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© 2000 American Society for Clinical Oncology
Are BRCA1- and BRCA2-Associated Breast Cancers Different? Prognosis of BRCA1-Associated Breast CancerFrom the Departments of Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Mark Robson, MD, Departments of Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email robsonm@ mskcc.org.
PURPOSE: To review the available literature regarding the outcome of breast cancer arising in the setting of a germline BRCA1 mutation. METHODS: Reports of relevant studies obtained from a search of MEDLINE and studies referenced in those reports were reviewed. In addition, data from a previously published study of breast conservation therapy among women of Ashkenazi descent were reanalyzed to discern the effect of germline BRCA1 status. RESULTS: Although BRCA1-associated breast cancers have been associated repeatedly with poor prognostic features, studies that examine the impact of germline BRCA1 status on outcome have not consistently shown an adverse effect of BRCA1 mutations. In part, this may result from methodologic limitations of earlier trials. Recent studies that examine relatively unselected groups of Ashkenazi women have indicated a negative prognostic effect of specific BRCA1 mutations. It remains to be determined, however, whether BRCA1 status is an independent prognostic factor and whether the findings can be generalized to other mutations. CONCLUSION: BRCA1-associated breast cancers present with histopathologic features that seem to confer an adverse prognosis, at least in certain subgroups. However, it is not clear whether BRCA1 status has an independent effect on outcome. Until further data become available, treatment for BRCA1-associated breast cancer should be determined by the same factors that influence therapy of nonhereditary disease.
IN POPULATION-BASED studies, approximately 3.3% of United States women with breast cancer have been shown to carry a pathogenic germline mutation in BRCA1.1 Mutations are more common in women with early-onset breast cancer, being found in nearly 6% of women diagnosed with breast cancer at or before the age of 35 years2,3 and in 12% of women diagnosed before the age of 45 years who have a first-degree relative with breast cancer.2,4 Mutations are more prevalent in women from certain ethnic groups, because of the presence of founder mutations in those populations. For instance, two specific BRCA1 mutations (185delAG and 5382insC) may be found in 6.9% of Ashkenazi women with breast cancer,5 13% of Ashkenazi women diagnosed before the age of 65 years,6 and 20% to 24% of Ashkenazi women diagnosed at or before the age of 42 years.7,8 Several studies have demonstrated that BRCA1-associated breast cancers manifest features that have been associated traditionally with a poorer prognosis.9 BRCA1-associated cancers are usually poorly differentiated with high proliferative rates. Infiltrating carcinoma of no special type is by far the most prevalent histology.10,11 In some series, medullary carcinoma is overrepresented, presumably because of the frequent presence of lymphocytic infiltration, pushing margins, and high histologic grade. However, concordance among pathologists for this diagnosis is not high, and an increase in medullary carcinoma has not been noted in all series. In addition to being highly proliferative, BRCA1-associated cancers usually fail to express hormone receptors and are often aneuploid. Overexpression of p53 (as determined by immunohistochemistry) is common, as are somatic p53 mutations. To date, no other somatic abnormalities have been reported consistently. Importantly, HER2 overexpression seems to be distinctly uncommon. Despite the adverse pathologic and immunohistochemical profile of BRCA1-associated breast cancers, it has been difficult to determine whether germline BRCA1 status has an effect on breast cancer outcome. This review will describe the available data bearing on this question in an attempt to address whether BRCA1-associated cancers should be treated differently from sporadic disease (Table 1).
The first studies to describe the breast cancer survival of BRCA1 carriers were reported by Porter et al,12,13 from Scotland. These investigators described the survival experience of 35 women with breast cancer from 15 families in whom the cancers were strongly linked to the BRCA1 locus. These women were considered likely mutation carriers on the basis of flanking marker data but were not genetically tested at the time of publication. Their outcome was compared with that expected from age-matched Scottish population tables for breast cancer survival and was found to be significantly better (5-year survival, 83% v 61%). Further analyses of the relationship between BRCA1 status and prognosis were performed by Marcus et al14 in 1996. In this study, the survival of 72 women from 26 families with breast cancer thought to be BRCA1-related was compared with that of 187 unselected tumor registry controls and 66 women from families with hereditary breast cancer not thought to be related to BRCA1. Of the 72 women, 16 were from families in whom BRCA1 linkage had not been demonstrated but in whom the pattern of predisposition was suggestive of BRCA1 (breast and ovarian cancer). Comparison of crude death rates suggested that women from BRCA1-related families were less likely to die of breast cancer than either the registry controls or the women from the other families with hereditary cancer. However, after adjustment for stage and age, the death rate hazard ratio was actually greater for BRCA1-associated cases. Comparison of breast cancer recurrence and breast cancer–specific survival between the BRCA1-related cases and the registry controls was not possible because of concerns regarding differences in follow-up methodology, but BRCA1-related cases seemed to fare better with regard to these parameters than those from the other families with hereditary breast cancer. These two studies are the only available reports that suggest a superior prognosis for women with BRCA1-associated breast cancer. In both, the strength of the conclusion is reduced by a number of potential biases. The cases in both series were not all demonstrated to be mutation carriers, which introduces the possibility that the results could be confounded by phenocopies. In addition, both series examined the outcomes of women who were members of families with breast cancer participating in research studies. There may have been a bias toward ascertaining living women in such studies, as only living women may donate DNA samples for linkage analysis. Thus, nonsurviving women from these families may have been less likely to be included in the analyses, artificially raising the apparent survival of the BRCA1-associated group. Finally, the controls in these studies may not have been matched for important characteristics, such as disease stage, which may have further confounded the comparison.
A number of studies have described the outcomes of women with BRCA1-associated breast cancer ascertained from familial cancer clinics. In the first of these, Verhoog et al15 described the survival of 49 women with follow-up from 20 families known to be transmitting a deleterious BRCA1 mutation. These 49 patients constituted 65% (49 of 75) of the known breast cancer cases in these families. Controls matched for age and date of diagnosis were selected from a hospital tumor registry. Disease-free and overall survival were not significantly different between women with BRCA1-associated breast cancer and controls. Because of concerns that inclusion of probands may have positively influenced the apparent survival of the group with BRCA1-mutations, the analyses were repeated after exclusion of these women. As expected, the observed 5-year survival of the hereditary group declined after exclusion of these women (from 63% to 56%), but there was still no statistically significant difference from controls. A clinic-based ascertainment from Sweden was reported by Johannsson et al,22 with similar findings to those of the Netherlands study. A group of 40 patients with BRCA1-associated breast cancer from 21 families was studied and their outcomes compared with population-based controls from the Swedish National Cancer Registry. Two comparison groups were selected from the national registry, one of which was age- and stage-matched to the cases. All of the BRCA1-associated cases were confirmed as being either mutation carriers or obligate heterozygotes, which allowed the exclusion of phenocopies. The survival of the women with BRCA1 mutations was not statistically different from that of the unselected population controls, although there was a trend toward a worse survival among those with BRCA1-associated cancer when the analysis was adjusted for age and calendar year of diagnosis (hazards ratio for death, 1.5; 95% confidence interval, 0.9 to 2.4). A similar trend toward an inferior outcome was observed when mutation carriers were compared with age- and stage-matched controls (hazards ratio, 1.5; 95% confidence interval, 0.6 to 3.7). Gaffney et al16 described 30 Utah women from seven families with BRCA1 mutations and compared their survival with that of women from the Utah Cancer Registry. There was no significant difference in 5-year overall survival between women with mutations and unselected registry controls (75% v 69%) or between women with mutations and controls matched for age, date of diagnosis, and tumor size (75% v 70%). A recent clinic-based study from Germany compared the outcomes of 36 BRCA1 mutation carriers from 13 families with 49 women from families with non-BRCA1 hereditary breast cancer.17 These women comprised 59% of the 61 breast cancer cases that were known to have occurred in the families with BRCA1 mutations. Disease-free survival was significantly worse for those with BRCA1 mutations (53% v 86.9% for noncarriers, P = .02), although overall survival was not different in the two groups. The findings were not altered by the exclusion of the probands from the families with BRCA1 mutation. Women with BRCA1 mutations were significantly younger at diagnosis than those without. A multivariate analysis was not performed to determine whether the effect of a germline status was independent of age at diagnosis. A large collaborative study from several institutions in the United States and Canada, reported only in abstract form, analyzed the survival of 73 women with documented BRCA1 or BRCA2 mutations who underwent breast conservation therapy and compared their outcome with that of presumed sporadic controls matched for age and date of diagnosis.18 In this brief report, there were no differences in 5-year overall or disease-free survival between the two groups. In summary, the clinic-based studies described above do not support the contention that women with breast cancer and BRCA1 mutations have an improved survival when compared with women without mutations. These studies are potentially subject to confounding from a number of sources. There are risks of incomplete ascertainment (failure to identify all heterozygotes in a given population) and incomplete follow-up (inability to determine outcomes for a proportion of heterozygotes in a given family). In addition, BRCA1-associated families are usually only identified by cancer family clinics after the study of a living, affected individual from a multiple-case family. Not only may this introduce a positive survival bias, but individuals from such families may or may not be representative of less-selected women with germline mutations.
Two studies have described the survival of BRCA1 mutation carriers ascertained from studies of women selected not for family history but for early-onset breast cancer. Ansquer et al19 from the Institut Curie reported on 15 women with BRCA1-associated breast cancer identified among a group of 123 women diagnosed with breast cancer before the age of 36 years. This study may have been subject to a survival bias, because the women were diagnosed between 1990 and 1995 but sampled for testing between 1993 and 1995. Nevertheless, women with mutations were found to have a significantly worse survival than those without (P = .04). Interestingly, this decrement in survival was observed despite the fact that disease-free survival was not significantly shorter. Causes of death were not described in this brief report, but the possibility exists that second malignancies (contralateral breast cancer, ovarian cancer) were important contributors to the observed differences in survival. Robson et al20 reported on 91 Ashkenazi women with breast cancer before the age of 42 years and compared disease-free survival in those with or without one of the three Ashkenazi founder mutations in BRCA1 or BRCA2. There was no statistically significant difference in relapse-free survival (65% v 69%) or event-free survival (57% v 68%) between women with and those without mutations. Because all women were alive at the time of testing, overall survival was high in both groups and was not significantly different. The prevalent survival bias may have obscured an adverse effect of germline mutations on early survival, as suggested by a trend toward worse event-free survival in women with mutations among those who were tested within 2 years of diagnosis. In addition, women with BRCA1 and BRCA2 mutations were not analyzed separately, which may have confounded the results. Neither of these studies indicate an improved survival for women with BRCA1-associated breast cancer, and the study from the Institut Curie suggests the opposite. Both studies may have been biased by selection for testing of women who survived some period of time after diagnosis.23 This bias, as well as the others described as potentially operating on clinic-based studies, can be circumvented through a design that allows the identification of all heterozygotes within an unselected group of breast cancer patients with complete follow-up.
A retrospective anonymized design allows the study of outcomes associated with specific BRCA1 mutations among unselected groups of women with breast cancer.24 In a retrospective anonymized study, an unselected group of women from the population of interest is identified. Pathologic material is retrieved for BRCA1 mutation analysis. Outcome data are collected for the entire group before mutation status is known. Because testing is being performed on pathologic material, there is no requirement that the subject be alive for mutation status to be determined. Once clinical data and outcomes are known for the entire group, all connections between patient-identifying information and the DNA specimen are irretrievably destroyed, while a link between the specimen identifier and the clinical data is maintained. After this anonymization, the specimens are analyzed for the presence or absence of specific mutations and the outcomes of women with or without those mutations are compared. Obviously, these studies can only be undertaken among populations in which specific founder mutations are prevalent. Women of Ashkenazi descent constitute such a population, and two groups have used this design to study outcomes of BRCA1-associated breast cancer in this population. The first study to use this design was reported by Foulkes et al,21 who described the outcome of 12 women with the BRCA1 mutation 185delAG or 5382insC identified from among a group of 117 Ashkenazi women diagnosed with breast cancer before the age of 65 years at a single institution. Although the number of cases was small, there was a marked difference in overall and disease-free survival between women with and those without these mutations. Distant disease-free survival at 5 years was 68.2% in carriers, compared with 88.7% in those without mutations, and 5-year overall survival was 64.3% in those with mutations, compared with 95.7% in those without. These results were confirmed by expansion of the series to 187 patients, 25 of whom were found to carry a BRCA1 founder mutation.6 In this extended series, the 5-year survival was 70.8% for carriers, compared with 85.9% in noncarriers. Another series of unselected Ashkenazi women with breast cancer has been reported by Robson et al,5 who examined the outcomes of 305 women undergoing breast conservation therapy at a single institution for invasive cancer. In the original report, women with BRCA1 and BRCA2 founder mutations were analyzed as a group, compared with women without any of the three founder mutations. Of the 305 women, founder mutations were identified in 28 (9.2%). These 28 women underwent lumpectomy and radiotherapy for 35 breast cancers (10.6% of all breast cancers). Women with mutations were younger and more likely to have axillary nodal involvement than those without. Distant disease-free, breast cancer–specific, and overall survival were all significantly worse among women with mutations. However, germline mutation status was not a statistically significant predictor of outcome in a Cox multivariate model that included tumor stage and nodal status. These data have been reanalyzed excluding the seven women with the BRCA2 mutation 6174delT, and the results are unchanged. At a median follow-up of 124 months, the 21 women with BRCA1 mutations were significantly more likely to suffer distant recurrence and die of their disease than women without mutations (Table 2). In multivariate analysis, however, BRCA1 mutation status was still not an independent predictor of outcome (Tables 3 and 4).
These two studies suggest that, among unselected Ashkenazi women, the presence of a germline BRCA1 mutation may negatively affect survival. The Robson study suggests that this effect is a result of a propensity of BRCA1-associated breast cancers to present with more advanced-stage disease. However, other studies have not found a higher rate of axillary nodal involvement among women with BRCA1 mutations, and the number of cases in this study was too small to completely exclude an independent effect of BRCA1 status on survival. In this regard, a recent further expansion of the anonymized study by Foulkes et al has indicated an adverse effect of germline BRCA1 mutations on the outcome of unselected Ashkenazi women with node-negative disease. In this additional analysis, 16 BRCA1 mutation carriers were identified among 118 Ashkenazi women with node-negative breast cancer.25 The 5-year overall survival of the node-negative mutation carriers was dramatically worse than that of the women without mutations (50% v 89.6%). Together, the results of these two studies suggest that specific mutations in BRCA1 can confer a worse prognosis. This negative effect seems to result from a tendency toward early metastasis, reflected in the higher rates of axillary node involvement in the Robson series and the higher rates of mortality among node-negative patients in the Foulkes series. Whether these results can be generalized to all women with BRCA1 mutations is not clear. The majority of the unselected Ashkenazi women in these studies had the 185delAG mutation (19 of 21 BRCA1 mutation carriers in the study of Robson et al and 11 of 16 in that of Foulkes et al). Further study will be necessary to determine whether similar negative effects result from other mutations. In conclusion, the relevance of a germline BRCA1 mutation to the prognosis of a woman with breast cancer has been the subject of active investigation, and the matter is not completely resolved. Many studies have indicated that BRCA1-associated breast cancers manifest pathologic and biologic characteristics that have previously been associated with a worse prognosis. Available studies of outcomes in this group of patients, however, have been inconsistent in their results. In part, this inconsistency may reflect the difficulty inherent in studying retrospective cohorts when mutation status cannot be reliably determined for all members of the group. Recent studies that examined ethnically restricted groups of unselected patients with breast cancer have suggested that the presence of specific BRCA1 mutations does, indeed, result in a worse prognosis. Larger studies will be required to determine whether this is an independent effect and whether the negative effect is similar for all BRCA1 mutations. At this point, the evidence is not yet strong enough to recommend more intensive systemic therapy solely on the basis of germline BRCA1 status. Until the results of more definitive studies are available, affected women who may be carriers of germline mutations should be apprised of the available data and their limitations when they are making decisions regarding the need for systemic adjuvant therapy.
1. Newman B, Mu H, Butler LM, et al: Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 279: 915-921, 1998 2. Malone KE, Daling JR, Neal C, et al: Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer 88: 1393-1402, 2000[Medline]
3.
Peto J, Collins N, Barfoot R, et al: Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91: 943-949, 1999
4.
Malone KE, Daling JR, Thompson JD, et al: BRCA1 mutations and breast cancer in the general population: Analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA 279: 922-929, 1998
5.
Robson M, Levin D, Federici M, et al: Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations. J Natl Cancer Inst 91: 2112-2117, 1999 6. Foulkes WD, Wong N, Rozen F, et al: Survival of patients with breast cancer and BRCA1 mutations. Lancet 351: 1359-1360, 1998[Medline] 7. Gershoni-Baruch R, Dagan E, Fried G, et al: Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 36: 983-986, 2000 8. Offit K, Gilewski T, McGuire P, et al: Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet 347: 1643-1645, 1996[Medline]
9.
Phillips KA, Andrulis IL, Goodwin PJ: Breast carcinomas arising in carriers of mutations in BRCA1 or BRCA2: Are they prognostically different? J Clin Oncol 17: 3653-3663, 1999 10. Pathology of familial breast cancer: Differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet 349: 1505-1510, 1997[Medline]
11.
Lakhani SR, Jacquemier J, Sloane JP, et al: Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90: 1138-1145, 1998 12. Porter DE, Dixon M, Smyth E, et al: Breast cancer survival in BRCA1 carriers. Lancet 341: 184-185, 1993 13. Porter DE, Cohen BB, Wallace MR, et al: Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 gene mutation in families linked to BRCA1 on chromosome 17q12- 21. Br J Surg 81: 1512-1515, 1994[Medline] 14. Marcus JN, Watson P, Page DL, et al: Hereditary breast cancer: Pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77: 697-709, 1996[Medline] 15. Verhoog LC, Brekelmans CTM, Seynaeve C, et al: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351: 316-321, 1998[Medline] 16. Gaffney DK, Brohet RM, Lewis CM, et al: Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations. Radiother Oncol 47: 129-136, 1998 [Medline] 17. Hamann U, Sinn HP: Survival and tumor characteristics of German hereditary breast cancer patients. Breast Cancer Res Treat 59: 185-192, 2000[Medline] 18. Pierce L, Strawderman M, Narod S, et al: No deleterious effects of radiotherapy in women who are heterozygote for a BRCA-1 or BRCA-2 mutation following breast conservation therapy. Proc Am Soc Clin Oncol 18: 86a, 1999 (abstr 326) 19. Ansquer Y, Gautier C, Fourquet A, et al: Survival in early-onset BRCA1 breast-cancer patients. Institut Curie Breast Cancer Group. Lancet 352: 541, 1998 20. Robson M, Gilewski T, Haas B, et al: BRCA-associated breast cancer in young women. J Clin Oncol 16: 1642-1649, 1998[Abstract]
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Foulkes WD, Wong N, Brunet JS, et al: Germ-line BRCA1 mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer. Clin Cancer Res 3: 2465-2469, 1997 22. Johannsson OT, Ranstam J, Borg A, et al: Survival of BRCA1 breast and ovarian cancer patients: A population-based study from southern Sweden. J Clin Oncol 16: 397-404, 1998[Abstract]
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Foulkes WD, Wong N, Brunet JS, et al: BRCA mutations and survival in breast cancer. J Clin Oncol 16: 3206-3208, 1998 24. ASHG report: Statement on informed consent for genetic research—The American Society of Human Genetics. Am J Hum Genet 59: 471-474, 1996[Medline]
25.
Foulkes WD, Chappuis PO, Wong N, et al: Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome. Ann Oncol 11: 307-313, 2000 This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
