Impact of SPARC expression on outcome in patients with advanced pancreatic cancer not receiving nab-paclitaxel: a pooled analysis from prospective clinical and translational trials

Abstract

Background: Conflicting results on the role of secreted protein acidic and rich in cysteins (SPARC) expression have been reported in resected pancreatic ductal adenocarcinoma (PDAC), and its prognostic and/or predictive role in advanced PDAC (aPDAC) has not been extensively investigated yet. This study was designed to evaluate SPARC expression as a biomarker in aPDAC patients (pts) not receiving nab-paclitaxel.

Methods: Using immunohistochemistry, we examined the stromal as well as the tumoral (i.e., cytoplasmic) SPARC expression in tumour tissue (primary tumours and metastases) of 134 aPDAC pts participating in completed prospective clinical and biomarker trials. The SPARC expression levels were correlated to the pts' clinicopathological parameters and survival times.

Results: Sixty-seven per cent of the analysed tumours showed high stromal SPARC expression, which was not associated with overall survival (OS, median 9.1 vs 7.6 months, P=0.316). A positive cytoplasmic SPARC expression was detected in 55% of the tumours and correlated significantly with inferior progression-free survival (PFS, 6.2 vs 8.6 months, P=0.004) and OS (7.8 vs 8.4 months, P=0.032). This association was strongest for pts, where primary tumour tissue was examined (PFS: 6.7 vs 10.8 months, P=0.004; OS: 7.9 vs 11.9 months, P=0.030), whereas no significant correlation was detected for pts, where only metastatic tissue was available (PFS: 5.8 vs 6.6 months, P=0.502; OS: 7.0 vs 7.8 months, P=0.452). In pts receiving gemcitabine-based chemotherapy cytoplasmic SPARC expression was significantly associated with an inferior PFS and OS (PFS: 6.2 vs 9.2 months, P=0.002; OS 7.3 vs 9.9 months, P=0.012), whereas no such association was detected for stromal SPARC expression or for pts receiving fluoropyrimidine-based chemotherapy.

Conclusion: We identified cytoplasmic SPARC expression in the primary tumour as a biomarker associated with inferior PFS and OS in aPDAC. Cytoplasmic SPARC expression may furthermore act as a negative predictive biomarker in pts treated with gemcitabine-based chemotherapy.

Figure 1

Variable stromal and cytoplasmic SPARC expression in PDAC tissue. Immunohistochemical staining of SPARC (ON-1) in exemplary PDAC tissue shows variable expression in the peritumoral stroma and tumoral cytoplasm. Magnification= × 200. Scale bars indicate 50 μm.

Figure 2

Cytoplasmic but not stromal SPARC expression correlates with inferior overall survival (A, C and E) and progression-free survival (B, D and F) of aPDAC patients. Univariate analysis (Kaplan–Meier curves and log-rank tests) of (A and B) stromal and (C and D) cytoplasmic SPARC expression as a biomarker in the tumour tissue of aPDAC pts treated with palliative, non-nab-paclitaxel containing chemotherapy; cytoplasmic SPARC expression in the (E and F) primary tumour subgroup. Crossed lines indicate censored cases.

Figure 3

Cytoplasmic SPARC expression as a potential negative predictive biomarker for overall survival (A and C) and progression-free survival (B and D) in gemcitabine-treated aPDAC patients. Univariate analysis (Kaplan–Meier curves and log-rank tests) of cytoplasmic SPARC expression in the tumour tissue of (A and B) gemcitabine-based treated aPDAC pts and (C and D) fluoropyrimidine-based treated aPDAC pts. Crossed lines indicate censored cases.