs were classified according to generally accepted criteria.31 Clinical and pathologic information, including age at diagnosis, overall survival, family history, surgical stage, tumor grade, and histologic subtype were abstracted from hospital records. This study was conducted under a protocol approved by the institutional review boards of both participating institutions.
Genotyping and Statistical Analyses Lifetime risks were calculated according to methods described previously for BRCA mutation carriers with ovarian or breast cancer.6,7 A control group of 3,434 Jewish women with no prior history of breast or ovarian cancer was obtained from a previously published series of Jewish volunteers in the Washington, DC, area.1 This group was used to calculate a population mutation prevalence and, in conjunction with the current series, the relative risk of mutation. Lifetime risks of FTC and PPC were calculated using the following two assumptions: the lifetime risks of FTC and PPC are proportional to the lifetime risk of EOC and the annual number of cases of FTC and PPC, and the annual rates of FTC and PPC are each 1% of all gynecologic malignancies. Therefore, the lifetime risk of FTC or PPC for the general population is given by the formula: A = B x C/D, where A is the lifetime risk of FTC or PPC, B is the lifetime risk of EOC, C is the annual incidence of FTC or PPC, and D is the annual incidence of EOC. The lifetime risk is expressed in terms of the population lifetime risk of FTC or PPC, the gene prevalence, and the relative risk of FTC or PPC in mutation carriers as follows: LRCFP = LRPFP x RRFP ÷ (PPMUTRRFP + 1 - PPMUT), where LRCFP is the lifetime risk of FTC or PPC in the BRCA heterozygotes, LRPFP is the lifetime risk of FTC or PPC in the general population, RRFP is the relative risk of FTC or PPC, and PPMUT is the prevalence of mutations in controls. Because of the small sample sizes available for the study, CIs are not shown, as stated in the Discussion section. These analyses were performed with the SPSS statistical software program (SPSS Inc, Chicago, IL).
Genotype analysis of this hospital-based retrospective cohort of Ashkenazi Jewish patients revealed BRCA mutations in five of 29 patients with FTC (17%) and nine of 22 patients with PPC (41%; Table 1 ). The mean age at diagnosis for the study population was 67 ± 9 years (range, 44 to 89 years). Patients with a BRCA mutation were diagnosed an average of 10 years earlier than those patients without germline mutations (P = .002; Table 2).
The majority (80%) of all patients in the study presented with stage III or IV disease and 48 tumors (94%) were of serous histology (Table 3 ). The clinical and pathologic characteristics of patients associated with a BRCA mutation are shown in Table 4. Of those cases associated with a BRCA mutation, all nine PPCs were stage III and of serous histology. In contrast, of the five BRCA-linked FTCs, two were stage I or II, and two were of transitional cell histology. Two patients had mutations in both BRCA1 and BRCA2. One was a 50-year-old patient diagnosed with stage IIIB serous PPC who is alive with disease 9 years after diagnosis. The other was a 65-year-old patient diagnosed with stage IC transitional cell FTC who has no evidence of disease 12 years after diagnosis.
Twenty-two patients (55%) had either a personal history of another primary cancer or a first-degree relative with invasive cancer. For nine of these patients, the additional primary cancer was from the breast or the cancer in a first-degree relative was from the breast or ovary. There was a trend for patients with a BRCA mutation to more likely have a personal history of breast cancer or a first-degree relative with a history of breast or ovarian cancer (42% v 14%; P = .10).
With a median follow-up of 37 months, 20 of 40 patients (50%) with available follow-up data have died. There was no difference in the overall median survival of the 18 FTC patients compared with the 22 PPC patients (62 and 55 months, respectively; P = .65; Fig 2
These data indicate that a substantial proportion (41%) of Ashkenazi Jewish women with PPC are BRCA mutation carriers (Table 6 ). This frequency is similar to that reported for Jewish women with EOC.4,23–25 The same conclusion was reached in a recent study comparing BRCA mutation frequency in Israeli Jewish women with EOC and PPC.18 A smaller proportion (17%) of Jewish patients with FTC carried a BRCA mutation, an incidence similar to that reported in an unselected population.17 A summary of these incidence data with those in the existing literature pertaining to BRCA and gynecologic cancers is presented in Table 6.
In this study, patients with BRCA-associated FTC or PPC were diagnosed approximately 10 years earlier than those patients without mutations, consistent with observations for BRCA-linked ovarian cancer patients.4,25 These patients were more likely to have a personal history or a family member with breast or ovarian cancer. The data also suggest that BRCA mutation carriers with FTC or PPC have an improved overall survival compared with patients without BRCA mutation. Although based on a small sample size, these findings are consistent with the improved survival observed for patients with BRCA-associated EOC.25,32,33 If confirmed, this finding may reflect the greater cellular proliferation rates seen in BRCA-associated tumors34 combined with an increased sensitivity to platinum-based chemotherapy conferred by loss of BRCA function,35–37 resulting in a more favorable response to chemotherapy. This study indicates that in BRCA mutation carriers, the lifetime risks of FTC (0.6%) and PPC (1.3%) are significantly higher than those of the general population but this risk is still substantially lower than the risk of EOC in BRCA mutation carriers. Only recently was FTC suggested to occur at a higher than expected frequency in a large cohort of BRCA mutation carriers.9 The number of FTC patient cases reported in that study was far smaller than that reported here, however. Similar data have not been presented for PPC. It is noteworthy that 88% of the patients in this study did not have a family history of breast or ovarian cancer, and among this subset, 26% carried BRCA mutations. The conclusions of this study are subject to several types of bias. The population is composed of patients self-reported to be Jewish at the time of hospital intake. Our experience at this institution is that more than 90% of self-described Jewish patients are of Central or Eastern European (Ashkenazi) descent, and any bias introduced through this study design is presumed to be small. A potential bias inherent in any study on FTC or PPC is the misclassification of patient cases. Several patient cases included in this study were not subject to pathologic review because of the unavailability of specimens, and misclassification of a small number of endometrial or ovarian carcinomas as FTC or PPC is possible. In addition, advanced-stage FTC or PPC may be misclassified as ovarian cancer, but it is difficult to predict how this may have affected our findings. A related issue is that this study included only patients with invasive FTC and excluded patients with purely in situ disease. Inclusion of the latter type of lesion, which is not uncommon in BRCA mutation carriers,38–40 would have affected all the conclusions of this study. Our assumption that FTC and PPC each represent 1% of gynecologic malignancies also affects the conclusion of the study; the lifetime risks would be overestimated if 1% is too high and underestimated if 1% is too low. Any error introduced by our estimates of prevalence for these malignancies is directly proportional to the estimates of lifetime risk. Finally, small sample size is a problem inherent in studies of a rare tumor. Variability surrounds any mathematical estimate, and the small sample size in this case is likely to be as responsible for the variation as the inherent variability of the data. Confidence intervals were therefore not included with the estimates presented. These findings have several clinical implications. Risk-reducing salpingo-oophorectomy is currently recommended for BRCA mutation carriers after completion of childbearing or at age 35 years.28 After removal of the fallopian tubes and ovaries, the peritoneum is still at risk for developing malignancy, reflecting its common embryologic origin with the ovarian epithelium. Previous estimates of this risk after prophylactic surgery are in the range of 0.5% to 2.0%,41–43 not dissimilar to the lifetime risk for PPC of 1.3% predicted by this study. Thus, the risk of PPC after risk-reducing salpingo-oophorectomy seems to be quite low. The lifetime risk of FTC (0.6%) predicted by these data is even lower than that for PPC. Although occult FTC has been found at the time of prophylactic salpingo-oophorectomy, there has been no reported patient with FTC developing after this procedure. Even with careful ligation of the fallopian tube at the uterine origin, a small interstitial portion of the fallopian tube is left in the uterine fundus. The histology of this segment is distinct from the remainder of the fallopian tube, perhaps placing it at less risk for malignant transformation. However, data on the occurrence of FTC in this region are not available to serve as a baseline to measure such risks. The data presented here suggest that the lifetime risk of FTC in BRCA mutation carriers is low and that when considered together with other published reports, there is little evidence to suggest that removal of the uterus to prevent FTC or uterine cancer is indicated at the time of prophylactic salpingo-oophorectomy.
The authors indicated no potential conflicts of interest.
We acknowledge the statistical advice and valuable comments of Jaya Satagopan, PhD, Memorial Sloan-Kettering Cancer Center.
Supported by a grant from the W.M. Keck Foundation. Presented in part at the 33rd Annual Meeting of the Society of Gynecologic Oncologists, Miami Beach, FL, March 16–20, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 and Student’s t test, as appropriate. Overall survival was estimated using the method of Kaplan and Meier, and comparison between groups was performed with the log-rank test. A Cox proportional hazards model was used to perform a multivariate analysis of survival. All statistical tests were two sided, and significance was taken at the level of P < .05 
