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The human oral microbiome is associated with chronic diseases including cancer. However, our understanding of its relationship with diet is limited. We assessed the associations between carbohydrate and glycemic index (GI) with oral microbiome composition in 834 nondiabetic subjects from the NCI Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the American Cancer Society Cancer Prevention Study II cohorts. The oral microbiome was characterized using 16Sv3-4 rRNA sequencing from oral mouthwash samples. Daily carbohydrate and GI were assessed from food frequency questionnaires. We used linear regression, permutational multivariate ANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, body mass index, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P value) of Significance: Taxonomic differences at the highest intake quintiles may reflect diet-induced increases in carcinogenic bacteria and decreases in protective bacteria. Genus Leptotrichia has been implicated in cancer and inflammatory disease, while immunostimulatory genus Gemella may increase inflammatory disease risk. These differences further our understanding of possible mechanisms leading to oral and systemic disease.

Population flow diagram

Sensitivity analyses, alpha diversity

The human oral microbiome is associated with chronic diseases including cancer. However, our understanding of its relationship with diet is limited. We assessed the associations between carbohydrate and glycemic index (GI) with oral microbiome composition in 834 nondiabetic subjects from the NCI Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the American Cancer Society Cancer Prevention Study II cohorts. The oral microbiome was characterized using 16Sv3-4 rRNA sequencing from oral mouthwash samples. Daily carbohydrate and GI were assessed from food frequency questionnaires. We used linear regression, permutational multivariate ANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, body mass index, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P value) of Ptrend = 0.06 and 0.07). Greater carbohydrate intake was associated with greater abundance of class Fusobacteriia (q = 0.02) and genus Leptotrichia (q = 0.01) and with lesser abundance of an Actinomyces operational taxonomic unit (q = 4.7E-04). Higher GI was significantly related to greater abundance of genus Gemella (q = 0.001). This large, nationwide study provides evidence that diets high in carbohydrates and GI may influence the oral microbiome.Significance:Taxonomic differences at the highest intake quintiles may reflect diet-induced increases in carcinogenic bacteria and decreases in protective bacteria. Genus Leptotrichia has been implicated in cancer and inflammatory disease, while immunostimulatory genus Gemella may increase inflammatory disease risk. These differences further our understanding of possible mechanisms leading to oral and systemic disease.

Supplementary Figures, Legends and Methods

Purpose:Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment.Experimental Design:Harmonic motion imaging (HMI) is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens.Results:In mice, we learned that stiffness increased during progression from preneoplasia to adenocarcinoma and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2–mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients.Conclusions:These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in PDA.

Supplementary Methods

Figure S1

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Purpose: Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment. Experimental Design: Harmonic motion imaging (HMI) is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens. Results: In mice, we learned that stiffness increased during progression from preneoplasia to adenocarcinoma and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2–mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients. Conclusions: These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in PDA.

In preclinical work, the inflammatory cytokine IL-1β was shown to be upregulated in pancreatic cancer tumors and to contribute to activation of pancreatic stellate cells and immunosuppression (Das et al 2020). We conducted an open-label multicenter Phase Ib study evaluating gemcitabine, nab-paclitaxel, canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) mAb, and spartalizumab (PDR001), a PD-1 mAb. Eligible subjects had previously untreated metastatic PDA and RECIST measurable disease. The primary objective was to confirm recommended phase II dose by evaluating the incidence of dose limiting toxicities (DLTs) in the first 56 days of dosing in at least 6 evaluable subjects utilizing a Bayesian logistic regression model. Subjects underwent baseline and on-study tissue and blood collection for correlative translational research. Results: 10 subjects were enrolled between Nov 2020 and Mar 2021. At the primary data cut off of May 23, 2021, 6 subjects were evaluable for DLT. There were no DLTs, the recommended Phase II dose was established as: gemcitabine (1000mg/m2 IV) day 1,8,15; nab-paclitaxel (125mg/m2 IV) day 1,8,15; canakinumab (250mg SC) day 1, spartalizumab (400mg IV) day 1; of each 28 day cycle. At the time of an updated database extraction on June 1, 2022, 2 subjects remain on study. Adverse events were consistent with those typically seen with chemotherapy. The most common Grade 3/4 AEs were neutropenia (60%) and anemia (50%), with no fatal AEs. One patient discontinued spartalizumab due to grade 3 pneumonitis. In preliminary efficacy analysis (n=10), there are 3 confirmed PRs, 5 subjects with stable disease, 2 subjects with progression as best response. Individual site data estimates that the 12 month OS rate is 60%; updated RR, PFS and OS data will be reported. Activation of CD8 T cells in peripheral blood and increased serum levels of IFN-induced chemokines CXCL9/10 were observed in both responder and non-responder patients. Using an in vitro suppression assay, we showed that baseline serum from responders could induce myeloid derived suppressor cells, an effect that was abrogated with treatment. Single cell transcriptional profiling, multiplex immunofluorescence and spatial transcriptomics also revealed treatment-dependent shifts in T cell activation state and myeloid cells in the tumors of patients experiencing clinical response. Conclusions: PanCAN-SR1 established the Phase II dose of canakinumab and spartalizumab with chemotherapy in first line metastatic PDA, based upon favorable benefit-risk assessment. Based on our comprehensive analysis of 10 patients treated with combination therapy including IL-1b blockade, we hypothesize that the definitive role of anti-IL-1b in human patients with pancreatic cancer is to reduce systemic immune suppression and to reduce immunosuppressive myeloid cell activation in the tumor. The clinical utility of targeting IL-1β in pancreatic cancer is being evaluated in a randomized Phase II/III study through the Precision Promise clinical trial network. NCT04581343. Citation Format: Paul E. Oberstein, Osama Rahma, Nina Beri, Amy Stoll-D'Astice, Emily A. Kawaler, Igor Dolgalev, Gregor Werba, Victoire Cardo-Ruffino, Naïma Böllenrücher, Andressa Dias Costa, Saloney Nazeer, Matthew Squires, Jonathan Nowak, Dafna Bar-Sagi, Brian Wolpin, Diane M Simeone, Stephanie K Dougan. Primary results of PanCAN-SR1, a phase 1b study evaluating Gemcitabine, nab-Paclitaxel, Canakinumab, and Spartalizumab to target IL-1β and PD-1 in metastatic pancreatic cancer with correlative tissue and blood biomarker analysis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR005.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression. Improving our understanding of the PDAC TME and its role in response to therapy via in-depth single cell characterization will have broad clinical implications for biomarker development and therapeutic design. In this study, we performed single-cell RNA sequencing on freshly collected human PDAC samples of primary (n=16) or metastatic (n=11) origin, either before (n=20) or after (n=7) chemotherapy. We found a heterogeneous mixture of basal and classical Moffitt cancer cell subtypes in all samples, along with distinct cancer-associated fibroblast (CAF) and tumor-associated macrophage (TAM) subpopulations. We identified the major CAF subpopulations as inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs); within these subpopulations were a very few cells expressing immunogenic features which have previously been associated with antigen presenting CAFs (apCAFs). Tumor-associated macrophages (TAMs) could be categorized into two major subpopulations, C1QC+ TAMs or SPP1+ TAMs, each with distinct functional characteristics. For example, phagocytosis-associated gene sets were enriched in C1QC+ TAMs, while angiogenesis-associated gene sets were enriched in SPP1+ TAMs. Comparison of naïve and chemotherapy treated primary PDAC samples revealed that classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy; this contrasts with some previous reports which posited a shift towards a basal-like transcriptional program among treated samples. We further noted that treated samples evinced fewer ligand-receptor interactions, particularly between TIGIT on CD8+ T cells and its ligand on cancer cells. We also identified TIGIT, not PD1, as the major inhibitory checkpoint molecule of CD8+ T cells in the PDAC TME. Altogether, our results suggest that chemotherapy impacts the PDAC TME and may further reduce response to immunotherapy. Citation Format: Daniel Weissinger, Emily A. Kawaler, Gregor Werba, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul E. Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos, Diane M. Simeone. Single-cell sequencing elucidates the effects of chemotherapy on cancer cell heterogeneity and the tumor microenvironment of human pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR010.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. Patients and Methods: Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1–5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability. Results: A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen. Conclusions: Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.

Despite efforts to enhance enrollment and the merger of national cooperative groups, < 5% of patients with cancer will enroll into a clinical trial. Additionally, clinical trials are affected by a lack of diversity inclusive of minority patients, rural residents, or low-income individuals. COVID-19 further exacerbated known barriers of reduced physician-patient interaction, physician availability, trial activation and enrollment, financial resources, and capacity for conducting research. Based on the cumulative insight of academic and community clinical researchers, we have created a white paper identifying existing challenges in clinical trial conduct and have provided specific recommendations of sustainable modifications to improve efficiency in the activation and conduct of clinical trials with an overarching goal of providing improved access and care to our patients with cancer.

Background Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients. Methods We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation. Results Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing. Conclusion PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and is notoriously refractory to multiple cancer treatments. In recent years, cancer therapy has expanded beyond traditional cytotoxic chemotherapy to targeted agents and immunotherapy which have been successfully implemented in many cancers. Despite robust pre-clinical research, these novel therapies have only had a small impact on PDAC. However, there have been successes with emerging clinical data supporting a potential role for checkpoint inhibitor therapy and targeted therapy with poly (ADP-ribose) polymerase inhibitors for select subsets of PDAC patients. In this clinical review, we discuss recent pre-clinical evidence for targeting metabolic pathways as well as prevalent intratumoral immune subsets, and focus on clinical trials designed to test novel agents in PDAC. The challenge of translating pre-clinical findings to patients remains substantial and many clinical trials yield negative results, but collaborative efforts and renewed focus on novel clinical trials have led to optimism that we will identify additional options for PDAC patients and change outcomes for this deadly disease.

Although degree of T-cell infiltration in CRC was shown to correlate with a positive prognosis, the contribution of phenotypically and functionally distinct T cell subtypes within tumors remains unclear. We analyzed 37,931 single T cells with respect to transcriptome, TCR sequence and 23 cell surface proteins, from tumors and adjacent normal colon of 16 patients. Our comprehensive analysis revealed two phenotypically distinct cytotoxic T cell populations within tumors, including positively prognostic effector memory cells and non-prognostic resident memory cells. These cytotoxic T cell infiltrates transitioned from effector memory to resident memory in a stage-dependent manner. We further defined several Treg subpopulations within tumors. While Tregs overall were associated with positive clinical outcomes, CD38+ peripherally-derived Tregs, phenotypically related to Th17 cells, correlated with poor outcomes independent of cancer stage. Thus, our data highlight the diversity of T cells in CRC and demonstrate the prognostic significance of distinct T cell subtypes, which could inform therapeutic strategies.

Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9–16.7): 13.2 (7.4–16.8) and 13.0 (9.2–20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7–33.8) in the total population: 21.3% (11.9–33.7) in treatment-naive and 28.9% (16.4–44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0–not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

Background and aims: Poor specificity and predictive values of current cross-sectional radiological imaging methods in evaluation of pancreatic adenocarcinoma (PDAC) limit the clinical capability to accurately stage the tumor pre-operatively and provide optimal surgical treatment and improve patient outcomes. Methods: In this study, we applied Harmonic Motion Elastography (HME), a quantitative ultrasound-based imaging method to calculate Young's modulus (YM) in PDAC mouse models (n = 30) and human pancreatic resection specimens of PDAC (n=32). We compared the YM to the collagen assessment by Picrosirius red (PSR) stain on corresponding histologic sections. Results: HME is capable of differentiating between different levels of fibrosis in transgenic mice. In mice without pancreatic fibrosis, the measured YM was 4.2 ± 1.3 kPa, in fibrotic murine pancreata, YM was 5.5 ± 2.0 kPa and in murine PDAC tumors, YM was 11.3 ± 1.7 kPa. The corresponding PSR values were 2.0 ± 0.8 %, 9.8 ± 3.4 %, and 13.2 ± 1.2%, respectively. In addition, three regions within each human surgical PDAC specimen were assessed: tumor, which had both the highest Young's modulus (YM > 40 kPa) and collagen density (PSR > 40 %); non-neoplastic adjacent pancreas, which had the lowest Young's modulus (YM < 15 kPa) and collagen density (PSR < 10%) and a transitional peri-lesional region between the tumor and non-neoplastic pancreas with an intermediate value of measured Young's modulus (15 kPa < YM < 40 kPa) and collagen density (15% < PSR < 35 %). Conclusion: In conclusion, a non-invasive, quantitative imaging tool for detecting, staging and delineating PDAC tumor margins based on the change in collagen density was developed.

Quantitative metrics to objectively assess the fidelity of cancer models, such as cell lines, organoids, or patient-derived xenografts (PDXs), remain elusive, with histological criteria or the presence of specific mutations often used as driving principles. We show that molecular criteria, based on the regulatory proteins responsible for maintaining transcriptional cell state and its regulatory network, are effective in identifying models that can recapitulate drug mechanism of action and drug sensitivity, independent of histological consideration.

Background: Improving outcomes of PDAC with checkpoint inhibitors (CPIs) have been ineffective, underscoring the need to co-target alternative pathways. Preclinical data showed that CXCR4-SDF1 axis modulates the tumor microenvironment (TME) in PDAC and that CXCR4 inhibition enhances T cell access to the TME, increasing tumor sensitivity to CPIs. This was confirmed in the COMBAT Cohort 1 (CC1) study showing that the dual combination M+P increases activated CD8+ T cells and decreases myeloid derived suppressor cells (MDSCs) within the TME. Moreover, our pre-clinical studies showed that adding C to M+P resulted in improved efficacy vs C alone. The COMBAT Cohort 2 (CC2) aims to test the safety and efficacy of the triple combination of M+P+C in 2L mPDAC. Methods: Single arm phase 2a study in mPDAC. In cohort 2, patients with stage IV PDAC at diagnose who had progressed to 1L gemcitabine-based C received 5 days M priming, followed by M BIW + P Q3W plus C [Irinotecan liposomal injection/5-FU/LV (OFL)] Q2W. The primary endpoint was RR. Results: A total of 43 patients with stage 4 PDAC, 98% of whom were diagnosed with stage 4 disease, were enrolled. Median age was 68 (40-85) and 74.4% had liver disease. The safety profile was consistent with the individual profiles of each treatment alone. Of note, the incidence of ≥G3 neutropenia (G3Neu) was 7% and ≥G3 infection was 7%, which is lower than expected for C (OFL) alone (20% and 17%, respectively). The levels of T-cells increased during M priming and returned to normal values, which remained stable across the study despite the OFL treatment. For the evaluable patients (N=38) the ORR was 21.1% with a 13.2% confirmed ORR (defined as two consecutive assessments showing PR) and a 63.2% DCR (PR+SD). Median duration of clinical benefit was 5.6 months. Median OS and PFS were 6.5 months and 4.0 months, respectively (6.6 months and 3.8 months, respectively, for the ITT population). Conclusions: The triple combination of M+P+C is tolerable and shows encouraging results with cORR 13.2%, mPFS 4.0 months and mOS 6.5 months (compared to 7.7%, ~3 months and 4.7 months, respectively, on a historical basis for OFL alone in the stage 4 diagnosis subpopulation). SD of 42.1% and DCR of 63.2% were also higher than historical data on SoC chemotherapy used in 2L patients. The incidence of severe neutropenia and infections is lower than the historical data on C. The results from the CC2 suggest that M+P may expand the efficacy and safety benefit of OFL in PDAC, and warrants further investigation in a randomized study. Citation Format: Manuel Hidalgo, Teresa Macarulla, Valerya Semenisty, Erkut Borazanci, Jaime Feliu, Mariano Ponz-Sarvise, David Gutierrez Abad, Paul Oberstein, Angela Alistar, Andres Muñoz, Ravit Geva, Carmen Guillén-Ponce, Mercedes Salgado Fernandez, Amnon Peled, Marya Chaney, Irit Glicko-Kabir, Liron Shemesh-Darvish, Debby Ickowicz, Ella Sorani, Shaul E. Kadosh, Abi Vainstein-Haras, Bruno Bockorny. A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT177.

437 Background: SM-88 (racemetyrosine, Tyme Inc) is a dysfunctional tyrosine derivative used with MPS (methoxsalen 10mg, phenytoin 50mg and sirolimus 0.5mg). SM-88 was well tolerated with improvement in survival among select heavily pretreated PDAC patients who achieved stable disease (HR 0.08, p = 0.02) (Noel et al. Annal Oncol 2019). Circulating tumor cells (CTCs) were prognostic in identifying a PDAC subgroup that may be more likely to benefit from SM-88. Preliminary radiomic analysis of the largest metastases at baseline correlated with baseline CTCs (Ocean et al, Annal Oncol 2019). Here we describe the subsequent randomized portion of the trial in third-line patients only, of SM-88 vs physician/patient choice chemotherapy, to evaluate the potential role of SM-88 in metastatic PDAC through analysis of CTCs and passively acquired biometrics data from a wearable device. Methods:Prospective open-label RCT (Tyme 88 Panc Part 2, NCT03512756) after 2 prior lines for metastatic PDAC. A cell adhesion matrix (CAM) was used to enrich solitary CTCs and cells in clusters floating in the medium after 24 hour culture. Isolated CTCs were collected each cycle on day 1, isolated, and enumerated by flow cytometry using the epithelial cell surface marker Epi+ and cellular uptake of green fluorescent labeled CAM (GCAM+). Results:As of Sept 15, 67 subjects were consented. Randomized and evaluable subjects (n=38) included: mean age 65y (45-86); BMI 24.6 (18.8-38.7); female 39.5%; White 76.3%. Of treated subjects 65.8% (25/38) had 166 AEs, with 25.7% (26/101) being at least possibly SM-88-related, with 1 Grade 3. Four CTC subpopulations defined by GCAM, Epi+ and cluster status, were enumerated and correlated to each other (r=0.03-0.71). At least one CTC subpopulation was detected at baseline (mean 33.8 cells/2mL) in all subjects (n=27). The longest metastatic lesion diameter at baseline correlated with baseline CTCs (r=0.55 for Epi+ cluster; r=0.52 for GCAM+ cluster). CTCs were successfully separated and enumerated at each cycle for correlation with survival, response and other parameters. The median baseline daily step count during the first two weeks on treatment was 3993.8 (IQR: 2745.6 - 5078) for those alive vs. 689.3 (IQR: 630.0-2083.6) among deaths in evaluable subjects (p = NS). Passively acquired mean heart rate during week 3 on trial was 89.3 (SD 10.5) among those who died vs. 78.0 (SD 9.2) among those living; medians are 87.0 for deaths vs. 79.2 for alive (p= NS). Conclusions: In a preliminary exploratory analysis, passively acquired biometrics from a wearable device can be collected for correlation with other clinical outcomes. CTC collection and enumeration is also feasible for correlation with traditional trial outcomes. Given that the longest lesion diameter is correlated with CTCs at baseline, additional radiologic feature analysis (eg radiomics) may be important predictor of CTCs. SM-88 was well tolerated with no treatment-related Grade 4 or 5 events. Clinical trial information: NCT03512756.

Quantitative metrics to objectively assess the fidelity of cancer models, such as cell lines, organoids, or patient-derived xenografts (PDXs), remain elusive, with histological criteria or the presence of specific mutations often used as driving principles. However, focusing on individual mutations inevitably ignores the effect of a large complement of additional, model-specific genetic and epigenetic events. As a result, effective model fidelity assessment is best performed a posteriori, for instance, by determining whether dependencies identified in a specific tumor model (e.g., a cell line or organoid) are recapitulated in vivo in PDXs or in patients, via pre-clinical or clinical trials. Unfortunately, such an approach is inefficient and time-consuming, creating an urgent need for methodologies capable of effectively and quantitatively assessing model fidelity a priori. This unmet need motivated us to develop and test a quantitative, molecular-level framework (OncoMatch), to assess the fidelity of a given tumor model in the context of a specific biological question, and in particular for addressing issues of drug sensitivity. We addressed this challenge by integrating two independent computational metrics to assess: (a) conservation of regulatory networks inferred from patient-derived samples in a model of interest, and; (b) overlap of master regulator (MR) proteins–i.e., proteins representing the mechanistic determinants of the transcriptional state associated with the phenotype of interest–as inferred from patient-derived and model-derived samples. We show that these molecular-level criteria can effectively identify cell lines that recapitulate patient-specific drug mechanism of action and drug sensitivity, independent of histological consideration. By leveraging gene expression profiles of drug-perturbations in primary cells and explants derived from gastroenteropancreatic-neuroendocrine tumor (GEP-NET) patients, we show that H-STS, an EBV-immortalized lymphoblastoid cell line, represents a high-fidelity model for the assessment of drug mechanism of action and drug sensitivity in these tumors. In particular, our analysis shows highly significant conservation of drug mechanism of action for 60 of 95 profiled drugs (63%, p < 10-10, Bonferroni's corrected), and higher conservation among drugs exhibiting greater bioactivity in this context. This rate is comparable and, in fact higher than what is achieved using tumor-type-matched cell line pairs representative of glioma, pancreatic and prostate carcinoma, and dramatically higher than the conservation observed between unrelated models, which we used as negative controls. Based on this systematic analysis, OncoMatch represents a valuable addition to our repertoire of tools for prioritizing cell lines, organoids and patient-derived xenograft models as high-fidelity human cancer models. We provide comprehensive prioritization of 921 cell lines as potential high-fidelity models for 10,024 human tumor samples in TCGA. This represents an actionable resource to guide selection of cell line models for specific drug mechanism of action and drug sensitivity studies. Citation Format: Mariano J. Alvarez, Yan Pengrong, Mary L. Alpaugh, Michaela Bowden, Ewa T. Sicinska, Chensheng W. Zhou, Charles Karan, Ronald B. Realubit, Prabhjot S. Mundi, Adina Grunn, Jager Dirk, John A. Chabot, Antonio T. Fojo, Paul E. Oberstein, Hanina Hibshoosh, Jeffrey W. Milsom, Matthew H. Kulke, Massimo Loda, Gabriela Chiosis, Diane L. Reidy-Lagunes, Andrea Califano. OncoMatch: Unbiased, quantitative assessment of cancer model fidelity for drug sensitivity and mechanism of action elucidation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-003.

ObjectivePancreatic ductal adenocarcinoma (PDA) has among the highest stromal fractions of any cancer and this has complicated attempts at expression-based molecular classification. The goal of this work is to profile purified samples of human PDA epithelium and stroma and examine their respective contributions to gene expression in bulk PDA samples.DesignWe used laser capture microdissection (LCM) and RNA sequencing to profile the expression of 60 matched pairs of human PDA malignant epithelium and stroma samples. We then used these data to train a computational model that allowed us to infer tissue composition and generate virtual compartment-specific expression profiles from bulk gene expression cohorts.ResultsOur analysis found significant variation in the tissue composition of pancreatic tumours from different public cohorts. Computational removal of stromal gene expression resulted in the reclassification of some tumours, reconciling functional differences between different cohorts. Furthermore, we established a novel classification signature from a total of 110 purified human PDA stroma samples, finding two groups that differ in the extracellular matrix-associated and immune-associated processes. Lastly, a systematic evaluation of cross-compartment subtypes spanning four patient cohorts indicated partial dependence between epithelial and stromal molecular subtypes.ConclusionOur findings add clarity to the nature and number of molecular subtypes in PDA, expand our understanding of global transcriptional programmes in the stroma and harmonise the results of molecular subtyping efforts across independent cohorts.

Purpose: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial. Patients and Methods: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses. Results: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9–5.3), 5.4 (4.2–6.4), and 4.6 (4.2–5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84–1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred. Conclusions: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262) See related commentary by Salas-Benito et al., p. 5435

In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-Kras+/G12D;Pdx1-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b+ myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Significance: Subdiaphragmatic vagotomy or Chrm1 knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. Cancer Discov; 8(11); 1458–73. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333

SummaryBulk tumor tissues comprise intermixed populations of neoplastic cells and multiple lineages of stromal cells. We used laser capture microdissection and RNA sequencing to disentangle the transcriptional programs active in the malignant epithelium and stroma of pancreatic ductal adenocarcinoma (PDA). This led to the development of a new algorithm (ADVOCATE) that accurately predicts the compartment fractions of bulk tumor samples and can computationally purify bulk gene expression data from PDA. We also present novel stromal subtypes, derived from 110 microdissected PDA stroma samples, that were enriched in extracellular matrix– and immune–associated processes. Finally, we applied ADVOCATE to systematically evaluate cross–compartment subtypes spanning four patient cohorts, revealing consistent functional classes and survival associations despite substantial compositional differences.

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

372 Background: Preoperative chemoRT is a standard-of-care as shown in the CROSS trial ( N Engl J Med 2012;366:2074-2084), Surgery is sometimes deferred in pts with clinical CR (cCR) based on lack of overall survival benefit ( J Clin Oncol 2005;23:2310-2317, J Clin Oncol 2007;25:1160-1168). Nivolumab has activity in advanced ESCC ( Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes. Methods: This phase I/II study was designed to assess the safety and tolerability and efficacy of nivolumab added to chemoRT (6 weekly carboplatin AUC 2, paclitaxel 50mg/m2, RT 50.4 Gy in 1.8 Gy fractions 5/7 days) for pts with TanyN1-3 or T3-4N0M0 ESCC. The phase I primary endpoint is “unacceptable toxicity” at 28 days after the last dose of chemotherapy. The phase II primary endpoints are cCR (endoscopy + PET/CT) and pCR rates for pts undergoing surgery. Nivolumab is given q2W ×2, then concurrent chemoRT with nivolumab q2W x3. If no cCR, pt proceeds to esophagectomy, then adjuvant nivolumab q2W ×3; if cCR, pt has an option of no surgery but receives nivolumab q2W ×3. Results: From 7/20/17 to 12/27/18, 6 pts were enrolled. No unacceptable or grade 5 toxicities were observed. The most common grade 1/2 AEs in >1 pt were anorexia, myelosuppression, elevated AST and nausea. Grade 3/4 AEs in >1 pt were lymphopenia and leukocytopenia. 2 pts required hospitalizations (dyspnea 1, colitis 1). All pts completed therapy; 1 pt had dose delay due to grade 2 esophagitis; 2 pts progressed, 4 achieved cCR. Of 4 pts with cCR, 2 pts chose surgery and both achieved pCR. None of the 4 pts recurred. Conclusions: ChemoRT with nivolumab is tolerable with manageable toxicities in locally advanced ESCC. Enrollment to the phase II portion ended because of slow accrual. Adverse Events. Grade 1 &2 in > 1 pt: 4/6: Anorexia & Anemia 3/6: Leukocytopenia Neutropenia Thrombocytopenia Nausea & Elevated AST 2/6: Hypomagnesemia Hypokalemia Grade 3 & 4 in > 1 pt: 5/6: Lymphopenia, 2/6: Leukocytopenia

TPS778 Background: Demoralization is a maladaptive coping response to stressful situations characterized by thoughts of hopelessness, helplessness, and loss of meaning and purpose. Psychometrically, it is measured using the Demoralization-Scale II (DS-II), a validated questionnaire that yields a patient-reported quantification (scale 0-32) of demoralization. Previous studies involving patients with progressive disease have uncovered a strong positive correlation between demoralization and depression, respectively measured by the DS-II and Patient Health Questionnaire-9 (PHQ-9) surveys. Here, we aim to characterize demoralization and its relationship to depression in pancreatic cancer patients, a unique patient population in terms of its poor prognosis. We hypothesize that demoralization is highly prevalent in the pancreatic cancer patient population and strongly correlated with depression. Methods: Eligible patients with an active pancreatic cancer diagnosis, after consenting to an IRB approved protocol, will be administered the DS-II and PHQ-9 surveys to yield psychometric measurements for analysis. The primary objective of this project is to determine the association between demoralization (DS-II) and depression (PHQ-9) in pancreatic cancer patients. Secondary objectives include associations between demoralization and ethnicity, sexual orientation, suicidal ideation, education, cancer stage, and disease progression. Data will be analyzed via simple linear regression. An ANOVA will also be conducted using DS-II groups as the categorical variable and PHQ-9 scores as the continuous variable, and vice versa. This is a multi-institutional study to be conducted at Cedars-Sinai Medical Center, New York University, University of Washington, UC San Francisco, and Lewis Katz Schools of Medicine.

TPS789 Background: Patients with metastatic pancreatic cancer who have progressed on two prior lines of therapy have a poor prognosis with an overall survival in the range of 2-2.5 months. (Manax, et al. J Clin Oncol 37, 2019 suppl 4; abstr 226). There is currently no standard of care for these patients that has demonstrated improved outcomes. SM-88 (D,L-alpha-metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS (Methoxsalen 10mg, Phenytoin 50mg and Sirolimus 0.5mg; all administered daily). SM-88 monotherapy was relatively well tolerated, with improvement in survival in select patients with heavily pretreated PDAC who achieved stable disease on therapy (HR 0.08, p = 0.02). Circulating tumor cells (CTC’s) were prognostic and decreased on therapy with SM-88 potentially identifying a subgroup of PDAC that may be most likely to benefit from therapy (Noel et al. Annal Oncol V30, Suppl 4, 2019). Preliminary radiomic analysis of the largest metastases at baseline suggested the same benefits including a correlation with baseline CTCs, changes in CTCs on therapy and OS (Ocean et al, Annal Oncol, V30, Suppl 5, 2019). Here, we describe a randomized, open-label, phase 2/3 trial evaluating the efficacy of SM-88 + MPS vs physician’s choice treatment as third line therapy for patients with metastatic PDAC. Methods: This is a multi-center Phase 3 study of patients ≥18 years with metastatic PDAC that progressed after 2 lines of chemotherapy (gemcitabine [gem] and 5-fluorouracil [5-FU] based) with an ECOG

TPS598 Background: Tyrosine kinase inhibitors can prolong survival in advanced HCC patients, but response rates have been minimal. Recently, immune checkpoint inhibition with nivolumab (nivo) demonstrated objective response rates (ORR) of 15% (escalation phase) and 20% (expansion phase) in the Checkmate 040 study. Pre-clinical and translational studies have demonstrated that IL-8 and tumor associated macrophages (TAMs) contribute to HCC progression and recurrence following treatment. Therefore, rationale exists to evaluate combinatorial approaches to target TAM function combined with checkpoint inhibitory therapy. This phase II, randomized study will evaluate the safety and efficacy of combined anti-CSF1R (Cabiralizumab) or anti-IL-8 (BMS-986253) in combination with Nivo in advanced HCC. Methods: Advanced HCC patients without prior systemic treatment and disease measurable by RECISTv1.1 with Childs A liver function are eligible. Patients will be enrolled (n=25 per arm) to Nivo 240 mg IV Q2 weeks monotherapy, Nivo 240 mg IV + BMS-986253 1200 mg IV Q2 weeks, or Nivo 240 mg IV + Cabiralizumab 4 mg/kg IV Q2 weeks. Primary endpoints include safety and ORR determined by RECISTv1.1. Secondary endpoints include time to response, duration of response, progression free survival, and overall survival. Exploratory endpoints include analysis of tumor microenvironment immune and tumor cell profiling of pre- and on-treatment tumor tissue. Clinical trial information: NCT04050462.

Acinar cell carcinoma (ACC) is an extremely rare cancer of the pancreas, accounting for less than 1 % of non-endocrine pancreatic tumors. The role for adjuvant radiation therapy (RT) in the management of this disease is unknown. The Survival, Epidemiology, and End Results 18 database, November 2012 submission, was queried for ACC of the pancreas reported between the years of 1998 and 2010. Baseline characteristics were compared with the chi-squared test. Overall survival (OS) and cause-specific survival (CSS) were estimated using the Kaplan–Meier method. Cox proportional hazard modeling was performed for multivariate analysis of factors associated with OS and CSS. Analyses were performed using SPSS, version 20. Two hundred nineteen patients with acinar cell carcinoma were identified. Median follow-up was 11 months. Median patient age was 66 (range 4–92). One hundred fourteen patients (52.1 %) had locoregional disease, while 105 patients (47.9 %) had metastatic disease at diagnosis. Median OS for all patients was 14 months (95 % confidence interval (CI) 9.24–18.77 months), and median CSS was 17 months (95 % CI 10.37–23.63 months). For patients with non-metastatic disease, median OS was 38 months (95 % CI 28.43–47.57). Among patients with non-metastatic disease, the use of adjuvant radiation was associated with increased median OS (56 months [95 % CI 21.67–90.33]), compared to patients not treated with radiation (27 months [95 % CI 4.06–49.94]), p = 0.046. Use of adjuvant radiation was associated with increased cause-specific survival (66 vs. 40 months), but this was not statistically significant (p = 0.104). On multivariate analysis, use of surgery and adjuvant radiation were both associated with improved OS for patients with non-metastatic disease (hazard ratio (HR) 0.517, p = 0.034 and HR 0.423, p = 0.009, respectively). Both surgery and radiation were associated with non-statistically significant improvement in ACC cause-specific survival, HR = 0.606 (95 % CI = 0.314–1.170), p = 0.136 and HR = 0.501 (95 % CI = 0.249–1.009), p = 0.053, respectively. Surgical resection with curative intent followed by adjuvant RT is associated with excellent long-term overall survival in patients with non-metastatic local-regional acinar cell carcinoma of the pancreas.

TPS4163 Background: Treatment of LAUPC most commonly involves chemotherapy +/- RT. Patients(pts) who can be downstaged and undergo R0 resection have significant improvement in overall survival, but conventional chemoRT converts < 10% of patients with LAUPC. If the effects of RT can be augmented then higher R0 resection rates may be achieved and improve survival. In pre-clinical models, RT leads to increased expression of M-CSF from pancreatic tumor cells and marked immune suppression within the tumor microenvironment via expansion of tumor associated macrophages (TAMs). Concurrent blockade of M-CSF with RT reduces TAM infiltration, prevents the generation of tumor promoting T cell populations, and increases the therapeutic effect of RT. RT also induces up-regulation of PD-L1 in TAMs, another mode of immune suppression that can account for RT resistance in LAUPC. (Seifert et al. 2016). These data suggest the efficacy of RT in LAUPC is limited by its promotion of innate and adaptive immune suppression. CSF1R blockade with Cabira combined with PD-1 blockade with Nivo may enhance the efficacy of SBRT by reprogramming the TAM compartment in tumors, thereby preventing an immune suppressive phenotype and augmenting T-cell mediated anti-tumor response. Methods: Single arm phase II study designed to evaluate safety, tolerability, and surgical resection rate in LAUPC pts treated with concurrent Nivo, Cabira, and SBRT. Exploratory endpoints include immune changes within blood and tissue following treatment and correlation with clinical endpoints. Key eligibility: completion of 2- 6 months standard induction chemotherapy, normal organ and marrow function, pre- and on-treatment biopsy, and PS ≤ 1. Following initial biopsy and placement of fiducials, Cabira 4mg/kg and Nivo 240mg are given D1 of every 14 day cycle. SBRT 6.6 Gy x 5 consecutive fractions starts D8. After 2 cycles, repeat biopsy and imaging is performed. Treatment with Cabira and Nivo continues every 2 weeks and imaging is done every 8 weeks, at which time pt is assessed for surgical resection. If pt is downstaged, treatment is discontinued and pt proceeds to surgery. Preliminary 6 pt safety cohort is monitored for unacceptable toxicities. If < 3 unacceptable toxicities in the first 6 subjects enrolled, then plan for expansion phase with 14 more pts. As of abstract submission, 3 pts have been enrolled. Clinical trial information: NCT03599362.

Targeted therapies and immunotherapy have changed the face of multiple solid malignancies, including metastatic melanoma and lung cancer, but no such therapies exist for pancreatic ductal adenocarcinoma (PDAC) despite the knowledge of key mutations and an increasing understanding of the tumor microenvironment. Until now, most clinical studies have not been biomarker driven in this highly immunosuppressive and heterogeneous cancer. Ongoing basic and translational studies are better classifying the disease in hopes of identifying critical pathways that distinguish the unique PDAC subtypes, which will lead to personalized therapies. In this review, we discuss the current treatment options for metastatic pancreatic cancer and highlight current ongoing clinical trials, which aim to target the stroma and the immune microenvironment either alone or in combination with standard chemotherapy. Identifying biomarkers and key resistance pathways and targeting these pathways in a personalized manner in combination with chemotherapy are likely to yield a more immediate and durable clinical benefit. Clin Cancer Res; 23(7); 1670–8. ©2017 AACR. See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”

No common malignancy is as rapidly and inevitably fatal as pancreatic ductal adenocarcinoma (PDA). This grim fact has driven substantial research efforts into this disease in recent decades. Unfortunately, the investment has yet to result in a meaningful increase in 5-year survival. This has prompted many pancreatic cancer researchers and advocates to redouble their efforts, but also requires one to step back and ask why the previous efforts were lacking and to consider why pancreatic cancer is so difficult to treat. The difficulties are legion. PDA is characterized by an insidious clinical syndrome, but is rarely diagnosed at a time when surgical resection is feasible. We lack markers of early detection and screening programs remain unproven even in high risk populations. The location of the tumor in the retroperitoneum, the advanced age of patients, and the systemic effects of disease limit the options for local therapy. Chemotherapy may provide a small benefit, but most efforts to improve on the current regimens consistently and stubbornly fail in advanced clinical trials. The molecular and cellular features of ductal pancreatic tumors are aggressive and underlay multiple levels of therapeutic resistance. Non-cell-autonomous features including stromal proliferation, reduced vascular density and immune suppression also contribute to therapeutic resistance. Growing awareness of these the fundamental features of PDA has begun to guide ongoing research efforts. Clinical trials are now specifically targeting these tumor properties and actively focusing on the therapeutic implications of tumor stroma. As reviewed here, reflecting on the fundamental question of why pancreatic cancer is so difficult to treat is a necessary and informative exercise that will aid our efforts to improve patient outcomes. These efforts will lead to improvements in clinical trial design, expand our focus to include the molecular and histologic implications of novel treatment paradigms, and ultimately change the lives of our patients.

Neuroendocrine tumors (NETs) consist of a diverse family of tumors which are derived from the neuroendocrine system. Most NETs are well or moderately differentiated tumors with a relatively indolent growth pattern. However, these tumors can cause significant clinical disease due to release of functional products that mediate the carcinoid syndrome and other diverse sequela. They also can grow progressively and cause symptoms from local invasion or distant metastasis. NETs are optimally treated with surgery and somatosatin analogs (SSAs) to control symptoms but are relatively insensitive to systemic chemotherapy. As a result, patients with advanced unresectable NETs have a poor prognosis. In 2011, two targeted therapies, sunitinib and everolimus were approved in the subset of progressive pancreatic NETs (pNETs). Everolimus is an oral inhibitor of the growth stimulatory mTOR pathway. In Phase 2 trials in NETs and pNETs, everolimus was well tolerated and associated with some response and widespread disease stabilization. In follow-up, randomized Phase 3 trials, everolimus was compared to placebo. In the RADIANT-2 trial, everolimus and a somatostatin analog were used in patients with functional NETs and treatment was associated with an an improvement in progression-free survival (PFS). In the RADIANT-3 trial, patients with pNET were randomized to receive everolimus or placebo along with best supportive care. Everolimus was again associated with improvement in PFS compared to placebo and it has been approved by the FDA for patients with progressive pNET. Everolimus is associated with frequent low grade toxicity but is also notable for increased rates of infection as well as non-infectious pneumonitis. mTOR inhibition with everolimus represents a significant advance in the treatment of advanced neuroendocrine tumors.

198 Background: When compared to healthy populations subjects are defined as sarcopenic if they have severe loss of lean muscle mass (LMM). Sarcopenia is associated with poor outcomes in some studies of pancreatic cancer (PDA) but the prevelance remains uncertain in resected patients and there is little data about changes in LMM during neoadjuvant chemotherapy. Muscle mass can be reliably quantified in cancer patients using routine imaging. We analyzed a large cohort of patients undergoing surgery at a high-volume center to quantify LMM at baseline and with treatment, and to determine the association of sarcopenia with tumor histology and outcomes. Methods: We analyzed subjects undergoing surgery for PDA at the Pancreas Center at Columbia University from 2011-2014. We utilized CT scans to measure cross sectional area of muscle at the L3 vertebral body (LMM in cm2) and used height to define a smooth muscle index (SMI-cm/m). Sarcopenia was determined based on SMI < 38.9 for females and < 55.4 for males. In subjects undergoing neoadjuvant chemotherapy, SMI was also calculated on post therapy scans. We collected information on clinical and pathological variables and performed statistical analyses utilizing SAS 9.4 software. Results: Among subjects with available imaging (n = 106) sarcopenia rates at initial staging were high whether they were immediately resectable (52%) or locally advanced (63%). Rates of sarcopenia were higher in males than females (77 vs 38%, p < 0.001). Sarcopenic status was not correlated with survival, tumor stage or grade but was associated with age, gender, and BMI. Among locally advanced subjects who proceeded to surgery after neoadjuvant chemotherapy (n = 40) there was no change in SMI or incidence of sarcopenia following treatment (median 171 days). Conclusions: Sarcopenia is highly prevalent at diagnosis in subjects undergoing surgery for PDA but was not associated with survival, tumor grade or stage in this cohort. Subjects who successfully completed neoadjuvant treatment did not experience significant loss in LMM despite extensive treatment suggesting that lack of change in LMM may assist in predicting favorable response to neoadjuvant therapy in PDA.