Journal of Clinical Oncology, Vol 20, Issue 2
(January), 2002: 463-466
© 2002 American Society for Clinical Oncology
Effect of BRCA Mutations on the Length of Survival in Epithelial Ovarian Tumors
By Y. Ben David,
A. Chetrit,
G. Hirsh-Yechezkel,
E. Friedman,
B.D. Beck,
U. Beller,
G. Ben-Baruch,
A. Fishman,
H. Levavi,
F. Lubin,
J. Menczer,
B. Piura,
J.P. Struewing,
B. Modan for the National Israeli Study of Ovarian Cancer
From the Department of Gynecology, Haemek Medical Center, Afula; Department of Clinical Epidemiology and Oncogenetic and Gynecology Oncology Units, Sheba Medical Center, Tel Hashomer; Department of Gynecology, Rambam Medical Center, Haifa; Department of Gynecology, Shaare Zedek Medical Center, Jerusalem; Department of Gynecology, Sapir Medical Center, Kfar Saba; Department of Gynecology, Rabin Medical Center, Petah Tikvah; Department of Gynecology, E. Wolfson Medical Center, Holon; Department of Gynecology, Soroka Medical Center, Beer Sheva; and Stanley Steyer Institute, Tel Aviv University Medical School, and Ariel College, Tel Aviv, Israel; and Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD.
Address reprint requests to Angela Chetrit, MSc Unit of Cancer Epidemiology, Gertner Institute, Chaim Sheba Medical Center, RamatGan, Israel; email: angelac{at}gertner.health.gov.il
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ABSTRACT
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PURPOSE: To study the role of BRCA mutations in ovarian cancer survival.
PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors.
RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v 37.8 months; 3-year survival, 65.8% v 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease.
CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.
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INTRODUCTION
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THE QUESTION OF WHETHER women with ovarian cancer who are carriers of BRCA germline mutations have specific prognostic patterns has not yet been resolved. Rubin et al1 reported an apparently significantly prolonged survival for ovarian cancer patients carrying the BRCA1 germline mutation, as compared with a matched control group of noncarrier patients. A similar observation was noted by Aida et al.2 However, this conclusion was challenged on methodologic grounds.3-5 In contrast, Johansson et al6 suggested that the survival of carriers of the BRCA1 mutation would be similar or worse than that of patients with breast and ovarian cancer in general. More recently, Boyd et al7 indirectly supported Rubin’s data. We attempted to assess this question on the basis of a nationwide ovarian cancer study.
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PATIENTS AND METHODS
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Study Population
Our national epidemiologic case-control study of ovarian cancer in Israel (the National Israeli Study of Ovarian Cancer)8 was designed to assess environmental, hormonal, and genetic risk factors for ovarian cancer. In this study, all newly diagnosed women with ovarian cancer in Israel between March 1994 and July 1999 were interviewed using questionnaires that covered a wide range of relevant factors associated with ovarian cancer etiology. When the study was initiated, the relationship of ovarian cancer with BRCA and appropriate laboratory technology had not yet been established; therefore, our molecular analysis started 2 years later. Blood samples or tumor tissues (whenever blood samples were not available) have been collected for analysis of the germline BRCA mutations since January 1996, when these tests became available to us.
Clinical data were abstracted from the medical records. For each patient, data on age at diagnosis, tumor type, and stage of tumor were recorded. All patients were treated by debulking surgery, followed by a platin-based combination chemotherapeutic regimen. Vital status was updated through the National Population Registry. A total of 1,269 women with epithelial ovarian cancer were interviewed. Of these, 896 were tested for BRCA mutations and followed for up to 5 years (median, 30.5 months). Among the 373 women who were not tested, there were 37 refusals and 22 incomplete mutation analyses; the rest of the women who were not tested were mostly women accrued to the study before the genetic component was initiated. Informed consent for the genetic analysis was obtained from all study subjects, and the study received the approval of the institutional review board and the Ministry of Health.
Mutation Analysis
Blood samples and/or tissue specimens of ovarian tumors at the time of primary surgery were obtained from each of the study patients. All subjects were tested for the two common founder mutations in BRCA1 (185delAG and 5382insC) and the single founder mutation in BRCA2 (617delT) using methods as described previously.9 Briefly, a multiplex polymerase chain reaction was designed to coamplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms using a genetic analyzer (model 310; Applied Biosystems, Foster City, CA) and Genescan software (Applied Biosystems). All molecular analysis was done at the United States National Cancer Institute Laboratory for Population Genetics under the supervision of J.P.S.9
Statistical Analysis
The 896 women who underwent molecular testing were initially compared with the 373 nontested women accrued in the entire nationwide study in order to assess the representativeness of the sample. The  2 test was used for comparison of categorical variables and one-way analysis of variance was used for continuous variables between the group of mutation carriers and the noncarriers. Survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test. Median survival time is presented with the Brookmeyer 95% confidence interval (CI).10,11 Stepwise Cox regression analysis was used to determine independent prognostic factors (age, stage, and family history).
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RESULTS
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The distributions of age and ethnic origin were not different among women with epithelial ovarian cancer in whom mutation testing was completed, as compared with the nontested group. However, fewer women from the low malignant potential (LMP) tumor category and more women with stage III-IV disease and a positive family history were tested for BRCA1/BRCA2 mutations; therefore, further analysis was stratified by these parameters.
Of the 896 epithelial-tested patients, 234 (26.1%) were found to be carriers of BRCA mutations (17.3% for BRCA1- 185delAG, 2.1% for BRCA1-5382insC, and 6.7% for BRCA2-6174delT). Median age at diagnosis of the carrier patients was 56.5 years, as compared with 59 years among the noncarriers (P = .001). The median follow-up time from diagnosis was 30.5 months.
Median survival from diagnosis for the total epithelial group was 51.2 months (95% CI, 45.1 to 63.1 months); for women in the LMP tumor category, over 76 months; for women in the invasive category, 40.9 months (95% CI, 38.0 to 45.3 months), and for women with stage III-IV disease, 35.9 months (95% CI, 33.2 to 39.1 months).
As expected, we observed a better survival for the group of women with tumors of LMP compared with women with invasive ovarian cancer (Fig 1). Also, a significantly smaller proportion of mutations was found (five women) in the LMP group as compared with the invasive group (2.1% v 16% respectively, P = .001). Further analysis was limited to the invasive category.
Three-year survival rates for carriers were found to be significantly higher than among the noncarriers (65.8% v 51.9%, P < .001) (Fig 2). This differential survival pattern between carriers and noncarriers persisted when age at diagnosis (not shown) and stage were considered (Fig 3). The survival of women with BRCA1 (185delAG and 5382insC) mutations was not significantly different than the survival of women with the BRCA2 (6174delT) mutation (Table 1).
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Fig 3. Survival of women with stage III-IV epithelial invasive ovarian cancer by presence of BRCA1/2 mutations.
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Median survival time among stage III-IV patients was 51.2 months (95% CI, 40.4 to 60.6 months) in carriers and 33.1 months (95% CI, 28.8 to 35.9 months) in noncarriers, and 3-year survival rates were 60.3% and 44.5%, respectively (Fig 3). This effect was also present when stages III and IV were analyzed separately. The dissimilar survival pattern between carriers and noncarriers persisted when adjustments for various prognostic factors, such as age, stage, and family history, were performed.
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DISCUSSION
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Our findings, which are based on nationwide data, underline the relatively superior survival of BRCA carriers, irrespective of age, stage, and family history. The fact that the effect was present in all disease stages indicates that the results are not due to early detection of the disease among BRCA carriers. It has been suggested recently that women with breast cancer who are carriers of BRCA mutations may have a pattern of disease different from that of noncarriers or those without hereditary disease. They were reported to have tumors with a higher histologic grade but nevertheless a more favorable course as compared with noncarriers with tumors of the same grades.12-15 Our findings support such a relationship in a nationwide study population, independently of the rate of mutations and stage at diagnosis, and are in line with the recent observation of Boyd et al7 and Rubin et al,1 who studied women with hereditary versus nonhereditary ovarian cancer. Boyd et al suggested two possible mechanisms for the better survival of BRCA carriers: a potential indolent clinical behavior through a slower rate of cell division or, alternatively, a more favorable response to chemotherapy. Other investigators suggested that the BRCA genes are involved in cellular response to DNA damage.16,17
As in many similar studies, our study has certain limitations. Paclitaxel has been used as a first-line chemotherapy agent in Israel only since late 1995. Therefore, its potential influence on survival of our study group is small and difficult to measure. Also, we assumed that all patients were uniformly treated by maximum debulking surgery followed by a cisplatin-based combination chemotherapy regimen in all hospitals, yet since no mandatory protocol was used, some women might have been treated otherwise.
Further follow-up of our ongoing study will allow us to clarify whether these results are maintained through a longer follow-up period or are just limited to the early period of the disease.
APPENDIX National Israeli Study of Ovarian Cancer Members
The members of the National Israeli Study of Ovarian Cancer are:Shmuel Anderman, MD; Marco Altaras, MD; Shaul Anteby, MD; Jack Atad, MD; Amiram Avni, MD; Amiran Bar-Am, MD; Dan Beck, MD; Uzi Beller, MD; Gilad Ben-Baruch, MD; Yehuda Ben-David, MD; Haim Biran, MD; Moshe Ben Ami, MD; Angela Chetrit, MSc; Shlomit Cohan, MD; Ram Dgani MD; Yehudit Fishler, CTR; Ami Fishman, MD; Eitan Friedman, PhD; Ofer Gemer, MD; Ruth Gershoni, MD; Reuvit Halperin, MD; Galit Hirsh-Yechezkel, BSc; David Idelman, MD; Rafael Katan, MD; Yuri Kopilovic, MD; Efrat Lahad, MD; Liat Lerner Geva, MD; Albert Levit, MD; Beatriz Lifschiz-Mercer, MD; Flora Lubin, MSc, RD; Zohar Liviatan, MD; Jacob Markovich, MD; Joseph Menzcer, MD; Baruch Modan, MD (Chairman); Hedva Nitzan, RN, MPH; Moshe Oettinger, MD; Tamar Peretz, MD; Benjamin Piura, MD; Shulamit Rizel, MD; Adi Shani, MD; David Schneider, MD; Michael Shtark, MD; Mariana Shteiner, MD; Zion Tal, MD; Chaim Yaffe, MD; Ilana Yanai, MD; Shifra Zohar, MD; and Ahuva Zoltan, RN, BA.
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ACKNOWLEDGMENTS
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Supported in part by grant no. CA 61126-03 from the National Cancer Institute, National Institutes of Health, Bethesda, MD, and a grant from the Israel Cancer Association.
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Submitted March 5, 2001;
accepted August 20, 2001.
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ABSTRACT
INTRODUCTION
