PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
Clinical validation of circulating cytokines as markers of prognosis and response to docetaxel in men with metastatic castration resistant prostate cancer
KL Mahon 1, , HM Lin 2, , M Lee-Ng 10 , D Cain 4 , C Jacobs 4 , MR Stockler 1, , H Gurney 3, , G Mallesara 12 , K Briscoe 13 , G Marx 14 , C Higano 7 , JS de Bono 5 , KN Chi 6 , SN Breit 10 , DA Brown 10 & LG Horvath 1,
1Chris O’Brien Lifehouse, Sydney, Australia; 2Garvan Institute of Medical Research, Sydney, Australia; 3University of Sydney, Sydney, Australia; 4Oncogenex Pharmaceuticals Inc, Bothell, WA, USA; 5Royal Marsden Hospital and Institute of Cancer Research, London, UK; 6University of British Columbia, BC Cancer Agency, Vancouver Prostate Centre, Vancouver, BC, Canada; 7University of Washington, Fred Hutchinson Cancer Research Centre, Seattle, WA, USA; 8University of NSW, Sydney, Australia; 9National Health and Medical Research Council Clinical Trials Centre, Sydney, Australia; 10St Vincent’s Centre for Applied Medical Research, Sydney, Australia; 11Westmead Hospital, Sydney, Australia; 12Calvary Mater, Newcastle, Australia; 13Coffs Harbour Hospital, Australia; 14Northern Haematology and Oncology Group, Sydney, Australia.
Background: Elevated circulating macrophage inhibitory cytokine -1/growth differentiation factor 15 (MIC-1/GDF15), interleukins 4 (IL4) and 6 (IL6) levels were associated with poor prognosis and resistance to docetaxel chemotherapy in an exploratory cohort of men with metastatic castration resistant prostate cancer (mCRPC). To establish level 2 evidence of biomarker utility, these cytokines were tested in internal and external validation cohorts.
Methods: Internal validation cohort: Plasma samples taken at baseline (BL) and preC2 docetaxel (n=120). MIC-1/GDF15, IL-4 and IL-6 measured by ELISA assay.
External validation cohort: Serum samples taken at BL and/or preC3 docetaxel in 430 men with mCRPC on phase III SYNERGY study (docetaxel ± custirsen as 1st line chemotherapy in mCRPC with no OS benefit in the experimental arm). MIC-1/GDF15 measured by ELISA assay.
Associations between cytokine levels, PSA response, time to PSA progression and OS were assessed by non-parametric tests and Cox Regression survival analyses.
Results: Internal validation: At a median follow-up of 14 months, higher MIC-1/GDF15 levels at BL and preC2 were associated with shorter OS (BL; HR 1.2 95%CI 1.0–1.4; P=0.03 and preC2; HR 1.3 95%CI 1.1–1.5; P=0.004). Increase in MIC-1/GDF15 after chemotherapy correlated with lack of PSA response (P<0.001). IL4 and IL6 did not correlate with survival or demonstrate additional value.
External validation: At a median follow-up of 23 months, higher MIC-1/GDF15 levels at BL and preC3 predicted shorter OS (BL; HR 1.4 95%CI 1.2–1.6; P<0.0001 and preC3; HR 1.6 95%CI 1.3–1.8; P<0.0001). Higher pre C3 MIC-1/GDF15 levels were also associated with shorter time to PSA progression (HR 1.2 95% CI 1.0–1.4; P=0.02). Rise in MIC-1/GDF15 from BL to preC3 correlated with lack of 50% PSA fall at 12 weeks (P<0.001).
Conclusion: Adherence to a biomarker development pipeline provides level 2 evidence of the prognostic value of circulating MIC-1/GDF15 in men with mCRPC receiving docetaxel. A prospective biomarker led study is now necessary to establish clinical utility.
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Oncology Abstracts
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