Poster Presentation 29th Lorne Cancer Conference 2017

Phase II trial of circulating cytokines as markers of docetaxel resistance in metastatic castrate-resistant prostate cancer (mCRPC). (#217)

Kate Mahon 1 2 , Hui-Ming Lin 2 , Calan Spielman 2 , Michelle Lee-Ng 3 , Howard Gurney 4 , Girish Mallesara 5 , Martin Stockler 1 , Karen Briscoe 6 , Gavin Marx 7 , Samuel N Breit 3 , David Brown 3 , Lisa Horvath 1 2
  1. Chris O'Brien Lifehouse, Camperdown, NSW, Australia
  2. Garvan Institute for Medical Research, Darlinghurst, NSW, Australia
  3. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
  4. Westmead Hospital, Sydney, Australia
  5. Calvary Mater Hospital, Newcastle, NSW, Australia
  6. Mid North Coast Cancer Institute, Coffs Harbour, NSW, Australia
  7. Sydney Adventist Hospital Cancer Centre, Sydney, NSW, Australia

Background:Docetaxel(DTX) improves symptoms and survival in mCRPC; however, ~ 50% of patients have chemoresistant disease. Early markers of chemoresistance will allow rapid cessation of ineffective therapy and enable progression to other available treatments. Increased levels of circulating macrophage inhibitory cytokine 1 (MIC1), interleukins 4 (IL4) and 6 (IL6) after 1 cycle of DTX predicted chemoresistance in a phase I exploratory cohort of men with mCRPC. This phase II biomarker study aims to validate these findings in an independent patient cohort.

 

Methods:Plasma samples pre-cycle 1 and pre-cycle 2 DTX were collected from 121 men with mCRPC. MIC1, IL4 and IL6 levels were measured by ELISA. Patients were grouped as partial responders (PR) and non-responders (progressive or stable disease) based on PSA response criteria (PR≥50% reduction in PSA within 3 months of commencing DTX). Associations between cytokine levels, response groups and overall survival(OS) were assessed by non-parametric tests, receiver operating curve(ROC) analysis and Cox regression survival analysis.

 

Results:After 1 cycle of DTX, non-responders had significantly greater increases in MIC1 (p<0.001) and IL6 (p=0.048). On ROC analysis, chemoresistance was predicted by early changes in MIC1 (AUC 0.7; p<0.001). In contrast to our phase I analysis, IL4 was not associated with response. Furthermore, combinations of cytokine changes did not improve on MIC1 alone as an early biomarker of response. With a median survival of 16 months with 84 deaths, higher levels of MIC1 at baseline and after cycle 1 DTX predicted shorter OS (HR 1.2, 95%CI 1.0-1.4; p=0.03 and HR 1.3, 95%CI 1.1-1.5; p=0.004, respectively). In a multivariable model including presence of visceral metastases (p=0.16), baseline ALP (p=0.13), baseline Hb (p=0.01), baseline PSA (p=0.9) and baseline MIC1 (p=0.08), post DTX MIC1 level was an independent predictor of OS (HR 1.9, 95% CI 1.1-3.4; p=0.02).

 

Conclusions:This phase II biomarker study has validated the utility of MIC1 as an early predictor of chemoresistance and OS in mCRPC. Conversely, IL4 and IL6 have not demonstrated additional value, emphasizing that adherence to a standardized biomarker development pathway is essential to efficiently move biomarkers into clinical practice. Independent phase III validation of MIC1 is now underway.