Abstract ES03-1: Clinical 101: The pathology of breast cancer

Numerous histological types of breast cancer are recognized based on their discrete architectural patterns and associated different risk factors, clinical presentations, pathological features, patterns of spread, response to therapy and outcomes. Traditional prognostic factors include tumor size, lymph node status, tumor grade, and immunohistochemical profile of Estrogen and Progesterone Receptor (ER and PR) and Her2/neu gene amplification status. Histological tumor grade assesses degree of differentiation (tubule formation and nuclear pleomorphism) and proliferative activity (mitotic index). The three histological grades mirror aggressiveness and correlate with survival. Expression profiling reveals only two genomic grades, low and high. The ER positive, HER2 positive and triple negative tumors have correlative molecular subtypes on transcriptome analysis; two ER positive groups, luminal A and B where B tumors have a high proliferation compared with A, a HER2 enriched group, and basal-like group corresponding to triple negative tumors. A molecular apocrine group is characterized by ER negative, Androgen Receptor positive status with paradoxical expression of ER related genes and often HER2. A subset of molecular apocrine carcinomas have a morphological correlate. The traditional prognostic factors used to determine therapy neither capture the complexity of breast cancer nor provide tailored enough treatment options for individual patients. Gene expression profiles which predict disease recurrence pick out the proliferation related genes and a number of different prognostic signatures despite them having < 25% of shared genes between the signatures (e.g. OncotypeDX, PAM50, Mammaprint) identify the Luminal A low risk subgroup, which does not benefit from chemotherapy. These prognostic signatures have no value in ER negative disease where there is a high rate of resistance to chemotherapy regimens. Predictors of sensitivity or resistance to specific regimens of chemotherapy in all tumors and predictors of resistance to hormone therapy in ER positive tumors are needed. The low and high grade genomic signatures reflect two distinct models of tumor progression. The low grade neoplasia pathway is characterized by simple diploid karyotypes, and luminal A type invasive carcinomas in this group share genetic and transcriptomic features with precursor lesions, ADH, FEA. Special subtype tumors in this pathway include tubular, lobular, cribriform, mucinous carcinomas and some neuroendocrine carcinomas. The high grade pathway encompasses high grade DCIS, and high grade invasive ductal carcinoma and is characterized by aneuploidy and complex karyotypes. Although tumors can be lumped broadly into low and high grade, there is enormous diversity between tumors even within the molecular subgroups. For example the basal-like/triple negative group includes tumors with distinct morphology, clinical presentation, prognosis and molecular profiles which requires tailoring of therapies. Two rare low grade clinically indolent basal-like tumors include Secretory carcinomas which harbor a characteristic recurrent balanced chromosomal translocation which leads to a fusion transcript ETV6-NTRK3 and Adenoid cystic carcinomas which have a MYB-NFIB fusion gene. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES03-1.