Molecular Cytogenetic Identification of Subgroups of Grade III Invasive Ductal Breast Carcinomas with Different Clinical Outcomes

Abstract

Tumor grade is an established indicator of breast cancer outcome, although considerable heterogeneity exists even within-grade. Around 25% of grade III invasive ductal breast carcinomas are associated with a "basal" phenotype, and these tumors are reported to be a distinct subgroup. We have investigated whether this group of breast cancers has a distinguishing pattern of genetic alterations and which of these may relate to the different clinical outcome of these patients. We performed comparative genomic hybridization (CGH) analysis on 43 grade III invasive ductal breast carcinomas positive for basal cytokeratin 14, as well as 43 grade-and age-matched CK14-negative controls, all with up to 25 years (median, 7 years) of clinical follow-up. Significant differences in CGH alterations were seen between the two groups in terms of mean number of changes (CK14؉ve ؊ 6.5, CK14؊ve ؊ 10.3; P ‫؍‬ 0.0012) and types of alterations at chromosomes 4q, 7q, 8q, 9p, 13q, 16p, 17p, 17q, 19p, 19q, 20p, 20q and Xp. Supervised and unsupervised algorithms separated the two groups on CGH data alone with 76% and 74% accuracy, respectively. Hierarchical clustering revealed distinct subgroups, one of which contained 18 (42%) of the CK14؉ve tumors. This subgroup had significantly shorter overall survival (P ‫؍‬ 0.0414) than other grade III tumors, regardless of CK14 status, and was an independent prognostic marker (P ‫؍‬ 0.031). These data provide evidence that the "basal" phenotype on its own does not convey a poor prognosis. Basal tumors are also heterogeneous with only a subset, identifiable by pattern of genetic alterations, exhibiting a shorter overall survival. Robust characterization of this basal group is necessary if it is to have a major impact on management of patients with breast cancer.

Distribution and significance of nerve growth factor receptor (NGFR/p75NTR) in normal, benign and malignant breast tissue

“…Out of these cases, 10 showed expression of basal/myoepithelial markers (ie, Ck5/6, Ck14, Ck17 and EGFR). 19,21,26,27,30,31 Although NGFR showed no prognostic significance in this cohort, when its expression was analysed in a cohort of 37 basal-like breast carcinomas, 26 NGFR showed a statistically significant association with lack of lymph node metastasis. In addition, initial analysis in 37 basal-like breast carcinomas has revealed statistically significant associations between NGFR expression and longer disease-free and overall survival.…”

“…Furthermore, recent data from our laboratory have suggested that basal tumours are heterogenous in terms of their molecular genetic profiles and that there might be a subgroup with a more favourable prognosis. 31 We hypothesised that, as NGFR is consistently expressed by myoepithelial cells of the breast, 5 it would also be expressed by a subset of basal-like breast carcinomas. Furthermore, given that NGFR may block tumourigenesis and induce apoptosis in some systems, it seemed possible that basal-like breast carcinomas with NGFR expression would have a more favourable prognosis compared to NGFR-negative basal-like breast carcinomas.…”

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…[90][91][92][93][94] This may be in part due to the presence of a dysfunctional BRCA1 pathway in these tumors. 32,82,83 BRCA1 gene promoter is methylated in 460% of medullary 95,96 and metaplastic 32 breast cancers of basal-like phenotype.…”

Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal-like breast carcinomas)

“…1 At diagnosis, approximately 70-80% of breast carcinoma are positive for estrogen receptors (ERs) and/or progesterone receptors (PgRs), and B20% overexpress Her-2/neu. [2][3][4] These findings could be related with gene expression-profiling studies, [5][6][7][8][9][10][11][12][13][14] which identify diverse varieties of breast carcinoma, mainly the 'luminal' one associated with hormone receptors, the 'Her-2/ neu-positive' and the 'basal' or 'triple negative' breast carcinoma (negative for ERs, PgRs and Her-2/neu).…”