A step towards personalizing next line therapy for resected pancreatic and related cancer patients: A single institution's experience.

BACKGROUND: There is a lack of precision medicine in pancreatic ductal adenocarcinoma (PDA) and related cancers, and outcomes for patients with this diagnosis remain poor despite decades of research investigating this disease. Therefore, it is necessary to explore novel therapeutic options for these patients who may benefit from personalized therapies. OBJECTIVE: Molecular profiling of hepatopancreaticobiliary malignancies at our institution, including but not limited to PDA, was initiated to assess the feasibility of incorporating molecular profiling results into patient oncological therapy planning. METHODS: All eligible patients from Thomas Jefferson University (TJU) with hepatopancreaticobiliary tumors including PDA, who agreed to molecular testing profiling, were prospectively enrolled in a registry study from December 2014 to September 2017 and their tumor samples were tested to identify molecular markers that can be used to guide therapy options in the future. Next generation sequencing (NGS) and protein expression in tumor samples were tested at CLIA-certified laboratories. Prospective clinicopathologic data were extracted from medical records and compiled in a de-identified fashion. RESULTS: Seventy eight (78) patients were enrolled in the study, which included 65/78 patients with PDA (local and metastatic) and out of that subset, 52/65 patients had surgically resected PDA. Therapy recommendations were generated based on molecular and clinicopathologic data for all enrolled patients. NGS uncovered actionable alterations in 25/52 surgically resected PDAs (48%) which could be used to guide therapy options in the future. High expression of three proteins, TS (p = 0.005), ERCC1 (p = 0.001), and PD-1 (p = 0.04), was associated with reduced recurrence-free survival (RFS), while TP53 mutations were correlated with longer RFS (p = 0.01). CONCLUSIONS: The goal of this study was to implement a stepwise strategy to identify and profile resected PDAs at our institution. Consistent with previous studies, approximately half of patients with resected PDA harbor actionable mutations with possible targeted therapeutic implications. Ongoing studies will determine the clinical value of identifying these mutations in patients with resected PDA.

Clinical Implications of Extensive Lymph Node Metastases for Resected Pancreatic Cancer.

BACKGROUND: Outcomes of patients with resected pancreatic ductal adenocarcinoma (PDA) and extensive lymph node metastases have not been fully characterized. METHODS: A total of 637 patients underwent resection for pancreatic ductal adenocarcinoma (PDA) between 2002 and 2014 at the Thomas Jefferson University. Positive lymph node count (LNC) and positive lymph node ratio (LNR) were analyzed as predictors of cancer-specific outcomes, with a focus on outcomes of patients with extensive lymph node burden. RESULTS: Resected patients with regional lymph node metastases had a median survival of 17.1 months (n = 425, 70%) compared with 25.5 months (n = 185, 30%) for patients without lymph node spread (N0) (hazard ratio [HR] = 1.9, p < 0.001). Overall survival decremented with increased lymph node spread, but plateaued for LNC ≥ 4 (HR 2.4 vs. N0, p < 0.001) and LNR ≥ 0.4 (HR 2.2, p < 0.001). Compared with historical cohorts with macroscopic metastatic disease, as opposed to microscopic, superior long-term survival was achieved in patients with extensive lymph node metastases (LNC ≥ 4); 24- and 36-month survivals were 25% (vs. 16%, p < 0.001) and 12% (vs. 6%, p < 0.001), respectively. Extensive lymph node burden was associated with increased baseline postoperative serum CA 19-9 (p = 0.044) and systemic recurrence (p < 0.001). CONCLUSIONS: The prognostic impact of extensive lymph node spread after resection for PDA plateaus above a specific threshold (LNC ≥ 4 or LNR ≥ 0.4), supporting the new 8th edition AJCC criteria for N2 disease. Clinically, lymph node spread above this threshold seems to correlate with occult systemic disease (elevated postoperative CA 19-9 and systemic pattern of failure).

Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype.

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States, whereas colorectal cancer is the third most common cancer. The RNA-binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) and colorectal cancer (HCT116) cell lines. HuR deficiency has a mild phenotype, in vitro, as HuR-deficient MIA PaCa-2 (MIA.HuR-KO(-/-)) cells had increased apoptosis when compared with isogenic wild-type (MIA.HuR-WT(+/+)) cells. Using this isogenic system, mRNAs were identified that specifically bound to HuR and were required for transforming a two-dimensional culture into three dimensional (i.e., organoids). Importantly, HuR-deficient MIA PaCa-2 and Hs 766T cells were unable to engraft tumors in vivo compared with control HuR-proficient cells, demonstrating a unique xenograft lethal phenotype. Although not as a dramatic phenotype, CRISPR knockout HuR HCT116 colon cancer cells (HCT.HuR-KO(-/-)) showed significantly reduced in vivo tumor growth compared with controls (HCT.HuR-WT(+/+)). Finally, HuR deletion affects KRAS activity and controls a subset of pro-oncogenic genes.Implications: The work reported here supports the notion that targeting HuR is a promising therapeutic strategy to treat GI malignancies. Mol Cancer Res; 15(6); 696-707. ©2017 AACR.