Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer

Kate L Mahon ^1,2,3, Sarah Im Sutherland ^1,2,4, Hui Ming Lin ^2,5

¹Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.
²Prostate Cancer Research Group, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
³Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
⁴Cancer Research Group, The ANZAC Research Institute, Sydney, New South Wales, Australia.
⁵School of Clinical Medicine, University of NSW, Sydney, New South Wales, Australia.
⁶Westmead Hospital, Sydney, New South Wales, Australia.
⁷Calvary Mater, Newcastle, New South Wales, Australia.
⁸Medical Oncology Department, Mid North Coast Cancer Institute, Coffs Harbour, New South Wales, Australia.
⁹Northern Haematology Oncology Group, Sydney, New South Wales, Australia.
¹⁰BC Cancer Agency, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
¹¹Royal Marsden Hospital and Institute of Cancer Research, London, UK.
¹²St Vincent's Centre for Applied Medical Research, Sydney, New South Wales, Australia.
¹³Concord Hospital, Sydney, New South Wales, Australia.

⁰Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.

The Prostate +

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March 28, 2024

View abstract on PubMed

Summary

Elevated growth differentiation factor (GDF15) indicates a poor prognosis for men with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel. GDF15 may signal innate immune system changes related to docetaxel resistance.

Area Of Science

Oncology
Immunology
Biomarker Discovery

Background

Metastatic castration-resistant prostate cancer (mCRPC) poses treatment challenges.
Previous studies suggested elevated cytokines, including GDF15, IL4, and IL6, correlate with docetaxel resistance in mCRPC.
This research aimed to validate these cytokine biomarkers.

Purpose Of The Study

To establish level 2 evidence for the utility of GDF15, IL4, and IL6 as biomarkers in mCRPC patients undergoing docetaxel treatment.
To investigate the association between these cytokine levels and patient outcomes, specifically overall survival (OS).

Main Methods

Two cohorts of mCRPC patients were analyzed: an internal validation group (n=120) and an external validation group (n=430).
Plasma and serum samples were collected at baseline and during docetaxel treatment (Day 21 or Day 42).
Cytokine levels (IL4, IL6, GDF15) were quantified using ELISA; in vitro experiments assessed GDF15's effect on immune cells.

Main Results

Higher baseline and on-treatment GDF15 levels were significantly associated with shorter overall survival (OS) in both cohorts (p<0.0001).
Elevated GDF15 levels correlated with increased CD86 expression on monocytes, suggesting an impact on innate immunity.
Interleukin 4 (IL4) and Interleukin 6 (IL6) levels did not show a significant association with patient outcomes.

Conclusions

Circulating GDF15 is a significant biomarker for poor prognosis in mCRPC patients treated with docetaxel.
GDF15 may reflect docetaxel-induced changes in the innate immune system, potentially mediating resistance.
These findings support GDF15's role in guiding therapeutic strategies, including combination therapies targeting the innate immune system.

Keywords:

biomarker docetaxel growth differentiation factor 15 metastatic castration‐resistant prostate cancer prognosis therapeutic response