Abstract P6-07-22: Association between SPARC mRNA expression, prognosis and response to neoadjuvant chemotherapy in early breast cancer (BC): a pooled in-silico analysis
Authors: Azim Jr HA , Singhal S , Michiels S , Ignatiadis M , Djazouli K , Fumagalli D , Desmedt C , Piccart M , Sotiriou C 
Published: August 2014

Abstract
Background: SPARC (Secreted Protein Acidic and Rich in Cysteine) is known to regulate cell growth and to inhibit cell-cycle progression. It has high affinity in binding albumin and hence has been suggested to predict benefit of albumin-bound cytotoxic agents. We conducted a pooled analysis to elucidate SPARC expression according to BC molecular subtypes and its association with clinical outcome in early BC.
Methods: We used publically available datasets and normalized microarray data as published by the original studies. Eligible patients were those who received no adjuvant systemic therapy (untreated series), were treated with tamoxifen (tam-treated series) or were treated with neoadjuvant anthracyclines ± paclitaxel or docetaxel (neoadjuvant series). We computed 2 SPARC modules, SPARC7 and SPARC8 that were composed of genes with an absolute correlation above 0.7 and 0.8 with SPARC, respectively. In the untreated series, we examined the expression of SPARC according to BC subtype defined by PAM50. We investigated the correlation with other gene modules representing diverse biological processes; proliferation (AURKA, GGI), immune (STAT1, IRM), and stroma (DCN, PLAU). We investigated the association with relapse-free survival (RFS) in univariate and multivariate models, both in the untreated and tam-treated series. This was performed in all patients and according to BC subtype. In the neoadjuvant series, we investigated the association with pathological complete response (pCR) in all patients and according to BC subtype. All multivariate models were adjusted for tumor size, nodal status, age and histological grade.
Results: 1008, 393 and 996 patients were included in the untreated, tam-treated and neoadjuvant series, respectively. SPARC expression was highest in luminal-A, small (&lt; 2 cm) and low histological grade tumors (all p &lt; 0.0001). We found high positive correlation between SPARC, SPARC modules and stroma-related modules (r = 0.90) but a negative correlation with proliferation (r = −0.66). No correlation was observed with immune-related modules. In the untreated series, SPARC was not associated with prognosis in the univariate model. However, restricting the analysis to the HER2 molecular subtype, high SPARC expression was associated with short RFS in both univariate and multivariate models (HR: 3; 95% CI [1.5–6.3], p = 0.002). In the tam-treated series, SPARC expression was not associated with clinical outcome neither in luminal-A nor luminal-B. In the neoadjuvant series, SPARC expression was not associated with pCR (p = 0.37) except in the HER2 subtype in which high expression was independently associated with low pCR rates in the multivariate model (OR: 0.32; 95% CI [0.1–0.9], p = 0.043). Similar associations were observed with SPARC7 and SPARC8 modules.
Conclusion: Two main conclusions could be drawn from our analysis 1) SPARC is highly expressed in low proliferative ER+ tumors; 2) High SPARC expression is associated with short RFS and poor response to neoadjuvant therapy in patients with HER2+ BC. These results could be relevant in the clinical development of albumin-bound compounds, in which SPARC expression is believed to identify patients who could benefit from these agents.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-22.