|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 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.
1. Struewing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401–1408, 1997 2. Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676–689, 1998[CrossRef][Medline]
3. Warner E, Foulkes W, Goodwin P, et al: Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91:1241–1247, 1999 4. Moslehi R, Chu W, Karlan B, et al: BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66:1259–1272, 2000[CrossRef][Medline] 5. Thompson D, Easton D, Breast Cancer Linkage Consortium: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68:410–419, 2001[CrossRef][Medline]
6. Satagopan JM, Offit K, Foulkes W, et al: The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 10:467–473, 2001
7. Satagopan JM, Boyd J, Kauff ND, et al: Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res 8:3776–3781, 2002
8. Thompson D, Easton DF, Breast Cancer Linkage Consortium: Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94:1358–1365, 2002
9. Brose MS, Rebbeck TR, Clalzone KA, et al: Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94:1365–1372, 2002
10. Breast Cancer Linkage Consortium: Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91:1310–1316, 1999 11. Levine DA, Lin O, Barakat RR, et al: Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol 80:395–398, 2001[CrossRef][Medline] 12. Goshen R, Chu W, Elit L, et al: Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecol Oncol 79:477–481, 2000[CrossRef][Medline] 13. Bandera CA, Muto MG, Schorge JO, et al: BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum. Obstet Gynecol 92:596–600, 1998[Abstract]
14. Schorge JO, Muto MG, Lee SJ, et al: BRCA1-related papillary serous carcinoma of the peritoneum has a unique molecular pathogenesis. Cancer Res 60:1361–1364, 2000 15. Zweemer RP, van Diest PJ, Verheijen RH, et al: Molecular evidence linking primary cancer of the fallopian tube to BRCA1 germline mutations. Gynecol Oncol 76:45–50, 2000[CrossRef][Medline] 16. Rose PG, Shrigley R, Wiesner GL: Germline BRCA2 mutation in a patient with fallopian tube carcinoma: A case report. Gynecol Oncol 77:319–320, 2000[CrossRef][Medline] 17. Aziz S, Kuperstein G, Rosen B, et al: A genetic epidemiological study of carcinoma of the fallopian tube. Gynecol Oncol 80:341–345, 2001[CrossRef][Medline] 18. Menczer J, Chetrit A, Barda G, et al: Frequency of BRCA mutations in primary peritoneal carcinoma in Israeli Jewish women. Gynecol Oncol 88:58–61, 2003[CrossRef][Medline] 19. Struewing JP, Abeliovich D, Peretz T, et al: The carrier frequency of the BRCA1 185delAG mutation is approximately 1% in Ashkenazi Jewish individuals. Nat Genet 11:198–200, 1995[CrossRef][Medline] 20. Oddoux C, Struewing JP, Clayton CM, et al: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 14:188–190, 1996[CrossRef][Medline] 21. Roa BB, Boyd AA, Volcik K, et al: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14:185–187, 1996[CrossRef][Medline] 22. Hartge P, Struewing JP, Wacholder S, et al: The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 64:963–970, 1999[CrossRef][Medline] 23. Beller U, Halle D, Catane R, et al: High frequency of BRCA1 and BRCA2 germline mutations in Ashkenazi Jewish ovarian cancer patients, regardless of family history. Gynecol Oncol 67:123–126, 1997[CrossRef][Medline] 24. Levy-Lahad E, Catane R, Eisenberg S, et al: Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: Frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet 60:1059–1067, 1997[CrossRef][Medline]
25. Boyd J, Sonoda Y, Federici MG, et al: Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 283:2260–2265, 2000 26. Rosenblatt KA, Weiss NS, Schwartz SM: Incidence of malignant fallopian tube tumors. Gynecol Oncol 35:236–239, 1989[CrossRef][Medline]
27. Schorge JO, Muto MG, Welch WR, et al: Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations. J Natl Cancer Inst 90:841–845, 1998 28. Rothacker D, Mobius G: Varieties of serous surface papillary carcinoma of the peritoneum in northern Germany: A thirty-year autopsy study. Int J Gynecol Pathol 14:310–318, 1995[Medline] 29. Narod SA, Boyd J: Current understanding of the epidemiology and clinical implications of BRCA1 and BRCA2 mutations for ovarian cancer. Curr Opin Obstet Gynecol 14:19–26, 2002[CrossRef][Medline] 30. Bloss JD, Liao SY, Buller RE, et al: Extraovarian peritoneal serous papillary carcinoma: A case-control retrospective comparison to papillary adenocarcinoma of the ovary. Gynecol Oncol 50:347–351, 1993[CrossRef][Medline] 31. Alvarado-Cabrero I, Young RH, Vamvakas EC, et al: Carcinoma of the fallopian tube: A clinicopathological study of 105 cases with observations on staging and prognostic factors. Gynecol Oncol 72:367–379, 1999[CrossRef][Medline]
32. Rubin SC, Benjamin I, Behbakht K, et al: Clinical and pathologic features of ovarian cancer in women with germ-line mutations of. BRCA1. N Engl J Med 335:1413–1416, 1996
33. Ben-David Y, Chetrit A, Hirsh-Yechezkel G, et al: Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20:463–466, 2002 34. Levine DA, Federici MG, Reuter VE, et al: Cell proliferation and apoptosis in BRCA-associated hereditary ovarian cancer. Gynecol Oncol 85:431–434, 2002[CrossRef][Medline]
35. Husain A, He G, Venkatraman ES, et al: BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res 58:1120–1126, 1998
36. Bhattacharyya A, Ear US, Koller BH, et al: The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 275:23899–23903, 2000 37. Lafarge S, Sylvain V, Ferrara M, et al: Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway. Oncogene 20:6597–6606, 2001[CrossRef][Medline] 38. Agoff SN, Mendelin JE, Grieco VS, et al: Unexpected gynecologic neoplasms in patients with proven or suspected BRCA-1 or -2 mutations: Implications for gross examination, cytology, and clinical follow-up. Am J Surg Pathol 26:171–178, 2002[CrossRef][Medline] 39. Paley PJ, Swisher EM, Garcia RL, et al: Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: A case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol 80:176–180, 2001[CrossRef][Medline] 40. Colgan TJ, Murphy J, Cole DE, et al: Occult carcinoma in prophylactic oophorectomy specimens: Prevalence and association with BRCA germline mutation status. Am J Surg Pathol 25:1283–1289, 2001[CrossRef][Medline] 41. Piver MS, Jishi MF, Tsukada Y, et al: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer: A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71:2751–2755, 1993[CrossRef][Medline]
42. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609–1615, 2002
43. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616–1622, 2002
44. Takahashi H, Behbakht K, McGovern PE, et al: Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res 55:2998–3002, 1995
45. Matsushima M, Kobayashi K, Emi M, et al: Mutation analysis of the BRCA1 gene in 76 Japanese ovarian cancer patients: Four germline mutations, but no evidence of somatic mutation. Hum Mol Genet 4:1953–1956, 1995
46. Takahashi H, Chiu HC, Bandera CA, et al: Mutations of the BRCA2 gene in ovarian carcinomas. Cancer Res 56:2738–2741, 1996
47. Stratton JF, Gayther SA, Russell P, et al: Contribution of BRCA1 mutations to ovarian cancer. N Engl J Med 336:1125–1130, 1997 48. Yamashita Y, Sagawa T, Fujimoto T, et al: BRCA1 mutation testing for Japanese patients with ovarian cancer in breast cancer screening. Breast Cancer Res Treat 58:11–17, 1999[CrossRef][Medline] 49. Tonin PM, Mes-Masson AM, Narod SA, et al: Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history. Clin Genet 55:318–324, 1999[CrossRef][Medline] 50. Risch HA, McLaughlin JR, Cole DE, et al: Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68:700–710, 2001[CrossRef][Medline] 51. Yazici H, Glendon G, Burnie SJ, et al: BRCA1 and BRCA2 mutations in Turkish familial and non-familial ovarian cancer patients: A high incidence of mutations in non-familial cases. Hum Mutat 20:28–34, 2002[CrossRef][Medline]
52. Modan B, Hartge P, Hirsh-Yechezkel G, et al: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345:235–240, 2001 53. Liu FS, Ho ESC, Shih RT, et al: Mutational analysis of the BRCA1 tumor suppressor gene in endometrial carcinoma. Gynecol Oncol 66:449–453, 1997[CrossRef][Medline] Submitted April 18, 2003; accepted August 25, 2003. This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
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 
