Abstract
BackgroundExtensive extracellular matrix (ECM) remodeling is a hallmark of metastatic pancreatic ductal adenocarcinoma (mPDA). We investigated fragments of collagen types III (C3M, PRO-C3), VI (PRO-C6), and VIII (C8-C), and versican (VCANM) in plasma as biomarkers for predicting progression-free survival (PFS) and overall survival (OS) in patients with mPDA treated with pegvorhyaluronidase alfa, a biologic that degrades the ECM component hyaluronan (HA), in a randomized phase 2 study (HALO109-202).MethodsHALO109-202 comprised a discovery cohort (Stage 1, n = 94) and a validation cohort (Stage 2, n = 95). Plasma ECM biomarkers were analyzed by ELISAs. Univariate Cox regression analysis and Kaplan–Meier plots evaluated predictive associations between biomarkers, PFS and OS in patients treated with pegvorhyaluronidase alfa plus nab-paclitaxel/gemcitabine (PAG) versus nab-paclitaxel/gemcitabine (AG) alone.ResultsPFS was improved with PAG vs. AG in Stage 1 patients with high C3M/PRO-C3 ratio (median cut-off): median PFS (mPFS) 8.0 vs. 5.3 months, P = 0.031; HR = 0.40; 95% CI 0.17–0.92). High C3M/PRO-C3 ratio was validated in Stage 2 patients by predicting a PFS benefit of PAG vs. AG (mPFS: 8.8 vs. 3.4 months, P = 0.046; HR = 0.46; 95% CI 0.21–0.98). OS was also improved in patients with high C3M/PRO-C3 ratio treated with PAG vs. AG (mOS 13.8 vs 8.5 months, P = 0.009; HR = 0.35; 95% CI 0.16–0.77). Interestingly, high C3M/PRO-C3 ratio predicted for a PFS benefit to PAG vs. AG both in patients with HA-low tumors (HR = 0.36; 95% CI 0.17–0.79) and HA-high tumors (HR = 0.20; 95% CI 0.06–0.69).ConclusionsThe C3M/PRO-C3 ratio measuring type III collagen turnover in plasma has potential as a blood-based predictive biomarker in patients with mPDA and provides additional value to a HA biopsy when applied for patient selection.Trial registration: NCT01839487. Registered 25 April 2016
Highlights
Extensive extracellular matrix (ECM) remodeling is a hallmark of metastatic pancreatic ductal adenocarcinoma
Using data from the HALO109202 study, we investigated whether plasma circulating biomarkers of ECM remodeling, i.e., PRO-C3, PRO-C6, Matrix metalloprotease-mediated degradation of type III collagen (C3M), C-terminal of type VIII collagen (C8-C), and Matrix metalloprotease-mediated degradation of versican (VCANM) correlated with survival outcomes in patients with metastatic pancreatic ductal adenocarcinoma (mPDA) following pegvorhyaluronidase alfa treatment, and could be used as biomarkers of response
Predictive value of ECM biomarkers for pegvorhyaluronidase alfa treatment Among 279 patients randomized into the HALO 109-202 study, 199 had both sufficient plasma samples for biomarker analysis and efficacy data; of these, 10 withdrew consent
Summary
Extensive extracellular matrix (ECM) remodeling is a hallmark of metastatic pancreatic ductal adenocarcinoma (mPDA). Pancreatic ductal adenocarcinoma (PDA), the most common type of pancreatic cancer, is largely resistant to systemic therapies, partly due to excessive accumulation of collagen, versican (VCANM), hyaluronan (HA), which form a dense desmoplasia composed of extra-cellular matrix (ECM) proteins, myofibroblastic-like pancreatic stellate cells and immune cells [3, 4]. This unique tumor microenvironment (TME), characterized by growth of dense, collagen-rich ECM and stroma around cancer cells (the desmoplastic reaction), promotes tumor growth and metastasis, forming a physical barrier to systemic therapies. HA is involved in type VI collagen synthesis and structural integrity, it induces type VIII collagen production, which is involved in angiogenesis and artery remodeling, and type I collagen in vitro [18,19,20,21]
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