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© 2002 American Society for Clinical Oncology Cancer Incidence in a Population of Jewish Women at Risk of Ovarian CancerByFrom the Centre for Research in Women’s Health, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada; and Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, and Department of Obstetrics and Gynecology, University of California–Los Angeles School of Medicine, Los Angeles, CA. Address reprint requests to S.A. Narod, MD, Centre for Research in Women’s Health, Sunnybrook and Women’s College Health Sciences Centre, 790 Bay St, Ste 750A, Toronto, Ontario M5G 1N8, Canada; email: alex.liede{at}swchsc.on.ca
PURPOSE: To evaluate the incidence and clinical characteristics of ovarian and other cancers in a cohort of women at risk of developing ovarian cancer. PATIENTS AND METHODS: The Gilda Radner Ovarian Cancer Detection Program in Los Angeles, CA, was established in 1991 to study the efficacy of screening in the early detection of ovarian cancer. We present findings from a historical cohort of 290 Jewish women who were offered BRCA testing for three common founder mutations (BRCA1 185delAG and 5382insC and BRCA2 6174delT). RESULTS: In 10 years, 17 cancers were observed (1,111 per 100,000 per year), including six breast and eight ovarian or related cancers. A high proportion of cancers of peritoneal origin was observed. The majority (86%) of women with incident breast or ovarian/peritoneal cancer carried a mutation in the BRCA1 gene. The overall cancer incidence among carriers of mutations in the BRCA1 gene was estimated to be 5,450 per 100,000 per year, corresponding to a cumulative incidence of 47.5% at 10 years. In contrast, the cumulative incidence of cancer among noncarriers was 2.5% (P < 10-8). After adjustment for sampling, the risks to BRCA1 mutation carriers at 10 years were estimated to be 21% for ovarian/peritoneal/tubal cancer, 16% for breast cancer, and 36% for all cancers. CONCLUSION: The excess risk of breast and ovarian cancer in Jewish women with a family history of ovarian cancer is largely attributable to mutations in BRCA1. Intensive surveillance by use of CA-125 and ultrasound does not seem to be an effective means of diagnosing early-stage ovarian cancer in this high-risk cohort.
THE STRONGEST RISK factor for ovarian cancer is the presence of an inherited mutation in one of the two ovarian cancer susceptibility genes, BRCA1 or BRCA2. It is estimated that more than 10% of women in North America with invasive ovarian cancer carry a BRCA1 or BRCA2 mutation.1 Other risk factors include a family history of ovarian cancer, a previous diagnosis of breast cancer, and Ashkenazi Jewish ethnicity.2 The highest recorded rates of ovarian cancer have been reported among Israeli Jews born in Europe or North America.3 The majority of these women are of Ashkenazi origin. The prevalence of founder germline BRCA mutations in the Jewish population contributes to the high cancer rate. Two mutations in BRCA1 (185delAG and 5382insC) and one in BRCA2 (6174delT) have a combined frequency of one in 45 Ashkenazi Jews.4-6 Several groups have estimated the prevalence of BRCA1 and BRCA2 mutations in Jewish ovarian cancer patients.7-10 In a study of 208 unselected North American Jewish ovarian cancer patients, the frequency of BRCA mutations11 was 41.3%. In a recent large study, 244 (29%) of 840 women with ovarian or peritoneal cancer in Israel had a founder mutation in BRCA1 or BRCA2.12 Regular ovarian surveillance is recommended for carriers of BRCA mutations, including rectovaginal pelvic examination, serum CA-125, and transvaginal sonography at annual or biannual intervals.13 However, there are few data that indicate that screening of high-risk women will reduce mortality from ovarian cancer.14 The cumulative lifetime risk of developing ovarian cancer to age 70 years associated with a BRCA1 or BRCA2 mutation has been estimated1,6,15 to be in the range of 16% to 60%, and the risk of breast cancer is estimated1,15-17 to be in the range of 28% to 87%. These estimates were based on the inspection of pedigrees of high-risk families from cross-sectional studies and may be subject to ascertainment and recall biases. Because of the wide ranges in risk, genetic counseling is difficult, and accurate estimates are desirable. In principle, cohort studies of healthy women who carry BRCA mutations are ideal for estimating the risk of cancer by the direct observation of cancer incidence. Participants of the Gilda Radner Ovarian Cancer Detection Program in Los Angeles, CA, were considered to be at increased risk of developing ovarian cancer, on the basis of their family histories of ovarian cancer, breast cancer, or both or a previous diagnosis of breast cancer. Many of these women have now been observed for 5 or more years, and many have undergone genetic testing. This cohort provides a unique opportunity to estimate cancer risk among female carriers of BRCA1 or BRCA2 mutations.
The Gilda Radner Ovarian Cancer Detection Program In July 1991, the Gilda Radner Ovarian Cancer Detection Program was established at the Cedars-Sinai Medical Center in Los Angeles, CA. The goals of this ovarian cancer screening program have been described.18 Briefly, women 35 years and older with a family history of ovarian, breast, colon, or endometrial cancer or with a personal history of breast cancer were eligible to participate at no cost. Screening with transvaginal ultrasonography with color Doppler imaging, as well as tumor marker testing, was performed biannually until July 1995. After 1995, the protocol was amended to annual screening interventions. Five tumor markers (CA-125, LASA, DM70K, UGP, and HER-2/neu) were used; however, only CA-125 has been accepted in clinical practice and is discussed here.
Study Population From 1991 to 2000, 1,261 women were enrolled onto the Gilda Radner program. A total of 475 subjects (38%) were Jewish (self-reported). Of these, 83 women were excluded because they did not provide 1 full year of follow-up. Some of these included women who elected to undergo oophorectomy and were therefore discharged from the screening program at the time of surgery. Our study cohort included women with a family history of ovarian cancer (any age) or breast cancer (younger than 50 years) in a first- or second-degree relative. Sixty-one women were excluded from the study on the basis of the family history criteria. Forty-one women with a past diagnosis of breast cancer were also excluded because of the possible effect of treatment on subsequent cancer risk. As a result, 290 potential subjects were eligible for analysis. Study procedures were approved by the institutional review boards of the Cedars-Sinai and Women’s College Hospitals. In 1998, women received a letter explaining the goals of the study with an invitation to participate in genetic testing. Women who agreed to participate contacted the Gilda Radner program directly. Women who agreed to genetic testing provided a blood specimen for DNA extraction. Participants were offered the results of the genetic testing by genetic counselors and physicians associated with the research program (1999 to 2000). The women were asked to provide details regarding cancer, surgery, and cancer occurrences in the family.
Mutation Detection We were able to genotype two women who had died. One patient with non-Hodgkin’s lymphoma was genotyped by using previously stored DNA specimens. Histologic slides were used to test one subject with peritoneal cancer who died in 1994. Testing of histologic slides was performed as previously described.19
Case Definitions Peritoneal serous papillary carcinoma was defined according to the criteria of the Gynecologic Oncology Group20: (1) the ovaries are normal in size or enlarged by a benign process; (2) the extraovarian sites of carcinoma are of significantly greater volume than the tumor present on either ovary; (3) the ovarian tumor component is nonexistent, is confined to the ovarian surface with or without stromal invasion measuring less than 5 x 5 mm, or is within the ovarian substance but measuring less than 5 x 5 mm; and (4) the histologic characteristics indicated serous papillary carcinoma of any grade. All pathologic findings and tissue blocks of ovarian cancer patients (including peritoneal cancer patients) were reviewed independently by two experts. Fallopian tube cancer in one patient was confirmed by surgical pathology review.
Statistical Analysis
Jewish Cohort The study cohort comprised 290 Jewish women. The mean age of the women at first contact was 44.8 years and was 40.4 years for carriers of mutations in BRCA1/2. Forty-three women (14.8%) had prophylactic bilateral salpingo-oophorectomy at a time from 1 to 9 years after study entry. Indications for surgery were given as abnormal ultrasound findings (20 of 43), prevention of ovarian cancer (16 of 43), increased CA-125 (four of 43), breast cancer diagnosis (two of 43), and uterine bleeding (one of 43). The mean follow-up was 5.3 ± 2.2 years for all study participants, and was 7.2 ± 1.7 years for carriers of mutations in BRCA1/2, with a maximal follow-up time of 10 years. Two women died, one as a result of peritoneal cancer (incident) and one as a result of non-Hodgkin’s lymphoma (incident). DNA specimens were available for 213 (73.4%) of the 290 eligible Jewish women. We were unable to obtain blood samples from the other 77 women in the cohort. Forty-eight women for whom no sample was obtained had not participated in the Gilda Radner program since 1996, and eight women were discharged after prophylactic oophorectomy. The remaining 29 women did not respond to a mailed invitation to participate in genetic testing or declined to participate. The similar characteristics of women who underwent genetic testing as compared with those who were not tested are listed in Table 1.
A total of 33 founder mutations (15.5%) were found among 213 Jewish program participants, including 31 in BRCA1 (27 in 185delAG and four in 5382insC) and two in BRCA2 (6174delT) (Table 2). Twelve of the 14 women who developed breast or ovarian cancer during the course of the program were carriers of a germline mutation in the BRCA1 gene. Two women with incident breast and ovarian cancers were offered comprehensive screening of BRCA1 and BRCA2 mutations with Myriad Genetic Laboratories after testing negative for the three common Ashkenazi Jewish mutations. No mutations were found for these two women.
Ten women had other cancers diagnosed before enrolling in the program, including a preinvasive breast cancer (lobular carcinoma-in-situ) and thyroid, cervical, and sebaceous gland (eye) cancer. Six women had skin cancer (basal cell carcinomas) (Table 2). Of the 10, seven women (70%) were tested, and three women with skin cancer were not tested. The thyroid cancer patient was found to carry the BRCA1 5382insC mutation.
Ovarian/Peritoneal/Tubal Cancer Risk
The characteristics of the eight patients with ovarian/peritoneal/tubal cancer are listed in Table 3. We have previously reported on six of these patients22; two additional patients are described here (patient nos. 11 and 12).
Six of the eight patients presented with stage IIIc disease, one with stage Ic, and one with stage IIc. Three of the eight women had at least one abnormally increased CA-125 level (> 35 U/mL) during routine screening before surgery (patient nos. 5, 7, and 9); all of these were diagnosed with stage IIIc disease. Patient no. 5 had two abnormally increased CA-125 levels at 1 and 2 months before surgery. Patient no. 7 had a modestly increased CA-125 level and was found to have synchronous primary cancers of the fallopian tube and peritoneum. Patient no. 9 had persistently increased CA-125 levels for 18 months, starting from her first visit to the program. She was monitored monthly for three visits and biannually for the last two visits. Because the CA-125 level was not increasing and the ovaries appeared normal on transvaginal ultrasonography, this was suspected to be caused by a benign gynecologic abnormality in a premenopausal woman.22 Patient no. 10 was diagnosed during pregnancy; she had normal screening CA-125 and ultrasound findings before pregnancy. Ultrasound findings were abnormal in two of the eight patients (nos. 3 and 7). Five of the eight women presented with abdominal pain or discomfort. All had normal ultrasound findings, three had a nonincreased screening CA-125 (patient nos. 6, 10, and 11), four were diagnosed with stage IIIc disease (nos. 6, 9, 10, and 12), and one was diagnosed with stage IIc disease (patient no. 11). Two patients (nos. 11 and 12) discontinued their participation in the Gilda Radner program several years before their diagnoses but continued to receive annual ovarian cancer screening with CA-125 and transvaginal ultrasound elsewhere. Patient no. 11 had a moderately increased CA-125 and presented with intermittent pelvic pain and ascites less than 2 months before her diagnosis. Patient no. 12 had normal ultrasound findings less than 2 months before she presented with pelvic pain and ascites; her CA-125 at the time of diagnosis was abnormally high. All six cases of peritoneal serous papillary carcinoma occurred among carriers of the 185delAG mutation. The cumulative risk of peritoneal cancer among carriers of the 185delAG mutation was estimated to be 20% at 10 years.
Breast Cancer Risk
Overall Cancer Risk Other incident cancers in the cohort included one case of bone cancer (osteosarcoma) in a BRCA1 185delAG carrier, one case of cervical cancer in a noncarrier, and one case of non-Hodgkin’s lymphoma in a noncarrier (Table 1). Overall, the incidence of any cancer among carriers of BRCA mutations was 14 times greater than that for noncarriers (RR = 14; 95% CI, 4.4 to 42). The 10-year risk of any cancer for mutation-positive participants was 47.5%. The cumulative 10-year risk for noncarriers was 2.5% (Fig 1C). In summary, 13 (76.5%) of the 17 women with incident cancer carried a BRCA1 mutation (including five of six women with breast cancer and seven of eight women with ovarian/peritoneal/tubal cancer), and four women were noncarriers.
Since 1991, the Gilda Radner Ovarian Cancer Detection Program at the Cedars-Sinai Medical Center in Los Angeles has observed women at risk of ovarian cancer. The majority (87.5%) of Jewish women in the program who developed these cancers were found to be carriers of the BRCA1 185delAG mutation. Only two Jewish women who developed ovarian or breast cancer during the course of the program did not carry a BRCA1 mutation; one was diagnosed with stage I ovarian cancer at age 48 years, and the other was diagnosed with breast cancer at age 69 years. No BRCA2 mutations were found among the cancer patients (Table 2). However, the age of onset of ovarian cancer in carriers of mutations in the BRCA2 gene is older than for carriers of mutations in BRCA1.1 The majority of BRCA2-associated ovarian cancers are diagnosed between the ages of 50 and 70 years, whereas BRCA1-associated ovarian cancers occur 4 to 5 years sooner than is usual for patients with ovarian cancer.1 In our study, the mean age of the study participants at entry was 44.8 years. Because ovarian cancer in carriers of BRCA2 mutations is diagnosed at a mean age of 62 years, we would have required additional follow-up to observe cancers in this cohort.11
In this population, intensive screening resulted in the diagnosis of only one early-stage ovarian cancer. We identified seven stage II or III ovarian, fallopian tube, or peritoneal serous papillary carcinomas, which had spread beyond the ovary at the time of diagnosis. Furthermore, four of the eight cancers presented in symptomatic women who had normal screening tests. Five of these had undergone screening Papillary serous carcinoma of the peritoneum is histologically indistinguishable from papillary serous ovarian cancer, and it is often multifocal in origin.22 The risk of peritoneal cancer is significant for carriers of germline mutations in the BRCA1 gene.20 In this study, the diagnosis of peritoneal serous papillary carcinoma is in accordance with the guidelines by the Gynecologic Oncology Group.20 The ovaries were present at the time of diagnosis; however, the extent of involvement at extraovarian sites was significantly greater, and the ovarian tumor component was either nonexistent or confined to the ovarian surface. It is important to discriminate peritoneal cancer from epithelial ovarian cancer because papillary serous carcinoma of the peritoneum may not be amenable to prevention by salpingo-oophorectomy. The majority of the ovarian-type cancers observed in our cohort were determined to be of peritoneal origin and, we believe, would not have been prevented through prophylactic salpingo-oophorectomy. Previously, a small study of 17 women with primary cancers of the peritoneum identified three BRCA1 mutations (18%), including two Jewish patients with the BRCA1 185delAG mutation.23 In our study, seven of eight patients with ovarian-related cancer, including all six with primary cancers of the peritoneum, were BRCA1 185delAG mutation carriers (Table 3). On the basis of the six cases of peritoneal cancer, we estimated the cumulative risk of peritoneal cancer among BRCA1 carriers to be 20% at 10 years. Carriers of mutations in the BRCA1 gene should be counseled about the persistent risk of peritoneal cancer after prophylactic surgical removal of the ovaries.20 One patient (no. 7) was diagnosed with synchronous primary cancers of the fallopian tube and peritoneum. Carcinoma of the fallopian tube is also a phenotypic variant of BRCA1 and BRCA2.24-27 In a recent study of 44 unselected cases of fallopian tube cancer in the province of Ontario, six germline BRCA mutations (9.1%) were detected, including two BRCA2 mutations.28 Carriers should be counseled about the risk of cancer of the fallopian tube, and prophylactic salpingectomy should accompany oophorectomy. These data provide one of the first risk estimates for BRCA carriers on the basis of a population of asymptomatic women who were observed prospectively. Generally, cross-sectional studies have been used to estimate the risk of cancer to female carriers of mutations in BRCA1 or BRCA2, relying mainly on the proband’s recall of cancer occurrence in the family. A cohort study design, such as the one presented here, is preferred in the estimation of risks or rates of disease in a population, in which new occurrences of the disease are observed and confirmed by the investigators.21 Recently, prospective data on female BRCA1 or BRCA2 mutation carriers participating in a breast cancer surveillance program in the Netherlands was presented.29,30 Meijers-Heijboer et al29 studied 139 BRCA1 or BRCA2 mutation carriers and reported eight incident cases of breast cancer in their cohort with a mean follow-up of 3 years, resulting in a 2.5% increase in breast cancer risk per year. The risk estimates presented here (eg, 2.1% breast cancer risk per year) are based on a longer mean follow-up of 7 years for BRCA1/2 mutation carriers. However, our estimates are likely to be high because of our study design. Because we had access to paraffin-embedded tumor specimens, we were able to test a higher proportion of women who developed cancer (100%) than women in the cohort who were not diagnosed with incident cancers (71.8%). Among women without incident cancers who were tested, the prevalence of BRCA mutations was 10.2% (20 of 196). If we assume the same mutation rate for the healthy women who were not tested, we would expect there to be an additional eight carriers; ie, the number of carriers in the cohort would increase by 24%, from 33 to 41. Therefore, it is likely that we have overestimated the cancer incidence rates among carriers by approximately 24%. Adjusting for sampling bias, the estimated risks for female carriers of germline mutations in the BRCA1 gene at 10 years are 21% for ovarian/peritoneal/tubal cancer (15% for peritoneal cancer alone), 16% for breast cancer, and 36% for any cancer. The lower risk of breast cancer in BRCA mutation carriers observed in our study as compared with the data from the Netherlands29,30 may be explained by random variation, by different populations, by mutation position, or by study design. Gayther et al31 proposed that germline mutations in the 5' region of the BRCA1 gene are associated with a greater risk of ovarian cancer than mutations in the 3' region. In support of this, we identified a greater number of exon 2 185delAG mutations (in the 5' end of the gene) among the study subjects than 5382insC mutations (a 3' mutation). The 185delAG mutation accounted for 27 of 33 mutations identified in the cohort and for 12 of 13 of the mutation-positive cancer patients. The 3' BRCA1 exon 20 5382insC mutation was detected in one incident breast cancer patient diagnosed at age 44 and in one thyroid cancer patient diagnosed at age 36. The 5382insC mutation is much less common than the 185delAG mutation in the Jewish population.4 By using a case-control approach, we have previously estimated an RR of 37 for ovarian cancer for the 185delAG mutation and of 21 for the 5382insC mutation.11 Because of the small number of cancers observed in the cohort, it was not possible to calculate age-specific risks. Our estimates are based on a population of Jewish women with a family history of ovarian cancer or breast cancer. It is not yet clear to what extent these risks are generalizable to carriers of other BRCA1 mutations, to those without a family history, or to those from a different ethnic group. In particular, the risk of peritoneal carcinomatosis was high in this cohort, but these cases seem to be caused by a single BRCA1 mutation. It may be that mutations in other regions of the BRCA1 gene are associated with a lower risk. It has not yet been established that carriers of BRCA2 are at increased risk of peritoneal cancer. In contrast to the BRCA1/2 mutation carriers presented by Meijers-Heijboer et al29 and Brekelmans et al,30 our study did not include a breast cancer screening protocol; however, women were advised to arrange breast cancer screening outside of the Gilda Radner Program. Magnetic resonance imaging was not available to our participants, and mammography was routinely recommended. Four of the six women with breast cancer reported that they detected the breast lump themselves, and one woman (who did not have a mutation) had a breast tumor detected by mammography (Table 3). Information on the detection method of breast cancer for one case was not available. Screening by ultrasound and CA-125 did not result in the identification of early-stage ovarian cancer in the Gilda Radner program. We believe that genetic testing is an option for the Ashkenazi Jewish woman at high familial risk for ovarian cancer, because the majority of Jewish women who have a family history and who develop breast or ovarian cancer will be carriers of BRCA mutations. These women may benefit from prophylactic bilateral salpingo-oophorectomy, including the reduction in the risk of subsequent breast cancer with the removal of the ovaries by decreasing levels of circulating estrogen.32,33 However, given the high proportion of cancers with peritoneal origins observed in our study, it is not clear to what extent the risk of cancer will be reduced by oophorectomy. Future follow-up studies of women with mutations who have undergone an oophorectomy will be critical to clarify this risk.
Supported in part by the Revlon/UCLA Women’s Cancer Research Program and Cedars-Sinai Research for Women’s Cancers. A.L.’s doctoral studies are supported by the Canadian Institutes of Health Research (formerly MRC) Doctoral Award. We thank Kendra Glover, Eloise Lopez-Luevanos, RN, Niki Lee, RN, Elaine Jack, Song Li, Shiyu Zhang, MD, and Roxana Moslehi, PhD, for their contribution to this study. We thank the women who participated in the Gilda Radner program, without whose cooperation this study would not have been possible.
1. Risch HA, McLaughlin JR, Cole DEC, et al: Prevalence and pene-trance 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]
2.
Helmrich SP, Shapiro S, Rosenberg L, et al: Risk factors for breast cancer. Am J Epidemiol 117: 35-45, 1983 3. Parkin DM, Whelan SL, Ferlay J, et al: Cancer Incidence in Five Continents (vol 7, no. 143). Lyon, France, International Agency for Research on Cancer, 1997 4. 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] 5. Struewing JP, Abeliovich D, Peretz T, et al: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11: 198-200, 1995[CrossRef][Medline]
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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 7. Abeliovich D, Kaduri L, Lerer I, et al: The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 60: 505-514, 1997[Medline] 8. 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]
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Muto MG, Cramer DW, Tangir J, et al: Frequency of the BRCA1 185delAG mutation among Jewish women with ovarian cancer and matched population controls. Cancer Res 56: 1250-1252, 1996 10. Modan B, Gak E, Sade-Bruchim RB, et al: High frequency of BRCA1 185delAG mutation in ovarian cancer in Israel: National Israel Study of Ovarian Cancer. JAMA 276: 1823-1825, 1996[Abstract] 11. 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]
12.
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 13. Burke W, Daly M, Garber J, et al: Recommendations for follow-up care of individuals with an inherited predisposition to cancer: II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 277: 997-1003, 1997[Abstract] 14. Bell R, Petticrew M, Sheldon T: The performance of screening tests for ovarian cancer: Results of a systematic review. Br J Obstet Gynaecol 105: 1136-1147, 1998[Medline] 15. Ford D, Easton DF, Bishop DT, et al: Risks of cancer in BRCA1 mutation carriers: Breast Cancer Linkage Consortium. Lancet 343: 692-695, 1994[CrossRef][Medline]
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Hopper JL, Southley MC, Dite GS, et al: Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Cancer Epidemiol Biomarkers Prev 8: 741-747, 1999
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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 18. Karlan BY, Raffel LJ, Crvenkovic G, et al: A multidisciplinary approach to the early detection of ovarian carcinoma: Rationale, protocol design, and early results. Am J Obstet Gynecol 169: 494-501, 1993[Medline] 19. Kuperstein G, Foulkes WD, Ghadirian P, et al: A rapid fluorescent multiplexed-PCR analysis (FMPA) for founder mutations in the BRCA1 and BRCA2 genes. Clin Genet 57: 213-220, 2000[CrossRef][Medline]
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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 21. Breslow NE, Day NE: Statistical Methods in Cancer Research, Vol 2: The Design and Analysis of Cohort Studies. Lyon, France, International Agency for Research on Cancer, 1987 22. Karlan BY, Baldwin RL, Lopez-Luevanos E, et al: Peritoneal serous papillary carcinoma, a phenotypic variant of familial ovarian cancer: Implications for ovarian cancer screening. Am J Obstet Gynecol 180: 917-928, 1999[CrossRef][Medline] 23. 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] 24. Tonin P, Weber B, Offit K, et al: Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 2: 1179-1183, 1996[CrossRef][Medline] 25. 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] 26. Sobol H, Jacquemier J, Bonaiti C, et al: Fallopian tube cancer as a feature of BRCA1-associated syndromes. Gynecol Oncol 78: 263-264, 2000[CrossRef][Medline]
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Cancer risks in BRCA2 mutation carriers: The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91: 1310-1316, 1999 28. 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]
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Meijers-Heijboer H, van Geel B, van Putten WL, et al: Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 345: 159-164, 2001
30.
Brekelmans CT, Seynaeve C, Bartels CC, et al: Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 19: 924-930, 2001 31. Gayther SA, Warren W, Mazoyer S, et al: Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet 11: 428-433, 1995[CrossRef][Medline] 32. Rebbeck TR: Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 18: 100S-103S, 2000 (suppl 21) 33. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study—Hereditary Breast Cancer Clinical Study Group. Lancet 356: 1876-1881, 2000[CrossRef][Medline] Submitted August 6, 2001; accepted November 26, 2001. This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
6 months before the diagnosis. 
