Maarten van der Doelen

Chapter 7

second-generation androgen signalling inhibitors and taxane-based chemotherapy, but not radium-223 therapy. (12) The present study aimed to strengthen the findings that mCRPC patients with DDR benefit more from radium-223 therapy than patients without DDR.

METHODS Study design and patient population

Metastatic CRPC patients who were treated with radium-223 therapy between February 2013 and June 2019 at Radboud university medical center (Radboudumc) or Johns Hopkins Hospital, and had undergone a comprehensive analyses of DDR genes through next generation sequencing (NGS) were consecutively included in this retrospective cohort study. Exclusion criteria were the presence of visceral metastases or prior treatment with radionuclides, PARP inhibitors or platinum chemotherapeutic agents preceding initiation of radium-223 therapy. The presence or absence of DDR mutations was not a criterium for start of radium-223 administration. All patients gave written informed-consent for NGS testing. This study was approved by the institutional review boards and local committees on research involving human subjects at both institutes. Data from the NGS reports, as well as histopathological, clinical and demographic data were collected and stored in an electronic clinical database. The study population was divided in subgroups based on the presence or absence of (likely) pathogenic somatic and/or germline aberrations in DDR genes (DDR+), or genes (in)directly involved in HR (HRD+), and mutation-negative (DDR- and HRD-) groups. Genetic panel of interest Tumor samples of all patients were previously sequenced by non-profit institutes (Center for Personalized Cancer Treatment (CPCT), by fee for service providers (Foundation Medicine (FoundationOne), Personal Genome Diagnostics, Color Genomics, Invitae) and/or by a custom in-house NGS panel using single molecule molecular inversion probe-based sequencing. (13) The DDR genetic panel of interest was chosen a priori and stated in the study protocol. The panel defined as DDR+ included ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHD1, CHEK1, CHEK2, ERCC2, ERCC4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI,

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