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Clinical Study

Circulating biomarkers and outcomes from a randomised phase 2 trial of gemcitabine versus capecitabine-based chemoradiotherapy for pancreatic cancer



The Phase 2 SCALOP trial compared gemcitabine with capecitabine-based consolidation chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC).


Thirty-five systematically identified circulating biomarkers were analysed in plasma samples from 60 patients enroled in SCALOP. Each was measured in triplicate at baseline (prior to three cycles of gemcitabine-capecitabine induction chemotherapy) and, for a subset, prior to CRT. Association with overall survival (OS) was determined using univariable Cox regression and optimal thresholds delineating low to high values identified using time-dependent ROC curves. Independence from known prognostic factors was assessed using Spearman correlation and the Wilcoxon rank sum test prior to multivariable Cox regression modelling including independent biomarkers and known prognostic factors.


Baseline circulating levels of C-C motif chemokine ligand 5 (CCL5) were significantly associated with OS, independent of other clinicopathological characteristics. Patients with low circulating CCL5 (CCL5low) had a median OS of 18.5 (95% CI 11.76–21.32) months compared to 11.3 (95% CI 9.86–15.51) months in CCL5high; hazard ratio 1.95 (95% CI 1.04–8.65; p = 0.037).


CCL5 is an independent prognostic biomarker in LAPC. Given the known role of CCL5 in tumour invasion, metastasis and the induction of an immunosuppressive micro-environment, targeting of CCL5-mediated pathways may offer therapeutic potential in pancreatic cancer.

Clinical trial registration

The SCALOP trial was registered with ISRCTN, number 96169987 (registered 29 May 2008).

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Fig. 1


  1. 1.

    Rahib, L., Smith, B., Aizenberg, R., Rosenzweig, A., Fleshman, J. & Matrisian, L. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).

    CAS  Article  Google Scholar 

  2. 2.

    Conroy, T., Hammel, P., Hebbar, M., Ben Abdelghani, M., Wei, A. C., Raoul, J. L. et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N. Engl. J. Med. 379, 2395–2406 (2018).

    CAS  Article  Google Scholar 

  3. 3.

    Hammel, P., Lacy, J., Portales, F., Sobrero, A., Pazo Cid, R., Manzano, Mozo, J. L. et al. Phase II LAPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC). J. Clin. Oncol. 36, 204–204 (2018).

    Article  Google Scholar 

  4. 4.

    Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A. M., Gingras, M. C. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    CAS  Article  Google Scholar 

  5. 5.

    Moffitt, R., Marayati, R., Flate, E., Volmar, K., Loeza, S., Hoadley, K. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).

    CAS  Article  Google Scholar 

  6. 6.

    Collisson, E., Sadanandam, Olson, P., Gibb, W. J., Truitt, M., Gu, S. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).

    CAS  Article  Google Scholar 

  7. 7.

    Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J. et al. Maintenance Olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381, 317–327, (2019).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Mukherjee, S., Hurt, C. N., Bridgewater, J., Falk, S., Cummins, S., Wasan, H. et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 14, 317–326 (2013).

    CAS  Article  Google Scholar 

  9. 9.

    Hurt, C., Falk, S., Crosby, T., McDonald, A., Ray, R., Joseph, G. et al. Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer. Br. J. Cancer 116, 1264–1270 (2017).

    CAS  Article  Google Scholar 

  10. 10.

    Yako, Y. Y., Kruger, D., Smith, M. & Brand, M. Cytokines as biomarkers of pancreatic ductal adenocarcinoma: a systematic review. PLoS ONE 11, e0154016 (2016).

    Article  Google Scholar 

  11. 11.

    McShane, L. M., Altman, D. G., Sauerbrei, W., Taube, S. E., Gion, M. & Clark, G. M. Statistics subcommittee of the NCI-EORTC working group on cancer diagnostics. REporting recommendations for tumour MARKer prognostic studies (REMARK). Br. J. Cancer 93, 387–391 (2005).

    CAS  Article  Google Scholar 

  12. 12.

    Byers, L. A., Holsinger, F. C., Kies, M. S., William, W. N., El-Naggar, A. K., Lee, J. J. et al. Serum signature of hypoxia-regulated factors is associated with progression after induction therapy in head and neck squamous cell cancer. Mol. Cancer Ther. 9, 1755–1763 (2010).

    CAS  Article  Google Scholar 

  13. 13.

    Torres, C., Linares, A., Alejandre, M. J., Palomino-Morales, R. J., Caba, O., Prados, J. et al. Prognosis relevance of serum cytokines in pancreatic cancer. Biomed. Res. Int 2015, 518284 (2015).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Błogowski, W., Deskur, A., Budkowska, M., Sałata, D., Madej-Michniewicz, A., Dabkowski, K. et al. Selected cytokines in patients with pancreatic cancer: a preliminary report. PLoS ONE 9, e97613 (2014).

    Article  Google Scholar 

  15. 15.

    Delitto, D., Black, B., Sorenson, H., Knowlton, A., Thomas, R., Sarosi, G. et al. The inflammatory milieu within the pancreatic cancer microenvironment correlates with clinicopathologic parameters, chemoresistance and survival. BMC Cancer 15, 783 (2015).

    Article  Google Scholar 

  16. 16.

    Wörmann, S., Diakopoulos, K., Lesina, M. & Algül, H. The immune network in pancreatic cancer development and progression. Oncogene 33, 2956–2967 (2014).

    Article  Google Scholar 

  17. 17.

    Mitsunaga, S., Ikeda, M., Shimizu, S., Ohno, I., Furuse, J., Inagaki, M. et al. Serum levels of IL-6 and IL-1β can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer. Br. J. Cancer 108, 2063–2069 (2013).

    CAS  Article  Google Scholar 

  18. 18.

    Carbone, A., Vizio, B., Novarino, A., Mauri, F. A., Geuna, M., Robino, C. et al. IL-18 paradox in pancreatic carcinoma: elevated serum levels of free IL-18 are correlated with poor survival. J. Immunother. 32, 920–931 (2009).

    CAS  Article  Google Scholar 

  19. 19.

    Farren, M. R., Mace, T. A., Geyer, S., Mikhail, S., Wu, C., Ciombor, K. et al. Systemic immune activity predicts overall survival in treatment-naïve patients with metastatic pancreatic cancer. Clin. Cancer Res. 22, 2565–2574 (2016).

    CAS  Article  Google Scholar 

  20. 20.

    Murooka, T. T., Rahbar, R. & Fish, E. N. CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation. Biochem. Biophys. Res. Commun. 387, 381–386 (2009).

    CAS  Article  Google Scholar 

  21. 21.

    Gao, D., Cazares, L. & Fish, E. CCL5-CCR5 interactions modulate metabolic events during tumor onset to promote tumorigenesis. BMC Cancer 17, 834 (2017).

    Article  Google Scholar 

  22. 22.

    Argyle, D. & Kitamura, T. Targeting macrophage-recruiting chemokines as a novel therapeutic strategy to prevent the progression of solid tumors. Front. Immunol. 9, 2629 (2018).

    Article  Google Scholar 

  23. 23.

    Tan, M., Goedegebuure, P., Belt, B., Flaherty, B., Sankpal, N., Gillanders, W. et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J. Immunol. 182, 1746–55 (2009).

    CAS  Article  Google Scholar 

  24. 24.

    Wang, X., Lang, M., Zhao, T., Feng, X., Zheng, C., Huang, C. et al. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3+Treg cells in pancreatic ductal adenocarcinoma. Oncogene 36, 3048–3058 (2017).

    CAS  Article  Google Scholar 

  25. 25.

    Jang, J. E., Hajdu, C. H., Liot, C., Miller, G., Dustin, M. L. & Bar-Sagi, D. Crosstalk between regulatory T cells and tumor-associated dendritic cells negates anti-tumor immunity in pancreatic cancer. Cell Rep. 20, 558–571 (2017).

    CAS  Article  Google Scholar 

  26. 26.

    Papadopoulos, K., Gluck, L., Martin, L., Olszanski, A., Tolcher, A., Ngarmchamnanrith, G. et al. First-in-human study of AMG 820, a monoclonal anti-colony-stimulating factor 1 receptor antibody, in patients with advanced solid tumors. Clin. Cancer Res. 23, 5703–5710 (2017).

    CAS  Article  Google Scholar 

  27. 27.

    Le, D., Picozzi, V., Ko, A., Wainberg, Z., Kindler, H., Wang-Gillam, A. et al. Results from a Phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE Study). Clin. Cancer Res. 25, 5493–5502 (2019).

    CAS  Article  Google Scholar 

  28. 28.

    Tsukhishiro, S., Suzumori, N., Nishikawa, H., Arakawa, A. & Suzumori, K. Elevated serum RANTES levels in patients with ovarian cancer correlate with the extent of the disorder. Gynaecol. Oncol. 102, 542–545 (2006).

    Article  Google Scholar 

  29. 29.

    Niwa, Y., Akamatsu, H., Niwa, H., Sumi, H., Ozaki, Y. & Abe, A. Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer. Clin. Cancer Res. 7, 285–289 (2001).

    CAS  PubMed  Google Scholar 

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Author information




C.N.H., E.O.N. and S.M. devised and led the translational component SCALOP trial. FW performed the in vitro measurement of biomarkers. C.M.C., C.S.W-B. and C.N.H. led the analysis of data, with contributions from E.E.P., A.G.A., R.O., A.S., C.M.J., D.L.I.H. and T.M. All authors (F.W., C.M.C., E.E.P., C.S.W-B., A.G.A., R.O., A.S., C.M.J., D.L.I.H., T.M., C.N.H., E.E.O.N., S.M.) contributed to the interpretation of the results. F.W., C.C., C.M.J. and S.M. authored the initial drafts of the paper. All authors have contributed to subsequent redrafting of the paper, and all have approved the final version. All authors agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Somnath Mukherjee.

Ethics declarations

Ethics approval and consent to participate

The trial protocol was approved by the UK Medicines and Healthcare Products Regulatory Agency and a multicentre research ethics committee. Written informed consent was obtained for all patients who participated in SCALOP, as well as for the optional translational sample collection component. The study was performed in accordance with the Declaration of Helsinki.

Consent to publish

No relevant identifiable patient data.

Data availability

Anonymised data available on request from the corresponding author.

Competing interests

The authors declare no competing interests.

Funding information

C.C., C.W.B. and C.N.H. are supported by Cancer Research UK Clinical Trials Unit core funding. C.M.J. is supported by a Wellcome Trust Clinical Research Fellowship. E.O.N. receives funding from the Kidani Memorial Trust and Cancer Research UK. S.M. is supported by funding from the NIHR Oxford Biomedical Research Centre.

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Willenbrock, F., Cox, C.M., Parkes, E.E. et al. Circulating biomarkers and outcomes from a randomised phase 2 trial of gemcitabine versus capecitabine-based chemoradiotherapy for pancreatic cancer. Br J Cancer 124, 581–586 (2021).

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