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Growth differentiation factor-15 (GDF-15) in localized pancreatic adenocarcinoma treated with multiagent
B Kimmel1,2, S T Löhnert1,2, F Wedekink3
1Department of Internal Medicine II, Medical Oncology, University Hospital Würzburg, Würzburg, Germany.
Background:
The prognostic and predictive role of growth differentiation factor-15 (GDF-15) in localized, non-metastatic pancreatic ductal adenocarcinoma (PDAC) has not yet been explored.
Patients And Methods:
During the prospective randomized phase II NEOLAP-1 (AIO-PAK-0113) trial for patients with therapy-naive locally advanced (borderline or unresectable) PDAC, blood (n = 131) and tumor tissue samples (n = 39) were collected. Using paired baseline and post-induction chemotherapy (ICT) samples, circulating GDF-15 (cGDF-15) levels were quantified by enzyme-linked immunosorbent assay, and local GDF-15 tumor expression (tGDF-15) was assessed by immunohistochemistry.
Results:
Lower baseline cGDF-15 levels (≤0.8 ng/ml) were significantly associated with increased median overall survival [21.92 (95% CI 19.73-24.16) versus 12.68 [95% confidence interval (CI) 10.56-14.81] months, P < 0.001, and significantly higher secondary R0 resection rates (36.5% versus 13.9%, P = 0.0051). In contrast to CA 19-9, cGDF-15 levels significantly increased after ICT [median 1.0 ng/ml [interquartile range (IQR) 0.62-1.5 ng/ml] at baseline versus median 2.37 ng/ml (IQR 1.32-4.43 ng/ml) at week 16], especially after treatment using platinum-based agents. In initial tumor specimens, GDF-15 expression was rare and predominantly confined to tumor cells. tGDF-15 correlated with high cGDF-15 levels at baseline [median 1.8 ng/ml (1.13-2.34 ng/ml) in positive tumor specimens, versus 0.76 ng/ml (0.55-1.17 ng/ml) in negative tumor specimens; P = 0.0087]. Similarly to cGDF-15, tGDF-15 expression increased after ICT (from 10% to 41% positive tumor specimens).
Conclusions:
High cGDF-15 levels at baseline are a negative prognostic and predictive biomarker in localized, non-metastatic PDAC. Considering that GDF-15 is further up-regulated by neoadjuvant multiagent chemotherapy, our data, together with recent findings on clinical effects of GDF-15, provide a strong rationale for upfront therapeutic GDF-15 blockade in localized PDAC.
