756P - An innate immune response to intrinsic DNA damage predicts resistance to docetaxel in prostate cancer

Date 09 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Prostate Cancer
Cancer Immunology and Immunotherapy
Presenter Catherine Davidson
Citation Annals of Oncology (2016) 27 (6): 243-265. 10.1093/annonc/mdw372
Authors C.J. Davidson1, S. Walker1, N. McCabe2, L. Hill2, E. Parkes1, S. Jain1, D. O'Rourke3, R. Kennedy1
  • 1Centre For Cancer Research And Cell Biology, Queen's University Belfast, BT9 7AB - Belfast/GB
  • 2Almac Diagnostics, Almac Group, Craigavon/GB
  • 3Clinical Oncology, Belfast City Hospital Northern Ireland Cancer Centre, School of Medicine, Dentistry & Biomedical Science, BT9 7AB - Belfast/GB

Abstract

Background

We have previously identified a molecular subtype in solid tumors which is characterised by STING mediated immune signalling due to abnormal DNA as a result of loss of DNA repair mechanisms. This subtype is characterised by activation of cytokines, such as CXCL10, which attract lymphocytic infiltration and upregulate immune checkpointing genes like PD-L1. This subtype is identified by a 44 gene expression signature, the DNA damage response deficient (DDRD) assay. It is well recognised, that while loss of DNA repair can sensitize to DNA damaging chemotherapy, it may also confer resistance to anti-microtubule agents. We hypothesized the DDRD positive molecular subtype in prostate cancer would confer a worse outcome following docetaxel treatment.

Methods

We used siRNA-mediated knockdown of DNA repair genes in DU145 cells to test for activation of the DDRD immune signal and sensitivity to docetaxel versus DNA damaging agents. We obtained FFPE diagnostic core biopsies from 52 men with Castrate Resistant Prostate Cancer (CRPC) treated with Docetaxel. Response to docetaxel was measured as a >50% decline in Prostate Specific Antigen (PSA). Samples were microarray profiled, signature scored and defined as DDRD positive or negative.

Results

siRNA mediated knockdown of BRCA1, BRCA2 and ATM resulted in increased resistance to docetaxel and increased sensitivity to cisplatin. Ten patients (19.23%) were DDRD positive and 42 (80.76%) were DDRD negative; 80% of DDRD positive and 47% of DDRD negative patients failed to benefit from docetaxel. DDRD positive tumour samples demonstrated an association with poorer overall survival post-docetaxel (HR 0.464; 95% CI 0.13 to 0.89; p = 0.0317; Median survival DDRD positive 12.43months vs. DDRD negative 21.83 months).

Conclusions

The DDRD positive molecular subtype of prostate cancer, characterised by an immune response to DNA damage, has a reduced benefit from docetaxel. We intend to validate this observation in the STAMPEDE trial, investigating advanced prostate cancer patients who received docetaxel as primary therapy. These studies may lead to clinical trials where DDRD positive patients receive specific DNA damaging agents like carboplatin or an immune targeted therapy such as a PD-L1 inhibitor.

Clinical trial identification

n/a

Legal entity responsible for the study

Queens University Belfast

Funding

Cancer Research UK

Disclosure

S. Walker: This Author is an employee for ALMAC diagnostics.

N. McCabe: Is an employee of Almac Daignostics and her research is funded by Almac in part.

L. Hill: Is an employee of ALMAC diagnostics and her work is funded by ALMAC.

R. Kennedy: Employee of Almac diagnostics.

All other authors have declared no conflicts of interest.