68 CHAPTER 3 NGS panels. Experts are able to circumvent some of the struggles by adding a custom design of polymorphous single nucleotid polymorphisms (SNP’s) around the BRCA1/2 genes, but this requires experience and expertise that is not widely available yet, and an uncertainty margin remains when NGS panels are used, especially for samples with lower tumor percentages. Due to the reliable detection of tumor purities, WGS facilitates the diagnostic process by accurately informing physicians on tumor specific bi-allelic loss of function of BRCA1/2 and HRD, as well as on the presence of additional mutations potentially causing resistance to PARPi, using a single assay. Prompt availability of this information allows for better patient selection for treatment with PARPi, preventing overtreatment of patients who will likely not benefit. The availability of WGS data also allowed to explore possible reasons for unexplained lack of clinical benefit upon PARPi treatment in patients with HRD and bi-allelic BRCA LoF. As described, in the four patients who had no CB despite having a favorable HRD molecular profile, another dominant non-HRD mutational process was identified as possible explanation for the lack of benefit. Pan-cancer, it is known that tumors have a mean number of 5.7 candidate genomic driver events per patient31, likely occurring at different stages of tumor evolution. Some tumors may have multiple drivers occurring as early events in tumor development. In tumors with HRD, not responding to PARPi, one could also hypothesize that bi-allelic BRCA LoF and HRD may simply manifest as a consequence of genomic instability rather than being an early driving genomic event, especially in late stage cancers such as in our cohort. Although we did find potential underlying tumor biology contributing to resistance in these patients, it is still hypothetical and needs further investigation. Although an association between clinical benefit from olaparib and platinum sensitivity has been described54,55, we here found that platinum refractory tumors can still respond to PARPi treatment. Seven out of 12 patients previously treated with platinum-containing chemotherapy had CB upon olaparib treatment, one of them was primary resistant to carboplatin, which indicates that platinum-sensitivity alone may not be a good predictive biomarker for olaparib treatment outcome. Baseline WGS was successfully performed on all biopsies that had sufficient tumor cellularity (N=15 (60%)). This is consistent with the overall WGS success rate within DRUP25 and within the Dutch CPCT-02 study31. Currently, the minimum required tumor cellularity for clinical-grade WGS analysis has been further downscaled from 30% to 20% due to ongoing technical improvements and optimized data analysis (bioinformatics)56, resulting in a current successful analysis of 71%57. The CBR observed in this cohort needs confirmation in a larger independent cohort. Currently, we are preparing an expansion cohort within DRUP. After the first example of a 3rd stage cohort “nivolumab for MSI tumors”, which is the first pilot of the new Dutch personalized reimbursement model that has been previously described30, negotiations with the manufacturer, payers and health authorities are currently ongoing to work towards a second expansion cohort in
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