Abstract B40: High circulating CCL5 is associated with poor prognosis in locally advanced pancreatic cancer (LAPC): Biomarker analysis from the randomized phase II SCALOP trial
Authors: Willenbrock Frances , Cox Catrin , Wilhelm-Benartzi Charlotte , Abraham Aswin , Owens Robert , Sabbagh Ahmad , Hurt Chris , Maughan Tim , O'Neill Eric , Mukherjee Somnath 
Published: March 2020

Background: SCALOP recruited 114 patients with LAPC. Induction chemotherapy consisted of 3 cycles of gemcitabine and capecitabine (GEMCAP). Patients with nonprogression (n=74) were randomized to GEM or CAP based CRT (50.4Gy/28 fractions). Blood samples collected at baseline were analyzed for 35 angiogenic and immune biomarkers reported to be of prognostic/predictive value in pancreatic cancer.

Methods: IGF-1, TGF-b1, and b-NGF were analyzed using R & D DuoSet ELISA systems and the signal detected using a POLARstar Omega plate reader. The remaining biomarkers were assessed using R & D multiplexed magnetic Luminex assays and measured using a Luminex Magpix. Assays were performed in triplicate.

Statistical Analysis: Univariate Cox proportional hazard models were used as continuous variable to determine the association with overall survival (OS). Multiple comparisons were adjusted using the False Discovery Rate (FDR). Those found to be significant at the q value &lt;0.2 were then further investigated for independence from existing clinical characteristics (i.e., CA19-9, WHO PS and age). Of those found to be independent, optimal thresholds delineating low to high values were found using the R “survivalROC” package based on time-dependent ROC curves from censored survival data and their corresponding area under the curve (AUC). The dichotomized biomarkers, split at the optimal threshold, were then associated with OS using univariate and multivariable Cox proportional hazard models.

Results: Biomarker data were available on 63/74 patients. 57% (36/63) were male, 56% (35/63) were age &lt;65, 59% (37/63) had WHO PS 0 compared to 1, 51% (32/63) received gemcitabine, median CA19.9 was 233IU/L (IQR 75,801) and median tumor diameter was 3.8cm (IQR 3, 4.8). Of the 35 biomarkers tested, only CCL5, IL3, and IFN had significant associations with OS. CCL5 and IL3 were then found to be independent of existing clinical characteristics and were taken forward, where their optimal thresholds were found to be 1.27 micg/ml (sensitivity 64%; specificity 100%) and 57.75 pg/ml (sensitivity 83%; specificity 100%), respectively. CCL5, but not IL3, was found to be significantly associated with OS once dichotomized at its optimal threshold, with a median OS of 18.5 (95% CI: 11.76-21.32) vs. 11.3 (9.86-15.51) months, HR 1.37 (95% CI:1.04-3.65; p=0.037) in the Cox multivariable model. Moreover, biomarker signatures incorporating both CCL5 and IL3 (continuous variable) with age, PS and CA19.9 were prognostic: CCL5 signature:19.2 vs. 10.8 mo (HR 2.79, p=0.001) IL3 signature: 18.5 vs. 11.2 mo (HR 2.35, p=0.006) CCL5/IL3 signature: 18.7 vs. 11.2 mo, (HR 2.25, p=0.11).

Conclusion: High circulating CCL5 has a significantly worse prognosis. This is consistent with preclinical literature that demonstrates the role of CCL5 in tumor invasion/metastasis and induction of an immunosuppressive microenvironment through Treg infiltration. We are currently conducting in vivo experiments involving CCR5 antagonists and immunotherapy in orthotopic mouse models.

Citation Format: Frances Willenbrock, Catrin Cox, Charlotte Wilhelm-Benartzi, Aswin Abraham, Robert Owens, Ahmad Sabbagh, Chris Hurt, Tim Maughan, Eric O'Neill, Somnath Mukherjee. High circulating CCL5 is associated with poor prognosis in locally advanced pancreatic cancer (LAPC): Biomarker analysis from the randomized phase II SCALOP trial [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B40.