Faculty Bibliography

Oncology research is increasingly incorporating molecular detection of circulating tumor DNA (ctDNA) as a tool for cancer surveillance and early detection. However, noninvasive monitoring of conditions with low tumor burden remains challenging, as the diagnostic sensitivity of most ctDNA assays is inversely correlated with total DNA concentration and ctDNA abundance. Here we present the Multiplex Enrichment using Droplet Pre-Amplification (MED-Amp) method, which combines single-molecule emulsification and short-round polymerase chain reaction (PCR) preamplification with digital droplet PCR detection of mutant DNA template. The MED-Amp assay increased mutant signal by over 50-fold with minimal distortion in allelic frequency. We demonstrate detection of as few as three mutant copies in wild-type DNA concentrations ranging from 5 to 50 ng. The MED-Amp assay successfully detected KRAS mutant ctDNA in 86% plasma samples obtained from patients with metastatic pancreatic ductal adenocarcinoma. This assay for high-sensitivity rare variant detection is appropriate for liquid biopsy samples or other limited clinical biospecimens.

Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing (Atdc) gene, whose human homolog is up-regulated in the majority of pancreatic adenocarcinoma, completely prevents PDA development in the context of oncogenic KRAS. ATDC is required for KRAS-driven acinar-ductal metaplasia (ADM) and its progression to pancreatic intraepithelial neoplasia (PanIN). As a result, mice lacking ATDC are protected from developing PDA. Mechanistically, we show ATDC promotes ADM progression to PanIN through activation of β-catenin signaling and subsequent SOX9 up-regulation. These results provide new insight into PDA initiation and reveal ATDC as a potential target for preventing early tumor-initiating events.

Basal subtype cancers are deadly malignancies but the molecular events driving tumor lethality are not completely understood. Ataxia-telangiectasia group D complementing gene (ATDC, also known as TRIM29), is highly expressed and drives tumor formation and invasion in human bladder cancers but the factor(s) regulating its expression in bladder cancer are unknown. Molecular subtyping of bladder cancer has identified an aggressive basal subtype, which shares molecular features of basal/squamous tumors arising in other organs and is defined by activation of a TP63-driven gene program. Here, we demonstrate that ATDC is linked with expression of TP63 and highly expressed in basal bladder cancers. We find that TP63 binds to transcriptional regulatory regions of ATDC and KRT14 directly, increasing their expression, and that ATDC and KRT14 execute a TP63-driven invasive program. In vivo, ATDC is required for TP63-induced bladder tumor invasion and metastasis. These results link TP63 and the basal gene expression program to ATDC and to aggressive tumor behavior. Defining ATDC as a molecular determinant of aggressive, basal cancers may lead to improved biomarkers and therapeutic approaches.

Photodynamic therapy (PDT) has seen long standing interest as a therapy for resistant cancers, but the main Achilles' heel for its successful clinical exploitation is the use of poorly penetrating visible light. This limitation could be overcome by using radioluminescent nanoparticles, which can be excited during radiation therapy (RT) with penetrating X-rays. When infused in tumors, X-ray activated-nanoscintillators act as internal light sources and excite nearby photosensitizers. Recent studies demonstrated that it is realistic to achieve low dose PDT with current nanoscintillators. However, as the origin of enhanced RT efficacy with nanoscintillators may have varying origins, we aimed to answer the basic question: Is a combination of low-dose PDT beneficial to the RT efficacy in clinically relevant models of cancer? Pancreatic cancer (PanCa) remains a lethal disease for which RT is part of the palliative care and for which PDT demonstrated promising results in clinical trial. We thus evaluated the combination of low-dose PDT and RT delivered in absence of nanoscintillators on various heterocellular spheroid models that recapitulate the clinical heterogeneity of PanCa. Although therapeutic effects emerged at different timepoints in each model, the RT/PDT combination uniformly achieved favorable outcomes. With RT providing stunted tumor growth while PDT drove adjuvant apoptotic and necrotic cell death, the combination produced significantly smaller and less viable PanCa spheroids. In conclusion, the beneficial RT/PDT treatment outcomes encourage the further development of nanoscinitillators for X-ray-activated PDT. Assessment of such combination treatments should encompass multiparametric and temporally-spaced assessment of treatment effects in preclinical cancer models.

PURPOSE/OBJECTIVE:An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. METHODS:ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members' curated files. PROVISIONAL CLINICAL OPINION/UNASSIGNED:All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

The tumor microenvironment plays a vital role in therapeutic resistance in pancreatic adenocarcinoma. We have created a 3D model to study the tumor microenvironment ex vivo that integrates tumor cells with tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs). The microtumor model recreates the complex histology of a primary tumor and can be analyzed histologically or with viability assays for therapeutic testing. Microtumors demonstrate increased resistance to gemcitabine when compared to tumor cells alone in a 3D spheroid, highlighting the contribution of TAMs and CAFs when designing models for therapeutic testing.

Purpose: To evaluate safety and preliminary efficacy of metronomic 5-fluorouracil plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin (FABLOx) in patients with newly diagnosed metastatic pancreatic cancer (MPC). Methods: A total of 12 treatment-naive patients (aged 18-65 years, Eastern Cooperative Oncology Group performance status [ECOG PS] ≤1) with MPC received 5-fluorouracil 180 mg/m² per day (days 1-14 continuous infusion); nab-paclitaxel 75 mg/m², leucovorin 20 mg/m², and oxaliplatin 40 mg/m² (days 1, 8, and 15); and bevacizumab 5 mg/kg (days 1 and 15) administered intravenously in each 28-day cycle. The primary end-point was incidence of dose-limiting toxicities (DLTs) in cycle 1. Safety was further evaluated as a secondary end-point; preliminary efficacy was also examined. Results: Two DLTs (grade 3 anemia requiring transfusion and grade 3 mucositis unresponsive to treatment within 4 days of onset) were observed in one of six patients enrolled in dose cohort 1. Cohort 1 was expanded from 6 to 12 patients to further evaluate safety, per the investigators' recommendation. All patients discontinued treatment. The most common grade ≥3 adverse events were abdominal pain, fatigue, mucositis, and decreased neutrophil count. Objective response rate was 33% (four partial responses). Median progression-free survival (PFS) and overall survival (OS) were 5.6 (95% confidence interval [CI], 1.7-11.3) and 9.9 (95% CI, 4.4-13.2) months, respectively; 1-year PFS and OS rates were 12.2% (95% CI, 0.7-40.8) and 38.9% (95% CI, 12.6-65.0). Conclusion: FABLOx is feasible and tolerable in patients newly diagnosed with MPC. However, preliminary efficacy data are inconclusive for continued investigation in a phase II trial.

The ineffectiveness of chemotherapy in patients with pancreatic cancer highlights a critical unmet need in pancreatic cancer therapy. Two commonly mutated genes in pancreatic cancer, KRAS and CDKN2A, have an incidence exceeding 90%, supporting investigation of dual targeting of MEK and CDK4/6 as a potential therapeutic strategy for this patient population. An in vitro proliferation synergy screen was conducted to evaluate response of a panel of high passage and patient-derived pancreatic cancer models to the combination of trametinib and palbociclib to inhibit MEK and CDK4/6, respectively. Two adenosquamous carcinoma models, L3.6pl and UM59, stood out for their high synergy response. In vivo studies confirmed that this combination treatment approach was highly effective in subcutaneously implanted L3.6pl and UM59 tumor-bearing animals. Both models were refractory to single agent treatment. Reverse phase protein array analysis of L3.6pl tumors excised from treated animals revealed strong down regulation of cyclooxygenase-2 (COX-2) expression in response to combination treatment. Expression of COX-2 under a CMV-driven promoter and shRNA knockdown of COX-2 both led to resistance to combination treatment. Our findings suggest that COX-2 may be involved in the improved therapeutic outcome seen in some pancreatic tumors that fail to respond to MEK or CDK4/6 inhibitors alone but respond favorably to their combination.

PURPOSE:The treatment of cancer is complex, which can overwhelm patients and lead to poor comprehension and recall of the specifics of the cancer stage, prognosis, and treatment plan. We hypothesized that an oncologist can feasibly record and deliver a custom video summary of the consultation that covers the diagnosis, recommended testing, treatment plan, and follow-up in < 5 minutes. The video summary allows the patient to review and share the most important part of a cancer consultation with family and caregivers. METHODS:At the conclusion of the office visit, oncologists recorded the most important points of the consultation, including the diagnosis and management plan as a short video summary. Patients were then e-mailed a link to a secure Website to view and share the video. Patients and invited guests were asked to respond to an optional survey of 15 multiple-choice and four open-ended questions after viewing the video online. RESULTS:Three physicians recorded and sent 58 video visit summaries to patients seen in multidisciplinary GI cancer clinics. Forty-one patients logged into the secure site, and 38 viewed their video. Fourteen patients shared their video and invited a total of 46 visitors, of whom 36 viewed the videos. Twenty-six patients completed the survey, with an average overall video satisfaction score of 9 on a scale of 1 to 10, with 10 being most positive. CONCLUSION:Video visit summaries provide a personalized education tool that patients and caregivers find highly useful while navigating complex cancer care. We are exploring the incorporation of video visit summaries into the electronic medical record to enhance patient and caregiver understanding of their specific disease and treatment.