An innate immune response to DNA damage in prostate cancer

Subsequently a siRNA mediated screen was completed to try and identify novel gene mutations, which may contribute to BRCAness phenotype. Formalin-fixed, paraffin- embedded (FFPE) diagnostic core biopsies were obtained from 52 men with Castrate Resistant Prostate Cancer (CRPC) treated with docetaxel in the NI Cancer Centre. Samples were microarray profiled, signature scored and defined as DDRD positive or negative.<br><br>Results<br>siRNA mediated knockdown of BRCA1, BRCA2 and ATM resulted in up regulations of DDRD associated chemokines and a lack of response to docetaxel and increased sensitivity to cisplatin and olaparib.

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 3.72; 95% CI 1.40 to 9.89 ; p=0.009; Median survival DDRD positive 12.43months vs. DDRD negative 21.83 months).<br><br>Conclusions.<br>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 a prospective clincal 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, olaparib.<br>