Breast Cancer Molecular Subtypes Respond Differently to Preoperative Chemotherapy

Abstract

Purpose: Molecular classification of breast cancer has been proposed based on gene expression profiles of human tumors. Luminal, basal-like, normal-like, and erbB2+ subgroups were identified and were shown to have different prognoses. The goal of this research was to determine if these different molecular subtypes of breast cancer also respond differently to preoperative chemotherapy. Experimental Design: Fine needle aspirations of 82 breast cancers were obtained before starting preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Gene expression profiling was done with Affymetrix U133A microarrays and the previously reported ''breast intrinsic''gene set was used for hierarchical clustering and multidimensional scaling to assign molecular class. Results: The basal-like and erbB2+ subgroups were associated with the highest rates of pathologic complete response (CR), 45% [95% confidence interval (95% CI), 24-68] and 45% (95% CI, 23-68), respectively, whereas the luminal tumors had a pathologic CR rate of 6% (95% CI, 1-21). No pathologic CR was observed among the normal-like cancers (95% CI, 0-31). Molecular class was not independent of conventional cliniocopathologic predictors of response such as estrogen receptor status and nuclear grade. None of the 61genes associated with pathologic CR in the basal-like group were associated with pathologic CR in the erbB2+ group, suggesting that the molecular mechanisms of chemotherapy sensitivity may vary between these two estrogen receptor^negative subtypes. Conclusions: The basal-like and erbB2+ subtypes of breast cancer are more sensitive to paclitaxel-and doxorubicin-containing preoperative chemotherapy than the luminal and normallike cancers.Breast cancer is a clinically heterogeneous disease. Histologically similar tumors may have different prognoses and may respond to therapy differently. It is believed that these differences in clinical behavior are due to molecular differences between histologically similar tumors. DNA microarray technology is ideally suited to reveal such molecular differences. A novel molecular classification of breast cancer based on gene expression profiles was recently proposed (1). The investigators identified a set of stably expressed genes (''intrinsic gene set''; n = 534) that accounted for much of the molecular differences between 42 breast cancers and did hierarchical cluster analysis to identify subgroups of cancers with separate gene expression profiles. Luminal, basal-like, normal-like, and erbB2+ subgroups were identified and were shown to have different prognoses (1 -4). These results were confirmed in follow-up experiments by the same group and others using larger numbers of cases. The basal-like (mostly estrogen receptor negative) and erbB2+ (mostly HER-2 amplified and estrogen receptor negative) subgroups had the shortest relapse-free and overall survival, whereas the luminal-type (estrogen receptorpositive) tumors had a more favorable clinical outcome (2 -4).

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

“…Luminal A cancers are usually of low histological grade, Table 3 The results of an analysis to identify genes whose expression is correlated with copy number: correlation between expression values and smoothed aCGH log2 ratios strong ERa expressers and rarely metastasise, whereas breast cancer cell lines harbour genomic features consistent with high histological grade (e.g., gains of 1q, 8q and 20q) [31], are usually derived from ERa negative samples and metastatic deposits [4]. Normal breast-like has been shown to be an unstable subgroup and there is evidence to suggest that samples pertaining to this subgroup are enriched for stromal cells [46,47]. Second, although numerous genetic changes are prevalent in all subgroups of breast cancer cell lines (e.g., gains of 1q, 8q and 20q), each subgroup seems to be characterised by a rather specific constellation of genetic changes (Figs.…”

Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy

“…Genomic expression profiling studies have identified distinct subtypes of breast carcinomas that are associated with different responses to chemotherapy and to different clinical outcomes in the preoperative setting [24]. Luminal types A, B, C, normal breast, HER2-positive, and basallike phenotypes have been reproducibly separated [25][26][27].…”

Breast-specific expression of MGB1/mammaglobin: an examination of 480 tumors from various organs and clinicopathological analysis of MGB1-positive breast cancers

“…The absence of weak intensity and ambiguous background staining made positive reactions very distinct. We used a molecular classification schema for breast cancers as reported 13,[16][17][18][19] to class those that were positive for MGB1. Basal cell-like subtypes were significantly less frequent among breast cancers that expressed MGB1 (w 2 test, P ¼ 0.01).…”