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© 2000 American Society for Clinical Oncology
Immunophenotypic and Pathologic Differences Between BRCA1 and BRCA2 Hereditary Breast CancersFrom the Peter MacCallum Cancer Institute, Victoria, Australia. Address reprint requests to Kelly-Anne Phillips, MB, BS, FRACP, Peter MacCallum Cancer Institute, Locked Bag No 1, A’Beckett St, Victoria 8006, Australia; email PhillipsKelly{at}petermac.unimelb .edu.au.
Morphologically and clinically, breast cancer is a heterogeneous group of diseases. This heterogeneity may be a manifestation of differences in the molecular genetic events underlying distinct breast cancer pathogenesis pathways. Examination of hereditary breast cancers (HBC), which have in common an underlying germline mutation in BRCA1 or BRCA2, may provide further insight into this concept. Multiple studies have confirmed that BRCA1-associated HBC (BRCA1-HBC) generally exhibit a specific phenotype that is characterized by high tumor grade and estrogen receptor negativity. Conversely, discrepancies exist between the findings of studies that have examined BRCA2-HBC, and a specific phenotype has not been consistently described. The characteristic phenotype of BRCA1-associated tumors may prove a useful additional tool in selecting individuals with breast cancer who should be offered BRCA1 mutation testing, although further studies are required. Lastly, evidence is emerging to suggest that BRCA1 might be involved in the pathogenesis of a subgroup of non-HBC (by gene underexpression rather than mutation) and that these tumors may exhibit the same phenotype as their hereditary counterparts.
WOMEN WHO INHERIT a mutation in BRCA1 or BRCA2 have a greatly increased risk for breast cancer, and the vast majority of breast cancers occurring in such women are attributable to the underlying germline mutation. Throughout this article, such breast cancers are referred to separately as BRCA1-associated hereditary breast cancers (BRCA1-HBC) or BRCA2-associated hereditary breast cancers (BRCA2-HBC), and together as BRCA1- or BRCA2-associated hereditary breast cancers (BRCA1/2-HBC). The molecular pathogenesis of BRCA1/2-HBC is believed to involve loss of the corresponding wild-type allele (the second hit) and the subsequent accumulation of additional genetic perturbations in that clonal population of cells.1 The pathogenesis pathways of breast cancers that occur because of an underlying germline mutation in BRCA1 or BRCA2 may thus be fairly distinct when compared with the heterogeneous pathogenesis of other (currently less well-defined) types of breast cancers. If BRCA1/2-HBC do proceed via a distinct series of molecular events, they might be expected to be relatively homogeneous with regard to their morphology and perhaps also in terms of their natural history and response to treatment. As outlined below, several studies have examined the histologic and immuno/molecular phenotype of BRCA1/2-HBC.2-22 The majority of these studies have examined tumors from individuals in families with multiple cases of breast cancer,2-4,9-11,13-17,19-22 although there are some data available from a population-based study7,8 and hospital-based series.5,6 The results of these studies indicate that BRCA1-HBC tend to exhibit a characteristic phenotype. Conversely, a distinct phenotype has not been clearly described for BRCA2-HBC. The identification of a particular phenotype for BRCA1-HBC has led to the suggestion that it might be possible to predict the presence of an underlying germline mutation in this gene from the tumor morphology. Interestingly, although BRCA1 and BRCA2 are not mutated in non-HBC,23-25 there seems to be a subgroup of these tumors that underexpress BRCA1, and these tend to exhibit a similar phenotype to their hereditary counterparts.26-29
Studies have consistently described phenotypic differences between BRCA1-HBC and those occurring in the absence of a germline BRCA1 mutation (Table 1). 2-18 The former are more frequently histologic grade 3,2-10,12,14,17,18 and they express receptors for estrogen and progesterone less often.3,4,6,8,9,11,12,16-18 In a number of studies, BRCA1-HBC have been documented to be more frequently of atypical medullary or medullary subtype, with features such as a prominent pushing margin and lymphocytic infiltrate.2,3,7,10,14 Although high histologic grade and hormone receptor negativity are features that are usually associated with a poorer prognosis in breast cancer, tumors of medullary subtype tend to have a better prognosis.
Preclinical data suggest that the p53 gene may be important in the pathogenesis of BRCA1/2-HBC. The protein products of BRCA1 and BRCA2 have been shown to interact with the Rad51 protein, which is involved in recombination and DNA double-strand repair.30-32 A cell lacking functional brca1 or brca2 protein may thus have a decreased ability to repair DNA damage, which would lead to genomic instability. If p53 were functional in that cell, p53-mediated cell cycle arrest or apoptosis would ensue. However, in the absence of functional p53, the clonal population of cells could continue to proliferate and accumulate further somatic genetic abnormalities, perhaps resulting in tumor progression. Thus, loss of p53 checkpoint control (by p53 mutation or other mechanisms) may be obligatory for malignant transformation in cells with a BRCA1 or BRCA2 mutation. This hypothesis is supported by data from murine models demonstrating that embryos lacking both functional p53 and brca1 proteins or lacking functional p53 and brca2 proteins live several days longer than those which retain p53 function in the setting of no functional brca1 or brca2.33,34 In keeping with this hypothesis, six of seven published studies have demonstrated a higher frequency of p53 mutations or immunopositivity for p53 in BRCA1-HBC compared with control tumors.3,8,9,14,17,18 This finding may have prognostic significance because breast carcinomas with p53 mutations tend to have a worse prognosis than those without.35 Three of five published studies have found a lower frequency of erbB-2 overexpression, evaluated by immunohistochemistry, in BRCA1-HBC compared with non-HBC.3,8,9,14,17 This suggests that overexpression of erbB-2 is unlikely to be an important part of the molecular pathogenesis of BRCA1-HBC, despite the fact that these tumors are usually of high histologic grade and hormone receptor-negative, features associated with erbB-2 amplification or overexpression in breast cancer in general. In addition, this finding may have prognostic implications as erbB-2 amplification/overexpression has been shown to be an independent predictor of adverse outcomes in breast cancer.36-41
Fewer studies of BRCA2-HBC have been performed. Review of these studies does not reveal consistent evidence of a distinct phenotype for these tumors (Table 2). 7-11,15,17,19,20,22 Studies that have examined the histologic grade of BRCA2-HBC have had discrepant results. One study found that BRCA2-HBC were more likely to be of lower histologic grade compared with controls,19 whereas three other studies showed that they were more likely to be of higher grade9,10,22; although in one of these, the mitotic count was significantly lower in the BRCA2-HBC.10 Two studies showed no difference in grades between the groups.
Similarly, the results of studies that have investigated the histologic subtype of BRCA2-HBC have been discordant. An excess of pleomorphic lobular or tubular-lobular group carcinomas arising in association with BRCA2 mutations has been documented in two studies7,19 but was not seen in the four other studies that have examined the histologic types of these tumors.9,17,21,22 In one of these studies,22 all of the tumors arose in the setting of the same BRCA2 mutation (the 999del5 Icelandic founder mutation), but they were not all of the same histologic subgroup; most had ductal carcinoma, two had lobular carcinoma, and one had medullary carcinoma. This finding indicates that the histologic appearance of BRCA2-HBC may be affected by factors other than just the specific site of BRCA2 mutation (eg, perhaps somatic mutations in other genes). Several studies have examined the hormone receptor status of BRCA2-HBC.9,11,17,21,22 One of these showed a statistically significant excess of hormone receptor-positive tumors in the BRCA2-associated group compared with controls,22 but the other four studies showed no difference between the groups. In contrast to the findings in BRCA1-HBC, an increase in the frequency of p53 mutations in BRCA2-HBC has not been clearly demonstrated. Five studies have examined the p53 mutation status of BRCA2-HBC, three by immunohistochemistry8,9,17 and two by direct mutation analysis.15,20 The three immunohistochemical studies show conflicting results, with one demonstrating a higher rate of p53 positivity for BRCA2-HBC compared with controls9 and the other two showing no difference. The two studies that did not use immunohistochemistry both showed a trend toward an increase in p53 mutations in the BRCA2 group (29% of 34 BRCA2-associated tumors v 17% of 368 controls20 and 63% of 22 BRCA2-associated tumors v 35% of 72 grade-matched controls15 ). Similarly, no difference in the erbB-2 status of BRCA2-HBC has been documented in the three studies that have examined this issue using immunohistochemical techniques.8,9,17
Although germline mutations in BRCA1 and BRCA2 are clearly important in a substantial proportion of HBC, these genes are rarely somatically mutated in nonhereditary forms of the disease.23-25 However, loss of heterozygosity at the chromosome regions which harbor the BRCA1 and BRCA2 genes (17q21 and 13q12-13) are frequent in non-HBC,42-44 suggesting that these genes may be inactivated by mechanisms other than coding region mutations in some of these tumors. Indeed, evidence that underexpression of BRCA1 may be involved in the pathogenesis of a subgroup of non-HBC is now emerging.26-29,45-47 Three recent studies26-29 have revealed that underexpression of BRCA1 occurs in a substantial proportion of invasive ductal breast cancers and that it is closely correlated with high histologic grade, a phenotypic feature of BRCA1-HBC. The mechanisms of BRCA1 underexpression have not been fully elucidated but include aberrant methylation.45,46 Wilson et al26 examined BRCA1 expression by immunohistochemistry in a random sample of 62 invasive ductal breast cancers. A highly significant inverse correlation was seen between BRCA1 staining (expression) and histologic grade. All 10 low-grade tumors showed moderate to strong staining, indicating expression of BRCA1, whereas 82% of the 28 high-grade tumors demonstrated weak or undetectable staining, indicating reduced expression. The staining intensities for the 24 intermediate-grade tumors were between these extremes, with 17% showing weak or undetectable staining. This group also examined 17 invasive lobular carcinomas, all of which exhibited strong (94%) or moderate (6%) staining for BRCA1. The steroid receptor status of the tumors was not examined. In a similar study, Lee et al27 evaluated BRCA1 expression by immunohistochemistry in 108 invasive ductal breast carcinomas. Loss of BRCA1 expression was seen in 20% of cases and correlated well with high histologic grade (31% of 16 grade 3 tumors v 3% of 31 grade 1 tumors; P < .025). BRCA1 underexpression was also seen more frequently in tumors that were estrogen receptor-negative (another documented phenotypic feature of BRCA1-HBC). Seery et al28 examined BRCA1 expression levels using reverse transcription polymerase chain reaction in a series of 53 sporadic breast carcinomas. Reduced expression of BRCA1 was seen in 28% of tumors, and these tumors were significantly more likely to be estrogen receptor-negative and to exhibit higher levels of proliferation (using Ki67 immunohistochemistry). Although further studies are required, these data suggest that there may be a subgroup of non-HBC with a similar molecular pathogenesis to BRCA1-HBC (but with somatic inactivation of BRCA1 rather than germline mutation) and that, therefore, exhibit similar phenotypic characteristics.
Currently, predictions about the likelihood of an individual harboring a germline mutation in BRCA1 or BRCA2 are based on clinical data, including family history, age of onset of breast cancer, and ethnicity. Family history, especially where there are clusters of breast and ovarian cancer, has the best positive predictive value of these three. However, family history data is often problematic as it relies on accurate recall of cancer events within the family and the ability to obtain pathology confirmation of those cancers. In addition, recent population-based studies have revealed that the majority of breast cancer patients who harbor a germline mutation in BRCA1 or BRCA2 do not have a family history of breast cancer,48,49 this may be because of factors such as paternal transmission of the mutated allele, relatively low penetrance alleles, or even (rarely) de novo mutations.50 The documentation of a distinct phenotype for BRCA1-HBC has led to the suggestion that the histologic phenotype of an individual woman’s breast cancer might be useful in predicting whether she has an underlying germline mutation in BRCA1. Eisinger et al13 have examined the relationship between germline BRCA1 mutation status and medullary carcinoma of the breast (a histologic subtype seen more frequently in some studies of BRCA1-HBC). Among 18 typical medullary carcinomas ascertained from a hospital-based registry, two had a protein-truncating mutation in BRCA1 and another two had a missense mutation of potential functional significance. Although this is a small study, the frequency of mutations is much higher than would be expected in breast cancer in general. The same researchers subsequently examined 70 population-based breast cancer cases diagnosed before the age of 35 years, regardless of family history. BRCA1 mutations were found in 8.6% of cases overall. Twenty-nine percent of the cases with estrogen receptor-negative and high-grade tumor morphology carried a mutation in BRCA1 compared with 3.6% of tumors with other morphologic profiles (P = .007).51 Most of the mutation carriers did not have a strong family history of breast cancer. Another recent study has reached similar conclusions.52 In that study, 97 breast carcinomas from women with a strong family history of breast (n = 51) and/or ovarian (n = 16) cancer or with breast cancer diagnosed before the age of 35 years (n = 30) were categorized into three groups based on their phenotypic features. Tumors in group A exhibited grade 3 histology, high proliferative rate (using Ki67 immunohistochemistry), and were negative for estrogen and progesterone receptors; those in group B were characterized by histologic grade 1 or 2, low proliferative rate, and positive hormone receptors; and tumors that did not fit either of these categories were categorized as group C. The BRCA1 mutation rate in group A tumors was 53% compared with 5% and 0% in groups B and C, respectively (P < .001). The authors concluded that a tumor phenotype that includes high grade, high proliferative rate, and hormone receptor negativity in patients with a strong family history or early age at diagnosis suggests a high probability of carrying a BRCA1 germline mutation. These data suggest that the addition of tumor morphologic characteristics to the clinical profile (family history and age of onset) might assist in better selecting individuals for BRCA1 mutation testing. There may also be substantial implications for cost-effectiveness. For example, Lidereau et al51 suggest that the cost of testing only patients with early-onset breast cancers (diagnosed before age 35 years) that are both estrogen receptor-negative and high-grade would be approximately 30% of the cost of testing all women with early-onset breast cancer. It will be important to attempt to reproduce these findings in large population-based samples of early-onset breast cancer patients. It will also be of interest to examine this question within other age groups of population-based cases. However, it is possible that with increasing age at diagnosis, the predictive value of tumor morphology will decline because the prior probability of having a mutation is less. To summarize, the evidence available to date suggests that BRCA1-HBC generally have a phenotype that includes high histologic grade and hormone receptor negativity and that they often exhibit a somatic p53 mutation. These tumors may also be more frequently of typical or atypical medullary type; however, this has not been seen in all studies. The relatively homogeneous phenotype of BRCA1-HBC may have implications for the prognosis of these tumors, although studies that have attempted to address this question have had conflicting results, perhaps because of problems in their methodology.53 Conversely, the phenotype of BRCA2-HBC seems to be more heterogeneous and they do not seem to be clearly and producibly distinguishable from non-HBC. In individuals with early-age onset breast cancer or with breast cancer that occurs in the setting of a strong family history of the disease, having a tumor with the classic phenotypic features of BRCA1-HBC may indicate a higher chance of there being an underlying germline BRCA1 mutation. However, the positive predictive value of having such a tumor phenotype has not been examined in a population-based group of breast cancer patients across a wider age range. In this situation, it may be much lower because the underlying mutation prevalence in such a population is less than in early-onset groups. In addition, it is becoming increasingly clear that there may be contamination by a group of non-HBC that exhibit the classic BRCA1 phenotype because of underexpression of BRCA1 rather than because there is an underlying germline mutation present. Further studies are required to help clarify these issues.
I thank Professor John Hopper and Dr Clare Scott for helpful discussions during the preparation of this manuscript.
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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
