Key words: Bilateral breast cancer; Risk factors; Clonality, BRCA genes; Mutations; Polymorphism; ERBB2; HER2; CHEK2; CYP19

Abstract

Bilateral breast cancer (biBC) offers intriguing possibilities for molecular genetic investigations, however it is disproportionally less studied than its unilateral counterpart. By now, genetic research has succeeded to resolve at least two important aspects of biBC pathogenesis. First, it has been confirmed, that the vast majority if not all biBC arise due to clonally independent events but not due to contralateral metastatic spread. Second, unselected biBC cases have been shown to have a modest prevalence of BRCA germ-line mutations (approximately 5%), although a considerable frequency of BRCA defects (up to 20%) has been observed in early-onset and/or familial forms of the disease. Other data related to biBC appear to be at suggestive stage. Recent reports demonstrate, that the tumors forming biBC pair may show similarities of their molecular portraits, especially if they develop synchronously. This observations imply that the host factors may determine not only the level of breast cancer susceptibility, but also the molecular variant of the disease development. Apart from this, biBC may serve as a very demonstrative case group in the studies of breast cancer predisposing low-penetrance gene polymorphisms, because it is more likely to accumulate unfavorable allele combinations than the unilateral patients. The utility of this approach has been already exemplified by several scientific publications. Further research on the biBC molecular pathogenesis may significantly contribute to the general understanding of the process of malignant transformation.

Clinical and epidemiological data

There are few paired organs in the human body, which combine both high cancer incidence and good cancer survival. Therefore, although the studies of bilateral forms of malignant disease appear to be very valuable for the understanding of systemic cancer-host interactions, they are often restricted by small series or even anecdotal cases. Bilateral breast cancer (biBC) holds an especial position within this category of tumors. The mere fact of considerable frequency of breast cancer increases the probability of its bilateral occurrence. Furthermore, thanks to relatively favorable prognosis of breast neoplasia, most of the patients have prolonged follow-up and thus have sufficient amount of time to develop a tumor in the contralateral organ subsequently to the first disease. These features result in an elevated incidence of biBC as well as in its pronounced diversity regarding age at onset, time interval between tumors, hormonal status of the patients, family history, outcome etc. Thus the phenomenon of biBC can be subjected to large, comprehensive, complex studies [1-4].

Despite intriguing clinical and fundamental aspects, bilateral breast cancer is disproportionally less studied as compared to its unilateral counterpart. Even the diagnostic criteria of biBC are the subject of controversy. The difficulty is caused by the need to discriminate between independent primary lesions and metastasis to the contralateral breast. The most strict and widely cited criteria have been summarized in the now-classical work of Chaudary et al. [5]. Bilateral carcinomas are considered independent if 1) the subsequent tumor has in situ component, or 2) the lesions are of distinct histological types, or 3) the subsequent cancer has greater (better) degree of differentiation, or 4) there is no evidence for metastatic spread from the ipsilateral lesion. Two of these rules are applicable only for metachronous but not for synchronous biBC; furthermore, this algorithm tends to be over-exclusive for the metastasis-positive cases. Some clinics include in the biBC category those histologically similar tumors, which show limited nodal involvement, but lack distant metastases and/or “metastatic track” across the midline. Long time interval between the tumors onset may also be regarded as a proof of the true bilaterality. Intramammary location of the lump has to be considered as well: it is known that metastatic cancers are usually located in the fat, whereas primary neoplasms affect the breast parenchyma. In addition, primary and secondary breast lesions produce somewhat different images upon mammographic examination [1, 2, 6-8].

Lack of strict diagnostic standards leads to significant discrepancies in the estimates of the biBC incidence. In the most of studies, the risk of contralateral lesion amounts to 0.4 - 0.8% per year, and remains relatively constant over the time. This is 2-6 times higher than the risk of primary breast cancer in general population [3, 4]. The figures of cumulative incidence of biBC are difficult to analyze, because they heavily depend on the life expectancy of the patients, length of follow-up, mode of tumor detection etc. Most of available studies report the values within 5-10% when non-invasive methods of cancer screening are applied [3, 4]. Noticeably, use of random biopsy or pathological examination for the remaining breast may increase the rate of detection of simultaneous contralateral neoplasia by more than an order of magnitude [3, 4, 9, 10]. The significance of these pathological findings is unclear, because they are in discordance with the rates of clinical manifestation of biBC. Moreover, similar studies on the randomly selected cancer-free women have also demonstrated high frequency of occult breast malignancies [11, 12].

Significant efforts have been invested to determine why selected breast cancer patients develop this disease twice. This knowledge is expected to be helpful in defining the subset of patients who need particularly tight surveillance after the first malignancy [reviewed in 3, 4]. A young age was reproducibly shown to increase the individual chances of contralateral malignancy, both due to longer overall life expectancy and due to accumulation of especially susceptible women among early-onset patients. Family history of breast cancer is also considered to be an indicator of elevated biBC risk. Many investigators reported an association between lobular histology of the first tumor and breast cancer bilaterality. Surprisingly, little attention has been paid to explain the biological or clinical basis for this relationship. Several studies analyzed the impact of reproductive variables (age at menarche, age at first birth, parity etc.), which are related to peculiarities of steroid metabolism and known to modify the risk of breast cancer. Although some trends have been observed, most of the series produced negative findings [3, 4 and references therein]. It is important to emphasize, that the absolute magnitude of the reported effects is weak, so the majority of biBC cases can not be justified by the excess of any known risk factor.

The question of clonality

The whole body of bilateral breast cancer research is based on the belief that biBC consists of 2 clonally independent malignancies. If the differential diagnosis between true biBC and contralateral metastasis is not reliable, the obtained conclusions would have very little value. Thus the question of clonality is absolutely vital for all activities in this field.

Advances in molecular biology have offered efficient tools for the studies of clonal origin of malignant growth. Noguchi et al. [13] and Shibata et al. [14] have demonstrated distinct clonality of selected biBC pairs using X chromosome inactivation test. Shibata et al. [14] have detected somatic p53 mutations in 13 out of 49 biBC patients, and none of these informative cases showed identical lesion. Stenmark-Askmalm et al. [15] and Janschek et al. [16] have confirmed the discordance of p53 mutational status in biBC, although single cases of the sharing of the same mutation have been observed as well; since the normal tissues were not analyzed in these series, it remains unclear whether the identity of p53 status indicate the metastatic origin of the contralateral tumor or germ-line defect. Our research group has performed an analysis of allelic imbalances in 28 biBC tumor pairs [17]. Common clonality could not be entirely excluded only in 1 out of 28 cases. In the light of recent genetic evidence, one has to mention the earlier work of Dawson et al. [18]. These authors investigated the expression of 6 breast cancer associated proteins in 51 biBC, and found only 1 instance of identical immunoreactivity within the pair. Although the expression profile within the tumor clone is certainly more flexible than mutation status, the level of diversity observed by Dawson et al. [18] appears to be incompatible with the metastatic origin of biBC. In summary, the molecular data indicate that the vast majority if not all clinically diagnosed biBC represent clonally independent disease.

It is necessary to comment, that the results of genetic investigations played rather confirmatory role and were expected from clinical and epidemiological assumptions. Indeed, if contralateral lesion of the breast would be of metastatic origin, bilateral breast cancer patients would have disproportionally elevated incidence of the metastatic spread and evidently poor survival after diagnosis of the second malignancy. However, there is a good agreement between the follow-up studies, that bilateral breast tumors affect the prognosis in an independent fashion, and the rate of biBC metastases does not significantly differ from the expected value [19-22].

The role of BRCA mutations

Tumor bilaterality has long been suspected to be a sign of a solid germ-line defect [23]. Increased occurrence of bilateral breast cancer was repeatedly demonstrated in large, multi-case breast cancer families [24, 25]. In accordance to expectations, studies on BRCA1 and BRCA2 mutation carriers have shown the elevation of the contralateral cancer risk by approximately an order of magnitude [25]. Impressive advances in familial cancer research led to the belief, that BRCA carriership and breast cancer bilaterality are highly related if not equivalent phenomena.

There is no doubt, BRCA defects increase the individual chances both for breast cancer in general and for its bilateral occurrence in particular. The magnitude of the effect is difficult to estimate, because the early studies have been based on extended breast cancer pedigrees and/or early-onset cases, i.e. biased towards highly penetrant BRCA lesions. More recent investigations suggest that the penetrance of BRCA mutations, and hence the corresponding uni- and bilateral breast cancer risk, were overestimated at least twice in the pioneering reports [25].

Furthermore, studies on randomly selected biBC patients show at best border-line if any increase in the incidence of BRCA mutations [26-28]. Importantly, when additional selection criteria, e.g. early age at onset and/or strong family history, are being added, the rate of positive findings increases; however similar trends are observed for unilateral cases as well [29-31]. Overall, the frequency of BRCA germ-line mutations in biBC arrives to approximately 5%, although it may exceed 20% in the early-onset and/or familial groups of patients. Hence, the majority of biBC cases can not be explained by BRCA carriership.

Similar results have been obtained regarding other breast cancer associated familial cancer genes. p53 germ-line mutations, which are associated with the Li-Fraumeni syndrome, appear to be extremely uncommon in biBC patients, although some exceptions have been reported [14, 32, 33]. ATM (ataxia-telangiectasia gene) heterozygotes were not detected in the biBC group by Shafman et al. [34], although Broeks et al. [35] reported an elevated incidence of ATM lesions in early-onset biBC cases.

Thus, in contrast to some rare tumor types, bilaterality of breast cancer per se may not be considered as a strong indicator of highly-penetrant germ-line defect. However, it retains a predictive value when taken together with other features of hereditary cancer syndromes.

Somatic mutations in bilateral breast carcinomas

Whereas alterations of oncogenes and suppressor genes in breast cancer have been investigated in great detail [36], little information is available for its bilateral form. Kollias et al. [29] and Imyanitov et al. [17] have performed the study of allelic imbalances in biBC. On the qualitative level, the detected chromosome abnormalities resembled the ones in unilateral carcinomas, however a quantitative comparison was not possible due to the lack of control series. Several groups examined p53 lesions in biBC. Three reports employed sequencing analysis for this purpose, and found somewhat low incidence of p53 mutations [14-16]. The results of the studies relying on immunohistochemistry and SSCP technique appear to be more variable [37-41]. Activation of ERBB2/HER2 oncogene was assessed only by means of protein detection but not by genomic analysis. Safal et al. [42] observed high frequency of ERBB2/HER2 overexpression (71%), however other investigations produced more modest estimates [18, 40, 41]. Our laboratory has compared the incidence of the high-level microsatellite instability (MSI-H) in biBC versus. unilateral cases [43]. MSI-H status was detected in 2 out of 46 carcinomas obtained from 23 biBC patients, but in none of unilateral breast neoplasms. Neither of 2 patients bearing MSI-H tumors had HNPCC syndrome features. However, the significance of this finding remains unclear due to its rarity.

Molecular pathogenesis of bilateral breast cancer: concordance or discordance?

Bilateral breast tumors share genetic background of the host, history of exposure to external hazards, and probably some essential features of the metabolic environment. The intriguing question is, how this similarity affects the molecular portrait of the disease. In other words, is there a tendency to concordance of genetic lesions in biBC, or, vice versa, paired breast neoplasms show the same level of heterogeneity as unrelated carcinomas?

We recently performed a comparative analysis of the allelic imbalances in paired biBC samples [17]. Our data demonstrated increased concordance of allelotypes in synchronous vs. metachronous biBC. This observation is logical, because simultaneously diagnosed tumors are more likely to have nearly identical natural history than those separated by a certain time interval. Furthermore, there was a regular relationship between the concordance of genetic alterations and menopausal status at the tumors onset. Premenopausal patients showed the highest level of similarity between carcinomas, whereas those women who experienced the cessation of menses between the first and consequent malignancy had the least level of concordance. These data support the contribution of hormonal environment in the breast cancer pathogenesis. Moreover, they confirm the presence of a solid trigger factor (be it BRCA mutation or other, yet unknown substance) in the youngest category of biBC cases, where double occurrence of the cancer can hardly be explained by a chance coincidence. Several related observations support our findings. Increased concordance of estrogen receptor status in synchronous vs. metachronous biBC has long been acknowledged [44, 45]. In addition, short time interval between the tumors onset was shown to correlate with morphological similarity of the bilateral breast neoplasms [46].

The weakness of the data presented above is related to the difficulty of discrimination between true biBC and contralateral metastasis. Indeed, although the chance of misdiagnosis is low, currently available tools do not allow to exclude the metastatic origin of biBC with a 100% reliability. Although the possibility of nearly identical pathogenesis in synchronously appearing malignancies is theoretically conceivable, similar molecular portraits of the tumors can be interpreted rather in favor of common clonal origin than as indicators of tumor-host interactions. Fortunately, strong confirmatory evidence have been provided recently by unique twin studies. Wistuba et al. [47] reported an impressively high similarity of the pattern of allelic imbalances in 2 simultaneously diagnosed tumors obtained from BRCA1-bearing monozygotic twin sisters. Delgado et al. [48] studied a monozygotic twin pair carrying BRCA2 germ-line mutation. The tumors, which were also diagnosed at the same age, shared similar profiles of expression of breast cancer associated proteins.

Taken together, the available data indicate that the host factors may determine not only the level of breast cancer susceptibility, but also the precise molecular variant of the disease development. However, further studies involving modern whole-genome approaches are required to define which genetic pathways are essential for these tumor-host relationships.

Polymorphic genes

Only a minor part of bilateral breast cancers can be explained by known risk factors. In this respect, biBC remains very similar to the unilateral form of the disease. Nonetheless, the very fact of double occurrence of breast cancer in biBC cohort implies that these patients accumulate a particularly susceptible part of female population. Since the most of biBC cases appear to be not related to the BRCA defects, or excessive exposure to environmental hazards, or phenotypic peculiarities of the steroid metabolism, one could suspect a contribution of unfavorable combination of low-penetrance polymorphic genes. It is likely, that if a particular allele indeed plays a predisposing role in breast cancer development, it would be overrepresented in bilateral cases more evidently, than in unilateral patients. Thus biBC appears to be a suitable, highly demonstrative group for molecular epidemiological case-control studies.

Unfortunately, the de facto efficiency of this approach is difficult to assess correctly, because no polymorphic genes demonstrated truly consistent associations with breast cancer risk [49]. However, the initial data suggest that the biBC genotyping can be helpful. Vahteristo et al. [50] reported gradual deviations of the frequency of the CHEK2 polymorphic variant from bilateral breast cancer patients to unilateral cases to non-affected females. The regularity of CHEK2 genotype distribution in the studied groups appeared to be a strong argument for the non-random character of the observed association. We recently presented the data regarding involvement of the CYP19 (aromatase) gene polymorphism in breast cancer risk [51]. The del3(TTTA)7 allele was found to be overrepresented in premenopausal patients, but underrepresented in the postmenopausal ones. This difference itself would have a moderate value because similar relationships are frequently attributed to the chance findings. However, striking support was obtained from genotyping of bilateral breast cancer cases, where the comparison of pre- and postmenopausal cases produced exactly the same trend as in the unilateral group. Our studies also indicate, that the analysis of biBC patients is unlikely to cause the data bias. For example, CYP17 and p53 gene polymorphisms, which appeared to be neutral for breast cancer risk in the most of studies, showed usual allele distribution in bilateral breast cancer patients [52 and Suspitsin et al., submitted].

Conclusion

Bilateral breast cancer is a common form of breast cancer. The achievements in genetic research helped to confirm that biBC consists of 2 clonally independent tumors, and the cases of misdiagnosis between true biBC and contralateral metastasis are rare. Contrary to some perceptions, bilaterality of breast cancer per se is not strongly associated with BRCA germ-line mutations. However, the chances to find BRCA defect increase substantially, when the diagnosis of biBC is combined with the early disease onset and/or strong family history. Recent investigations of biBC as well as twin studies noticed considerable molecular similarity of synchronous breast tumors. These data suggest the role of host factors in defining the variant of breast cancer pathogenesis. Also, biBC appears to be a highly demonstrative case group for the analysis of breast cancer predisposing gene polymorphisms, because it accumulates particularly susceptible patients. The utility of biBC genotyping has been already demonstrated in several case-control studies. Further research on biBC may contribute to the general understanding of the process of malignant transformation.

Acknowledgements

The work was supported by INTAS (grant 96-1551) and RFBR (grant 02-04-49890).

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