163 Discussion and future perspectives patients, and somatic LoF mutations in 1.8% of patients across 38 histological tumor types26. Of these patients, 53% had one of the four BRCA-associated tumor types: ovarian, breast, prostate and pancreatic cancer. In these patients, biallelic inactivation of BRCA was seen in 61%, while only 28% of patients with non-BRCA associated malignancies had bi-allelic inactivation. In fact, somatic loss of the pathogenic germline BRCA allele occurred twice as often in the last group. These findings indicate that dependency on BRCA pathway dysfunction for tumorigenesis differs between tumor lineages, and in many cases, the BRCA mutations are neutral passenger mutations that are rather a consequence of genomic instability than a cause of tumorigenesis26. This is in line with our observation that in patients with bi-allelic BRCA LoF who had no benefit upon treatment with olaparib, another dominant genomic oncogenic driver was identified. While BRCA LoF can cause HRD, BRCA1/2 mutations are not 100% synonymous with HRD. Approximately 40% of ovarian cancers are HRD without a pathogenic BRCA1/2 mutation27. And vice versa, in tumors harboring a pathogenic BRCA1/2 mutation, HRD can be reversed by a secondary mutation that restores BRCA function28. Also, an HRD-permissive tumor microenvironment may play an important role in BRCA-associated tumors26. Albeit more complex, an accurate estimate of HRD may be a better predictor of response to PARP inhibition and may have more potential as tumor-agnostic biomarker. Various functional HRD assays27,29 and classifiers30,31 have been developed that can accurately detect HRD in tumor tissue. Histology-agnostic studies in which patients are selected for treatment with PARPi based on a HRD signature have not yet been reported. Within the DRUP trial, the potent PARP inhibitor talazoparib is available for patients with a HRD genomic signature in their tumor DNA, but without a pathogenic mutation or deletion in one of the known HRD genes. This histology-agnostic cohort is currently accruing patients. DEVELOPMENT OF PHOSPHOPROTEOMICS-BASED BIOMARKERS FOR PRECISION ONCOLOGY The presence of a clear tissue-based biomarker predictive of treatment outcome is considered a corner stones of precision oncology. A strong example is the BRAF V600 mutation as a biomarker for response to treatment with BRAF/MEK-inhibition in advanced melanoma, glioma32 and anaplastic thyroid cancer33. However, some tyrosine kinase inhibitors (TKI’s) are used without the presence of a molecular biomarker, such as sunitinib, which is used as first-line treatment for patients with advanced renal cell cancer (RCC)34. RCC is not a mono-genetic driven disease35 and tissue-based biomarkers for response are lacking. Sunitinib is a multi-targeted TKI targeting mainly the Vascular Endothelial Growth Factor Receptors (VEGFR 1 and 2), Platelet-Derived Growth Factor Receptors (PDGFR-alpha and PDGFR-beta) and stem cell factor receptor (KIT), though many off-target effects are observed36. Despite the absence of a predictive biomarker, treatment of RCC with sunitinib has proven to be quite effective, resulting in a median progression free survival (PFS) of 8.4 - 11 months37,38 and an improved overall survival compared to interferon alfa34, with an objective response rate of 25 - 47%37,38. Upfront identification of patients for whom sunitinib will fail to provide clinical benefit is crucial to prevent unnecessary side effects of the drug. 6
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