Clinical and Pathological Features of Ovarian Cancer in Women with Germ-Line Mutations of BRCA1
Stephen C. Rubin, M.D., Ivor Benjamin, M.D., Kian Behbakht, M.D., Hiroyuki Takahashi, M.D., Ph.D., Mark A. Morgan, M.D., Virginia A. LiVolsi, M.D., Andrew Berchuck, M.D., Michael G. Muto, M.D., Judy E. Garber, M.D., Barbara L. Weber, M.D., Henry T. Lynch, M.D., and Jeff Boyd, Ph.D.
Background We tested the hypothesis that ovarian cancers associatedwith germ-line mutations of BRCA1 have distinct clinical andpathological features as compared with sporadic ovarian cancers.
Methods We reviewed clinical and pathological data on patientswith primary epithelial ovarian cancer found to have germ-linemutations of BRCA1. Survival among patients with advanced-stagecancer and such mutations was compared with that in controlpatients matched for age and stage, grade, and histologic subtypeof the tumors. A combination of single-strand conformation andsequencing analyses was used to examine the 22 coding exonsand intronic splice-donor and splice-acceptor regions of BRCA1for mutations in pathological specimens. Alternatively, somepatients were known to be obligate carriers of the mutant BRCA1gene because of their parental relationships with documentedmutant-gene carriers.
Results We identified 53 patients with germ-line mutations ofBRCA1. The average age at diagnosis was 48 years (range, 28to 78). Histologic examination in 43 of the 53 patients showedserous adenocarcinoma. Thirty-seven tumors were of grade 3,11 were of grade 2, 2 were of grade 1, and 3 were of low malignantpotential. In 38 patients, the tumors were of stage III; 9 patients(including those with tumors of low malignant potential) hadstage I disease, 5 had stage IV, and 1 had stage II. As of June1996, with a median follow-up among survivors of 71 months fromdiagnosis, 20 patients had died of ovarian cancer, 27 had noevidence of the disease, 4 were alive with the disease, and2 had died of other diseases. Actuarial median survival forthe 43 patients with advanced-stage disease was 77 months, ascompared with 29 months for the matched controls (P<0.001).
Conclusions As compared with sporadic ovarian cancers, cancersassociated with BRCA1 mutations appear to have a significantlymore favorable clinical course.
Adenocarcinoma of the ovary causes the death of more Americanwomen each year than all other gynecologic cancers combined.About 5 to 10 percent of ovarian cancers are familial, and severalfamilial-cancer syndromes that include ovarian cancer have beenidentified.1 In most families affected with the breast-and-ovarian-cancersyndrome or site-specific ovarian cancer, genetic linkage hasbeen found to the BRCA1 locus on chromosome 17q21.2,3 Allelicdeletion at the BRCA1 locus in tumors from these linked familymembers invariably involves the wild-type chromosome, suggestingthat BRCA1 functions as a tumor-suppressor gene.4 The cloningof BRCA15 has allowed direct identification of BRCA1 mutationsin both sporadic and hereditary ovarian cancer. Although allelicdeletions in the region of the BRCA1 locus are common in sporadicovarian cancers, the recent finding that BRCA1 mutations insporadic tumors are rare suggests the involvement of an additionaltumor-suppressor gene in this region of chromosome 17q.6
The likelihood that distinct molecular abnormalities contributeto the pathogenesis of hereditary and sporadic ovarian cancersraises the question of whether these tumors also have distinctclinical and histopathological characteristics. In this report,we examine the clinical and pathological characteristics ofovarian cancers in 53 women with documented germ-line mutationsof BRCA1.
Methods
Mutational Analysis
The molecular-analysis technique used in our laboratory hasbeen described in detail elsewhere.6 This technique, or minorvariations of it, was also used at the centers participatingin this study. In brief, specimens of epithelial ovarian cancerwere obtained from the tissue-bank archives of the participatinginstitutions. The study was approved by the respective institutionalreview boards, and informed consent was obtained before tissuecollection and analysis. Corresponding normal tissues used forthe analysis of germ-line DNA were either peripheral-blood lymphocytesor normal gynecologic tissues removed at the time of surgery.All tumors used in this study were obtained from primary-siteovarian cancers in previously untreated patients.
The polymerase chain reaction was used to amplify genomic DNAfor single-strand conformation polymorphism analysis. Intron-basedprimers surrounding each of the 22 exons of BRCA1 were used,with the exceptions that 16 overlapping primer sets were usedto examine exon 11 and that 2 additional primer sets were designedto amplify exons 6 and 7 as two separate products. Exons 1 and4 are noncoding and were not examined. All variants of single-strandconformation polymorphisms were examined by direct sequenceanalysis to determine mutations. Alternatively, some patientswere obligate carriers of the mutant BRCA1 gene, on the basisof their parental relationships with documented mutant-genecarriers, as determined by pedigree analysis.
Pathological and Clinical Analyses
At each participating center, investigators identified all thepatients with ovarian cancer who had germ-line mutations ofBRCA1 and for whom the necessary pathological and clinical datawere available, including the date of diagnosis; age; stage,histologic subtype, and grade of the tumor; and clinical follow-up.It was not necessary for the patients to have been seen at theparticipating institution. In many instances, clinical carehad been rendered in the community, and patients were identifiedas carriers of BRCA1 mutations only after death, through molecularanalysis of archival specimens or pedigree analysis initiatedby a relative. The data were abstracted from the medical recordsand recorded in a spreadsheet for statistical analysis. Patientsfor whom histologic specimens were available and reviewed included11 patients at the University of Pennsylvania and 3 at DukeUniversity.
The long-term survival of the patients with mutant BRCA1 geneswas compared with that of a control group of patients with ovariancancer selected from the clinical data base of the Society ofGynecologic Oncologists in use at the University of Pennsylvaniasince 1989, which currently contains data on 594 patients withovarian cancer.7 Each patient was matched to a control subjectfor age (within five years) and tumor stage, histologic subtype,and grade. All the controls had had their disease diagnoseda minimum of three years before the time of analysis, and nonehad family histories suggestive of hereditary cancer syndromes.Survival data were calculated by the method of Kaplan and Meier8 and compared by the log-rank test.9
Results
A total of 53 patients with ovarian cancer and germ-line mutationsof BRCA1 were identified: 29 from the University of Pennsylvania,9 from Creighton University, 8 from Dana–Farber CancerInstitute, 4 from Duke University, and 3 from Brigham and Women'sHospital. BRCA1 mutations were identified in 45 patients bymolecular analysis, and 8 patients were determined to be obligatemutation carriers by pedigree analysis. The mean age at diagnosisamong the 53 patients was 48 years (range, 28 to 78); the meanin the control group was 49 years. Table 1 shows the stage,histologic grade, and histologic subtype of the tumors fromthe 53 women. Two of the tumors of low malignant potential wereof the serous type; one was mucinous.
Table 1. Stage, Grade, and Histologic Subtype of Ovarian Cancers Occurring in 53 Women with Germ-line Mutations of BRCA1.
The median follow-up for all surviving patients was 71 monthsfrom the time of diagnosis. As of June 1996, 20 patients haddied of ovarian cancer a median of 35 months from diagnosis.Twenty-seven remained alive with no evidence of disease, fourremained alive with ovarian cancer, and two had died of otherdiseases with no evidence of ovarian cancer present. Figure 1shows the actuarial survival of the 43 patients with advanced-stagedisease (38 with stage III and 5 with stage IV) as comparedwith the survival of the matched control group. The differencein survival is significant at the P<0.001 level. There wasno correlation between any of the clinicopathological featureswe examined and a particular BRCA1 mutation.
Figure 1. Actuarial Survival among 43 Patients with Advanced-Stage Ovarian Cancer and Germ-Line BRCA1 Mutations, as Compared with Matched Controls without Such Mutations.
P<0.001 by the log-rank test. The triangles and inverted triangles indicate the durations of follow-up among surviving patients.
Discussion
In our study of the clinical features of ovarian cancers inwomen with documented germ-line mutations of the BRCA1 gene,the average age at diagnosis, 48 years, was more than 10 yearsless than the mean age of 61 reported in a large sample of patientswith ovarian cancer.10 Tumors of the serous type, which constituteabout 46 percent of all epithelial ovarian carcinomas,11 predominateamong women with BRCA1 mutations. The distribution of patientsaccording to stage and grade appears fairly typical, and itis apparent that tumors of low malignant potential can arisein association with BRCA1 mutations. Because our patients wereseen at several institutions and in some cases received primarytreatment elsewhere, some relevant clinical information, includingthe extent of surgical tumor resection and the type of chemotherapyused, was not available. From the information we obtained, however,it appears that hereditary ovarian cancers arising in associationwith germ-line mutations of BRCA1 may differ substantially fromthose that arise sporadically.
The survival of patients with BRCA1 mutations and advanced-stageovarian cancers appears to be notably longer than the survivalof matched controls not known to have hereditary cancers. Ouradvanced-stage control group had an actuarial median survivalof 29 months, similar to that typically seen in patients withadvanced ovarian cancer before the advent of paclitaxel chemotherapy,12whereas the BRCA1-related cases have an actuarial median survivalof 77 months (P<0.001).
The selection of a historical control group must always be approachedcautiously, but it is likely that our use of the control groupwe selected actually resulted in an underestimate of the magnitudeof the survival difference. There is strong evidence from large-scaleprospective, randomized trials that a patient's age is an importantindependent prognostic factor for survival in advanced-stageovarian cancer.13 By selecting age-matched controls, we defineda population of relatively young patients with ovarian cancer,who on the basis of age alone would be expected to have morefavorable outcomes than older patients.
The youth of the control group also increased the likelihoodthat patients with undetected BRCA1 mutations were includedin this group. In two recent studies of patients with breastcancer who were 35 years of age or younger, 7.5 percent of thewomen under 3514 and 13 percent of the women under 3015 werefound to have BRCA1 mutations that were unsuspected on the basisof their family histories. In view of the considerable survivaladvantage among patients known to have BRCA1-related ovariancancers, it seems likely that a factor in the favorable prognosisof younger women with ovarian cancer is the relatively highfrequency of BRCA1 mutations in this population. Our controlpopulation was made up of women who were treated relativelyrecently by gynecologic oncologists at an academic medical center— a fact that might improve their survival relative tothat of the patients with BRCA1 mutations, many of whom weretreated less recently in a community setting16: in 16 of the43 patients (37 percent) with advanced-stage cancer in our series,as compared with 10 of 43 controls (23 percent), the diseasewas diagnosed before 1986.
The process we used to identify patients with BRCA1-relatedovarian cancer was intended to yield a representative population,without favoring long-term survivors. All such patients identifiedat each participating institution for whom the basic clinicalinformation was available were included. There was no requirementfor the patients to have been treated at the institution. Inmany instances, cases of BRCA1-related ovarian cancer were identifiedby molecular analysis of tissue blocks at the request of relativesafter the patients' deaths. In addition, the participation ofseveral investigators at different institutions in the processof identifying patients should lessen the possibility of a selectionbias.
In some previous reports of the clinical characteristics ofcancers that arise in association with predisposing germ-linemutations, patients were identified by linkage analysis or examinationof family pedigrees; this process left open the possibilitythat sporadic cases were also included. In a report on 35 patientswith breast cancer who were probable carriers of a BRCA1 mutation,on the basis of linkage analysis, Porter et al.17 suggestedthat these patients had a relatively indolent clinical course,but they did not include prognostic factors, such as tumor stageand grade. Eisinger et al.18 found a higher incidence of poorlydifferentiated tumors in 27 patients with breast cancer anddocumented germ-line BRCA1 mutations but did not report on follow-upor survival in this group. Marcus et al.19 studied patientswith BRCA1-related breast cancer and other forms of hereditarybreast cancer, including BRCA2-related cases, and found thatthe BRCA1-related hereditary breast cancers were more frequentlyaneuploid and showed higher tumor-proliferation rates than theother hereditary cases. Although there were adverse prognosticfeatures in the BRCA1-related patients, they had paradoxicallylower recurrence rates than the other patients with hereditarybreast cancer.
Other evidence suggests a relatively favorable prognosis forhereditary colorectal cancer in patients carrying mutationsof genes responsible for DNA mismatch repair. A recent studyof data from the Finnish Cancer Registry showed significantlylonger recurrence-free survival (at five years) in a group ofpatients with hereditary colorectal cancer than in a controlgroup with sporadic colorectal cancer.20
With regard to ovarian cancer, a previous pedigree analysisfound that a relatively large proportion of possibly hereditaryovarian cancers are of the serous-cell subtype14 but did notprovide information on survival. Interestingly, Buller et al.15compared the survival of 11 patients with family histories ofovarian cancer with that among matched controls who had no suchfamily history; they found longer survival among the women withthe possibly familial cases.
Germ-line BRCA1 mutations occur in only a small proportion ofall ovarian cancers, but they appear to be the most importantprognostic factor yet identified for patients with advanced-stagedisease. The distinctive clinical behavior of BRCA1-relatedovarian cancers could have implications for disease managementand the design of clinical trials. The reasons for the relativelyindolent course of BRCA1-related ovarian cancers are not immediatelyobvious from our data. We have been unable to obtain informationabout some well-known clinical prognostic factors, includingthe extent of tumor before and after initial surgery and thechemotherapy regimens used. It seems likely that explanationswill come from a better understanding of the function of theBRCA1 tumor-suppressor gene and that the difference in clinicalbehavior between BRCA1-related and sporadic ovarian cancersreflects distinct profiles of somatic mutations in other cancer-relatedgenes.
Source Information
From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology (S.C.R., I.B., K.B., H.T., M.A.M., J.B.), the Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine (V.A.L.), and the Division of Hematology and Oncology, Department of Medicine (B.L.W.), University of Pennsylvania Medical Center, Philadelphia; the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, N.C. (A.B.); the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston (M.G.M.); the Division of Cancer Epidemiology and Control, Dana–Farber Cancer Institute, Boston (J.E.G.); and the Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebr. (H.T.L.).
Address reprint requests to Dr. Rubin at the Division of Gynecologic Oncology, University of Pennsylvania Medical Center, 3400 Spruce St., Philadelphia, PA 19104.
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