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Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. Germline testing for hereditary genetic abnormalities is recommended for all patients with PDA and somatic molecular testing is recommended for all patients with locally advanced or metastatic disease. KRAS mutations are present in 90% of PDA, while 10% are KRAS wild type and are potentially targetable with epidermal growth factor receptor blockade. KRASG12C inhibitors have shown activity in G12C-mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. DNA damage repair abnormalities, germline or somatic, occur in 5–10% of patients and are likely to benefit from DNA damaging agents and maintenance therapy with poly-ADP ribose polymerase inhibitors. Fewer than 1% of PDA harbor microsatellite instability high status and are susceptible to immune checkpoint blockade. Albeit very rare, occurring in <1% of patients with KRAS wild-type PDAs, BRAF V600E mutations, RET and NTRK fusions are targetable with cancer agnostic Food and Drug Administration-approved therapies. Genetic, epigenetic, and tumor microenvironment targets continue to be identified at an unprecedented pace, enabling PDA patients to be matched to targeted and immune therapeutics, including antibody–drug conjugates, and genetically engineered chimeric antigen receptor or T-cell receptor – T-cell therapies. In this review, we highlight clinically relevant molecular alterations and focus on targeted strategies that can improve patient outcomes through precision medicine. [ABSTRACT FROM AUTHOR]

Background KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA). Materials and Methods We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model. Results One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS. Conclusions Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA. We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA. Pancreatic cancers rarely benefit from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME include low- and poor-quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach. [ABSTRACT FROM AUTHOR]

Background: Gemcitabine and cisplatin has limited benefit as treatment for advanced biliary tract cancer (BTC). The addition of an anti-programmed death receptor (PD-1)/PD-ligand (L1) antibody to either systemic chemotherapy or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody has shown benefit in multiple solid tumors.Methods: In this phase 2 trial, patients 18 years or older with advanced BTC without prior systemic therapy and Eastern Cooperative Oncology Group Performance Status 0-1 were randomized across six academic centers. Patients in Arm A received nivolumab (360 mg) on day 1 along with gemcitabine and cisplatin on days 1 and 8 every 3 weeks for 6 months followed by nivolumab (240 mg) every 2 weeks. Patients in Arm B received nivolumab (240 mg) every 2 weeks and ipilimumab (1 mg/kg) every 6 weeks.Results: Of 75 randomized patients, 68 received therapy (Arm A = 35, Arm B = 33); 51.5% women with a median age of 62.5 years. The observed primary outcome of 6-month progression-free survival (PFS) rates in the evaluable population was 59.4% in Arm A and 21.2% in Arm B. The median PFS and overall survival (OS) in Arm A were 6.6 and 10.6 months, and in Arm B 3.9 and 8.2 months, respectively, in patients who received any treatment. The most common treatment-related grade 3 or higher hematologic adverse event was neutropenia in 34.3% (Arm A) and nonhematologic adverse events were fatigue (8.6% Arm A) and elevated transaminases (9.1% Arm B).Conclusions: The addition of nivolumab to chemotherapy or ipilimumab did not improve 6-month PFS. Although median OS was less than 12 months in both arms, the high OS rate at 2 years in Arm A suggests benefit in a small cohort of patients. [ABSTRACT FROM AUTHOR]

Irinotecan (Camptosar©, CPT-11), a topoisomerase I inhibitor, is a commonly used cytotoxic chemotherapeutic in the treatment of multiple malignancies, particularly of gastrointestinal origin. Dysarthria secondary to irinotecan has been described as a rare side effect in a few case reports with limited data to recommend appropriate management. We describe herein a large single institution experience of patients with gastrointestinal malignancies who experienced dysarthria while being treated with irinotecan-based chemotherapy regimens (FOLFIRINOX or FOLFIRI+/−bevacizumab). Eighteen patients developed neurological manifestations during irinotecan infusion with the majority (n = 17) developing dysarthria. Patients also experienced other known side effects including cholinergic effects (abdominal bloating, diarrhea, facial flushing, diaphoresis, and rhinorrhea), nausea, fatigue, perioral paresthesia and musculoskeletal discomfort. The dysarthria occurred as early as with the first infusion of irinotecan (n = 9), but several patients did not develop symptoms until subsequent infusions (range, 1–6). Dose alterations of irinotecan did not obviously impact the reccurrence or severity of dysarthria. Management strategies included close observation, atropine, slower irinotecan infusion rate, and reassurance. Dysarthria resolved without consequence in all patients within hours of completion of the infusion. Oncologists and pharmacists should be aware of irinotecan-associated dysarthria as a rare, self-limited phenomenon with no long-term sequelae, and appropriately counsel patients and infusion nurses to avoid inadvertently withholding potentially beneficial therapy for patients with gastrointestinal malignancies. [ABSTRACT FROM AUTHOR]

Background: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, clinically heterogeneous disease due to heritable mutations that lead to misfolding of a precursor protein and multisystem disease. This study sought to define the clinical characteristics, distribution of mutations and phenotypic presentation of patients presenting to our center with hereditary ATTR amyloidosis. Methods: With institutional review board approval, the study retrospectively identified patients who had hereditary ATTR amyloidosis and presented to Mayo Clinic in Rochester, Minnesota, from 1 January 1970, to 29 January 2013. Results: Of the 266 patients with the diagnosis of hereditary ATTR amyloidosis, a pathogenic mutation was identified in 206; the most common mutation was Thr60Ala (68 patients [25%]). Median age at diagnosis was 63.3 years; median survival after diagnosis was 56.8 months (10th-90th percentile, 16.0-297.9). On multivariate analysis, age at diagnosis (risk ratio, 15.65; p < 0.0001), Thr60Ala mutation (risk ratio, 1.52; p = 0.04), Val122Ile mutation (risk ratio, 2.83; p = 0.003), peripheral neuropathy (risk ratio, 1.69; p = 0.013) and weight loss (risk ratio, 1.81; p = 0.002) were risk factors for death. Conclusion: Our data characterize the features of hereditary ATTR amyloidosis in a large cohort, demonstrate the heterogeneity among mutations and support the need to better characterize the clinical progression of individual mutations. [ABSTRACT FROM AUTHOR]