162 CHAPTER 6 targeted agents based on their broad panel NGS results. A matching score was computed for each patient, reflecting what percentage of potential targets was covered by the treatment regimen. A higher matching score was associated with a better treatment outcome13. In DRUP, the combination treatment approach was also debated, but to date it is considered to be outside the scope of the trial, since some non-established combinations of drugs would require new dose-finding studies before patients could safely be subjected to them. Without a doubt, the implementation of specialized multidisciplinary Molecular Tumor Boards (MTBs) plays an essential role in determining the most appropriate molecular-guided treatment strategy22-24. Their experience and expertise may guide physicians’ choice for therapy and may suggest extra treatment options within clinical trials, as well as educate physicians in the interpretation of molecular diagnostic test results. Obviously all the efforts regarding data interpretation, precision oncology clinical trial design and developing algorithms to optimize molecular-guided targeted therapy selection will only succeed if patients have access to the molecular diagnostics that are the foundation of precision oncology. If patients cannot access modern diagnostics, all our efforts would reach only few patients, and inequality of healthcare based on geographical location of the patient impends. Surely it will not be possible for each hospital to obtain all technical methods and expertise in house. But strengthening the collaboration and sharing knowledge and resources is necessary to translate advances in precision oncology into benefits for patients with cancer25. In chapter 3 we describe the results of a second positive cohort in the DRUP trial. Twenty-four patients with nine different histological tumor types harboring deleterious mutation of the BRCA1 or BRCA2 gene in their tumor DNA, and with no standard treatment options available, were treated with olaparib, an oral inhibitor of PARP1. Pathogenic BRCA1/2 loss of function (LoF) mutations can result in homologous recombination repair deficiency (HRD) in tumor cells, causing the inability to repair DNA double strand breaks. When PARP1 is inhibited, DNA single strand break repair is hampered, causing a multitude of double strand breaks, that also cannot be repaired, leading to cancer cell cytotoxicity and apoptosis. Fifty-eight percent had clinical benefit upon treatment with olaparib. Among patients with complete biallelic LoF of BRCA, 73% had clinical benefit. Seven out of 24 patients had non-BRCA-associated tumor types for which PARPi are not registered to date, and four of them had clinical benefit. This shows that PARPi is a promising treatment strategy for patients with non-BRCA associated histologies harboring bi-allelic BRCA LoF. The clinical benefit rate in this cohort warrants further investigation and confirmation in patients with non-BRCA histologies. This is currently in preparation within DRUP, an independent expansion cohort (stage 3) is planned to open soon, again making use of the personalized reimbursement model10. Although our findings strongly suggest that PARP inhibition is an effective treatment option in non-BRCA associated tumor types, it is not undisputed whether BRCA1/2 mutations are valid tumor-agnostic biomarkers for PARP inhibitor therapy. A large pan-cancer study by Jonsson et al. showed that (likely) pathogenic germline BRCA1/2 mutations occur in 2.7% of
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