65 Olaparib in patients with biallelic BRCA1/2 inactivation no evidence of HRD. This suggests that the BRCA mutations found in these patients are likely neutral passenger mutations and a consequence rather than a cause of tumorigenesis, in line with previous reports13. Both patients had TP53, APC and KRAS mutations and one also had a SMAD4 mutation. One patient with adrenal gland carcinoma had bi-allelic BRCA LoF and HRD, however, a CTNNB1 (β-catenin) p.Ser45Pro mutation was found, suggestive for WNT pathway activation, which is a known mechanism of PARPi resistance via N6-methyladenosine modification of FZD10 mRNA, correlating with increased homologous recombination activity and reduced PARPi sensitivity39. Additionally, this patient had a TP53 mutation and RB1 deletion (Supplementary Table 1). LACK OF BENEFIT DUE TO OTHER DOMINANT NON-HRD MUTATIONAL PROCESSES Apart from the patient with adrenal gland carcinoma described above, three other patients had no CB, despite having BRCA-associated tumor types, confirmed bi-allelic BRCA LoF and a high HRD-score. We analyzed WGS data to search for indicators of primary resistance to PARPi. In each patient, WGS analysis showed the presence of another (strong) oncogenic driver mutation that was not previously implied as possible PARPi resistance mechanism. One patient had breast cancer with an amplification (18 copies) of Fibroblast Growth Factor Receptor 1 (FGFR1), which is found in 6.9 - 19.7% of patients with metastatic breast cancer31,40 and has been reported as a possible driver alteration and potential therapeutic target in breast cancer41-43. Another patient with pancreatic cancer had a homozygous loss of CDKN2A and a duplication of exon 3-6 of TGFBR2, likely leading to inactivation. CDKN2A (p16) is deleted or inactivated in 67% of patients with metastatic pancreatic cancer31. If expressed, it compromises efficient BRCA1 dependent DNA repair44 and it is associated with better radiosensitivity in vitro45, while we hypothesize that the opposite may result in lower sensitivity to PARPi. Inactivation of TGFRB2 may also contribute to decreased sensitivity to PARPi because active TGFβ signaling in tumors enhances sensitivity to PARPi in vitro46. In the third patient, also with pancreatic cancer, a KEAP p.Cys434* inactivating mutation, which is associated with drug resistance by regulation of expression of plasma membrane efflux pumps and detoxifying enzymes47, and a KRAS p.Gly12Arg activating hotspot mutation were detected. In-vitro cell line data have indicated a role of KRAS mutation for PARPi resistance48, but the clinical relevance remains uncertain. In all these patients, it is likely that the tumors were not dependent on BRCA, but rather on another dominant non-HRD mutational process. SAFETY Serious adverse events (SAE’s) occurred in 37% of the enrolled patients (Table 2). No unexpected toxicity or CTCAE Grade ≥ 4 events were reported. Review of SAE’s by the IDMC raised no safety concerns. 3
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