A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer

Abstract

To better understand the relationship between tumor-host interactions and the efficacy of chemotherapy, we have developed an analytical approach to quantify several biological processes observed in gene expression data sets. We tested the approach on tumor biopsies from individuals with estrogen receptor-negative breast cancer treated with chemotherapy. We report that increased stromal gene expression predicts resistance to preoperative chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) in subjects in the EORTC 10994/BIG 00-01 trial. The predictive value of the stromal signature was successfully validated in two independent cohorts of subjects who received chemotherapy but not in an untreated control group, indicating that the signature is predictive rather than prognostic. The genes in the signature are expressed in reactive stroma, according to reanalysis of data from microdissected breast tumor samples. These findings identify a previously undescribed resistance mechanism to FEC treatment and suggest that antistromal agents may offer new ways to overcome resistance to chemotherapy.

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…In ER-breast cancers, gene expression patterns typical of reactive stroma predicted resistance to chemotherapy, though no link was found between this signature and outcome in untreated patients [10]. Similarly, tumor stiffness measured with ultrasound elastography predicted residual tumor burden after chemotherapy [104][105][106].…”

“…Recent work has linked the ECM in tumors to dormancy [9], resistance to chemotherapy or radiation [10][11][12], metastasis and metastasis tropism [13] again demonstrating the importance of understanding cell-ECM interactions. It has become apparent from both in vitro and clinical work that the ECM signals to cells through both biochemical and physical means with complex interactions between ECM composition, splicing, microstructure, and biomechanics.…”

Tumor microenvironment and breast cancer progression

“…Thus, Farmer showed that increased stromal gene expression is predictive of resistance to chemotherapy in the setting of a randomized controlled trial. 43 …”

Stromal expression of matrix metalloproteinase 2 in cancer-associated fibroblasts is strongly related to human epidermal growth factor receptor 2 status in invasive breast carcinoma

“…Certain breast CAFs, which are characterized by SMA expression and are referred to as PMYs, appear to play an important role in metastasis, including lymph node metastasis (3,4). Therefore, similar to the epithelial counterpart, it was hypothesized that the tumor's aggressiveness may be affected by the stromal composition, as well as the stroma's own biological properties ('stromal signature') (15,16). In the present study, we demonstrated that the stromal expression of MMP2, which is known to promote cancer invasion and metastasis by degrading various components of the extracellular matrix, varies according to the different tumor subtypes.…”