62 CHAPTER 3 Table 1. Baseline characteristics of the 27 patients enrolled in the cohort “Olaparib for tumors with a BRCA1 or BRCA2 mutation” (continued) n = 27 WHO Performance Status WHO 0 7 26% WHO 1 18 67% Not available 2 7% Primary tumor types Prostate cancer 11 41% Breast cancer 4 15% Pancreatic cancer 3 11% Ovarian cancer 2 7% Colorectal cancer 2 7% Cholangiocarcinoma 2 7% Renal cell carcinoma 1 4% Adrenal gland carcinoma 1 4% Endometrial cancer 1 4% Number of prior systemic therapy lines Median (range) 4 (1 – 6)* PRE-ENROLLMENT MOLECULAR CHARACTERISTICS Seventeen patients were included based on a BRCA2 mutation, and seven patients had a BRCA1 mutation. In 14 of 24 patients, the BRCA alteration was discovered by WGS, performed as part of the Dutch CPCT-02 study27. In five patients, the target was found using an NGS panel (smMIP and/or MLPA). Four patients were included based on a germline test only, and in one patient, a germline test combined with two functional HRD tests was performed. This patient with breast cancer had a germline mono-allelic BRCA2 c.9104A>C mutation that was classified as a variant of uncertain significance. Functional characterization of this variant using embryonic stem cell complementation showed 50% reduction in HR functionality37. Additionally, a Recombination Capacity (RECAP) test38 showed negative RAD51 staining after ex vivo irradiation of the tumor tissue, which is highly suggestive of HRD. Based on these results, the study team granted a waiver to include the patient. Twelve patients had a germline BRCA mutation. Six of them also had a somatic event in BRCA, or LOH in tumor tissue, resulting in complete BRCA LoF. Twelve patients were included based only on somatic BRCA alterations. In six of them, complete LoF of BRCA was confirmed pre-enrollment or based on the baseline WGS data (Supplementary Table 1). BASELINE BIOPSIES AND WGS RESULTS Baseline study biopsies were performed in 22 out of 24 patients. For two patients, a biopsy was not possible for medical reasons. Thirteen (59%) biopsies were successfully sequenced.
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