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© 2000 American Society for Clinical Oncology
Prognostic Significance of Germline BRCA2 Mutations in Hereditary Breast Cancer PatientsFrom the Family Cancer Clinic, Department of Medical Oncology, Daniel den Hoed Cancer Center; Department of Pathology, Josephine Nefkens Institute, University Hospital Rotterdam; and Department of Clinical Genetics, Erasmus University, Rotterdam, the Netherlands. Address reprint requests to J.G.M. Klijn, MD, PhD, Family Cancer Clinic, Department of Medical Oncology, Daniel den Hoed Kliniek and University Hospital, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email bos{at}onch.azr.nl
PURPOSE: Breast cancer in BRCA2 gene mutation carriers differs from BRCA1-associated breast cancer or so-called sporadic breast cancer in clinical features and behavior. These differences may be of importance for the prevention, screening, and ultimately treatment of breast cancer in women with such germline mutations. METHODS: We reviewed the few studies that have reported on survival in patients with BRCA2-associated breast cancer. In this article we discuss why family history is no substitute for hereditary breast cancer with regard to studying survival and possible reasons why studies using family history yield contradictory results, why BRCA2-associated breast cancer should be considered a unique entity, and what methodological problems may exist, especially with regard to family-based studies. RESULTS: Five studies have reported on survival in BRCA2-associated breast cancer. Two studies showed a statistically significant worse survival for BRCA2 patients, but the patients from one of these studies were later claimed to have a trend toward better prognosis when controls were matched for age and year of diagnosis. The other study found that the unfavorable prognosis of BRCA2 patients was, to a great extent, due to a worse stage of the disease at time of diagnosis. The remaining three studies showed no significant effect of germline BRCA2 mutations on survival. The numbers of BRCA2 patients investigated in these studies were 42, 20, 23, 28, and 54 patients. Five-year overall survival in these patients varied from 65% to 74%. CONCLUSION: No definite conclusion can be made with regard to the prognosis of BRCA2-associated breast cancer, but large differences in comparison with sporadic breast cancer are not likely to exist. Breast cancer caused by BRCA2 mutations is also a distinct entity with its own features when compared with BRCA1-associated breast cancer. In contrast with BRCA1-associated breast cancer, BRCA2 tumors tend to be more often steroid receptor–positive.
THE DISEASE-FREE AND overall survival rate for invasive breast cancer is modified by a large variety of clinical, pathologic, and cell biologic factors. For breast cancer to occur, normal cells have to undergo growth transformation, which is the result of a multistep process as a consequence of an accumulation of several genetic alterations. Of special interest are inherited genetic alterations (ie, germline mutations) in so-called cancer susceptibility genes. Inheritance of mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 is thought to be responsible for 5% to 10% of all breast cancers.1-3 Over recent decades, an increasing number of cell biologic parameters, such as oncogenes, tumor suppressor genes, hormone receptors, growth factors, and secretory proteins, have been discovered that seem to influence strongly the behavior of a tumor with respect to growth rate, apoptosis, extent of cellular differentiation, metastatic pattern, and development of resistance to therapy. The possibility that a hereditary aspect of breast cancer might modify these aspects and thus influence prognosis was already investigated before the identification of the breast cancer susceptibility genes BRCA1 and BRCA2.4 The tumorigenic pathway by which breast tumors arise in the mammary tissue of BRCA1 or BRCA2 germline mutation carriers may partly differ from each other and from their sporadic counterparts. This is well illustrated by the specific histologic features of BRCA1- and BRCA2-associated breast cancers, although there is considerable overlap in histology with sporadic tumors as well. Both BRCA1- and BRCA2-related tumors do not have a single cytoarchitectural type or uniform grade.5-8 Identifying differences in survival and tumor characteristics of hereditary breast cancers may have important implications. The efficacy of screening, the benefit of (contralateral) prophylactic surgery or chemoprevention, and the optimal treatment of hereditary breast cancer are all in a way related to the prognosis of these tumors. Moreover, such information is crucial for the women who are carriers of a BRCA1 or BRCA2 germline mutation.9
A positive family history for breast cancer is an established risk factor for the disease. It has also been extensively investigated as a prognostic feature, but results are conflicting. A positive family history for breast cancer has been correlated with better, similar, and worse prognosis relative to nonfamilial breast cancer.10 This may readily be explained by the fact that, apart from being ill-defined, familial breast cancer is a heterogeneous entity. Methodological differences too are likely to play a role in the diverging results from these studies. Depending on how familial breast cancer is defined, up to 20% of the women diagnosed with breast cancer have at least one relative who is also affected by the disease.11 Fig 1 gives a simplified diagram of how BRCA1- and BRCA2-associated breast cancer relate to hereditary, familial, sporadic, and thus overall breast cancer. Because breast cancer is not an infrequent disease in Western countries, a significant proportion of the familial breast cancer cases will result from chance clustering alone as well as shared environmental factors and not a predominant genetic susceptibility.
Far from all cases of hereditary breast cancer are explained by BRCA1 and BRCA2. A number of genes are known in which germline mutations give rise to an increased susceptibility for breast cancer (see review in Martin and Weber12 ), like the p53 gene in the Li Fraumeni syndrome13 and PTEN in Cowden’s disease.14 Although these other susceptibility genes only explain a small proportion of hereditary breast cancer, there is compelling evidence that other major breast cancer susceptibility genes (BRCAX) in non BRCA1/2 breast cancer must exist.8,15-17 To further complicate matters, population-based studies have shown that not all women with hereditary breast cancer caused by BRCA1 or BRCA2 will have a close (first-degree) relative affected by the disease.18-20 These patients are represented in Fig 1 by the part of the diagram of "Hereditary" not overlapping with "Familial" breast cancer patients. This fact can simply be the result of the composition of a family (for instance, paternal inheritance in combination with a small family and predominant male sibships). On the other hand, these population-based studies have raised questions of whether the initial breast cancer risks given for carriers of a BRCA1 or BRCA2 germline mutation may have been too high, due to the fact that these were estimates based on high-risk families with multiple women affected by breast cancer.21 The final reason why family history is a poor substitute for investigating the role of genetic susceptibility as a prognostic factor is the fact that the ratios of BRCA1 versus BRCA2 and BRCA1/2 versus the total group of hereditary and familial breast cancer will differ between specific populations. This is best illustrated by the example of the Icelandic population in which the vast majority of proven hereditary breast cancer families are caused by one single mutation in BRCA2 (999del5).22 In the end, the prevalence of breast cancer and exogenic causes of breast cancer will also influence the proportions in a population, as shown in Fig 1.
Besides their gene names, a number of similarities exist between BRCA1 and BRCA2 and their associated phenotypes when these genes are mutated. Both genes were found as a result of an extensive genome-wide search in families with multiple early-onset breast cancer patients, so not surprisingly, germline mutations in both confer strongly elevated lifetime risks for breast cancer.23 Again not surprisingly, a young age at onset and an elevated risk for bilateral breast cancer are characteristics shared by both BRCA1 and BRCA2. Perhaps the best reason to consider breast cancer associated with either one of these tumor suppressor genes as a single entity is the fact that of the nuclear proteins for which BRCA1 and BRCA2 encode, both are postulated to play a role in DNA damage–response pathways and interact with each other and the RAD51 protein, thus confirming their function in some of the same cellular pathways.24 In addition to this, both genes are very rarely somatically mutated in nonhereditary breast cancer.25-28 It is therefore not uncommon to see epidemiologic studies that combine carriers of BRCA1 and BRCA2 germline mutations and consider them as a single group.29-32 From a biologic point of view, the differences between the two genes are of great interest. Risk calculations for premenopausal BRCA2 carriers with regard to breast cancer turn out to be somewhat lower than for BRCA1. However, the risk for BRCA2 carriers continues to increase after menopause, whereas that of BRCA1 carriers levels off.23 In line with these calculations, we recently reported a lower risk with regard to contralateral breast cancer in postmenopausal BRCA1 carriers.33 It is tempting to relate these differences to hormone-dependent pathways, and in this light, the distinction with regard to the presence of steroid receptors between BRCA1 and BRCA2 tumors is striking34-37 (Table 1). In our own updated experience, we currently know the steroid receptor status from 26 BRCA2-associated breast tumors, of which 92% (n = 24) are estrogen receptor–positive and 95% (20 of 21) are positive for progesterone receptor. In contrast, only one third of the BRCA1 tumors are steroid receptor–positive. This difference in steroid receptor status might be of special importance with regard to chemoprevention of breast cancer with antiestrogens.38
Differences between BRCA1 and BRCA2 also exist with respect to histology.6,7,39,40 Although both BRCA1 and BRCA2 tumors have been found to be more often of high grade as compared with age-matched controls, multivariate analysis shows that in BRCA2 this is mostly due to the formation of less tubular structures in a tumor, whereas BRCA1 tumors have high mitotic counts.7 Both BRCA1 and BRCA2 have a higher proportion of their tumor perimeter with a continuous pushing margin, a feature that they share with breast carcinomas of the medullary type. Medullary carcinomas in this context are of special interest because they have been associated with a more favorable prognosis than ordinary ductal carcinomas of the breast.40 Possibly BRCA2-associated tumors more often have an extensive intraductal component as compared with BRCA1 tumors.41 An extensive intraductal component is one of the risk factors for local recurrence after breast-conserving therapy.42 It could also point to a more indolent behavior of an in situ cancer until the invasive cancer arises, and this might point to opportunities for intervention by screening in BRCA2 mutation carriers. For the reasons mentioned above, despite the fact that only a small proportion of all breast cancer cases are caused by germline mutations in BRCA2, it is of major interest to investigate these patients as a distinct group.
Although some reports failed to discriminate between BRCA1 and BRCA2 mutations, a limited numbers of studies have looked at survival of BRCA2 mutation carriers with breast cancer as a separate entity (Table 2). The first study to report on the outcome of BRCA2-associated breast cancer patients was by Sigurdsson et al, 43 who studied 42 Icelandic breast cancer patients from families with evidence for linkage to BRCA2. They found a significantly worse disease-free survival for BRCA2-associated cases as compared with sporadic controls matched for age but not for year of diagnosis. Most likely, not matching for year of diagnosis led to large differences in the treatment of these patients as well as differences in the distribution of stage of the disease. However, in an other study these authors investigated grade and histology of partly the same BRCA2-associated patients and reported a trend towards a more favorable outcome when controls were matched for year of diagnosis.34
Gaffney et al44 studied survival in 20 BRCA2-associated breast cancer patients, also from families that previously had shown positive linkage for BRCA2. These patients were matched to controls from a population-based cancer registry, not only for age and year of diagnosis, but also for tumor size. Unfortunately, information about the control patients, such as surgical procedure or nodal status, was otherwise limited, but no significant difference in survival was detected. The study by Lee et al45 was unique because, so far, it is the only population-based study on survival performed by recruiting volunteers from Ashkenazi Jewish descent. The figures for overall survival of BRCA2-associated cases in this study are those of breast cancer patients who tested positive for the presence of the Ashkenazi BRCA2 founder mutation, 6174delT, in addition to those of affected relatives who were not tested. The design of the study was that of a combined BRCA1/2 study with an inferred mutation carrier status using the kin-cohort method.21 In this way, no data were available on clinical presentation and stage of the disease. No significant prognostic differences were detected. At the Daniel den Hoed Cancer Center, we investigated tumor characteristics and survival of 28 breast cancer patients from the first 14 consecutive families with an identified BRCA2 germline mutation.35 Despite a somewhat larger tumor size at time of diagnosis, no difference in survival could be demonstrated in comparison with controls matched for age and year of diagnosis. Interestingly, the axillary lymph node status was not more often positive. The stage-adjusted recurrence and death rates of BRCA2-associated breast cancer patients versus sporadic breast cancer patients were nonsignificantly better (hazards ratio = 0.84 and 0.59, respectively; P = .61 and .19). The recent study of Loman et al46 has the largest number of BRCA2-associated breast cancer patients (n = 54) in a single study, and the patients were identified through oncogenetic counseling. In their study, the patients with BRCA2-associated breast cancer had a significantly worse disease-specific survival. To a great extent, this was due to the fact that significantly more BRCA2-associated cases presented with axillary lymph node involvement or stage IV breast cancer at the time of diagnosis. After adjusting for stage, the breast cancer–specific survival was no longer significantly worse for the BRCA2-associated cases (relative risk = 1.6; 95% confidence interval, 0.85 to 3.1). Differences in tumor biology were given as the most likely explanation for the more aggressive clinical presentation of BRCA2-associated breast cancer. The authors also investigated the possibility that families with more breast cancer deaths might have preferably been included in their study, but this seemed to be an unlikely explanation. This is not surprising, because selection bias is generally believed to lead to the inclusion of families with breast cancer patients who have a better prognosis.
Studying survival in BRCA1/2-associated breast cancer is further complicated by a number of methodological problems. Probably the best way to investigate the prognostic relevance of BRCA2 germline mutations is in a population-based group of BRCA2-associated breast cancer patients.48 However, to obtain sufficiently large numbers of patients, thousands of breast cancer patients would have to be tested for the presence of BRCA1/2 mutations in a prospective manner. Apart from the long time it would take for results from such a study to emerge, the costs of screening for mutations in BRCA1/2 in unselected breast cancer patients would probably be too high. The most straightforward results are to be expected from relatively easy studies in populations in which founder mutations are prevalent, like the Ashkenazi Jewish and Icelandic populations. This could be done in a historical cohort by looking for mutations in archival paraffin-embedded tissue blocks.48 To establish carrier status, these samples would only have to be tested for a limited number of mutations. However, studying a limited number of mutations may have its drawbacks as well. Some reports initially stated that tumor grade was related to the position of the mutation in the BRCA1 gene but this has remained unconfirmed.5 However for BRCA2 mutations such a genotype-phenotype correlation is not inconceivable.49 Moreover these mutations are studied against a specific genetic and environmental background which may also influence survival of both cases and controls. On hypothetical grounds, studying survival in self-ascertained families is said to lead to selection for longevity of cases.50 This bias would result first from families with more living affected breast cancer patients being more likely to be (self) referred to a family cancer clinic, and, second, patients alive at the time of study being more likely to be included in the study sample. Missing data and lack of adequate follow-up or histopathologic confirmation of individuals who died early and are therefore not included in the study sample might also play an important role. In support of this, we found that after exclusion of breast cancer patients who were the first family members to visit our family cancer clinic (ie, the probands), there was a trend toward a worse outcome for patients with BRCA1-associated breast cancer.37 It is of interest that this phenomena was observed in BRCA1-associated families but not after exclusion of probands in BRCA2-associated families. Moreover, including the BRCA2-associated patients who were identified by constructing a pedigree but for whom insufficient pathology or follow-up were available did also not show a trend toward selection for longevity.36 One might hypothesize that selection toward longevity in family-based breast cancer patients is more readily apparent when carriage of a germline mutation is a strong adverse prognostic factor. However, the notion that a family comes to the attention merely on the basis of living breast cancer patients is, within the setting of our family cancer clinic, a misconception. Most probands themselves are unaffected by breast cancer and visit our family clinic because of obvious familial clustering of breast cancer. Whether the breast cancer patients are alive is of little influence on the individuals who will seek oncogenetic counseling. Moreover, genetic testing can sometimes be offered without living affected family members being available for mutation analysis, that is by performing mutation analysis in a number of unaffected first-degree relatives. Finally, studies that have reported adverse pathobiologic characteristics in BRCA1- and BRCA2-associated breast cancer were liable to the same sort of bias, because the tumors that have been investigated are family-based in a manner similar to that of patients in survival studies.8 Despite this disadvantage, these studies were able to demonstrate a higher tumor grade and poor prognostic characteristics in tumors from these patients, whereas if this selection bias had played a significant role, then the prognostic better tumors would have been ascertained. In conclusion, patients with hereditary breast cancer resulting from a BRCA2 mutation have not been conclusively shown to have a different prognosis when compared with age-matched sporadic breast cancer patients. Although breast cancer associated with BRCA2 mutations as well as sporadic breast cancer and breast cancer associated with BRCA1 mutations is a heterogenic group, such cases have unique features that may be of importance for the prevention, screening, and, ultimately, the treatment of breast cancer in women with BRCA2 germline mutations. Studying the outcome and natural history of BRCA2-associated breast cancer may prove to be of great value for understanding the molecular genetics and tumorigenesis of this group of tumors and in this way help to better understand breast cancer as a whole.
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Miki Y, Swensen J, Shattuck Eidens D, et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66-71, 1994 3. Wooster R, Bignell G, Lancaster J, et al: Identification of the breast cancer susceptibility gene BRCA2. Nature 378: 789-792, 1995[Medline] 4. Lynch HT, Albano WA, Recabaren JA, et al: Survival in hereditary breast and colon cancer. JAMA 246: 1197, 1981 (letter)[Medline]
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Lakhani SR, Gusterson BA, Jacquemier J, et al: The pathology of familial breast cancer: Histological features of cancers in families not attributable to mutations in BRCA1 and BRCA2. Clin Cancer Res 6: 782-789, 2000 9. Meijers-Heijboer EJ, Verhoog LC, Brekelmans CTM, et al: Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355: 2015-2020, 2000[Medline]
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Birch J, Hartley AL, Tricker KJ, et al: Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res 54: 1298-1304, 1994 14. Liaw D, Marsh DJ, Li J, et al: Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16: 64-67, 1997[Medline] 15. Sobol H, Birnbaum D, Eisinger F: Evidence for a third breast-cancer susceptibility gene. Lancet 344: 1151-1152, 1994[Medline] 16. Kerangueven F, Essioux L, Dib A, et al: Loss of heterozygosity and linkage analysis in breast carcinoma: Indication for a putative third susceptibility gene on the short arm of chromosome 8. Oncogene 10: 1023-1026, 1995[Medline] 17. Serova OM, Mazoyer S, Puget N, et al: Mutations in BRCA1 and BRCA2 in breast cancer families: Are there more breast cancer-susceptibility genes? Am J Hum Genet 60: 486-495, 1997[Medline]
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Struewing JP, Hartge P, Wacholder S, et al: Cancer risk with 185delAG and 5382insC mutations of BRCA1 and the 6174delT mutation of BRCA2 among Ashkenazi Jews. N Engl J Med 336: 1401-1408, 1997 22. Thorlacius S, Olafsdottir G, Tryggvadottir L, et al: A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13: 117-119, 1996[Medline] 23. Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62: 676-689, 1998[Medline] 24. Chen J, Silver DP, Walpita D, et al: Stable interaction between the products of BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell 2: 317-328, 1998[Medline] 25. Futreal PA, Liu Q, Shattuck-Eidens D, et al: BRCA1 mutations in primary breast and ovarian carcinomas. Science 266: 120-122, 1995 26. Lancaster JM, Wooster R, Mangion J, et al: BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13: 238-240, 1996[Medline] 27. Teng D, Bodgen R, Mitchell J, et al: Low incidence of BRCA2 mutations in breast carcinomas and other cancers. Nat Genet 13: 241-244, 1996[Medline] 28. Miki Y, Katagiri T, Kasumi F, et al: Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet 13: 245-247, 1996[Medline] 29. Robson M, Gilewski T, Haas B, et al: BRCA-associated breast cancer in young women. J Clin Oncol 16: 1642-1649, 1998[Abstract] 30. Osin P, Crook T, Powles T, et al: Hormone status of in-situ cancer in BRCA1 and BRCA2 mutation carriers. Lancet 351: 1487, 1998 (letter)
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Foulkes WD, Wong N, Brunet J-S, et al: Germ-line BRCA1 mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer. Clinical Cancer Res 3: 2465-2469, 1997 49. Neuhausen SL, Godwin AK, Gershoni-Baruch R, et al: Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study. Am J Hum Genet 62: 1381-1388, 1998[Medline] 50. Foulkes WD, Wong N, Rozen F, et al: Survival of patients with breast cancer and BRCA1 mutations. Lancet 351: 1359-1360, 1998[Medline] 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
