Benjamin Christopher

OBJECTIVE: To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer. DESIGN: A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing. RESULTS: Of the 53 UM patients studied, a single patient was identified with a germline BAP1 truncating mutation, c. 799 C→T (p.Q267X), which segregated in several family members and was associated with UM and other cancers. Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation. Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients. CONCLUSION: This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers. The results indicate that BAP1 is the candidate gene in only a small subset of hereditary UM, suggesting the contribution of other candidate genes.

The reported frequencies of germline mutations in the melanoma candidate genes are low in patients with uveal melanoma (UM). However, the number of families studied is limited and the majority of the published reports used low-sensitivity techniques for mutational screening. Identifying the frequency of alterations in any of the melanoma genes in patients with UM with increased hereditary cancer risk is important for proper counseling of these patients. We studied a total of 47 patients with UM including three with a family history of UM, 18 with a family and/or personal history of cutaneous melanoma (CM), three with early age at diagnosis (<30), 11 with increased risk for a known familial cancer syndrome, and 12 with a second primary tumor. Germline screening for mutations in CDKN2A, p14ARF, and exon 2 of CDK4 was carried out by direct sequencing. We identified a variant (IVS1-69 C>T) of uncertain significance in exon 1b of p14ARF in one of the patients with UM and his mother who also had UM. The variant was neither detected in any of the other patients with UM nor in 146 controls. We did not identify pathogenic mutations in CDKN2A nor exon 2 of CDK4 gene. Our study supports the low frequency of germline mutation of the CM candidate genes in patients with UM with family histories suggestive of a high risk for hereditary cancer. Germline testing for CDKN2A might be reserved for patients with UM with a family history of two or more CM.

547 Background: Metastatic biliary tract cancer (mBTC) is a lethal malignancy with median 5 year OS of less than 10%. Immunotherapy, particularly single agent anti-PD-1/PD-L1, has limited efficacy in mBTC with ORR~9-15%. Recently presented data shows responses in metastatic MSS pancreatic or colon cancer with combination anti-PD-1/CTLA-4 and radiation (XRT) to produce systemic response (abscopal effect) (Parikh A, GI ASCO 2019, ASCO 2019.). We evaluate safety and efficacy of dual PD-1/CTLA-4 inhibition with XRT in MSS mBTC. Methods: 15 of a planned 15 mBTC patients were enrolled. Eligible pts had histologically-confirmed mBTC, ECOG-PS 0/1, and must have progressed on at least one line of previous therapy or refused standard therapy. Safety cohort of 6 pts of durva 1500 mg/treme 75 mg q4w was enrolled. If &gt; 2 DLTs, patients were enrolled subsequently to dose level -1 (durva 1125 mg/ treme 75 mg q4w). 3 fractions of 8 Gy of radiation at C2D1 every other day to a single metastatic site. Durva/treme continued for 4 cycles, followed by 4 cycles of maintenance durva until progressive disease, discontinuation or withdrawal. Endpoints include disease control rate (DCR (SD+PR+CR)), PFS and OS and safety. Radiological evaluations were done q2 mo. Results: 15 mBTC pts enrolled and evaluable from May 2018 to March 2019. Median age 63 years (range 48-75), 47% male. DLTs occurred in 3 patients during the safety run-in. One patient experienced DLT at dose level -1 and subsequent expansion. 3 patients did NOT reach radiation therapy. DCR was 27% with a 13% PR and 7% CR. Of those who reached radiation, DCR was 33% with a 17% PR and 8% CR. At time of analysis, median PFS was 54 days for ITT mBTC. Duration of response for 4 patients with DCR was 26, 52, 122, 254+ days. Treatment-related adverse events were reported in 12/15 patients (80%). Grade ≥3 toxicities were seen in 9/15 pts (60%) with lymphopenia (5 grade 3) and elevated LFTs (2 grade 4 and 4 grade 2) being the main adverse events. All patients with disease control were not MSI. Conclusions: Combination of durva/treme XRT is feasible and shows preliminary activity in metastatic BTC. An expansion cohort is being planned to confirm activity. Clinical trial information: NCT03482102.