Maarten van der Doelen

Impact of DNA damage repair defects on response to radium-223 therapy in mCRPC patients

INTRODUCTION Prostate cancer is the cancer with the highest incidence and the second leading cancer related cause of death in men worldwide. (1) Since 2004, several new life-prolonging systemic therapies have been registered for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, evidence-based guidelines on sequencing of these therapies are lacking and biomarkers are needed to help guide clinicians. Radium-223 is a therapeutic option for mCRPC patients with symptomatic bone metastases and no evidence of visceral metastases. (2) Radium-223 is an alpha emitter, that selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha particles of short range (<100 μm), causing double-strand DNA breaks (DSBs). (3) DNAdamage response (DDR) genesplayacrucial role inprotectingthegenomic integrity, through detection of DNA damage, signalling to cell-cycle checkpoints, and DNA repair. (4) The repair of DSB in eukaryotic cells is mediated through homologous recombination (HR), error-prone non-homologous end-joining (NHEJ), and microhomology-mediated end-joining. The inability to repair DNA damage by NHEJ or other mechanisms can lead to accumulation of deletions and mutations. (5) Germline mutations in selected DDR genes not only result in an increased incidence of prostate cancer but are also associated to a more aggressive disease course. (6, 7) Genomic aberrations that impair DNA repair occur at a frequency of 20-25% in advanced prostate cancer. (8) Mutations in HR genes, such as BRCA1 , BRCA2 , PALB2 or other genes constituting the DNA damage machinery, such as ATM , ATR , or CHEK2 , are candidate predictive biomarkers for targeted therapies like poly-ADP ribose polymerase (PARP) inhibitors. Following radium-223 treatment, prostate cancer cells with HR deficiency (HRD) accumulate irreparable DNA damage which subsequently may result in cellular death through apoptosis. Therefore, cells with mutated HR genes might be more vulnerable to radionuclides such as radium-223. Mutations in HR genes have been associated with sensitivity to radium-223 therapy in two small cohort studies. (9, 10) A recent retrospective single-institution study demonstrated that mCRPC patients carrying germline and/or somatic mutations in HR genes more commonly showed ≥30% alkaline phosphatase (ALP) responses, longer time to ALP progression, and a trend toward longer overall survival (OS). (11) Another recent retrospective study showed that patients with germline defects in DDR genes appeared to benefit from all standard therapies similarly to the overall population of patients with mCRPC. However, this study included only

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