Extracellular matrix protein expression is associated with chemotherapy resistance in breast cancer Purpose: Biomarkers to predict sensitivity and resistance to chemotherapy are still lacking. A recent study reported that stromal gene signatures in breast cancer may predict chemoresistance. We aim to determine the changes of 5 extracellular matrix (ECM) proteins in response to neoadjuvant chemotherapy in breast cancer. Experimental design: 100 female patients with locally advanced or metastatic breast cancer were treated with 6 cycles of pre-operative alternating sequential doxorubicin and docetaxel. Immunohistochemistry staining for thrombospondin 1 (THBS1), tenascin C (TNC), fibronectin (FN), smooth muscle actin-α (α-SMA) and secreted protein acidic and rich in cysteine (SPARC) was performed on pre- and post-treatment core biopsies, and correlated with estrogen receptor status, intrinsic chemotherapy response, pathological lymph node involvement and survival. Changes in THBS1 and TNC in relation to chemoresponse was additionally evaluated with mass spectrometry, and further validated with immunohistochemistry in an independent cohort of 31 breast cancer patients. Results: High baseline THBS1 and SPARC and high post-treatment α-SMA expression were associated with poor overall survival (p<0.05 for each marker). High expression of combined baseline ECM proteins was an independent predictor for poor progression-free survival (HR 2.22, 95% CI 1.06-4.64, p=0.034) and overall survival (HR 5.94, 95% CI 2.25-15.71, p<0.001). After 1-2 cycles of chemotherapy, increased expression of THBS1 and TNC compared to baseline was seen in intrinsically resistant tumors (p<0.05 for both), and in patients with pathological lymph node involvement (p<0.05 for both), but not in sensitive ones. Mass spectrometric analyses revealed >2 fold increase in THBS1 and TNC expression compared to baseline in tumors that were intrinsically resistant to doxorubicin relative to sensitive ones. The association between THBS1 and TNC immunohistochemistry changes and chemotherapy resistance was confirmed in the validation cohort. Conclusions: Up-regulation in ECM proteins after chemotherapy was associated with clinical and pathological response to doxorubicin- and docetaxel-based neoadjuvant chemotherapy in breast cancer. Assessment of these proteins may uncover strategies to overcome drug resistance. Key words: ECM proteins, neoadjuvant chemotherapy, breast cancer, drug resistance

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2460. doi:1538-7445.AM2012-2460