Molecular Classification of Breast Cancers

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Chennai Breast Centre, Chennai, India

Gene expression profiling studies have revealed the presence of multiple molecular subtypes or intrinsic subtypes of breast cancer and have also shown that the critical determinants of the biological behavior of breast cancers are hormone receptor–related genes, HER2-related genes, and proliferation-related genes. Clarity on the molecular classes of breast cancer will lead to a better understanding of the biology of breast cancer and may result in improved therapies directed toward particular molecular subsets.

Four main molecular/intrinsic breast cancer subtypes with prognostic significance have been identified. These subtypes are luminal A, luminal B, HER2-related, and basal-like. A fifth, “normal breast–like” category has not been reproducibly defined. These subtypes, although originally defined by gene-expressing profiling, have been shown to be reproducible groupings using different platforms, including genomic DNA copy number arrays, DNA methylation, exome sequencing, micro RNA sequencing, and reverse-phase protein assays.

Luminal A cancers express higher levels of ER and ER-related genes and lower levels of proliferation-related genes. They are associated with a low histologic grade and a relatively indolent clinical course with a better prognosis compared with Luminal B and other subtypes. They may, however, experience late recurrences.

Luminal B cancers have lower levels of ER and ER-related gene expression and higher expression of proliferation-related genes. They demonstrate a higher histologic grade and are more likely to be lymph node positive. They show lower expression levels of ER receptors by IHC and may be PR negative; 30 % of Luminal-B tumors also overexpress HER2 (IHC & FISH+). They are associated with a more aggressive clinical course and a worse prognosis than Luminal A cancers.

Luminal A and Luminal B cancers differ in their expression of proliferation-related genes and most probably represent two poles in the spectrum of ER-positive disease.

KI-67 proliferation index may be useful in separating Luminal B from Luminal A tumors.

The HER2+ related cancers, as defined by gene expression profiling, are ER- with overexpression of other genes in the HER2-amplicon (GRB7, TOP2A). They show a high proliferative index and are likely to harbor p53 mutations. They are associated with a higher histologic grade, younger age at presentation, an aggressive clinical course, and a poor prognosis.

The basal-like subtype cancers are also associated with a poor prognosis. They show typical histologic features such as pushing borders, geographic areas of necrosis, and dense lymphocytic infiltrates. Basal-type cancers are generally “triple negative” (ER/progesterone receptor (PR) and HER2 negative) and positive for cytokeratin (CK) 5/6 or epidermal growth factor receptor (EGFR).

Most BRCA1-associated breast cancers exhibit a basal-like molecular profile, possibly due to common pathway of carcinogenesis in these patients. However, all basal-like or triple-negative tumors are not related to BRCA1 mutations.

Molecular Pathways of Carcinogenesis

Molecular studies have provided evidence to support the existence of multiple pathways of development in breast cancers; different subgroups are associated with specific patterns of genetic alterations, without significant overlap. For instance, ER-positive cancers frequently exhibit deletions of 16q and gains of 1q which are uncommon in ER-negative cancers. The latter group tends to be genomically unstable with a high incidence of p53 mutations, HER2 amplifications, and BRCA1 dysfunction. New evidence has also emerged to suggest that ER-positive tumors can progress from low to high grade with up to 50 % of Grade 3 tumors harboring identical 16q and 1q alterations as Grade 1 ER-positive cancers, indicative of a common pathway of carcinogenesis. High-grade tumors have accrued additional genetic alterations during their evolution, rendering them genetically unstable with higher proliferative indices.

Current evidence also indicates that lobular cancers are genetically very similar to ductal cancers; they also exhibit 16q and 1q alterations but additionally reveal loss of E-cadherin expression in the lobular phenotype. Flat epithelial atypia, atypical ductal hyperplasia, and lobular in situ neoplasias also show similar molecular profiles and frequently coexist in the same tumor, pointing to a common pathway of progression in low grade lesions.

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