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 1.01.4; P=0.03 and preC2; HR 1.3 95%CI 1.11.5; 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 1.21.6; P<0.0001 and preC3; HR 1.6 95%CI 1.31.8; P<0.0001). Higher pre C3 MIC-1/GDF15 levels were also associated with shorter time to PSA progression (HR 1.2 95% CI 1.01.4; 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.
17 Mar 2019 - 20 Mar 2019