Abstract
IntroductionSPARC is an important regulator of the extracellular matrix and has been suggested to improve delivery of albumin-bound cytotoxics. However, little is known regarding its role in breast cancer (BC).MethodsWe conducted a pooled analysis of publically available datasets, in which BC patients who received no systemic therapy or received neoadjuvant chemotherapy were eligible. Patients were assigned to molecular subtypes using PAM-50. We computed a SPARC module (SPARC7), composed of genes with an absolute correlation with SPARC >0.7. In the systemically untreated cohort, we evaluated 1) expression of SPARC/SPARC7 according to breast cancer subtype, 2) association between SPARC/SPARC7 and biological processes related to proliferation, immune and stroma, and 3) association between SPARC/SPARC7 and relapse-free survival in a Cox model in all patients and in the different molecular subtypes adjusted for tumor size, nodal status, histological grade, and age. In the neoadjuvant cohort, we evaluated the association between SPARC and pCR in a logistic regression model, adjusted for the same clinicopathologic factors.Results948 (10 datasets), and 791 (8 datasets) patients were included in the systemically untreated and neoadjuvant cohorts, respectively. High SPARC expression was associated with small tumor size, low histological grade and luminal-A tumors (all p<0.0001). There was a positive correlation between SPARC and stroma-related modules but negative correlation with proliferation modules. High SPARC expression was associated with poor prognosis in patients with basal and HER2+ breast cancer even after adjusting for clinicopathologic parameters. In the neoadjuvant cohort, a subgroup analysis suggested that high SPARC is associated with low rates of pCR in the HER2 subtype. Same results were observed on replacing SPARC by SPARC7.ConclusionThis analysis suggests a potential role of SPARC in determining prognosis and response to primary chemotherapy in early BC. This information could guide further development of albumin-bound cytotoxics in BC.
Highlights
SPARC is an important regulator of the extracellular matrix and has been suggested to improve delivery of albumin-bound cytotoxics
To address whether SPARC expression is associated with response to preoperative chemotherapy, we investigated the effect of SPARC, SPARC7 as a continuous variable on pathological complete response in the neoadjuvant cohort in a logistic regression model adjusted for the same clinicopathologic parameters
In the systemically untreated cohort (n = 948), we evaluated the association between SPARC/SPRAC7expression, breast cancer subtypes (Figure 1) and clinicopathologic parameters (Table 1)
Summary
SPARC is an important regulator of the extracellular matrix and has been suggested to improve delivery of albumin-bound cytotoxics. Among the key factors that govern tumor progression is the cross-talk between the cancer cell and the surrounding microenvironment, which includes stromal and immune cells as well as the extracellular matrix (ECM) [8,9]. The latter provides a structural framework for the cells and plays a vital role in regulating cell differentiation, migration, proliferation and survival [10]. It has been shown to bind with high affinity to albumin, which raised some interest in its possible role in improving the delivery of albumin-bound cytotoxics to the tumor [15,16]
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