brca

Improved Survival for BRCA2-AssociatedSerous Ovarian Cancer Compared With BothBRCA-Negative and BRCA1-AssociatedSerous Ovarian CancerDavid M. Hyman, MD1; Qin Zhou, MA2; Alexia Iasonos, PhD2; Rachel N. Grisham, MD1; Angela G. Arnold, MS, CGC3;

Mary F. Phillips1,4; Jasmine Bhatia, BS3; Douglas A. Levine, MD4; Carol Aghajanian, MD1; Kenneth Offit, MD3;

Richard R. Barakat, MD4; David R. Spriggs, MD1; and Noah D. Kauff, MD3,4

BACKGROUND: Multiple observational studies have suggested that breast cancer gene (BRCA)-associated ovarian can-

cers have improved survival compared with BRCA-negative ovarian cancers. However, most of those studies combined

BRCA1 and BRCA2 patients or evaluated only BRCA1 patients. The objective of the current study was to examine whether

BRCA1-associated and BRCA2-associated ovarian cancers were associated with different outcomes. METHODS: This was

a single-institution, retrospective analysis of patients who had a new diagnosis of histologically confirmed stage III or IV

serous ovarian, fallopian tube, or primary peritoneal cancer between January 1, 1996 and February 1, 2011 and who under-

went BRCA mutation testing on 1 of 2 institutional review board-approved follow-up studies. Patients who had been

tested for BRCA mutations beyond 24 months of diagnosis were excluded from analysis to minimize selection bias from

including patients who were referred for genetic testing because of long survival. RESULTS: Data from 190 patients (143

BRCA-negative patients, 30 BRCA1-positive patients, and 17 BRCA2-positive patients) were analyzed. During the study pe-

riod, 73 deaths were observed (60 BRCA-negative patients, 10 BRCA1-positive patients, 3 BRCA2-positive patients). The

median follow-up for the remaining 117 survivors was 2.5 years. At 3 years, 69.4%, 90.7%, and 100% of BRCA-negative

patients, BRCA1-positive patients, and BRCA2-positive patients were alive, respectively. On univariate analysis, age, BRCA2

mutations, debulking status, and type of first-line therapy (intravenous or intraperitoneal) were significant predictors of

overall survival. On multivariate analysis, BRCA2 mutations (hazard ratio, 0.20; 95% confidence interval, 0.06-0.65; P ¼.007), but not BRCA1 mutations (hazard ratio, 0.70; 95% confidence interval, 0.36-1.38; P ¼ .31), predicted for improved

overall survival compared with BRCA-negative patients. When carriers of BRCA2 mutations were directly compared with

carriers of BRCA1 mutations, BRCA2 mutations appeared to confer improved overall survival (hazard ratio, 0.29; 95% con-

fidence interval, 0.08-1.05; P ¼ .060), although this finding did not reach significance. CONCLUSIONS: The current data

suggests that BRCA2 mutations confer an overall survival advantage compared with either being BRCA-negative or

having a BRCA1 mutation in high-grade serous ovarian cancer. This finding may have important implications for clini-

cal trial design. Cancer 2012;118:3703-9. VC 2011 American Cancer Society.

KEYWORDS: ovarian cancer, BRCA1, BRCA2, poly(ADP-ribose), polymerase inhibitors.

INTRODUCTIONOvarian cancer is the leading cause of death from gynecologic malignancies in the United States and is the fourthmost common cause of cancer death in women.1 An estimated 21,000 cases are diagnosed in the United States each year,resulting in 15,000 deaths. It is now recognized that approximately 10% of unselected cases and 16% to 21% of the high-grade serous subtype are caused by a hereditary susceptibility, of which breast cancer gene 1 (BRCA1) and breast cancergene 2 (BRCA2) mutations account for the majority.2-4

Although BRCA1 and BRCA2mutations both are implicated in the development of hereditary ovarian cancers, eachrepresents a clinically distinct entity in several important ways. The penetrance of ovarian cancer differs in these 2

DOI: 10.1002/cncr.26655, Received: August 11, 2011; Revised: September 20, 2011; Accepted: October 4, 2011, Published online December 2, 2011 in Wiley

Online Library (wileyonlinelibrary.com)

Corresponding author: Noah D. Kauff, MD, Clinical Genetics and Gynecology Services, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 295,

New York, NY 10065; Fax: (646) 888-4075

1Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; 2Department of Epidemiology

and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; 3Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering

Cancer Center, New York, New York; 4Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

Cancer August 1, 2012 3703

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populations, with a lifetime risk of 36% to 60% inBRCA1 mutation carriers and 16% to 27% in BRCA2mutation carriers.5-7 BRCA1 mutation carriers also de-velop ovarian cancers approximately 10 years earlier thanBRCA2 mutation carriers (median age at diagnosis, 53years and 62 years, respectively).8,9 The distinct underly-ing biology of BRCA1 and BRCA2-associated ovarian can-cers also has been characterized in comparative gene arrayprofiles, which demonstrated >100 nonredundant geneswith significantly different expression levels.10

Despite these clear biologic and clinical differences,investigators typically have grouped together BRCA1 andBRCA2 mutation carriers when investigating the progno-sis and survival of this subset of women with ovarian can-cer. In several observational studies, BRCA-associatedovarian cancers have been associated with improved over-all survival (OS).9,11-19 The majority of those studies,including the 3 largest to date, combined BRCA1 andBRCA2 mutation carriers in their survival analyses.9,14,19

Only 1 report independently evaluated the survival ofBRCA1 and BRCA2 mutation carriers, but the power ofthat analysis was limited because of the inclusion of only 6BRCA2-associated serous ovarian cancers.16 Given theseissues, we investigated survival with BRCA1-associated andBRCA2-associated ovarian cancers independently inpatients who received primary therapy at our institution.Our objective was to determine whether these 2 ovariancancer syndromes were associated with different prognoses.

MATERIALS AND METHODS

Patients

Institutional Review Board/Privacy Board (IRB/PB) ap-proval was obtained for this retrospective analysis. Eligiblepatients were seen at Memorial Sloan-Kettering CancerCenter (MSKCC) between January 1, 1996 and February1, 2011 for a new diagnosis of histologically confirmed,stage III or IV, serous ovarian, fallopian tube, or primaryperitoneal cancer and underwent germline BRCAmutationtesting on 1 of 2 IRB/PB-approved follow-up studies thatwere being conducted by the Clinical Genetics Service toinvestigate the clinical significance of germline BRCAmutations. Details of these 2 follow-up studies have beenpublished previously.20 For the current study, patients withnonhigh-grade histology (lowmalignant potential or Inter-national Federation of Gynecology and Obstetrics grade 1)and/or recurrent disease were excluded. Diagnoses wereconfirmed by a full-time gynecologic pathologist at a high-volume comprehensive cancer center. In the event there

was uncertainty regarding the diagnosis, the case wasreviewed at a gynecologic pathology consensus conference.Patients who were tested for BRCA mutations beyond 24months from diagnosis were excluded from the analysis tominimize the selection bias that could result from includ-ing patients who were referred for genetic testing becauseof long survival. Patients were considered to have a BRCA-associated cancer if their BRCA1 or BRCA2 mutation waspredicted to be deleterious. Patients with variants ofunknown significance were considered to be BRCA nega-tive. All patients received cytotoxic chemotherapy accord-ing to the appropriate institutional protocol at the time ofdiagnosis. This therapy could be intravenous alone (IV) orcombined intravenous and intraperitoneal (IP). Becausethe standard regimen for IP chemotherapy changed overthe time studied, patients were considered to have receivedIP chemotherapy if they received any IP cisplatin as part offirst-line therapy.

Statistical Methods

This was a single-institution, retrospective analysis withthe primary objective of determining OS of patients byBRCAmutation status (BRCA1-positive, BRCA2-positive,and BRCA-negative). The associations between clinicalfactors and BRCA mutation status were tested by eitherusing the Wilcoxon rank-sum test or the Kruskal-Wallistest for continuous variables or the Fisher exact test forcategorical variables. OS was calculated from the date of di-agnosis to the date of either death or last follow-up. Univar-iate OS analyses for BRCA mutation status, age, anddisease stage were performed using the log-rank test for cat-egorical variables or the Wald test based on Cox propor-tional hazards model for continuous variable. A landmarksurvival analysis was used to evaluate time-dependent cova-riates, such as timing of chemotherapy initiation or anattempt at surgical debulking.21 That analysis was condi-tional on being at risk at the landmark; therefore, patientswho had a follow-up time shorter than the landmark timewere excluded. Variables were regarded significant at a sig-nificance level of .05. A forward-selection technique wasused to build multivariate model using a significance levelof .05 for the variable to remain in the model.22 Analyseswere conducted using the SAS statistical software package(version 9.2; SAS Institute, Cary, NC).

BRCA Testing

During the study period, patients who presented for thetreatment of newly diagnosed pelvic serous cancerat MSKCC were not required to undergo genetic

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3704 Cancer August 1, 2012

counseling or testing. Between 1996 and 2008, patientstypically were referred based on at least 1 of the following:1) family history of breast cancer before age 50 years orovarian cancer at any age in a first-degree or second-degreerelative, 2) Eastern European (Ashkenazi) Jewish heritage,3) patient request, or 4) physician request. Since July 2008,genetic counseling has been offered to (but not required of)all patients diagnosed with high-grade serous ovarian can-cer irrespective of family history. For patients whose 4grandparents all were of Ashkenazi Jewish heritage,germline DNA was screened for the 3 Ashkenazi foundermutations (BRCA1*185delAG, BRCA1*5382insC, andBRCA2*6174delT). If these were wild-type and there was astrong family history of ovarian or early onset breast cancer,then sequencing of the entire coding and flanking intronicregions of both BRCA1 and BRCA2was performed byMyr-iad Genetics (Salt Lake City, Utah). For participants whowere not of exclusive Ashkenazi ancestry, sequencing ofBRCA1 and BRCA2 was performed in all cases. Testing forstructural rearrangements was obtained based on individualpatient characteristics and testing coverage.

RESULTSIn total, 190 patients (143 BRCA-negative patients, 30BRCA1-positive patients, and 17 BRCA2-positivepatients) were eligible for analysis. No patient had muta-tions in both BRCA1 and BRCA2. Sixty-eight (36%)patients reported 4 Ashkenazi Jewish (AJ) grandparents,

18 (9%) reported at least 1 AJ grandparent, and theremaining 104 (55%) were of entirely non-AJ decent.Baseline demographic and treatment data are listed in Ta-ble 1. There were no significant differences between theBRCA1-positive patients and the BRCA2-positive patientsin distribution according to age, disease stage, debulkingoutcomes (optimal vs suboptimal), or first-line therapy(IV vs IP). Comparing across all 3 groups, the BRCA-posi-tive patients were more likely to be younger, to haveundergone optimal debulking and to have received IP-based first-line chemotherapy.

Survival data and univariate OS analysis are pre-sented in Table 2. During the period of follow-up, therewere 73 deaths (10 deaths in BRCA1-positive patients, 3deaths in BRCA2-positive patients, and 60 deaths inBRCA-negative patients). The OS rate at 3 years for theBRCA-negative, BRCA1-positive, and BRCA2-positivepatients was 69.4%, 90.7%, and 100%, respectively.The median survival for BRCA-negative and BRCA1-positive patients was 4.3 years and 5.6 years, respectively.At median follow-up of 5.3 years for the survivingBRCA2-positive patients, the median survival hadnot yet been reached. The median follow-up for theremaining 117 surviving patients was 2.5 years (range,0.47-13.1 years).

The impact of age, disease stage, debulking status,and type of first-line therapy (IV or IP) on OS was ana-lyzed using univariate analyses. Of these variables, onlyage (10-year hazard ratio [HR], 1.38; 95% confidence

Table 1. Patient Demographics

No. of Patients (%) P

Variable All BRCANegative

BRCA1Positive

BRCA2Positive

Test forGroup

Test for BRCA1vs BRCA2

All patients 190 143 30 17

Age at diagnosis, yMedian [mean] 59 [58.45] 61 [59.72] 55 [53.7] 56 [56.12] .008 .41

Range 32-78 37-78 32-73 40-74

StageIII 148 (77.9) 110 (76.9) 23 (76.7) 15 (88.2) .63 .46

IV 42 (22.1) 33 (23.1) 7 (23.3) 2 (11.8)

Optimal debulkingNo 45 (23.7) 41 (28.7) 2 (6.7) 2 (11.8) .012 .61

Yes 145 (76.3) 102 (71.3) 28 (93.3) 15 (88.2)

IP/IVa

IV 95 (50.5) 82 (57.7) 10 (33.3) 3 (18.8) .001 .49

IP 93 (49.5) 60 (42.3) 20 (66.7) 13 (81.3)

Abbreviations: BRCA1/BRCA2, breast cancer genes 1 and 2, respectively; BRCA negative, negative for mutations in both BRCA genes; IP, combined intrave-

nous and intraperitoneal therapy; IV, intravenous therapy alone.a Two patients were missing information.

Improved Survival in BRCA2þ Ovarian Ca/Hyman et al


interval [CI], 1.08-1.77), optimal debulking status (HR,0.50; 95% CI, 0.31-0.82), and IP therapy (HR, 0.51;95% CI, 0.32-0.83) were statistically significant predic-tors of survival. Surgical stage (III vs IV) was not associ-ated significantly with survival, although the majority of

patients had stage III disease (78%; 148 of 190 patients).When BRCA mutation status (BRCA1-positive, BRCA2-positive, and BRCA-negative) was examined in univariatefashion, BRCA2 mutations (HR, 0.19; 95% CI, 0.06-0.62), but not BRCA1 mutations (HR, 0.61; 95% CI,0.31-1.20), were a significant predictor of OS (Figure 1).

The effect of BRCA mutation status on OS also wasevaluated in a multivariate analysis. The results are pre-sented in Table 3. By using a forward-selection technique,the covariates age, optimal versus suboptimal debulking,and BRCA mutation status were selected for inclusion inthe final multivariate model. The type of first-line therapywas not included, because it did not reach statistical signif-icance in the final model. This probably was because ofthe substantial correlation between debulking status and

Table 3. Multivariate Overall Survivala

Variable HR (95% CI) P

Age at diagnosis; 10-y HR 1.32 (1.02-1.71) .035

BRCA1 positive vs BRCA negative 0.70 (0.36-1.38) .31

BRCA2 positive vs BRCA negative 0.20 (0.06-0.65) .007

Optimal vs suboptimal debulking 0.60 (0.36-1.00) .050

Abbreviations: BRCA1/BRCA2, breast cancer genes 1 and 2, respectively;

BRCA negative, negative for mutations in both BRCA genes; CI, confidence

interval; HR, hazard ratio.a Landmark analysis was used to build this multivariate model.

Figure 1. Kaplan-Meier curves illustrating overall survival forpatients with breast cancer gene (BRCA)-negative, BRCA1-posi-tive, and BRCA2-positive high-grade serous ovarian cancer.

Table 2. Univariate Overall Survival Analyses

Variable No. ofPatients

No. ofDeaths

3-YearOS rate(95% CI), %

MedianSurvival(95% CI), y

HR(95% CI)

Log-Rank P

All 190 73 75.8 (67.7-82.1) 5.4 (4.2-5.9)

BRCA mutation statusBRCA negative 143 60 69.4 (59.4-77.3) 4.3 (3.6-5.5) Ref .005a

BRCA1 positive 30 10 90.7 (67.6-97.6) 5.6 (3.5-Not estimable) 0.61 (0.31-1.2)

BRCA2 positive 17 3 100 Not reached 0.19 (0.06-0.62)

Age at diagnosis; 10-y HR 1.38 (1.08-1.77) .01

StageIII 148 58 79.7 (70.9-86.1) 5.4 (4.3-6.0) Ref .38

IV 42 15 60.3 (39.4-76.1) 3.5 (2.7-Not estimable) 1.29 (0.73-2.29)

Optimal debulkingb

No 44 23 45.6 (27.2-62.3) 3.0 (1.7-4.0) Ref .005

Yes 144 50 70.6 (60-78.9) 4.9 (3.7-5.8) 0.5 (0.31-0.82)

IP/IVc

IV 94 47 58.1 (45.3-69) 3.7 (2.7-5.0) Ref .005

IP 93 26 74.2 (60.3-83.9) 5.0 (3.8-Not Estimable) 0.51 (0.32-0.83)

Abbreviations: BRCA1/BRCA2, breast cancer genes 1 and 2, respectively; BRCA negative, negative for mutations in both BRCA genes; CI, confidence interval;

HR, hazard ratio; IP, combined intravenous and intraperitoneal therapy; IV, intravenous therapy alone; OS, overall survival; Ref, reference level.a The log-rank P value was .150 for BRCA1 positive vs BRCA negative, .003 for BRCA2 positive vs BRCA-negative, and .050 for BRCA1 positive vs BRCA2 positive.b Two patients were excluded from the landmark analysis.c Two patients were missing information, and 1 patient was excluded from the landmark analysis.

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receipt of IP chemotherapy. In the final multivariatemodel, only BRCA2 mutation status (HR, 0.20; 95% CI,0.06-0.65; P ¼ .007) and age (10-year HR, 1.32; 95%CI, 1.02-1.71; P ¼ .035) remained significant predictorsof OS. Optimal debulking status had borderline signifi-cance, and BRCA1 mutation status was not a significantpredictor of survival (HR, 0.70; 95% CI, 0.36-1.38; P ¼.31). When carriers of BRCA2 mutations were compareddirectly with carriers of BRCA1 mutations in our multi-variate model setting, BRCA2 mutations appeared to pre-dict for substantially improved survival (HR, 0.29; 95%CI, 0.08-1.05; P ¼ .06), although this finding did notquite reach statistical significance.

DISCUSSIONOur data suggest that women who have BRCA2-associ-ated serous ovarian cancer may have a meaningfully differ-ent outcome compared not only with women who haveBRCA-negative disease but also compared with those whohave BRCA1-associated, high-grade serous ovarian cancer.This finding, if confirmed, will have an important impacton clinical trial design given the 16% to 21% prevalenceof germline BRCA mutations in unselected patients withserous ovarian cancer. The ongoing and upcoming trialsof poly(ADP-ribose) polymerase (PARP) inhibitors inhigh-grade epithelial ovarian cancer, many of which willspecifically enrich for BRCA1 and BRCA2 carriers, may beat particular risk for confounded results if stratification ofthese 2 groups is not considered.

Our analysis has several strengths. Unlike severalother survival analyses of BRCA-associated ovarian can-cers, we restricted our analysis to only advanced-stage (III/IV), high-grade serous tumors, the ovarian cancer subtypethat accounts for the majority of the morbidity and mor-tality related to ovarian cancer.23 We also chose to limit orcohort to patients who presented to our institution at thetime of diagnosis, because the likelihood of recurrence af-ter initial therapy may be linked to BRCA status. Further,the patients in the present analysis were treated almostexclusively at a single institution with common surgicaland medical standards over the study period, minimizingthe possibility that our analysis was confounded by subtledifferences in surgical or chemotherapeutic managementstyles across institutions or time. Our analysis also waslimited to patients who had been tested for BRCA muta-tions within 2 years of their initial diagnosis of ovariancancer. This restriction, which caused us to remove 43patients from the analysis, eliminated patients who mayhave undergone BRCA testing because of unexpected lon-

gevity or persistent sensitivity to chemotherapy. Finally,all control (BRCA-negative) patients in our analysis wereconfirmed noncarriers rather then untested, matched con-trols, which was the case in some previously publishedreports.11,17

This analysis does have several limitations. Our find-ings are based on a convenience sample of patients whowere tested for BRCA mutations. During the periodincluded in this report, our institution treated approxi-mately 1200 unique cases of newly diagnosed and recur-rent, stage III/IV, high-grade serous ovarian cancers,which means that only approximately 15% of potentialcases were captured for our analysis. This relatively lowcapture rate reflects several factors, including the lack ofuniversal BRCA mutation testing and the use of strictinclusion and exclusion criteria in the study design tominimize bias. In addition, only patients who were testedfor BRCA mutations on 1 of 2 IRB-approved follow-upprotocols were included because of unique patient issuesand privacy concerns related to germline genetic testing.It is not possible to speculate how a higher rate of capturewould have affected our results.

Differences in the BRCA1-associated, BRCA2-asso-ciated, and BRCA-negative cohorts are also worth address-ing. The BRCA2-associated cohort included only 11.8%of stage IV patients compared with 23.3% and 23.1% inthe BRCA1-associated and BRCA-negative cohorts.Although neither difference was statistically significant, arepeat analysis limited to stage III patients did not changethe conclusions presented here (data not shown). Patientswith BRCA1 or BRCA2 mutations also were more likelyto have undergone optimal debulking and to havereceived IP-based first-line chemotherapy. Because IPchemotherapy traditionally has been restricted to patientswho undergo optimal debulking, it is likely that these 2findings were correlated.

Our analysis revealed a trend toward improved sur-vival in BRCA1 mutation carriers compared with BRCA-negative patients, although this finding did not reach sig-nificance (HR, 0.70; 95% CI, 0.36-1.38; P ¼ .31). Thisis consistent with other published data. In the large, mul-tivariate analysis reported by Chetrit et al, BRCA1 muta-tions demonstrated a similar impact on survival (HR,0.82; 95% CI, 0.63-1.05; P ¼ .10).14 It is unclearwhether this result would reach statistical significance inan even larger cohort.

Finally, the data presented here do not provideinsight into the reason for improved survival in BRCA2mutation carriers compared with BRCA1 mutation



carriers and BRCA-negative patients. The relative contri-butions of improved chemotherapy sensitivity versusunderlying differences in tumor biology are unclear. Acase-control study by Tan and colleagues revealed higherrates of platinum sensitivity across first-line, second-line,and third-line therapy for patients with BRCA1/BRCA2mutation-positive ovarian cancer compared with matchedcontrols.18 However, their report included only 22 BRCAmutation carriers (17 BRCA1 mutation carriers and 5BRCA2 mutation carriers) and did not attempt to compareBRCA1-associated and BRCA2-associated outcomes. Morerecently, our group examined predictors of survival in a sub-set of the patients included in the current report.15 In thatprevious work, both the presence of a BRCA mutation andplatinum sensitivity were independent predictors of survival,suggesting that both tumor biology and chemotherapy sensi-tivity may contribute to prolonged survival. However, thatearlier study also was not powered to examine at differencesbetween carriers of BRCA1 mutations and BRCA2 muta-tions. Ultimately, the mechanisms through which BRCA1and BRCA2mutations may result in different tumor biologyare poorly understood and require further research.

Until recently, all ovarian cancers have been man-aged similarly regardless of germline BRCA mutation sta-tus. Although it has been suggested for more than adecade that BRCA1/BRCA2-associated ovarian cancershave a more favorable prognosis compared with BRCA-negative tumors, there have been no targeted therapiesavailable to exploit the underlying biologic differencesbetween these tumors. Since the development of PARPinhibitors, which may be specifically active in BRCA-defi-cient tumors, the molecular subclassification of ovariancancers has become increasingly important.24 BRCA-defi-cient tumors have alterations in homologous recombina-tion, the DNA repair pathway responsible for high-fidelity resolution of double-stranded DNA breaks andcross-links.25 PARP inhibitors block base excision repair,a lower fidelity salvage DNA repair pathway necessary tomaintain genomic stability in tumors deficient in homol-ogous recombination, and are an extremely promisingclass of agents for treating BRCA-deficient ovarian can-cer.26 However, the mechanism of BRCA inactivation, andthe associated loss of homologous recombination function,may be important. Hennessy et al reported on a cohort of44 ovarian cancer specimens that were tested for BRCA1/BRCA2 mutations.27 Thirty-three (75%) of the mutationswere germline, and the remaining 11 (25%) were somatic.In that analysis, patients who had loss of BRCA functionthrough either mechanism had improved progression-free

survival compared with patients who had intact BRCAfunction. However, those authors did not report the out-comes of germline and somatically mutated tumors sepa-rately. Finally, their analysis did not examine specimens forepigenetic BRCA inactivation. Recent data generated byThe Cancer Genome Atlas Ovarian Project demonstratethat, although approximately 50% of high-grade serousovarian tumors have alterations in the homologous recom-bination pathway by BRCA1/BRCA2 germline mutation,somatic mutation, epigenetic silencing, or other putativehomologous recombination defects, patients who havetumors with epigenetically silenced BRCA1 have signifi-cantly worse outcomes than patients who had tumors withgermline and somatic BRCA1/BRCA2 mutations.19 Likeour current findings, these results strongly suggest that themethods and types of BRCA inactivation may have differ-ent prognostic implications.

Although our analysis indicates that presence of aBRCA2 mutation is an important predictor of survivalcompared with both being BRCA-negative or having aBRCA1 mutation, it seems appropriate to consider thisreport hypothesis generating rather then definitive giventhe relatively small number of patients and events (only 3deaths in the BRCA2-associated cohort). These conclu-sions certainly will need to be validated in prospectivedata sets. However, our findings indicate that, in theemerging era of targeted therapies for molecularly charac-terized subtypes of ovarian cancer, the grouping ofBRCA1 and BRCA2 mutations, which cause two relatedbut distinct cancer susceptibility syndromes, may not beappropriate, and strong consideration should be given tostratifying future studies in ovarian cancer according toBRCA1 and BRCA2mutation status.

FUNDING SOURCESThis work was supported by Project Hope for Ovarian CancerResearch and Education, the Kaleidoscope of Hope Foundation,the Genet Fund, and by NIH Grant # P01-CA52477-17.

CONFLICT OF INTEREST DISCLOSURESN.D.K. has received consulting fees and has been an expertwitness for Pfizer.

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