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PurposeUsing a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; MethodsWe analyzed matched whole-transcriptome and DNA sequencing data from 2430 patient samples (YOPC, n=292; AOPC, n=2138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data was obtained from insurance claims (n=4928); Kaplan-Meier estimates were calculated for age-and molecularly-defined cohorts. Significance was determined as FDR-correctedP-values (Q)ResultsYOPC patients had higher proportions of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H),BRCA2-mutant, andPALB2-mutant tumors compared with AOPC patients, but fewerSMAD4-, RNF43-, CDKN2A-, andSF3B1-mutant tumors. Notably, YOPC patients demonstrated significantly lower incidence ofKRASmutations compared with AOPC patients (81.3% vs. 90.9%;Q=0.004). In theKRAS-wildtype subset (n=227), YOPC tumors demonstrated fewerTP53mutations and were more likely driven byNRG1andMETfusions, whileBRAFfusions were exclusively observed in AOPC patients. Immune deconvolution revealed significant enrichment of natural killer (NK) cells, CD8+T cells, monocytes, and M2 macrophages in YOPC patients relative to AOPC patients, which corresponded with lower rates ofHLA-DPA1homozygosity. There was an association with improved OS in YOPC patients compared with AOPC patients withKRAS-wildtype tumors (median 16.2 [YOPC-KRASWT] vs. 10.6 [AOPC-KRASWT] months;P=0.008) but notKRAS-mutant tumors (P=0.084).ConclusionIn this large, real-world multi-omic characterization of age-stratified molecular differences in PDAC, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

BackgroundPartial/complete pathologic response following neoadjuvant chemotherapy (NAC) in pancreatic cancer (PDAC) patients undergoing pancreatectomy is associated with improved survival. We sought to determine whether neutrophil-to-lymphocyte ratio (NLR) dynamics predict pathologic response following chemotherapy in PDAC, and if manipulating NLR impacts chemosensitivity in preclinical models and uncovers potential mechanistic underpinnings underlying these effects.MethodsPathologic response in PDAC patients (n=94) undergoing NAC and pancreatectomy (7/2015-12/2019) was dichotomized as partial/complete or poor/absent (case-cohort design). Bootstrap-validated multivariable models assessed associations between pre-chemotherapy NLR (%neutrophils÷%lymphocytes) or NLR dynamics during chemotherapy (ΔNLR=pre-surgery—pre-chemotherapy NLR) and pathologic response, disease-free survival (DFS), and overall survival (OS). To preclinically model effects of NLR attenuation on chemosensitivity, C57BL/6 mice (n=8-10/arm) were orthotopically injected with KrasG12D/+;Trp53fl/+;PdxCre(KPC)cells and randomized to vehicle, NLR-attenuating anti-Ly6G, gemcitabine/paclitaxel, or gemcitabine/paclitaxel+anti-Ly6G treatments.ResultsIn 94 PDAC patients undergoing NAC (median:4 months), pre-chemotherapy NLR (P+-degranulating CD8+ T-cells (Pin vivo. Neutrophil-derived IL-1β emerged as a novel mediator of stromal inflammation, inducing inflammatory CAF polarization and CAF-tumor cell IL-6/STAT-3 signaling in ex vivo co-cultures.ConclusionsTherapeutic strategies to mitigate neutrophil-CAF-tumor cell IL-1β/IL-6/STAT-3 signaling during NAC may improve pathologic responses and/or survival in PDAC.

Co-occurrent KRAS and TP53 mutations define a majority of patients with pancreatic ductal adenocarcinoma (PDAC) and define its pro-metastatic proclivity. Here, we demonstrate that KRAS-TP53 co-alteration is associated with worse survival compared with either KRAS-alone or TP53-alone altered PDAC in 245 patients with metastatic disease treated at a tertiary referral cancer center, and validate this observation in two independent molecularly annotated datasets. Compared with non-TP53 mutated KRAS-altered tumors, KRAS-TP53 co-alteration engenders disproportionately innate immune-enriched and CD8+ T-cell-excluded immune signatures. Leveraging in silico, in vitro, and in vivo models of human and murine PDAC, we discover a novel intersection between KRAS-TP53 co-altered transcriptomes, TP63-defined squamous trans-differentiation, and myeloid-cell migration into the tumor microenvironment. Comparison of single-cell transcriptomes between KRAS-TP53 co-altered and KRAS-altered/TP53WT tumors revealed cancer cell-autonomous transcriptional programs that orchestrate innate immune trafficking and function. Moreover, we uncover granulocyte-derived inflammasome activation and TNF signaling as putative paracrine mediators of innate immunoregulatory transcriptional programs in KRAS-TP53 co-altered PDAC. Immune subtyping of KRAS-TP53 co-altered PDAC reveals conflation of intratumor heterogeneity with progenitor-like stemness properties. Coalescing these distinct molecular characteristics into a KRAS-TP53 co-altered “immunoregulatory program” predicts chemoresistance in metastatic PDAC patients enrolled in the COMPASS trial, as well as worse overall survival.

Background Irreversible electroporation (IRE) is a local ablation technique utilizing high voltage, low energy direct current to create nanopores in cell membrane which disrupt homeostasis and leads to cell death. Previous reports have suggested IRE may have a role in treating borderline resectable and unresectable Stage 3 pancreatic tumors. Methods Patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) will be enrolled in either a randomized, controlled, multicenter trial (RCT) or a multicenter registry study. Subjects enrolled in the RCT must have no evidence of disease progression after 3 months of modified FOLFIRINOX (mFOLFIRINOX) treatment prior to being randomization to either a control or IRE arm. Post-induction and post-IRE treatment for the control and IRE arms, respectively, will be left to the discretion of the treating physician. The RCT will enroll 528 subjects with 264 per arm and include up to 15 sites. All subjects will be followed for at least 24 months or until death. The registry study will include two cohorts of patients with Stage 3 PDAC, patients who received institutional standard of care (SOC) alone and those treated with IRE in addition to SOC. Both cohorts will be required to have undergone at least 3 months of SOC without progression prior to enrollment. The registry study will enroll 532 patients with 266 patients in each arm. All patients will be followed for at least 24 months or until death. The primary efficacy endpoint for both studies will be overall survival (OS). Co-primary safety endpoints will be 1) time from randomization or enrollment in the registry to death or new onset of Grade 4 adverse event (AE), and (2 high-grade complications defined as any AE or serious AE (SAE) with a CTCAE v5.0 grade of 3 or higher. Secondary endpoints will include progression-free survival, cancer-related pain, quality of life, and procedure-related pain for the IRE arm only. Discussion These studies are intended to provide Level 1 clinical evidence and real-world data demonstrating the clinical utility and safety of the use of IRE in combination with chemotherapy in patients with Stage 3 PDAC. Trial registration Clinicaltrials.gov NCT03899636 and NCT03899649. Registered April 2, 2019. Food and Drug Administration (FDA) Investigational Device Exemption (IDE) trial G180278 approved on May 3, 2019.

Background FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated. Methods We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III–IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method. Results We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III–IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX. Conclusions This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune exclusion, stromal desmoplasia, and resistance to immune checkpoint inhibition (ICI). We have previously demonstrated that reciprocally activated RAS/RAF/MEK/ERK and JAK/STAT3 pathways mediate therapeutic resistance, while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes this resistance in preclinical PDAC models. Given the dramatic decrease in tumor burden observed following MEKi+STAT3i, we investigated its effect on the stromal and immune microenvironment. Methods: Ptf1aCre/+KrasG12D/+Tgfbr2flox/flox (PKT) mice were treated with vehicle, trametinib (MEKi, 3.3 mg/Kg, oral gavage three times weekly), ruxolitinib (STAT3i, 20 mg/Kg, oral gavage three times weekly), αPD-1 antibody (200 µg/mouse, i.p. injection twice weekly), combined MEKi+STAT3i or MEKi+STAT3i with αPD-1 beginning at 4-4.5 weeks of age. Mice were sacrificed after four weeks of treatment and tumors were harvested for single cell RNA sequencing, and high-dimensional immune-profiling by mass cytometry and flow cytometry. Results: Single-cell transcriptomic analysis revealed that combined MEKi+STAT3i not only altered stromal architecture but also reprogramed tumor-resident CAFs from Il6/Cxcl1-expressing inflammatory phenotype towards Ly6a/Cd34-expressing fibroblast phenotype with both mesenchymal and hematopoietic progenitor-like properties. This stromal plasticity was associated with a striking attenuation and reprogramming of F4/80+ macrophages, M2-like macrophages (F4/80+CD206+), and MDSCs (CD11b+F4/80-Ly6G+/Ly6C+), as well as enhanced trafficking of CD4+ and CD8+ T-cells which exhibited a distinct effector and anti-apoptotic transcriptional program. The addition of MEKi+STAT3i to PD-1 blockade overcomes immune checkpoint resistance by significantly augmenting anti-tumor responses and dramatically improving survival in PKT mice, compared with vehicle treatment (median 181 vs. 44 days, p Conclusion: These data uncover a novel paradigm in which combined MEKi+STAT3i reprograms stromal inflammation and immune tolerance to overcome immunotherapy resistance in PDAC. The clinical efficacy of combined MEKi+STAT3i and anti-PD1 treatment provides encouraging signals for its translatability and is currently being pursued in a clinical trial. Citation Format: Vanessa Tonin Garrido, Jashodeep Datta, Xizi Dai, Anna Bianchi, Iago De Castro Silva, Purushottam Lamichhane, Siddharth Mehra, Samara P. Singh, Austin R. Dosch, Oliver Umland, Michael n N. VanSaun, Peter J. Hosein, Nagaraj Nagathihalli, Nipun Merchant. Combined MEK and STAT3 inhibition reprograms the tumor microenvironment to overcome immunotherapy resistance in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4187.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune exclusion, pro-inflammatory polarization of cancer-associated fibroblasts (CAF), and resistance to immune checkpoint inhibition (ICI). We have previously demonstrated that reciprocally activated RAS/MEK/ERK and JAK/STAT3 pathways mediate therapeutic resistance, while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance in preclinical models. We now show that combined MEKi+STAT3i not only alters stromal architecture but also uncovers stromal plasticity by revealing a substantial attenuation of Il6/Cxcl1-expressing secretory and Lrrc15-expressing myofibroblastic CAF phenotypes with a concomitant enrichment of Ly6a/Cd34-expressing CAF phenotypes exhibiting mesenchymal progenitor-like properties via single-cell RNA sequencing in Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox(PKT) mice. This remodeling of CAF heterogeneity is associated with reprogramming of immunosuppressive myeloid populations and enhanced trafficking of CD8+ T-cells which exhibit a distinct effector transcriptional program. These MEKi+STAT3i-mediated repercussions are in part CAF-dependent, since CRISPR/Cas9 genetic silencing of CAF-restricted Mek1/Stat3 mitigates inflammatory CAF polarization and myeloid infiltration in vivo. Addition of MEKi+STAT3i to PD-1 blockade overcomes ICI resistance by significantly augmenting anti-tumor responses and dramatically improving survival in PKT mice compared with anti-PD-1 monotherapy. The addition of MEKi+STAT3i to PD-1 blockade not only augments the recruitment of activated and memory T-cell populations, but also improves their degranulating capacity and functional cytotoxicity compared to PD-1 blockade alone. Importantly, treatment of a patient with chemotherapy-refractory metastatic PDAC with MEKi (Trametinib), STAT3i (Ruxolitinib), and PD-1 inhibitor (Nivolumab) was well-tolerated and yielded clinical benefit. These data uncover a novel paradigm in which combined MEKi+STAT3i reprograms stromal inflammation and immune tolerance to overcome immunotherapy resistance in PDAC.

Introduction The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20–30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Methods Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher’s exact test was used for statistical analysis. Results The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3–4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3–4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3–4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3–4 FrAEs (p = 0.1108). Conclusion The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.

The phase III MPACT trial for metastatic pancreatic cancer (PC) showed improved overall survival (OS), progression free survival (PFS) and response rates (RRs) for first-line nab-paclitaxel (Abraxane) and gemcitabine (the AG combination) compared to gemcitabine monotherapy. The safety and efficacy of the AG combination has not been systematically studied as second-line therapy or beyond for metastatic PC. We conducted an IRB-approved retrospective analysis of all patients diagnosed between September 2010 and August 2014 with advanced refractory PC that received combination treatment with AG at our institution. Demographic and survival data were extracted from the registry. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 and on days 1, 8 and 15 of a 28-day cycle with subsequent dose modifications based on tolerance. Data on 59 patients was available; the median age was 61; 55% were male; 56% received AG as second line therapy and 44% received it as third-line or beyond. Five (10%) patients had a confirmed partial response (PR), 23 (47%) had stable disease (SD) and 21 (43%) had disease progression as their best response. Among the 31 (52%) patients who received prior gemcitabine, 18 (58%) had clinical benefit; 3 had a PR and 15 had SD. The median OS was 3.9 months and the median progression-free survival was 3 months. Toxicity was similar to what was reported in the MPACT trial. This retrospective analysis suggests that AG is active in PC patients previously treated with either fluoropyrimidine-based therapy or gemcitabine-based therapy with manageable toxicities.

Background Describe a single-center real-world experience with comprehensive genomic profiling (CGP) to identify genotype directed therapy (GDT) options for patients with malignancies refractory to standard treatment options. Methods Patients who had CGP by a CLIA-certified laboratory between November 2012 and December 2015 were included. The medical records were analyzed retrospectively after Institutional Review Board (IRB) approval. The treating oncologist made the decision to obtain the assay to provide potential therapeutic options. The objectives of this study were to determine the proportion of patients who benefited from GDT, and to identify barriers to receiving GDT. Results A total of 125 pediatric and adult patients with a histologically confirmed diagnosis of malignancy were included. Among these, 106 samples were from adult patients, and 19 samples were from pediatric patients. The median age was 54 years for adults. The majority had stage IV malignancy (53%) and were pretreated with 2–3 lines of therapy (45%). The median age was 8 years for pediatric patients. The majority had brain tumors (47%) and had received none or 1 line of therapy (58%) when the profiling was requested. A total of 111 (92%) patients had genomic alterations and were candidates for GDT either via on/off-label use or a clinical trial (phase 1 through 3). Fifteen patients (12%) received GDT based on these results including two patients who were referred for genomically matched phase 1 clinical trials. Three patients (2%) derived benefit from their GDT that ranged from 2 to 6 months of stable disease. Conclusions CGP revealed potential treatment options in the majority of patients profiled. However, multiple barriers to therapy were identified, and only a small minority of the patients derived benefit from GDT.

Although adjuvant therapy (AT) is a necessary component of multimodality therapy for pancreatic ductal adenocarcinoma (PDAC), its application can be hindered by post-pancreaticoduodenectomy (PD) complications. The primary aim of this study was to evaluate the impact of post-PD complications on AT utilization and overall survival (OS).Patients undergoing PD without neoadjuvant therapy for stages I-III PDAC at a single institution (2007-2015) were evaluated. Ninety-day postoperative major complications (PMCs) were defined as grade ≥3. Records were linked to the Kentucky Cancer Registry for AT/OS data. Early AT was given8 wk; late 8-16 wk. Initiation16 wk was not considered to be AT. Complication effects on AT timing/utilization and OS were evaluated.Of 93 consecutive patients treated with surgery upfront with AT data, 64 (69%) received AT (41 [44%] early; 23 [25%] late). There were 32 patients (34%) with low-grade complications and 24 (26%) with PMC. With PMC, only six of 24 patients (25%) received early AT and 13 of 24 (54%) received any (early/late) AT versus 35 of 69 (51%) early AT and 51 of 69 (74%) any AT without PMC. PMCs were associated with worse median OS (7.1 versus 24.6 mo, without PMC, P 0.001). Independent predictors of OS included AT (hazard ratio [HR]: 0.48), tumor2 cm (HR: 3.39), node-positivity (HR: 2.16), and PMC (HR: 3.69, all P 0.02).Independent of AT utilization and biologic factors, PMC negatively impacted OS in patients treated with surgery first. These data suggest that strategies to decrease PMC and treatment sequencing alternatives to increase multimodality therapy rates may improve oncologic outcomes for PDAC.

Introduction The dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (13 patients [46%]) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD*9A variant and to confirm the genotype-phenotype correlation. Patients and Methods Between 2011 and 2018, in addition to genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies treated with fluoropyrimidines. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Fisher exact test was used for statistical analysis. Results Heterozygous and homozygous DPYD*9A genotypes were identified in 46 (41%) and 11 (10%) patients, respectively. Among patients with DPYD*9A genotypes (n = 57), men and women represented 30 (53%) and 27 (47%) patients, respectively. Caucasian, African American, and other ethnicities represented 29 (50.9%), 26 (45.6%), and 2 (3.5%) patients, respectively. Grade 3/4 toxicities were experienced in 26 patients with DPYD*9A genotype (3 patients had homozygous status) and in 20 patients with wild type DPYD*9A (P = .4405). In patients who received full-dose fluoropyrimidines (n = 85), Grade 3/4 toxicities were experienced in 22 patients with DPYD*9A genotype (2 patients had homozygous status), and in 17 patients with wild type DPYD (P = .8275). Conclusion In our updated analysis, the prevalence of heterozygous and homozygous DPYD*9A genotypes were 41% and 10%, respectively. The correlation between DPYD*9A genotype and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias.

Background Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response. Methods Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features. Results A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-β levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10. Conclusions Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-β could be a predictive biomarker for response to pembrolizumab.

4145 Background: Despite increased utilization of neoadjuvant therapy for pancreatic cancer (PC), a substantial proportion of patients never receive adjuvant therapy. We examined if total neoadjuvant therapy (TNT) would facilitate delivery of all prescribed (≥6 months) non-surgical therapy (NST: chemotherapy ± radiation) to improve oncologic outcomes. Methods: Patients receiving neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ±radiation followed by pancreatectomy at 7 centers were reviewed. Patients receiving TNT (≥6 months NST pre-resection) were compared to those receiving < 6 months ( < TNT). Primary outcomes were major (complete/near-complete) pathologic response (MPR) and overall survival (OS). Results: Of 504 patients, 105 (21%) were selected for TNT. TNT and < TNT patients had similar performance status and rates of borderline resectable/locally advanced disease (82% vs. 80%). TNT patients were significantly more likely to receive ≥6 months NST (100% vs. 31%; p < 0.001) vs. < TNT. While selection of chemotherapy regimen (FOLFIRINOX or gemcitabine/nab-paclitaxel) did not differ between TNT and < TNT cohorts, TNT patients were more likely to receive neoadjuvant radiation (44% vs. 25%, p < 0.001). Rates of vascular resection, postoperative complications, and mortality were similar between groups. TNT was associated with decreased rates of lymphovascular/perineural invasion (p = 0.002) and nodal positivity (p = 0.001), and increased rates of MPR (41% vs. 23%; p = 0.001) and pathologic complete response (13% vs. 6%; p = 0.02). TNT was associated with improved OS compared with < TNT (median 38 vs. 30 months; p = 0.039). Both MPR (median 38 [MPR] vs. 28 [limited response] months; p = 0.002) and ≥6 months NST (TNT or peri-operative) (median 38 [≥6m] vs. 26 [ < 6m] months; p = 0.001) were associated with improved OS. Addition of radiation was not associated with MPR or OS. Conclusions: The TNT approach allows more patients with localized PC to receive ≥6 months NST and is associated with improved rates of MPR and OS. TNT should be considered for all patients with operable PC when possible.

96 Background: In patients with unresectable liver-confined CRLM, regional chemotherapy via HAI in combination with modern systemic chemotherapy (CT) can achieve hepatic disease control and expand surgical resectability. We describe patient selection and early outcomes following implementation of a HAI program at our tertiary referral academic center. Methods: We analyzed demographics, previous systemic treatment, primary tumor location, molecular profiling, extent of hepatic/extrahepatic disease, perioperative HAI outcomes (toxicity, conversion to resection/ablation, radiographic response), and overall survival (OS) in CRLM patients selected for HAI treatment (01/2018—06/2020) after multidisciplinary review. Results: Of 35 patients with unresectable CRLM (primary: colon, n = 24; rectum, n = 11) selected for HAI, 57% were heavily pre-treated (with at least 2 lines of pre-HAI systemic chemotherapy), 71% had a Fong clinical risk score ≥3, 86% presented with synchronous disease, 80% had bilobar metastasis, and 86% had > 5 tumors. All tumors were microsatellite stable, with 20% harboring KRAS/NRAS mutations and none had class I/II BRAF mutations. HAI was initiated at a median 14 (IQR 3, 64) months after CRLM diagnosis, and administered for a median of 7 (range 2, 16) cycles; 91% of patients (31/34) received concurrent HAI and systemic chemotherapy. Although most (69%) patients experienced some degree of hepatic toxicity during HAI therapy resulting in FUDR dose reduction and steroid administration, biliary sclerosis requiring intervention was observed in only 3 (9%) of patients. The overall perioperative morbidity was 17%, and there were no surgical-related 90-day mortalities following HAI pump placement. Excluding patients who initiated HAI treatment within the last 3 months of the study period (n = 3), 13 of 32 patients (41%) were rendered disease-free in the liver following complete resection and/or ablation in combination with HAI/systemic chemotherapy; in the remaining 19 patients (59%), hepatic progression-free survival was 7.3 months (IQR 4, 12). At a median follow-up of 11.2 months, post-HAI median OS for the overall cohort was 12.3 (IQR 7, 20) months. Patients undergoing complete resection/ablation demonstrated improved survival compared with those with progressive disease (median 20 vs 12 months, respectively). Conclusions: Implementation of a HAI program for multimodality liver-directed management of unresectable CRLM is feasible and is associated with meaningful clinical outcomes unlikely to be achieved with systemic therapy alone in heavily pre-treated patients.

TPS354 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm multicenter study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and Eastern Cooperative Oncology Group performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort A has fully enrolled. Cohort B enrollment continues to a maximum of 47 total evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. NCT03207347 Clinical trial information: NCT03207347. [Table: see text]

Angiogenesis is a multistep process that plays a key role in cancer growth and metastases. It is mediated through multiple vascular endothelial growth factor receptors (VEGFRs) and their ligands. The expression of VEGFR-2 is upregulated in tumor endothelial cells, and it is considered to be the primary receptor driving malignant angiogenesis. Ramucirumab (IMC-1121B, LY3009806) is a fully human monoclonal antibody that directly binds to VEGFR-2 with high affinity and specificity. It is also the most recent addition to our armamentarium of anti-angiogenic drugs approved for the treatment of metastatic colorectal cancer (CRC). The aim of this review is to summarize the pre-clinical and clinical development of ramucirumab and discuss its place in the current treatment paradigm for metastatic CRC.

Background & Aims Microsatellite instability (MSI) in colorectal cancer cells results from deficient mismatch repair (MMR) protein function, either acquired or from germline alterations such as in patients with Lynch syndrome. Universal screening initiatives for Lynch syndrome have been encouraged. However, little is known about the true prevalence of MMR deficiency and MSI in colorectal tumors among individuals from different racial and ethnic subgroups or their clinical effects in these populations. Methods We performed a retrospective analysis of 253 surgically resected, primary colorectal adenocarcinoma specimens identified from the University of Miami tumor registry from 2005 through 2010. We collected clinical data, including overall survival (OS), the proportion of patients alive at specific intervals, from non-Hispanic white, Hispanic, and black patients matched by stage. We performed immunohistochemical staining to detect MMR proteins in all specimens and polymerase chain reaction analysis of 51 tumors to detect MSI. Results We detected MMR deficiency in 28 of 253 cases (11.1%), evenly distributed among blacks (9.6%), non-Hispanic whites (10.4%), and Hispanics (12.6%) ( P = .79). Combined deficiencies in MLH1 and PMS2 were found in 23 of 28 MMR-deficient samples (82.1%); MSH2 and MSH6 were most frequently absent in tumor samples from Hispanics ( P = .03). Eleven of 51 tumor samples (21.6%) had high levels of MSI, and we observed a high level of concordance between MMR and MSI (κ = .81). OS was significantly better in patients whose tumors had deficient MMR (hazard ratio for patients with MMR-deficient tumors vs MMR proteins intact = 0.37; 95% confidence interval, 0.15–0.91; P = .03). Race and ethnicity were not significant predictors of OS. Conclusions MMR deficiency in colorectal tumors occurs with similar rates among patients of different racial and ethnic groups, which is based on immunohistochemical analysis of 253 primary tumor specimens. This finding indicates the potential value of universal testing of colorectal cancer by immunohistochemistry in minority populations and confirms the benefit of MMR deficiency to OS.

Background Long-term results of the ESPAC-3 trial suggest that while completing adjuvant therapy (AT) is necessary after resection of pancreatic ductal adenocarcinoma (PDAC), early initiation (within 8 weeks) may not be associated with improved overall survival (OS). The primary aim of this study was to evaluate the OS impact of early versus late AT in a statewide analysis. Methods Patients with stages I–III PDAC in the Kentucky Cancer Registry (KCR) from 2004 to 2013, were evaluated. Those undergoing pancreatectomy were stratified into two groups (“early,”

BackgroundMixed hepatocellular and cholangiocarcinoma (HCC-CC) have been associated with a poor prognosis after liver transplantation (LT). We aimed to evaluate long-term outcomes in patients undergoing LT for HCC-CC versus patients with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC).MethodsRetrospective analysis of the United Network for Organ Sharing (UNOS) database from 1994–2013. Overall survival (OS) in patients with HCC-CC, HCC, and CC, were compared.ResultsWe identified 4049 patients transplanted for primary malignancy (94 HCC-CC; 3515 HCC; 440 CC). Mean age of patients with HCC-CC was 57 ± 10 years, and 77% were male. MELD score did not differ among the groups (p = 0.637). Hepatitis C virus was the most common secondary diagnosis within the HCC-CC (44%) and HCC (36%) cohorts, with primary sclerosing cholangitis in the CC (16%) cohort. OS rates at 1, 3 and 5 years for HCC-CC (82%, 47%, 40%) were similar to CC (79%, 58%, 47%), but significantly worse than HCC (86%, 72%, and 62% p = 0.002).DiscussionPatients undergoing LT for HCC had significantly better survival compared to those transplanted for HCC-CC and CC. LT for mixed HCC-CC confers a survival rate similar to selected patients with CC. Efforts should be made to identify HCC-CC patients preoperatively.

754 Background: Immune checkpoint inhibitors (ICI’s) have not shown meaningful clinical activity in unselected pts with PDAC. BRCA-deficient tumors have increased genomic instability, including increased tumor mutation burden (TMB), more tumor-infiltrating immune cells, and enrichment of a T cell-inflamed signature. We hypothesized that pts with mutations in BRCA or other homologous recombination repair genes may be sensitive to ICI’s. Methods: Utilizing the IRB-approved PDAC database at the University of Miami, we identified pts with relapsed/refractory PDAC with pathogenic germline mutations who were treated with combination ICI’s (ipi 1mg/kg and nivo 3mg/kg every 21 days followed by nivo 240mg every 2 weeks). Results: Five pts were identified (1 BRCA1, 2 BRCA2, 1 RAD51C and 1 RAD51D). Among the 3 evaluable pts, there was one complete response (CR), one partial response (PR) and one had progressive disease (PD). The pt with a CR had BRCA1; he had resection followed by adjuvant gem/cape and had a biopsy-proven recurrence in the lung and retroperitoneum 1y after the end of adjuvant therapy. He received ipi/nivo at recurrence and achieved a CR, ongoing for 17m on nivo maintenance. The patient with a PR had RAD51C; he was diagnosed with mPDAC and received FOLFIRINOX for 6m, followed by olaparib on a trial for 12m. Upon PD, the disease quickly progressed on 5FU/liposomal irinotecan, gemcitabine/nab-paclitaxel/cisplatin and FOLFIRINOX. He then started ipi/nivo with immediate improvement in pain and tumor markers. A radiological PR was seen after 2 doses and is ongoing for 3m with continued clinical and tumor marker improvement. The 3rd evaluable pt had BRCA2 and had PD with an exponential rise in tumor markers accompanied by clinical deterioration. Response data on the final two pts were pending at the time of submission and will be presented at the meeting. Conclusions: In this biomarker selected cohort, 2 out of 3 evaluable pts with PDAC had impressive responses to ipi/nivo. PDAC has generally been refractory to ICI therapy but this series suggests that this subgroup may be responsive to ICI’s. Further evaluation is warranted.

731 Background: Chemotherapy is the standard of care for patients with mPDAC but there are no biomarkers to aid in treatment selection. Nal-IRI with 5-fluorouracil/folinic acid (FUFA) improves survival over FUFA in the second-line treatment of mPDAC. Nal-IRI is a topoisomerase inhibitor and its action produces DNA damage leading to cell death. We hypothesize that tumors with dDDR, a process that is altered in a subset of patients with PDAC, may be more sensitive to the effects of nal-IRI. Methods: Utilizing the IRB-approved pancreas cancer databases at the University of Miami and Wake Forest University, we identified patients with mPDAC treated with nal-IRI and FUFA who had germline and/or somatic mutation testing. We conducted a retrospective chart review to extract demographic and clinical characteristics including treatments received, response, and survival. Results: Among 31 patients identified, the median age was 66y and 47% were female. Nine patients had a DDR mutation; 6 germline and 3 somatic. Median progression-free survival (PFS) in patients with any germline or somatic DDR mutation was 3.2m vs 3.9m for those without (log-rank p = 0.7). When restricted to germline DDR mutations only, the median PFS was not reached with germline dDDR vs 4m for those without (log-rank p = 0.22). Presence of dDDR was associated with a higher clinical benefit rate (CBR = partial response + stable disease); a DDR mutation was present in 36% of patients who showed clinical benefit vs 15% in those without clinical benefit (p = 0.21). Conclusions: DDR mutations appear to define a subset of patients with mPDAC who may be more sensitive to nal-IRI and FUFA. The PFS and CBR were numerically but not statistically superior, especially in patients with germline DDR mutations. Larger data sets and longer follow-up are needed to confirm this trend.

Pancreatic cancer is projected to become the second leading cause of cancer death in the United States by 2030. Deleterious germline mutations can contribute to pancreatic cancer susceptibility. Herein we report a case of a patient with metastatic pancreatic adenocarcinoma to the lung and liver who was found to have a deleterious germline mutation in RAD51C who had a remarkable response to chemotherapy with FOLFIRINOX, a platinum-containing regimen.

Background/aim Combination nab-paclitaxel/gemcitabine (AG) is superior to gemcitabine in patients with metastatic pancreatic cancer (PC). There are limited data for AG in borderline resectable (BR) or locally advanced pancreatic cancer (LAPC). Herein, we report our experience with neoadjuvant AG for BR/LAPC in patients ineligible for FOLFIRINOX. Patients and methods This retrospective series, included patients with BR/LAPC who received AG as neoadjuvant therapy for 3-4 months followed by radiation, then re-evaluation for surgery. Results Between 10/2013-2/2018, 32 patients (22 BR, 10 LAPC) were treated with this approach. Median age was 70 years. Nine patients were converted to resectability by imaging; six had R0 resections (19%), five (16%) achieved a partial response and 24 (75%) had stable disease. Conclusion In this small series, the R0 resection rate and response rate were 19% and 16% respectively. These data suggest that neoadjuvant AG may be an alternate option for patients ineligible for FOLFIRINOX.

The phase III MPACT trial for metastatic pancreatic cancer (PC) showed improved overall survival (OS), progression free survival (PFS) and response rates (RRs) for first-line nab-paclitaxel (Abraxane) and gemcitabine (the AG combination) compared to gemcitabine monotherapy. The safety and efficacy of the AG combination has not been systematically studied as second-line therapy or beyond for metastatic PC. We conducted an IRB-approved retrospective analysis of all patients diagnosed between September 2010 and August 2014 with advanced refractory PC that received combination treatment with AG at our institution. Demographic and survival data were extracted from the registry. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 and on days 1, 8 and 15 of a 28-day cycle with subsequent dose modifications based on tolerance. Data on 59 patients was available; the median age was 61; 55% were male; 56% received AG as second line therapy and 44% received it as third-line or beyond. Five (10%) patients had a confirmed partial response (PR), 23 (47%) had stable disease (SD) and 21 (43%) had disease progression as their best response. Among the 31 (52%) patients who received prior gemcitabine, 18 (58%) had clinical benefit; 3 had a PR and 15 had SD. The median OS was 3.9 months and the median progression-free survival was 3 months. Toxicity was similar to what was reported in the MPACT trial. This retrospective analysis suggests that AG is active in PC patients previously treated with either fluoropyrimidine-based therapy or gemcitabine-based therapy with manageable toxicities.

Lynn G Feun,¹ Medhi Wangpaichitr,² Ying-Ying Li,¹ Deukwoo Kwon,³ Stephen P Richman,¹ Peter J Hosein,¹ Niramol Savaraj¹,² ¹Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, ²Department of Surgery, Miami VA Healthcare System, Research Service, ³Biostatistics and Bioinformatics Core, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA Background: A phase II trial of pasireotide was performed to assess its efficacy and safety in advanced or metastatic hepatocellular carcinoma (HCC).Patients and methods: Patients with advanced HCC and Child–Pugh score ≤7 received pasireotide LAR 60 mg intramuscularly every 28 days. Primary endpoint was disease control rate. Secondary endpoints were time to tumor progression, response rate, treatment-related adverse events, and overall survival. Serum insulin growth factor-1 was measured before and after pasireotide.Results: Twenty patients were treated and evaluable. Eighteen patients (90%) had prior therapy; 16 patients (80%) had multiple therapies. Median age was 65, 75% had Barcelona Clinic Liver Cancer stage C, and 55% had metastatic disease. The main toxicity was hyperglycemia. Rare adverse effects included reversible grade 4 elevation in alanina transaminase/aspartate transaminase in one patient. The best response was stable disease in 9 patients (45%). Median time to tumor progression for the 20 patients was 3 months, and median survival was 9 months.Conclusion: Pasireotide had limited clinical benefit as second-line or third-line treatment in patients with advanced or metastatic HCC. Low baseline insulin growth factor-1 level may be indicative when SOM230 treatment may be ineffective, and decreasing levels after treatment may be indicative of disease control. Keywords: pasireotide, hepatocellular carcinoma, insulin growth factor-1&nbsp

Background The efficacy of FOLFIRINOX for metastatic pancreatic cancer has led to its use in patients with earlier stages of disease. This study retrospectively analyzed a cohort of patients with locally-advanced pancreatic cancer (LAPC) treated with FOLFIRINOX. Methods Between 2008 and 2013, 51 treatment-naive patients with LAPC at a single institution received first-line FOLFIRINOX with neoadjuvant intent, at the full dose as described in the PRODIGE 4/ACCORD 11 study. Combined chemoradiation was administered for those who remained unresectable after maximum response to chemotherapy. The primary outcome measure was overall survival (OS), and secondary outcomes were progression-free survival (PFS) and margin-negative (R0) resection rate, and toxicity profile. Results A total of 429 cycles of FOLFIRINOX were given with a median of 8 cycles (range 2–29) per patient; 66% of cycles were full dose. After chemotherapy, 27 (53%) received chemoradiation. The median OS was 35.4 months (95% CI 25.8–45). Ten (4 borderline resectable and 6 unresectable) patients had successful R0 resections; those who had R0 resections had a significantly longer survival than those who did not (3-year OS rate 67% versus 21%, log rank p = 0.042). Increasing number of full-dose cycles was significantly associated with increased survival. The toxicity profile was similar to previous reports of this regimen. Conclusions FOLFIRINOX is feasible as neoadjuvant therapy for LAPC. Although the R0 resection rate was only 20%, the median OS of almost 3 years appears promising. Dose intensity and duration were associated with increased survival in this study, arguing against dose attenuated versions of this regimen.

A phase II trial of R-MACLO-IVAM followed by thalidomide maintenance for mantle cell lymphoma (MCL) demonstrated promising progression-free survival (PFS) and overall survival (OS) rates. Thalidomide maintenance was associated with significant toxicity and was subsequently modified to rituximab maintenance. Herein, we present updated results and follow-up. Two sequential phase II trials included chemotherapy-naive patients with MCL up to 75 years old. Four cycles of R-MACLO-IVAM chemotherapy were delivered as previously described. Patients who achieved complete responses (CR) were eligible for thalidomide or rituximab maintenance therapy. Among 36 patients enrolled, the MCL International Prognostic Index (MIPI) was low in 53%, intermediate in 36% and high in 11%. Thirty-five patients completed at least 2 cycles of chemotherapy; 34 (94%) achieved a CR. After a median follow-up of 74.4 months, the 5-year PFS was 51% (95% CI 33–68%) and the 5-year OS was 85% (95% CI 73–97%). Two deaths occurred during the chemotherapy phase due to disease progression and neutropenic sepsis, respectively. One patient developed secondary acute myeloid leukemia after 7 years. R-MACLO-IVAM chemotherapy is effective for patients with newly diagnosed MCL. Am. J. Hematol. 90:E111–E116, 2015. © 2015 Wiley Periodicals, Inc.

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow-up of 4·5 years (range 0·6-20·6 years), the Kaplan-Meier estimated median progression-free survival was 10·4 years (95% confidence interval [CI] 5·8-14·9 years), and the median overall survival was 14·6 years (95% CI 10·2-19 years). Twelve patients (16%) had CNS relapse. A low stage-modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage-modified IPI score is associated with survival.

2617 Background: ICI benefit certain patients (pts) with various malignancies and discovering biomarkers for response is an active research field. Recently, higher TMB (top 20% in each histology) based on nonsynonymous single nucleotide variants from MSK-IMPACT was shown to correlate with superior survival in a pancancer cohort. Fsindels may generate more immunogenic neoantigens and robust T cell infiltrates, thus predicting better responses to ICI. We previously demonstrated the clinical implication of fsindel in lung cancer pts on ICI. However, its value in other solid cancers has not been evaluated. Methods: Comprehensive genomic profiling (CGP) of the tumors was performed by FoundationOne to derive fsindel and TMB as previously described. Pts with advanced solid cancers who received ICI and had CGP available were included. We categorized pts into two groups; 0 fsindel (FS-) and more than 1 fsindel (FS+). Also, they were categorized into TMB high (top 20%) and TMB low (bottom 80%) within their own histology. Progression free survival (PFS) and overall survival (OS) were compared. Results: One hundred thirty-one pts excluding lung cancer were included. There were 11 histology groups: 14 soft tissue sarcomas, 19 GU, 23 GI, 23 skin, 10 HEENT, 10 RCC, 9 GYO, 6 pancreas, 5 mucosal melanoma, 4 breast, and 8 others. 74 pts received pembrolizumab, 25 nivolumab, 29 ipilimumab/nivolumab, and 3 atezolizumab. All pts had metastatic disease, mean age was 61 years and 55 (42%) were women. Among the 131 pts, 74 were FS- and 57 FS+. The presence of fsindel (FS+) was significantly correlated with overall response (p = 0.032) and clinical benefit rates (p = 0.025). TMB-high did not show any significant difference in PFS (p = 0.1) or OS (p = 0.28) when compared to the TMB low. However, in a combined model of TMB and fsindel, TMB high and FS+ patients had significantly better PFS compared to patients who had either TMB high or FS+ or neither (TMB low and FS-) (p = 0.021). Conclusions: Combined model of TMB high and fsindel (+) correlated with superior PFS in advanced solid cancer pts on ICI, in concordance with previous report for lung cancer. Validation in a larger cohort is underway.

e14043 Background: Pembrolizumab (PEM) has been approved as second line therapy for the treatment of hepatocellular carcinoma (HCC). We conducted a single institution investigator-initiated clinical/biomarkers trial to assess potential biomarkers to predict response in unresectable HCC patients (pts) receiving PEM. Methods: PEM was administered at 200mg iv. every 3 weeks for advanced HCC pts who progressed on, were intolerant of, or refused sorafenib. The circulating levels of cytokines/chemokines included IL-1β, IL-6, IL-8, IL-12, IL-18, IFN-γ, TGF-β, IL-10, CXCL9, CCL4, CCL5, as well as PD-1, PD-L1, PD-L2 were measured by ELISA at baselines and at day 60-90. PD-L1 expression in tumor was also assessed by histopathological staining. Results: 29 pts have been treated and 28 were evaluated for response. One pt had complete response, 8 had partial response and 4 had stable disease. Among all the biomarkers tested, only TGF-β at baseline predict response. The mean of plasma TGF-β in responders were 141.9pg/ml vs. 1071.8pg/ml in nonresponders. The cut-off values was determined based on the near medians. The plasma concentration of TGF-β of ≥200pg/ml was an index for nonresponder (P = 0.003). Kaplan-Meier analysis showed that the median overall survival (OS) and progression-free survival (PFS) in pts with TGF-β ≥200pg/ml were 7 months and 2 months, respectively, while in pts with TGF-β < 200 pg/ml, the OS and PFS were over 25 months(P = 0.005 and P = 0.008, respectively). Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1/PD-L-1 (P < 0.05). Since tumor PD-L1 expression is upregulated by IFN-γ, and IL-10, and interacts with PD-1 to suppress T cell, to confirm these relationships, the linear regression was used to analyze the data. Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1 and PD-L1 levels ( P < 0.05). Nine of these 24 patients had tumor available for PD-L1 scoring (PD-L1-positive:3 pts and PD-L1-negative:6pts). Similar to plasma PD-L1 concentration, pts with positive tumor PD-L1 had high levels of plasma IFN-γ or IL-10 ( P < 0.05). Conclusions: Our study confirmed that PEM is active in HCC and TGF-β is a predictive markers for tumor response, PFS, and OS. Support by grant from Merck

545 Background: Fluoropyrimidines are antimetabolites that target the S phase of the cell cycle. The active metabolite, 5-fluorodeoxyuridine monophosphate inhibits thymidylate synthase (TS) enzyme, thus preventing DNA synthesis and ultimately cell death. While controversy exists in the literature, polymorphism in the promoter region of thymidylate synthase gene (TYMS) that decrease TS expression has been associated with increased fluoropyrimidines-associated toxicities. This study explored the association between polymorphism in the promoter region of TYMS gene and fluoropyrimidines-associated toxicities in patients with gastrointestinal malignancies with mixed racial background. Methods: Between 2011 and 2018, 126 patients were genotyped for TYMS. Patients with known high-risk dihydropyrimidine dehydrogenase gene variants were excluded. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institiute Common Terminology Criteria for Adverse Events (v 5.0). Fisher’s exact test was used for statistical analysis. Results: TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 toxicity (22%) while among patients with genotypes that predict decreased TS expression, 30 patients had grade 3-4 toxicities (42%) (P = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3-4 toxicity (P = 0.0039) and 15 out 40 patients (38%) with 2R/3RC and 3RC/3RC TYMS genotype had grade 3-4 toxicity (P = 0.1108). Among patients with 2R/2R TYMS, Caucasians represented 61% and African Americans represented 39%. Females represented 65% of the patients. Conclusions: Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3-4 fluoropyrimidines-associated toxicities.

266 Background: Germline genetic testing and somatic genomic profiling using commercial multigene panels are now routine in mPDAC. A subset of these patients have deleterious alterations in genes involved with DDR. Herein we investigate the role of daDDR as a predictive biomarker for response to first-line platinum-based chemotherapy. Methods: Utilizing the IRB-approved pancreas cancer and genetics clinic databases at the University of Miami, we identified all patients with mPDAC who had germline and/or somatic mutation testing. We performed a retrospective chart review to extract demographic and clinical characteristics including treatments received, response and survival. Results: Between 2012 and 2018, 116 patients with mPDAC underwent germline (using Invitae, Ambry Counsyl or Myriad) and/or somatic testing (using FoundationOne CDx). Among these, 40 received first-line therapy with FOLFIRINOX (95%) or gemcitabine/cisplatin (5%). The median age was 59 years and 15 (38%) were female. The majority (70%) were Hispanic and 63% had de-novo mPDAC (treatment-naïve). Germline testing revealed daDDR in 5 patients and somatic NGS found an additional 4 patients with daDDR (total of 9 (23%), including 5 with BRCA2, one each with BRCA1, RAD51C, ATM and MUTYH). The median progression-free survival (PFS) was significantly longer in patients with daDDR than without (17.3 vs 7.8 months, log-rank p = 0.01). The median overall survival (OS) was not statistically different between the two groups. Three patients with daDDR had complete or near-complete radiological and tumor marker responses to FOLFIRINOX and were treated with olaparib (a PARP inhibitor) as maintenance and remain progression-free after 7, 12.4 and 13.6 months respectively. Conclusions: daDDR appears to define a subset of patients with mPDAC who may be more sensitive to platinum agents. There are currently no biomarkers for selection of first-line therapy in patients with mPDAC and we demonstrate that this composite biomarker which is easily done via commercially available assays may be able to inform treatment selection.

544 Background: The correlation between DPYD*9A (c.85T > C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In our cohort of 28 patients with gastrointestinal malignancies (GI) treated with fluoropyrimidines, DPYD*9A was the most commonly diagnosed variant (46%) and there was a noticeable genotype-phenotype correlation (Khushman et al). In this updated analysis, a larger cohort of a mixed racial background was genotyped for DPYD*9A variant to confirm the incidence and genotype-phenotype correlation. Methods: Between 2011 and 2018, in addition to genotyping for high risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (v 5.0). Results: DPYD variants were identified in 61 patients. DPYD*2A was identified in 3 patients and DPYD*9B was identified in 2 patients (one patient had double heterozygous *9A and *9B). Heterozygous DPYD*9A was identified in 46 patients (41%) and homozygous DPYD*9A was identified in 11 patients (10%). Among patients with DPYD*9A variant, Caucasians represented 51% and African Americans represented 46%. 27 patients (47%) were females. Grade 3-4 toxicities were experienced in 26 patients with mutant DPYD*9A (3 patients had homozygous DPYD*9A) and in 20 patients with no identified DPYD mutation (P = 0.7035). In patients who received full dose fluoropyrimidines (N = 85), grade 3-4 toxicities were experienced in 22 patients with mutant DPYD*9A (2 patients had homozygous DPYD*9A) and in 17 patients with no identified DPYD mutation (P = 0.8275). Conclusions: In our updated analysis, DPYD*9A variant was the most commonly diagnosed variant. The correlation between DPYD*9A variant and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely due to small sample size and patients’ selection and testing bias.

nab-Paclitaxel has been shown to disrupt pancreatic cancer stroma and was effective in combination with gemcitabine in a phase I/II trial. This study was designed to determine the efficacy of nab-paclitaxel monotherapy in previously treated pancreatic cancer patients.In this phase II trial, patients with advanced pancreatic cancer who progressed on gemcitabine-based therapy, received nab-paclitaxel 100 mg/m over 30 minutes on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was 6-month overall survival (OS). Secondary endpoints were response rate (by Response Evaluation Criteria In Solid Tumors), progression-free survival, safety, and toxicity profile.Among 19 patients treated, the median age was 61 years, 9 (47%) were male patients and 18 (95%) had stage-IV disease. The primary endpoint of the study was reached with a 6-month OS of 58% [95% confidence interval (95% CI), 33%-76%] and an estimated median OS of 7.3 months (95% CI, 2.8-15.8 mo). The median progression-free survival was 1.7 months (95% CI, 1.5-3.5 mo). One patient had a confirmed partial response and 6 (32%) had stable disease as their best response. Nonhematological toxicities were generally mild with grades 1-2 nausea, anorexia, hypocalcemia, and vomiting occurring in 63%, 47%, 37%, and 26% of patients, respectively. Grades 3-4 neutropenia, neutropenic fever, and anemia occurred in 32%, 11%, and 11% of patients, respectively. Only 2 of 15 available tumors stained positive for secreted protein acid rich in cysteine, and neither of these patients benefited from the therapy.nab-Paclitaxel was well tolerated, and it demonstrated preliminary evidence of activity in a subset of patients who progressed on gemcitabine-based therapy.

Purpose Treatment of unresectable locally advanced pancreatic cancer (LAPC) usually includes chemotherapy and/or radiation therapy in an attempt to downstage these tumors to the extent of resectability, but outcomes remain poor. Irreversible electroporation (IRE) is an ablative modality that may be useful in this population. The aim of this study was to evaluate the safety of percutaneous IRE in patients with pancreatic adenocarcinoma. Materials and Methods IRE was performed in patients with pancreatic cancer whose tumors remained unresectable after, or who were intolerant of, standard therapy. The procedures were all done percutaneously under general anesthesia. Patients were then followed for adverse events, tumor response, and survival. Results Fifteen IRE procedures were performed in 14 patients (one was treated twice). Three patients had metastatic disease and 11 had LAPC. All patients had received chemotherapy previously, and 11 had received radiation. The median tumor size was 3.3 cm (range, 2.5–7 cm). Immediate and 24-hour postprocedural scans demonstrated patent vasculature in the treatment zone in all patients. Two patients underwent surgery 4 and 5 months after IRE, respectively. Both had margin-negative resections, and one had a pathologic complete response; both remain disease-free after 11 and 14 months, respectively. Complications included spontaneous pneumothorax during anesthesia (n = 1) and pancreatitis (n = 1), and both patients recovered completely. There were no deaths directly related to the procedure. All three patients with metastatic disease at IRE died from progression of their disease. Conclusions Percutaneous IRE for pancreatic adenocarcinoma is feasible and safe. A prospective trial is being planned.

Purpose To describe safety and effectiveness of percutaneous irreversible electroporation (IRE) for treatment of unresectable, locally advanced pancreatic adenocarcinoma (LAPC). Materials and Methods This retrospective study included 50 patients (23 women, 27 men; age range, 46–91 y; median age, 62.5 y) with biopsy-proven, unresectable LAPC who received percutaneous computed tomography (CT)–guided IRE. The primary objective was to assess the safety profile of the procedure; the secondary objective was to determine overall survival (OS). All patients had prior chemotherapy (1–5 lines, median 2), and 30 (60%) of 50 patients had prior radiation therapy. Follow-up included CT at 1 month and at 3-month intervals thereafter. Results There were no treatment-related deaths and no 30-day mortality. Serious adverse events occurred in 10 (20%) of 50 patients (abdominal pain [n = 7], pancreatitis [n = 1], sepsis [n = 1], gastric leak [n = 1]). Median OS was 27.0 months (95% confidence interval [CI], 22.7–32.5 months) from time of diagnosis and 14.2 months (95% CI, 9.7–16.2 months) from time of IRE. Patients with tumors ≤ 3 cm (n = 24) had significantly longer median OS than patients with tumors > 3 cm (n = 26): 33.8 vs 22.7 months from time of diagnosis ( P = .002) and 16.2 vs 9.9 months from time of IRE ( P = .031). Tumor size was confirmed as the only independent predictor of OS at multivariate analysis. Conclusions Percutaneous image-guided IRE of unresectable LAPC is associated with an acceptable safety profile.

Long-term results of the ESPAC-3 trial suggest that while completing adjuvant therapy (AT) is necessary after resection of pancreatic ductal adenocarcinoma (PDAC), early initiation (within 8 weeks) may not be associated with improved overall survival (OS). The primary aim of this study was to evaluate the OS impact of early versus late AT in a statewide analysis.Patients with stages I-III PDAC in the Kentucky Cancer Registry (KCR) from 2004 to 2013, were evaluated. Those undergoing pancreatectomy were stratified into two groups ("early,"8 weeks, vs. "late," 8-16 weeks).Of 2,221 diagnosed patients with stages I-III, 831 (37.4%) underwent pancreatectomy upfront. Of these, only 420 (50.5%) received AT. Initiation date of AT was not associated with OS (median OS: early, 20.2 vs. late, 19.0 months, P = 0.97). On multivariate analysis, factors that affected OS included stage (II, HR-1.82, P = 0.017; III, HR-3.77, P 0.001), node positivity (HR-1.51, P = 0.004), poorly/undifferentiated grade (HR-1.34; P = 0.011), but not AT initiation date.In this statewide analysis, there was no difference in OS between early and late AT initiation for resected PDAC. The ideal window for AT initiation remains unknown as tumor biology continues to trump regimens from the past decade. J. Surg. Oncol. 2016;114:451-455. © 2016 Wiley Periodicals, Inc.

Summary Background 35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population. Methods We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan–Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model. Findings We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0–16·0) to 32·7 months (23·1–42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7–26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5–34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8–16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3–81·6, I 2 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2–31·9, I 2 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2–92·2, I 2 64%). Interpretation Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months—longer than that reported with gemcitabine (6–13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX. Funding None.

A 66-year-old female developed progressive multifocal leukoencephalopathy (PML) 17 months after treatment with bendamustine and rituximab chemoimmunotherapy. During her evaluation for PML, she was found to have a CD4 count of 176 cells/μL (reference range 492-1740). The patient demonstrated spontaneous recovery of symptoms that occurred in parallel with recovery of the CD4 counts. While PML is associated with rituximab therapy, the timing and patients' clinical course are atypical, raising the possibility of a previously unreported association with bendamustine therapy.