Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC. Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. .
BACKGROUND: Biliary tract cancers are rare, aggressive neoplasms. Most patients present with advanced/unresectable or metastatic disease at diagnosis, and no second-line regimen has demonstrated clinical benefit. This was a phase 2 study evaluating the efficacy and safety of regorafenib in patients who had advanced/unresectable or metastatic disease after receiving standard therapy. METHODS:In this single arm-study, patients with advanced/unresectable or metastatic biliary tract cancer who failed at least 1 line of systemic chemotherapy received regorafenib once daily on a schedule of 21-days on/7-days off in a 28-day cycle. Patients initially received a standard 160 mg dose. After toxicity assessments in the first 3 patients, the dose was reduced to 120 mg for subsequent patients, as preplanned. The primary endpoint was progression-free survival (PFS). Secondary objectives included overall survival (OS), the objective response rate, and the disease control rate. RESULTS: Forty-three patients received at least 1 dose of regorafenib, and 34 patients who received at least 1 cycle of treatment were evaluable for tumor response. The median PFS was 15.6 weeks (90% confidence interval, 12.9-24.7 weeks), and the median OS was 31.8 weeks (90% confidence interval, 13.3-74.3 weeks), with survival rates 40% at 12 months and 32% at 18 months. A partial response was achieved in 5 patients (11%), and 19 had stable disease (44%), for a disease control rate of 56%. The toxicity profile was as expected, with grade 3 and 4 adverse events reported in 40% of patients. The most common toxicities were hypophosphatemia (40%), hyperbilirubinemia (26%), hypertension (23%), and hand-foot skin reaction (7%). CONCLUSIONS: The current results suggest promising efficacy of regorafenib in patients with chemotherapy-refractory, advanced/ metastatic biliary tract cancer, warranting further studies to confirm its clinical efficacy. There is a clear unmet need for effective therapies in patients who have advanced and metastatic biliary tract cancer. Cancer 2019;125:902-909.
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