Abstract
BackgroundToday, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. In this respect, high resolution genomic profiling may provide a more reliable approach than conventional histopathological and tumor biological factors.Methods32 K tiling microarray-based comparative genomic hybridization (aCGH) was used to explore the genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs, and was compared with histopathological and tumor biological parameters.ResultsBased on global copy number profiles and unsupervised hierarchical clustering, five of ten (p = 1.9 × 10-5) unilateral tumor pairs displayed similar genomic profiles within the pair, while only one of eight bilateral tumor pairs (p = 0.29) displayed pair-wise genomic similarities. DNA index, histological type and presence of vessel invasion correlated with the genomic analyses.ConclusionSynchronous unilateral tumor pairs are often genomically similar, while synchronous bilateral tumors most often represent individual primary tumors. However, two independent unilateral primary tumors can develop synchronously and contralateral tumor spread can occur. The presence of an intraductal component is not informative when establishing the independence of two tumors, while vessel invasion, the presence of which was found in clustering tumor pairs but not in tumor pairs that did not cluster together, supports the clustering outcome. Our data suggest that genomically similar unilateral tumor pairs may represent a more aggressive disease that requires the addition of more severe treatment modalities, and underscores the importance of evaluating the clonality of multiple tumors for optimal patient management. In summary, our findings demonstrate the importance of evaluating the properties of both tumors in order to determine the most optimal patient management.
Highlights
Today, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers
Since the extent of genomic imbalances can be determined with greater mapping precision due to the high resolution and large number of data points [19], microarray-based comparative genomic hybridization (aCGH) in particular may be of clinical value in differentiating new primary tumors from recurrent lesions and genomic analysis can help reveal the relationship between multiple tumors
Similar results have been obtained by analyzing unilateral breast tumors using metaphase comparative genomic hybridization (CGH) and unsupervised hierarchical clustering; one such study revealed that paired tumors from three of four unilateral breast cancer patients demonstrated a clonal relatedness based on copy number profiles [16]
Summary
No objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. When multiple breast tumors are detected synchronously the question arises whether these tumors represent independent primary lesions or whether they are genetically similar. Chaudary et al have set up criteria used to discriminate between independent primary lesions and metastases in synchronous bilateral breast cancer [1]. Contralateral metastasis as a first event is very rare, but cannot be completely excluded if the two tumors appear histologically very similar
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