Synchronous Multiple Breast Cancers-Do We Need to Reshape Staging?

Background and Objectives: Current recommendations and treatment regimens in breast cancer are a reflection of its heterogeneity on multiple levels including histological subtypes, grading, molecular profiling, and numerous prognostic indices. Although based on extensive research, current guidelines are not explicit in the case of surgical specimens showing various degrees of mismatch between different parts of the same tumor and even more so between multicentric lesions. Synchronous breast cancer is the ideal prototype for studying inter- and intra-tumoral heterogeneity, therefore we envisaged that a study on patients with multicentric and multifocal lesions could contribute to the reshaping of the staging, prognosis, and treatment of breast malignancies. Material and Methods: A prospective observational study was conducted between January 2013 and May 2017 on 235 patients diagnosed with breast cancer (BC) and surgically treated at Emergency University Hospital, Bucharest. Thirty-seven patients had multiple breast tumors and were eligible for assessment of the heterogeneity of their lesions. Results: 6 were multicentric and 31 multifocal. The number of foci varied from 2 to 11. We encountered numerous mismatches between the index and the secondary tumors, as follows: 3 cases (8.1%) with histopathological mismatch, 13 (35.1%) with different grades of differentiation, 11 (29.8%) with ER (Estrogen Receptors) status mismatch, 12 (32.4%) with PR (Progesterone Receptors) status mismatch, 8 (21.6%) with molecular phenotype mismatch, and 17 (45.9%) cases with variable Ki-67. After careful analysis of index and secondary tumors, apart from the mismatches reported above, we discovered that the secondary tumors were actually dominant in 5 cases (13.5%), and therefore at least those cases had to be reclassified/restaged, as the supplementary data commanded changes in the therapeutic decision. Conclusions: For synchronous breast tumors, the current Tumor-Node-Metastasis (TNM) staging system ignores not only the histopathological and immunohistochemical characteristics of the secondary foci, but also their size. When secondary lesions are more aggressive or their cumulative mass is significantly bigger than that of the index tumor, the treatment plan should be adapted accordingly. We believe that information obtained from examining secondary foci in synchronous breast cancer and assessment of the cumulative tumoral mass should be reflected in the final staging and definitive treatment. The clinical benefit of staging the patients based on the most aggressive tumor and the cumulative tumoral burden rather than according to the biggest single tumor, will avoid under-treatment in cases with multifocal/multicentric BC displaying intertumoral mismatch.