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ImportanceThe potential relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in patients with late-stage disease. Increased body mass index may negate aspirin use for cancer prevention, but its role as a factor on the effectiveness of postdiagnosis aspirin use is unclear.ObjectiveTo evaluate how prediagnosis obesity and postdiagnosis aspirin use may be associated with overall survival in patients with late-stage colorectal cancer.Design, Setting, and ParticipantsThis cross-sectional study used self-reported data from patients with metastatic or treatment-refractory disease who consented to a clinical protocol at MD Anderson Cancer Center, a large US cancer treatment center. Patients were enrolled between 2010 and 2018 and followed up for mortality through July 2020. Analyses were conducted through March 2022.ExposuresBody mass index in the decade prior to initial diagnosis and regular aspirin use at survey completion.Main Outcomes and MeasuresOverall survival was measured from stage IV diagnosis until death or last follow-up. Cox proportional hazards models were constructed to estimate associations of prediagnosis obesity and postdiagnosis aspirin use with overall survival.ResultsOf 656 patients included in this analysis, 280 (42.7%) were women, 135 (20.6%) were diagnosed with CRC before age 45 years, 414 (63.1%) were diagnosed between ages 45 and 65 years, and 107 (16.3%) were diagnosed at 65 years or older; 105 patients (16.0%) were Black or Hispanic, and 501 (76.4%) were non-Hispanic White. Controlling for age, sex, race, stage at initial diagnosis, and weight change between prediagnosis and survey date, patients with obesity in the decade prior to CRC diagnosis had significantly higher likelihood of death (hazard ratio, 1.45; 95% CI, 1.11-1.91) compared with those with normal prediagnosis body mass index. Furthermore, only patients with normal prediagnosis body mass index experienced significant survival benefit with postdiagnosis aspirin use (hazard ratio, 0.59; 95% CI, 0.39-0.90).Conclusions and RelevanceIn this cross-sectional study, our findings suggest potentially differential tumor development in the long-term physiologic host environment of obesity. Confirmation and further evaluation are needed to determine whether prediagnosis body mass index may be used to estimate the benefit from postdiagnosis aspirin use.

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with unpredictable responses to chemotherapy. Approaches to assay patient tumors before treatment and identify effective treatment regimens based on tumor sensitivities are lacking. We developed an organoid-based platform (OBP) to visually quantify patient-derived organoid (PDO) responses to drug treatments and associated tumor-stroma modulation for personalized PDAC therapy.METHODSWe retrospectively quantified apoptotic responses and tumor-stroma cell proportions in PDOs via 3D immunofluorescence imaging through annexin A5, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK-19) levels. Simultaneously, an ex vivo organoid drug sensitivity assay (ODSA) was used to measure responses to standard-of-care regimens. Differences between ODSA results and patient tumor responses were assessed by exact McNemar's test.RESULTSImmunofluorescence signals, organoid growth curves, and Ki-67 levels were measured and authenticated through the OBP for up to 14 days. ODSA drug responses were not different from patient tumor responses, as reflected by CA19-9 reductions following neoadjuvant chemotherapy (P = 0.99). PDOs demonstrated unique apoptotic and tumor-stroma modulation profiles (P0.0001). α-SMA/CK-19 ratio levels of more than 1.0 were associated with improved outcomes (P = 0.0179) and longer parental patient survival by Kaplan-Meier analysis (P = 0.0046).CONCLUSIONHeterogenous apoptotic drug responses and tumor-stroma modulation are present in PDOs after standard-of-care chemotherapy. Ratios of α-SMA and CK-19 levels in PDOs are associated with patient survival, and the OBP could aid in the selection of personalized therapies to improve the efficacy of systemic therapy in patients with PDAC.FUNDINGNIH/National Cancer Institute grants (K08CA218690, P01 CA117969, R50 CA243707-01A1, U54CA224065), the Skip Viragh Foundation, the Bettie Willerson Driver Cancer Research Fund, and a Cancer Center Support Grant for the Flow Cytometry and Cellular Imaging Core Facility (P30CA16672).

PURPOSE: The primary aim of this study was to determine the attitudes and beliefs of hematology and medical oncology (HMO) fellows regarding palliative care (PC) after they completed a 4-week mandatory PC rotation. METHODS: The PC rotation included a 4-week standardized curriculum covering all PC domains. HMO fellows were provided educational materials and attended all didactic sessions. All had clinical rotation in an acute PC unit and an outpatient clinic. All HMO fellows from 2004 to 2017 were asked to complete a 32-item survey on oncology trainee perception of PC. RESULTS: Of 105 HMO fellows, 77 (73%) completed the survey. HMO fellows reported that PC rotation improved assessment and management of symptoms (98%); opioid prescription (89%), opioid rotation (78%), and identification of opioid adverse effects (87%); communication with patients and families (91%), including advance care planning discussion (88%) and do-not-resuscitate discussion (88%); and they reported comfort with discussing ethical issues (74%). Participants reported improvement in knowledge of symptom assessment and management (n = 76; 98%) as compared with efficacy in ethics (n = 57 [74%]; P = .0001) and for coping with stress of terminal illness (n = 45 [58%]; P = .0001). The PC rotation educational experience was considered either far better or better (53%) or the same (45%) as other oncology rotations. Most respondents (98%) would recommend PC rotations to other HMO fellows, and 95% felt rotation should be mandatory. CONCLUSION: HMO fellows reported PC rotation improved their attitudes and knowledge in all PC domains. PC rotation was considered better than other oncology rotations and should be mandatory.

Objectives Epithelial-mesenchymal transition (EMT) plays an important role in the progression, metastasis, and chemoresistance of pancreatic duct adenocarcinoma (PDAC); however, the expression of EMT markers and their clinical significance in PDAC patients who received neoadjuvant therapy (NAT) are unclear. Methods We examined the expression of EMT markers, including Zeb-1 (zinc finger E-box-binding homeobox 1), E-cadherin, and vimentin by immunohistochemistry in 120 PDAC patients who received NAT and pancreatectomy from 1999 to 2007. The results were correlated with clinicopathologic parameters and survival. Results Among 120 cases, 45 (37.5%) and 14 (11.7%) were positive for Zeb-1 and vimentin, respectively, and 25 (20.8%) were E-cadherin-low. The median overall survival and disease-free survival were 35.3 (standard deviation [SD], 2.8) and 15.9 (SD, 3.6) months, respectively, in vimentin-negative group compared with 16.1 (SD, 1.1) (P = 0.03) and 7.0 (SD, 1.1) months (P = 0.02) in the vimentin-positive group. In multivariate analysis, vimentin expression was an independent predictor of shorter disease-free survival (hazard ratio, 2.50; 95% confidence interval, 1.31-4.78; P = 0.016) and overall survival (hazard ratio, 2.55; 95% confidence interval, 1.33-4.89; P = 0.01). Conclusions Epithelial-mesenchymal transition markers are frequently expressed in treated PDAC. Vimentin expression is a prognostic biomarker for survival in PDAC patients who received NAT.

BACKGROUND: There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC. METHODS: A multicenter, cooperative group, single-arm phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were eligible. Patients (n=123) received an eight-week cycle of G+E before and after surgery. The primary endpoint was two-year overall survival (OS), and secondary endpoints included toxicity, response, resection rate, and time to progression. Resectability was assessed retrospectively by central review. The study closed early due to slow accrual; no formal hypothesis testing was performed. RESULTS: One hundred fourteen patients were eligible, consented, and initiated protocol treatment. By central radiologic review, 97 (85%) of the 114 patients met protocol resectability criteria. Grade 3+ toxicity was reported in 60% and 79% of patients during the neoadjuvant phase and overall, respectively. Twenty-two of 114 (19%) patients did not proceed to surgery, 83 patients (73%) were successfully resected. R0 and R1 margins were obtained in 67 (81%) and 16 (19%) resected patients, respectively. Fifty-four patients completed postoperative G+E (65%). The two-year OS rate for the entire cohort (n=114) was 40% (95%CI 31–50) with a median OS of 21.3 months (95%CI 17.2–25.9). The two-year OS for resected patients (n=83) was 52% (95%CI 41–63) with a median OS of 25.4 months (95%CI 21.8–29.6). CONCLUSIONS: For resectable PDAC, perioperative G+E is feasible. Further evaluation of neoadjuvant strategies in resectable PDAC is warranted with more active systemic regimens.

OBJECTIVE: We sought to identify potential radiologic and serologic markers of pancreatic tumor response to therapy, using pathologic major response (pMR) as the objective endpoint. BACKGROUND: We previously demonstrated that a pMR to preoperative therapy, defined as detection of

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

BackgroundMonotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.MethodsOpen-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4.ResultsTwenty nine treated pts include 48% females, median age 48 years (range 28–75), and median prior therapies 2 (range 1–5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1–9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively).ConclusionsT+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials.Trial registration numberNCT03428126.

2514 Background: Checkpoint inhibitors (CPIs) are usually ineffective in patients (pts) with immune-cold microsatellite stable colorectal cancer (MSS-CRC) or pancreatic cancer (PDAC) and in those who progressed on previously treated with antibodies against PD1 or PD-L1. Here, we report the combination of NT-I7 plus pembrolizumab (pembro) on CPI-naïve MSS-CRC and PDAC cohorts, and patients (pts) with CPI-treated triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) cohorts of this ongoing phase 2a trial. Methods: Pts with CPI-naïve relapsed/refractory (R/R) MSS-CRC and PDAC, and CPI-treated R/R TNBC, NSCLC, and SCLC, were enrolled. NT-I7 (efineptakin alfa) 1200 µg/kg intramuscularly every 6 weeks and 200 mg pembro intravenously every 3 weeks were administered until disease progression/unacceptable toxicity. The primary endpoint of the Phase 2a is the objective response rate (ORR), assessed by RECIST v1.1 and iRECIST. The secondary endpoints are duration of response (DoR), disease control rate, progression-free survival, and overall survival. Results: As of 14 Jan 2022, 92 pts with metastatic or locally advanced cancer who had received a median of 3 prior treatments were enrolled in the study; 32 in PDAC, 28 in MSS-CRC, 22 in NSCLC, 6 in TNBC, and 4 in SCLC. The median age was 62 years [29-81], ECOG PS 0 in 23 (25%), 1 in 68 (74%) and 2 in 1 (1%). Among 71 evaluable pts, the median follow up (months) was 7.7, 5.3, 5.0, 3.7, and 2.4 in TNBC, MSS-CRC, NSCLC, PDAC and SCLC, respectively. The ORR was 50% (1/2) in SCLC, 12% (3/25) in MSS CRC, 8% (2/26) in PDAC 6% (1/16) in NSCLC and 0% (0/2) in TNBC per iRECIST; and 50% (1/2) in SCLC, 4% (1/25) in MSS CRC, and 4% (1/26) in PDAC per RECIST 1.1. All 7 responders are ongoing. The two PDAC pts had DoR over 1.35 months (mos) and 6.64 mos with the best tumor reduction 100% and 72% respectively. The one SCLC pt had DoR over 1.5 mos with the tumor reduction 67%. The one NSCLC pt had DoR over 2.73 mos with the tumor reduction 60%, and the three MSS-CRC pts had DoR 6.34, 2.96, and 0.03 mos with the tumor reduction 60%, 56%, and 43% respectively. A sustained and significant (approximate 3X from baseline) increase of peripheral lymphocytes in all arms was observed as shown in our previous report. Among 92 treated pts, NT-I7-related adverse events (AEs) occurred in 67 (72.8%) pts, including 52 (56.5%) Grade (G)1-2, 13 (14.1%) G3, and 2 (2.2%) G4. There were no NT-I7 related G5 AEs. Additional updated efficacy, safety and biomarker data will be presented. Conclusions: The combination of NT-I7 and pembro demonstrated antitumor activity and manageable toxicity profile in heavily pretreated pts with CPI-naïve MSS-CRC and PDAC and CPI-treated TNBC, NSCLC, and SCLC, suggesting that the addition of NT-I7 to CPI can overcome the primary resistance to CPI in the former group and acquired resistance in the latter. Clinical trial information: NCT04332653.

2536 Background: TIL therapy has been used extensively in metastatic melanoma patients for many years, now with ongoing efforts to commercialize treatment. The efficacy of TIL outside of melanoma is largely unknown thus we designed and implemented a trial using TIL manufactured at a single academic center for treatment refractory metastatic colorectal (CRC), pancreas (PDAC) and ovarian (OVA) cancers. Methods: Patients with CRC, PDAC and OVA refractory to standard therapies with ECOG PS 0-1 and normal organ function were eligible for TIL harvest. Ex vivo TIL expansion and manufacturing was conducted at the MD Anderson TIL lab under conditions that included IL2 and 41BB stimulation (using urelumab). All patients received a lymphodepletion regimen consisting of cyclophosphamide 60mg/kg days -7 and -6 and fludarabine 25mg/m2 days -5 through day -1, followed by infusion of pooled ex-vivo expanded TIL. Patients received up to 6 doses of high dose IL-2 (600,000 IU/kg) after TIL infusion. The primary endpoint was evaluation of the objective response rate (ORR) using RECIST 1.1 criteria with secondary endpoints including disease control rate, duration of response, PFS, OS and safety. Results: A total of 17 patients underwent TIL harvest and 16 were treated on protocol; including 8 CRC, 5 PDAC and 3 OVA. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). Median number of TIL infused was 76 X 109 (range 20.3 x 109-150 x 109). Median doses of cyclophosphamide and fludarabine administered were 2 (range, 2-2) and 3 (range, 1-5), respectively. Median doses of IL-2 administered was 6 (range, 1-6). There were no responders. Best response included prolonged SD in a patient with PDAC lasting until 18 months. Grade 3 or higher toxicities attributable to therapy was seen in 14 subjects (87.5%; 95% CI: 61.7 – 98.4) with the majority of toxicities representing expected pancytopenia from lymphodepletion. Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type. Early on-treatment biopsy of PDAC patient with prolonged SD showed presence of proliferating (KI67+) CD4+ and CD8+ TIL. Conclusions: Generation of TIL at a single academic center for CRC, PDAC and OVA is feasible and treatment is associated with no new safety signals. For these tumor types, further research is required to identify host factors associated with resistance to TIL therapy and optimize manufacturing processes to create more effective TIL cell therapy. Clinical trial information: NCT03610490.

3598 Background: Treatment with encorafenib (E) and cetuximab (C) offers response and survival benefit for patients (pts) with MSS, BRAFV600E metastatic colorectal cancer (CRC). BRAF + EGFR inhibition induced a transient MSI-H phenotype in preclinical models of MSS, BRAFV600E CRC and may prime these tumors for response to immunotherapy with anti-PD-1 antibodies like nivolumab (N). Methods: In this single-arm, single-institution, phase I/II clinical trial, pts with treatment-refractory MSS, BRAFV600E metastatic CRC were eligible. No prior BRAF, MEK, or ERK inhibitors, anti-EGFR antibody, or immunotherapy was permitted. Pts received E (300 mg PO daily), C (500 mg/m2 IV q14 days), and N (480 mg IV q28 days). The primary endpoints were best overall response (RECIST 1.1) and safety/tolerability (CTCAE v5). A Simon two-stage design (H0: p≤.22; Ha: p≥.45, where p = percentage of pts with radiographic response) was employed using a one-sided α =.05 and β =.20. Median progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier. To measure ex vivo treatment responses with an E-slice assay (EMPIRI), 300 µm fresh tissue slices from core biopsies were generated and cultured in serum-free media with E, C, and N. Longitudinal changes in viability were measured at days 4, 8, and 12 and compared to baseline viability in each tissue. Ex vivo “response” was defined if < 1X baseline tumor cell viability. Results: With a data cutoff of 2/8/2022, all pts are enrolled: 26 evaluable for toxicity and 23 for response. Median age is 60 years (range, 32-85), and 16 (62%) are female. Grade 3-4 treatment-related adverse events (AE) have occurred in 5/26 (19%) patients: colitis, maculopapular rash, leukocytosis, and myositis/myocarditis (all N = 1); asymptomatic elevated amylase/lipase (N = 2). Overall response rate is 48% (95% CI, 27-69), and disease control rate is 96% (95% CI, 78-100). Median PFS is 7.4 months (95% CI, 5.6-NA). For the 11 pts with responses, median duration of response is 7.7 months (95% CI, 4.5-NA). Median OS is 15.1 months (95% CI, 7.7-NA). E-slices showed concordance between pts with radiographic responses and reduction in cell viability, and between non-responders and increase in cell viability. Final results will be presented. Conclusions: E + C + N appears to be effective and well-tolerated for pts with MSS, BRAFV600E metastatic CRC. Ex vivo analysis of pretreatment tissue predicted eventual clinical response in matched patients. A follow-up randomized phase II trial (SWOG 2107) to evaluate encorafenib/cetuximab with or without nivolumab in pts with MSS, BRAFV600E metastatic CRC will activate in 2022. Clinical trial information: NCT04017650.

3520 Background: In RAS/RAF WT colorectal cancer (CRC), rechallenge with anti-EGFR therapy (EGFRi) in patients (pts) with prior response leads to clinical benefit, with response rates up to 30% in prior trials. However, secondary MTs in the MAPK signaling pathway have been implicated in resistance to EGFRi. We designed a phase 2 trial to evaluate the efficacy of EGFRi rechallenge +/- a MEK inhibitor (trametinib) based on pre-treatment ctDNA MTs. Methods: This trial evaluated the efficacy and safety of EGFRi rechallenge +/- trametinib in pts with RAS/BRAF WT, MSS, treatment refractory mCRC who achieved clinical benefit with prior EGFRi based therapy for ≥16 weeks with subsequent progression. Pre study ctDNA was used to enroll in one of 3 arms: Arm A: Pts with an acquired EGFR ECD MT but absence of RAS/BRAF/MAP2K1 or with absence of any acquired resistance MT (Arm C) at time of study initiation received panitumumab 6 mg/kg IV Q2 wks. Arm B: Pts with an acquired RAS/BRAF/MAP2K1 MT received panitumumab 4.8 mg/kg plus trametinib 1.5 mg PO daily. Pts in Arms A and C were allowed to cross over on progression. The primary endpoint was ORR by RECIST v1.1. Results: 54 pts were enrolled, with 52 evaluable for efficacy. Median age is 59 yrs (range, 37-78), and 23 (46%) are female. Median number of prior therapies was 3. Three, 20, and 31 pts were enrolled in Arms A, B, C, respectively. Grade 3 TREAs occurred in 29 (54%) pts (all receiving the doublet regimen) and included acneiform rash in 17 (31%) and others occurring in < 5% of pts. There were no grade 4 TRAEs. In pts with no acquired MTs (Arm C), ORR was 20% (6/30) (95% CI, 0.07-0.37), DCR 67% (20/30) (95% CI, 0.45- 0.81), and median PFS and OS 4.1 mo and 11.2 mo, respectively. The median DOR was 5.5 mo. 22 patients crossed over to add trametinib at time of progression, without any responses. In contrast, in pts with acquired RAS/RAF/MAP2K1 MTs (Arm B), there were no responses, with DCR of 63% (12/19) (95% CI, 0.36-0.81), and median PFS and OS 2.1 mo and 5.9 mo, respectively. Only 3 pts were identified with EGFR ECD MTs (Arm A), and ORR is 0% (0/3) in this cohort, with DCR 67% (2/3) (95% CI, 0.09-0.99). Pts with PR had a longer median interval from prior EGFRi and longer time on prior EGFRi than those with SD+PD (5.5 vs 3.6 mo; p = 0.03, and 9.5 vs. 8.8 mo; p = 0.03, respectively). Conclusions: CtDNA guided rechallenge leads to responses in 20% of pts without acquired resistance MTs, with DCR of 67%. This exceeds current third line standard options. While panitumumab has the potential to block EGFR ECD mutations arising from cetuximab, these mutations in isolation were uncommon and there were no signals of efficacy. Although the acneiform rash induced by the combination of MEK and EGFR inhibition was manageable with close dermatologic management, the combination failed to improve outcomes for pts with acquired resistance. Alternative approaches to downstream MAPK blockade should be explored to improve outcomes. Clinical trial information: NCT03087071.

4010 Background: Preclinical and small clinical studies of chemoimmunotherapy for metastatic pancreatic ductal adenocarcinoma (mPDAC) point to a yet unrealized potential of clinically significant immune activation. In our phase II study of the CD40 agonist antibody sotigalimab (sotiga) and/or nivolumab (nivo) with gemcitabine and nab-paclitaxel (chemo), we observed promising improvements in overall survival (OS) in 105 patients with newly diagnosed mPDAC (NCT03214250); the primary endpoint of 1-year OS rate was 57.7% (p = 0.006) in the nivo/chemo arm, 48.1% (p = 0.062) in the sotiga/chemo arm and 41.3% (p = 0.233) in the nivo/sotiga/chemo arm (O’Hara, ASCO 2021) as compared to a historical control of 35%. Here, we report results of multi-omic translational analyses designed to identify signatures predictive of OS benefit. Methods: Longitudinal blood and tumor tissue samples were collected for immune and tumor biomarker analysis. Tumor samples underwent RNA sequencing and multiplex immunofluorescence (mIF). Peripheral blood was analyzed by mass cytometry time of flight (CyTOF), high parameter flow cytometry, and proteomics. Machine learning (ML) algorithms were applied to the data to identify biosignatures related to OS in each arm. Results: Comprehensive multi-omic, multi-parameter immune and tumor biomarker analyses identified distinct pretreatment immune signatures predictive of longer OS specific to nivo/chemo or sotiga/chemo (Table, representative examples). Because patients in each arm received chemotherapy, these and other arm-unique biomarkers suggest a relationship to the immunotherapy rather than chemotherapy in this randomized study. There was evidence of immune exhaustion in the sotiga/nivo/chemo arm that may explain the lack of survival benefit. Conclusions: From in-depth translational and ML analyses of randomized phase II trial of first-line chemoimmunotherapy in mPDAC patients, we identified novel biomarkers that associated with OS distinctly in each arm. Clinical trials in first-line mPDAC exploiting these previously unappreciated biomarkers and aiming to enrich patients for response, are warranted to further advance chemoimmunotherapy in this disease. Clinical trial information: NCT03214250. [Table: see text]

3592 Background: While BRAFV600E accounts for the majority of BRAF mutations in mCRC, non-V600 BRAF variants (a BRAF) have emerged in recent years as a distinct molecular subtype. There are no consensus recommendations regarding management. This study provides a comprehensive profile of a BRAF, their clonalities and co-mutations in mCRC using a large genomic database as well as a prospective treatment cohort of patients with a BRAF and mCRC managed at a single center. Methods: A systematic analysis was performed of patients with mCRC who underwent ctDNA testing (Guardant360 platform, Guardant Health) from September 2014 to May 2021. A variant was defined as clonal if the mutant allele frequency (MAF) was greater than 50% of the highest somatic MAF in the sample; otherwise it was defined as subclonal. Co-mutation analysis was conducted with BRAF, KRAS, NRAS, NF1, ERBB2, PIK3CA and SMAD4. Treatment history and overall survival (OS) for patients with a BRAF mCRC from MD Anderson Cancer Center were included. Results: 1,733 out of 14,742 mCRC patients had at least one BRAF variant, including 6.5% of patients with BRAFV600E variants and 6.2% with a BRAF variants (1.1% with class II, 1.9% with class III, and 3.2% with unclassified variants). 431 unique BRAF variants were identified in a total of 1,905 BRAF variants. BRAF class II and III variants showed a higher rate of co-occurring KRAS mutations (25.6% and 21.5%) and co-occurring NRAS mutations (5.8% and 2.7%) compared with BRAFV600E variants (2.4% for KRAS and 0.1% for NRAS); however, co-occurring KRAS G12C was only noted in one patient. In our MDACC cohort, 38 patients were included in the analysis. The median age was 55, 81% were Caucasian, and 74 % had left sided primary tumors (45% rectal, 24% sigmoid) with 37% being exposed to at least 2 lines of therapy. The most common mutations in clinical practice were class III, D594G (39%), followed by class II G469A (10%), & class III G466E (7%). The median follow-up time was 23.8 months (mo). While there were no survival differences between a BRAF classes II and III, there was a significant difference in OS in patients with RAS co-mutation (28.3 mo vs not reached [NR], p = 0.05) or liver involvement (28.8 mo vs NR, p = 0.02). Patients < 50 years of age had extremely poor survival with OS of 16.3 mo (vs. NR) and HR 7.51 (95% CI 1.82-31.0, p = 0.005). Treatment with anti-EGFR or use of metastasectomy was not associated with improved survival. Conclusions: a BRAF mutations have historically been considered a favorable prognostic marker in mCRC. Co-mutation with RAS is frequent for both classes and portends poor survival in our real-world cohort. Furthermore, early onset a BRAF mCRC is associated with more aggressive disease. These factors highlight the need for dedicated clinical trials for this unique subset of mCRC and may represent an opportunity to improve management in early onset colorectal cancer.

2548 Background: Circulating tumor DNA (ctDNA) is increasingly used as a prognostic marker with high ctDNA shedding associated with poor survival. Gene-, but not variant-specific, differences in ctDNA shedding have been reported. Tumor burden, mitotic rate, and cell death rate have been proposed as contributors to ctDNA shedding. Here we investigate associations of ctDNA shedding for the two most common mPDAC KRAS variants, G12D and G12V, with tumor burden, mitotic score, and overall survival (OS). Methods: Pretreatment (baseline) ctDNA was analyzed by droplet digital PCR for 86 (including 44 G12D, 30 G12V) patients with mPDAC receiving front-line chemoimmunotherapy in a randomized open-label Phase II study (NCT03214250). Baseline tumor burden in total, within the pancreas, and distally, was assessed by sum of RECIST target lesion diameters. Tumor tissue variant allele fraction (tVAF) and mitotic score (geometric mean expression of 65 mitosis-associated genes) were calculated from DNA and RNA sequencing. Results: ctKRAS shedding (dichotomized at median mutant copies/mL) was associated with OS for G12D bearing tumors (p = 0.03) but not G12V (p = 0.17, log-rank test). To identify variant-specific features of shedding, we examined the Spearman correlation for total tumor burden and ctKRAS shedding; G12D but not G12V shedding was correlated with tumor burden (p = 0.01 and p = 0.22 respectively). However, the higher tVAF in G12V compared to G12D tumors (p = 0.048, Mann-Whitney test) could result from differences in purity, ploidy, and KRAS copy number. Thus, we used tVAF as a scalar to calculate an adjusted tumor burden which was significantly correlated with both G12D and G12V ctDNA shedding (p = 0.004 and 0.02, respectively). When a patient’s distal vs. pancreatic lesions were analyzed separately, pancreatic tumor burden was not correlated with G12D or G12V shedding (p = 0.10 and 0.33, respectively) but distal burden was correlated with both (p = 0.001 and 0.02, respectively). While there was no difference by KRAS variant for the correlation between adjusted tumor burden and shedding, these results do suggest that, in patients with mPDAC, distal rather than primary tumor burden may drive ctDNA shedding. Finally, tumor mitotic rate was combined with adjusted total tumor burden in a linear regression model; both were significant for predicting G12D shedding (p = 0.007 and p < 0.0001, respectively) but not for G12V (p = 0.045 and p = 0.16, respectively). Conclusions: These data suggest that ctDNA shedding and survival associations may be KRAS variant-specific in mPDAC. Tumor mitotic score and location of tumors may explain some variant-specific differences in shedding. As clinical ctDNA tests become more widely used, further investigation of variant-specific shedding in KRAS and other genes may be key for proper interpretation of ctDNA tests.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology. Experimental Design: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology. Results: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth. Conclusions: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.

Purpose The most common cause of death in advanced/metastatic hepatocellular carcinoma (HCC) is liver failure due to tumor progression. While retrospective studies and meta-analyses of systemic therapy combined with liver-directed therapy have been performed, prospective studies of safety/efficacy of antiangiogenesis followed by intra-arterial therapies are lacking. We tested our hypothesis that sorafenib followed by yttrium 90 glass microspheres (90Y GMs) is safe and that survival outcomes may improve by controlling hepatic tumors. Methods We enrolled 38 Child–Pugh A patients with advanced/metastatic HCC. In sum, 34 received sorafenib, followed after 4 weeks by 90Y GMs. Analysis of safety and survival outcomes was performed to assess adverse events, median progression-free survival, and overall survival. Results A total of 34 patients were evaluable: 14 (41.2%) with chronic hepatitis, nine (26.5%) with vascular invasion, and eleven (32.4%) with extrahepatic diseases. Safety analysis revealed that the combination therapy was well tolerated. Grade III–IV adverse events comprised fatigue (n=3), diarrhea (n=2), nausea (n=1), vomiting (n=2), hypertension (n=4), thrombocytopenia (n=1), hyperbilirubinemia (n=1), proteinuria (n=1), hyponatremia (n=1), and elevated alanine or aspartate aminotransferase (n=5). Median progression-free and overall survival were 10.4 months (95% CI 5.8–14.4) and 13.2 months (95% CI 7.9–18.9), respectively. Twelve patients (35.3%) achieved partial responses and 16 (47.0%) stable disease. Median duration of sorafenib was 20 (3–90) weeks, and average dose was 622 (466–800) mg daily. Dosimetry showed similar mean doses between planned and delivered calculations to normal liver and tumor:normal liver uptake ratio, with no significant correlation with adverse events at 3 and 6 months post-90Y treatment. Conclusion This is the first prospective study to evaluate sorafenib followed by 90Y in patients with advanced HCC. The study validated our hypothesis of safety with encouraging efficacy signals of the sequencing treatment, and provides proof of concept for future combination modalities for patients with advanced or metastatic HCC. Clinical Trial Registration Number NCT01900002.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

BackgroundGlucose-regulated protein 78 (GRP78) plays an essential role in protein folding, transportation, and degradation, thus regulates ER homeostasis and promotes cell survival, proliferation and invasion. GRP78 expression in PDAC patients who received neoadjuvant therapy has not been reported.MethodsThis retrospective study of resected PDAC patients included 125 patients treated with neoadjuvant therapy (NAT) and 140 patients treated with surgery first (SF). The expression of GRP78 was evaluated by immunohistochemistry on tissue microarrays and the results were correlated with clinicopathologic parameters and survival.ResultsGRP78 expression was higher in SF patients compared to NAT patients (P&nbsp

IMPORTANCE: The subtype of pancreatic ductal adenocarcinoma cancer (PDAC) with DNA damage repair (DDR) deficiency from BRCA1/2 variants has a favorable prognosis and is sensitive to platinum analogues and poly–(adenosine diphosphate–ripose) polymerase (PARP) inhibition with olaparib. Approximately 10% to 20% of patients with PDAC have DDR genetic alterations other than germline BRCA variants. This population has been termed as having BRCAness. An opportunity exists to define the clinical phenotype, molecular underpinnings, and effectiveness of PARP inhibitors for this population. OBJECTIVE: To examine the therapeutic effectiveness of the PARP inhibitor olaparib for patients with pancreatic cancer with BRCAness. DESIGN, SETTING, AND PARTICIPANTS: Two parallel phase 2 nonrandomized clinical trials were conducted from November 11, 2016, to October 2, 2018, among 46 patients in Israel and Texas to determine the effectiveness of olaparib as monotherapy in advanced, previously treated PDAC with BRCAness. Inclusion criteria were treatment with 1 or more prior systemic therapies for advanced PDAC, Eastern Cooperative Oncology Group performance status of 0 to 1, and lack of the germline BRCA1/2 variant. BRCAness in these studies was defined as previously known DDR genetic alterations (DDR-GAs), personal or family history of BRCA-associated cancers (without DDR-GAs), or ATM protein loss as determined by immunohistochemistry. MAIN OUTCOMES AND MEASURES: The primary study end point was the objective response rate, and the secondary end points were progression-free survival and overall survival (OS). RESULTS: Forty-eight patients were enrolled, and 46 (26 women [57%]; mean [SD] age, 65.5 [11.1] years) were evaluable. The median treatment duration with olaparib was 3.0 months (interquartile range, 1.8-6.4 months). A total of 24 patients had the DDR phenotype (DDR-GAs), 17 had a family history of BRCA-associated cancers without DDR-GAs, and 5 had ATM loss as determined by immunohistochemistry. The DDR-GAs included ATM (n = 14), PALB2 (n = 2), ARID1A (n = 3), BRCA somatic (n = 1), PTEN (n = 1), RAD51 (n = 1), CCNE (n = 1), and FANCB (n = 2). Common toxic effects were grade 1 to 2 anemia, fatigue, anorexia, and nausea. One patient had a confirmed partial response (2%), 33 patients experienced stable disease (72%), of whom 11 (24%) experienced disease stability longer than 4 months and 12 patients had progressive disease (26%). The response duration for the patient with confirmed partial response was 3.9 months. Median progression-free survival was 3.7 months (95% CI, 2.9-5.7) and was significantly higher for patients with DDR-GAs (5.7 months; 95% CI, 3.6-8.8 months; P = .008) and platinum-sensitive PDAC (4.1 months; 95% CI, 3.6-7.8 months; P = .01). The estimated median OS was 9.9 months (95% CI, 7.6-16.1 months) in the study and 13.6 months (95% CI, 9.69 to not reached) in the prespecified DDR-GA cohort. CONCLUSIONS AND RELEVANCE: The definition of the BRCAness phenotype in PDAC may be limited to patients harboring DDR-GAs. In these 2 phase 2 nonrandomized clinical trials, olaparib was well tolerated and showed limited antitumor activity in patients with advanced, platinum-sensitive PDAC with DDR-GAs. These conclusions suggest a potential therapeutic opportunity for a subset of patients with PDAC.

BACKGROUND: CD73, a newly recognized immune checkpoint mediator, is expressed in several types of malignancies. However, CD73 expression and its impact on tumor microenvironment and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) remain unclear. METHODS: This study included two cohorts: 138 patients from our institution (MDA) and 176 patients from TCGA dataset. CD73 expression, CD4+, CD8+, CD21+ and CD45RO+ tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry using tissue microarrays. The results of CD73 expression were correlated with clinicopathologic parameters, survival and TILs. RESULTS: CD73 overexpression correlated with poorly differentiation (P = 0.002) and tumor size (P = 0.049). For CD73-low group, median overall survival (OS) and recurrence-free survival (RFS) were 26.9 ± 3.8 months and 12.6 ± 2.6 months, respectively, compared to 16.9 ± 4.4 months (P = 0.01) and 7.9 ± 1.2 months (P = 0.01), respectively, in CD73-high group. CD73 was an independent predictor for both RFS (P = 0.015) and OS (P = 0.01) by multivariate variate analysis. Similarly, CD73-high tumors had significantly shorter OS than CD73-low tumors in TCGA dataset (P < 0.0001). CD73-high correlated with decreased CD4+ TILs in MDA cohort and decreased CD8A and CR2 (CD21) expression in TCGA cohort. CONCLUSIONS: CD73 overexpression is associated with poor differentiation, tumor size, and shorter survival, and is an independent prognostic factor in PDAC patients. CD73 overexpression is associated with decreased CD4+, CD8+ and CD21+ TILs. Our data support that CD73 plays an important role in immunosuppressive tumor microenvironment and promote tumor progression in PDAC.

Summary Background Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. Methods This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov , NCT03214250 and is ongoing. Findings Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). Interpretation APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. Funding Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.

BACKGROUND: Objective responses to first-line systemic chemotherapy in metastatic pancreatic cancer patients are seen in less than one third of cases. Unfortunately, a significant amount will have disease progression (PD) on their first restaging imaging. With patients’ short life expectancy, it is crucial for clinicians to be prudent when deciding whom and when to treat. Our study aimed to evaluate outcomes of patients that progressed on their first restaging imaging on 1(st) line therapy. METHODS: We retrospectively analyzed patients diagnosed between 2010–2017 whose first restaging imaging demonstrated PD. The primary outcome was overall survival (OS) from metastatic diagnosis date to death. Patients who were lost to follow-up were excluded. RESULTS: Out of 262 total patients reviewed, 98 patients (37%) were included. Sixty-five (66%) received 2(nd) line therapy, and 33 (34%) did not. Reasons patients did not pursue 2(nd) line therapy were performance status (PS) decline, organ dysfunction, or patient choice for alternative therapy. Median ages for patients who did and did not receive 2(nd) line therapy were 61 and 67, respectively (P

Previously, we characterized qualitative imaging-based subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed tomography (CT) scans. Conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we developed a quantitative classification of this imaging-based subtype (quantitative delta, q-delta). Retrospectively, baseline pancreatic protocol CT scans of three cohorts (cohort#1 = 101, cohort#2 = 90 and cohort#3 = 16 [external validation]) of patients with PDAC were qualitatively classified into high and low delta. We used a voxel-based method to volumetrically quantify tumor enhancement while referencing normal-pancreatic-parenchyma and used machine learning-based analysis to build a predictive model. In addition, we quantified the stromal content using hematoxylin- and eosin-stained treatment-na&iuml, ve PDAC sections. Analyses revealed that PDAC quantitative enhancement values are predictive of the qualitative delta scoring and were used to build a classification model (q-delta). Compared to high q-delta, low q-delta tumors were associated with improved outcomes, and the q-delta class was an independent prognostic factor for survival. In addition, low q-delta tumors had higher stromal content and lower cellularity compared to high q-delta tumors. Our results suggest that q-delta classification provides a clinically and biologically relevant tool that may be integrated into ongoing and future clinical trials.

Background Sorafenib was the first systemic therapy approved for the treatment of Child-Turcotte-Pugh (CTP) class A patients with advanced hepatocellular carcinoma (HCC). However, there are no biomarkers to predict survival and treatment outcomes and guide HCC systemic therapy. Type 1 insulin-like growth factor (IGF-1)/CTP composite score has emerged as a potential hepatic reserve assessment tool. Our study investigated the association of the IGF/CTP score with overall survival (OS) and progression-free survival (PFS) of HCC patients treated with sorafenib. Materials and methods In this prospective study, patients with HCC were treated with sorafenib and followed up until progression/death. We calculated the IGF/CTP score and used the Kaplan-Meier method and log-rank test to estimate and compare the time-to-event outcomes between patient subgroups. Results 171 patients were included, 116 of whom were CTP class A. Median PFS for IGF/CTP score AA and AB patients were 6.88 and 4.28 months, respectively (p = 0.1359). Median OS for IGF/CTP score AA and AB patients were 14.54 and 7.60 months, respectively (p = 0.1378). The PFS and OS was superior in AA patients, but the difference was not significant, likely due to the sample size. However, there was a significant difference in early OS and PFS curves between AA and AB (p = 0.0383 and p = 0.0099), respectively. Conclusions In CTP class A patients, IGF/CTP score B was associated with shorter PFS and OS, however, study was underpowered to reach statistical significance. If validated in larger cohorts, IGF/CTP score may serve as stratification tool in clinical trials, a hepatic reserve assessment tool for HCC outcomes prediction and to assist in therapy decisions.

Objective Small bowel adenocarcinoma (SBA) is a rare malignancy with limited evidence regarding outcomes after curative resection of localised disease. We aimed to evaluate presentation and prognostic factors affecting overall survival (OS), relapse-free survival (RFS) and recurrence of SBA. Methods Consecutive patients with completely resected localised SBA (1979–2019) were retrospectively reviewed for presentation, patient and tumour characteristics, perioperative treatment, recurrence, outcomes, and prognostic factors. Results Among 257 total patients, median age was 58 years. Primary location was in the duodenum, jejunum and ileum in 52%, 29%, and 19% of patients, respectively. Median OS was 57.5 months and median follow-up was 40 months. In multivariate analysis, lymph node involvement, lymphovascular invasion, histologic grade and race were independent predictors of RFS, while race, stage and histologic grade were independent predictors of OS. No significant difference in OS or RFS was seen when evaluating the role of perioperative treatment. Median time to diagnosis from first medical evaluation was 31 days and did not change over time. Overall recurrence rate was 56%. Recurrence rate was higher in ileal (77%), than duodenal (54%) and jejunal (65%) SBA (p=0.01). Recurrence presented most commonly as distant metastasis (71%). Proficient mismatch repair was associated with decreased risk of locoregional recurrence (LR) but increased risk of distant recurrence (DR) when compared with deficient mismatch repair (dMMR) in univariate analysis. Conclusions Despite advances in diagnostic modalities, this study did not show any improvement in earlier diagnosis of SBA over the course of the past three decades. The predominant pattern of disease recurrence was distant across all SBA locations, but dMMR status demonstrated a robust predilection for LR as opposed to DR. Perioperative treatment did not improve outcomes; however, a lower stage disease was seen in patients that received neoadjuvant therapy, suggesting further exploration of this approach.

Many individuals are wearing face masks improperly at ‘half mask’ and potentially breathing out microbes that can contaminate the air as well as anything below the nose. This note provides the first report that bacteria and fungi breathed out during nasal air exhalation are able to be cultured after landing on blood agar plates. The CFU’s are higher after both 10 breaths and extremely significant for 20 breaths compared to the control plates exposed to the air. Implications of this finding are that going ‘nose commando’ may be able to continue the spread of respiratory diseases such as COVID-19. Minute bioaerosols carrying bacteria may be designated as microsnot.

IMPORTANCE: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nanoparticle albumin-bound (nab)–paclitaxel (GA) are first-line chemotherapy regimens for pancreatic cancer. Their relative efficacy in the setting of localized disease is unknown. OBJECTIVE: To evaluate radiographic and serologic measures of responses associated with first-line chemotherapy with FOLFIRINOX or GA, and to determine the association between these drug regimens, putative measures of response, and survival. DESIGN, SETTING, AND PARTICIPANTS: This case series assessed 485 consecutive patients who were diagnosed as having previously untreated localized pancreatic ductal adenocarcinoma at The University of Texas MD Anderson Cancer Center between January 1, 2010, and December 31, 2017, and who received at least 3 cycles of first-line chemotherapy with FOLFIRINOX or GA. The median (range) follow-up duration was 33 (2-28) months. EXPOSURES: Administration of FOLFIRINOX (285 patients [59%]) or GA (200 patients [41%]) as first-line chemotherapy. MAIN OUTCOMES AND MEASURES: Resection rate, radiographic metrics (Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, and change in tumor volume or anatomic staging), a serologic metric (serum cancer antigen 19-9 level), and overall survival after administration of first-line chemotherapy. RESULTS: In total, 485 patients (266 [55%] male) were included in the analysis. Patients treated with FOLFIRINOX were generally younger (median [range] age at diagnosis: 61 [30-81] vs 71 [36-89] years; P = .001) and had better performance status as indicated by the Eastern Cooperative Oncology Group scale (range 0-4, with lower numbers representing better performance) score of 2 or lower (274 patients [96%] vs 165 patients [82%] P = .001) but more invasive tumors than patients who received GA (91 [32%] vs 90 [45%] resectable tumors; P = .01). After propensity score matching to control for these biases, many objective serologic and radiographic metrics of response associated with administration of FOLFIRINOX or GA—including low rates of local tumor downstaging—did not differ. However, RECIST partial response was more common among patients treated with FOLFIRINOX (27 of 140 patients [19%]) than with GA (8 of 140 patients [6%]; P = .001). Moreover, (chemo)radiation (50% vs 34%; P = .001) was more commonly administered to and pancreatectomy (27% vs 16%; P = .01) was subsequently performed more frequently for patients initially treated with FOLFIRINOX. The overall survival duration of patients treated with either regimen was similar (hazard ratio, 1.48; 95% CI, 0.97-2.26; P = .07). CONCLUSIONS AND RELEVANCE: In this cohort of patients with localized pancreatic adenocarcinoma who received FOLFIRINOX or GA as their first line of therapy, FOLFIRINOX was associated with higher rates of RECIST partial response and subsequent pancreatectomy than GA, but the overall survival associated with these regimens was similar.

PURPOSE: KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS: We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS: Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION: PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

Introduction It has been determined that right-sided metastatic colorectal cancer (mCRC) has a worse prognosis for overall survival (OS). Currently, there is no consensus on the best systemic regimen for treatment-naive right-sided tumors. We compared the impact of subsequent therapies on OS of patients treated with FOLFOXIRI (leucovorin, 5-fluorouracil, oxaliplatin, irinotecan) versus doublet regimens. Patients and Methods Data of patients with treatment-naive right-sided mCRC who received FOLFOXIRI or doublet regimens between January 2001 to December 2018 were retrospectively analyzed. OS was compared between the two groups, and prognostic factors were assessed by multivariate analysis. Results A total of 196 patients were selected; 33 patients received FOLFOXIRI and 163 patients doublet therapy. Median follow-up was 82.3 months. The FOLFOXIRI cohort received fewer subsequent lines of therapies (61% vs. 78%, P = .043). The greater the number of subsequent lines of therapy, the lower the risk of death (hazard ratio [95% confidence interval] 0.67 [0.46-0.99], 0.62 [0.45-0.86], and 0.56 [0.39-0.81] for > 1, > 2, and > 3 lines, respectively). By multivariate analysis, metastasectomy and bevacizumab with subsequent lines of therapy were the variables with greatest positive impact on OS (respectively, hazard ratio [95% confidence interval] 0.54 [0.38-0.78] and 0.61 [0.44-0.84]). Conclusion Patients with treatment-naive right-sided mCRC who received front-line FOLFOXIRI had a lower number of subsequent therapies than patients who received doublet regimens. Our findings highlight the relevance of the continuum of care in mCRC, regardless of the first-line regimen, and the importance of careful selection of patients for the FOLFOXIRI regimen.

Background Antiangiogenics attenuate chemotherapy-related hepatotoxicity and portal hypertension. The potential impact of bevacizumab on the efficacy and safety of partial splenic embolization (PSE) in the management of chemotherapy-induced hypersplenism (CIH) has never been investigated. Patients and Methods We conducted a retrospective study with gastrointestinal cancer patients who have undergone PSE for the treatment of thrombocytopenia resulting from hypersplenism. Pre- and post-PSE platelet count (PC), the percentage of patients who resumed systemic therapy, and complication rates were compared between patients exposed and not exposed to bevacizumab. Results A total of 110 patients were eligible. Colorectal cancer was the predominant neoplasm (60%), and 5-fluorouracil, oxaliplatin, and bevacizumab were the most commonly provided drugs (70%, 65%, and 65% of patients, respectively). After PSE, 80% of patients recovered PC ≥ 100 × 109/L (100K). Systemic therapy was resumed in 81% of patients. Seventy-one patients exposed to bevacizumab had a median PC before PSE of 77.5K and after PSE of 167.0K, with a mean difference of 108K (P Conclusion PSE is a safe and effective procedure in the management of CIH, regardless of the provision of bevacizumab. Splenic infarction rate should be optimized to enhance patient outcomes.

Background Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population. Methods We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT). Results 24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0–5.7) with a median OS of 11.6 months (95% CI: 6.14–15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0–12.8) and 12.2 months (95% CI: 4.8–30.8), respectively. Conclusions In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.

Four years of observing the respiratory hygiene behaviors or cough etiquette of people in public locations resulted in observing less than two percent properly covering their coughs and sneezes. 86% coughed into their hands, did not immediately clean them, and 11% did not cover their coughs or sneezes. To reduce the spread of respiratory infections there needs to be an increase in proper hygiene behaviors. This is the first study of directly observed respiratory hygiene behaviors while coughing and sneezing among the public in the United States. The study involved observations of 1000 c/s incidents by individuals in public locations, and was concluded at the end of June 2018. The result revealed the percentage of observed behaviors ranged from .3% to 86.2 %. This information is currently critical to reduce the spread of SARS-CoV-2 and the impact of COVID-19 illness. An addendum of observations during the pandemic resulted in observing that 38% did not cover at all, not even into their masks.

TPS633 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with few effective therapeutic options. Over 90% of patients with PDAC harbor activating mutations in KRAS, a known oncogenic driver of tumor growth, cancer cell survival and metastasis thus making for an attractive therapeutic target. However, targeting the most common KRAS mutations in pancreatic cancer (KRASG12D and KRASG12V) remains a pharmacological challenge. Exosomes are extracellular nano-vesicles that are efficiently internalized by target cells and are under investigation as a drug-delivery vehicle for various therapeutic payloads, including nucleic acids such as small interfering RNA (siRNA). Previously published pre-clinical data demonstrate effective delivery of exosomes loaded with siRNA targeting KRASG12D leading to tumor control in various murine models of PDAC. Methods: This is a single arm, single institution, phase I trial evaluating treatment with KRASG12D-siRNA loaded exosomes. Large-scale production of KRASG12D-siRNA loaded exosomes from mesenchymal stromal cells will be performed at the MD Anderson Cancer Center using pre-specified GMP-compliant protocols. The primary endpoints of this study are to determine a maximum tolerated dose (MTD) of KRASG12D-loaded exosomes and to identify dose-limiting toxicities (DLT). Key secondary endpoints include the pharmacokinetics of circulating exosomes, overall response rate, disease control rate (defined as partial responses and patients with stable disease), median progression-free survival (PFS) and median overall survival (OS). Key inclusion criteria include histologically confirmed metastatic pancreatic ductal adenocarcinoma, documented progression on one or more lines of systemic therapy, and documented presence of a KRASG12D mutation. Selected correlative studies include measurement of circulating siRNA and KRASG12D DNA using PCR. This trial will enroll up to 28 patients and will follow a 3+3 design for dose escalation. This trial is actively accruing and has enrolled six patients at the time of submission. Clinical trial information: NCT03608631.

TPS634 Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a dearth of effective therapeutic options. Over 90% of PDAC harbor activating mutations in the KRAS oncoprotein, which in turn leads to activation of downstream effector proteins in the the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling cascade serving to promote tumor cell survival, growth and metastasis. Unfortunately, single agent treatment with MAPK-inhibitors have had limited therapeutic efficacy in patients with PDAC owing to development of various tumor-cell intrinsic resistance mechanisms, including upregulation of autophagy. Hydroxychloroquine is an antimalarial drug that functions to inhibit autophagy by inhibiting acidification of lysosomes. Previously published preclinical data suggest combination therapy with binimetinib, a MEK 1/2 inhibitor, and hydroxychloroquine leads to enhanced killing of PDAC cells in vitro and in vivo. Methods: This is a single arm, single center phase I trial of binimetinib plus hydroxychloroquine in patients with metastatic pancreatic cancer harboring a KRAS mutation. All patients will receive binimetinib at a fixed dose of 45mg PO twice daily (14-day cycles) while hydroxychloroquine will be dosed at 400mg PO twice daily (14-day cycles) and dose escalated using a Bayesian optimal interval design with a target toxicity rate of 0.3. Key eligibility criteria include histologically confirmed metastatic pancreatic adenocarcinoma, prior treatment with at least one line of systemic therapy and a documented KRAS mutation. An estimated 24 patients will be enrolled in the first phase of this study and up to 15 patients in the dose expansion cohort. The primary endpoint of this study is to determine the maximum tolerated dose (MTD) of hydroxychloroquine when combined with a fixed dose of binimetinib. Key secondary endpoints include safety and toxicity profile, response rate, progression free survival (PFS) and overall survival (OS). This study is ongoing and has enrolled 10 patients at the time of submission. Clinical trial information: NCT04132505.

577 Background: Immune-checkpoint inhibitors (ICI) have altered the treatment landscape of various solid tumors, but clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) continue to remain dismal. Data are needed to determine prognostic factors of survival to ICI-therapies in pancreatic cancer to better inform future recruitment in immunotherapy-based early clinical trials. Methods: This is a single center, retrospective analysis of patients with PDAC treated with ICI-based therapy as part of phase I trials at MD Anderson Cancer Center. Patients enrolled in a phase I study and treated between 2014 to 2021 were included in the analysis. Descriptive analysis included patient characteristics, progression free survival (PFS) and overall survival (OS). Cox proportional hazards were used to assess associations between patient or tumor characteristics and survival endpoints. Results: One hundred and twenty-two patients were included in this study and received a median of two prior lines of therapy (IQR 1-3). The most commonly utilized ICI were PD-L1 inhibitors (56%) and PD-1 inhibitors (34%). Most patients (96%) received ICI in combination with another investigational agent and 9% of patients received ICI in combination with chemotherapy. The median duration of treatment was 1.38 months (IQR 0.69-2.56). The median PFS was 1.81 months (95% CI 1.78-2.04) and the median OS was 4.83 months (95% CI 4.08-5.92). Univariate analysis showed improved PFS in patients with an albumin of ≥3.5 (1.94 vs 1.32 months, HR 0.29, 95% CI 0.14-0.60, p = 0.001) and Hgb ≥10.5 (1.87 vs 1.81 months, HR 0.63, 95% CI 0.4-0.98, p = 0.039); a longer OS was demonstrated in patients who had lung only metastases (7.92 vs. 4.18 months, HR 0.4, 95% CI 0.21-0.76, p = 0.006), albumin ≥3.5 (5.52 vs. 1.68 months, HR 0.4, 95% CI 0.2-0.8, p = 0.010), and a Hgb ≥10.5 (5.29 vs 4.11 months, HR 0.59, 95% CI 0.38-0.93, p = 0.022). Patients with an ANC/ALC ratio of ≥5 had a shorter OS compared to patients with an ANC/ALC ratio of < 5 (3.98 vs 6.54 months, HR 1.78, 95% CI 1.17-2.69, p = 0.007). Multivariate analysis showed that an albumin ≥3.5 predicted improved PFS (HR 0.41, 95% CI 0.19-0.90, p = 0.026) and an ANC/ALC ratio of ≥5 predicted shorter OS (HR 2.59, 95% CI 1.59-4.19, p < 0.001). Conclusions: Results of this large, single center retrospective study demonstrate that most patients with PDAC treated with ICI based therapies as a part of early phase clinical trials experience disease progression shortly after initiation of therapy and have a limited overall survival. Pretreatment albumin ≥3.5 predicted improved PFS and ANC/ALC ratio ≥5 predicted shorter OS.

12 Background: Encorafenib (E) and cetuximab (C) offers short-lived response and survival benefit for patients (pts) with MSS, BRAFV600E metastatic colorectal cancer (CRC). BRAF + EGFR inhibition induced a transient MSI-H phenotype in preclinical models of MSS, BRAFV600E CRC and may prime these tumors for response to immunotherapy with anti-PD-1 antibodies like nivolumab (N). Methods: In this single-arm, single-institution, phase I/II clinical trial, pts with treatment-refractory MSS, BRAFV600E metastatic CRC were eligible. No prior BRAF inhibitors, anti-EGFR antibody, or immunotherapy was permitted. Pts received E (300 mg PO daily), C (500 mg/m2 IV q14 days), and N (480 mg IV q28 days). The primary endpoints were best overall response (RECIST 1.1) and safety/tolerability (CTCAE v5). A Simon two-stage design (H0: p≤.22; Ha: p≥.45, where p= percentage of pts with radiographic response) was employed using a one-sided α=.05 and β=.20. In the first stage, ≥ 4/15 responses were needed in order for the trial to enroll 11 additional pts. Median progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier. Results: All 26 pts have been enrolled - 23 patients treated, and 21 evaluable for response so far. Median age is 59 years (range, 32-85), and 14 (54%) are female. No dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events (AE) occurred in 4/22 (18%) patients. Grade 3 AEs included colitis, maculopapular rash, leukocytosis, and elevated amylase/lipase (all N=1). Grade 4 AEs in a single patient were myositis/myocarditis. Overall response rate is 45% (95% CI, 23-68), and disease control rate is 95% (95% CI, 75-100). Median PFS is 7.3 months (95% CI, 5.5-NA). Median OS is 11.4 months (95% CI, 7.6-NA). For the 9 pts thus far with responses, median duration of response is 8.1 months (95% CI, 7.3-NA). Updated results will be presented. Conclusions: E + C + N is effective and well-tolerated for pts with MSS, BRAFV600E metastatic CRC. The E+C+N regimen met its predefined efficacy endpoint and suggests a role for immunotherapy as a novel combination approach for this specific subpopulation of MSS metastatic CRC. A follow-up randomized phase II trial (SWOG 2107) to evaluate encorafenib/cetuximab with or without nivolumab in pts with MSS, BRAFV600E metastatic CRC will activate in early 2022. Clinical trial information: NCT04017650.

Preoperative chemotherapy provides early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy for localized pancreatic ductal adenocarcinoma (PDAC). For locally advanced (LA) PDAC, induction chemotherapy is the standard of care. This study evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy for localized PDAC. Clinicopathologic features, treatment, and outcomes were evaluated for 99 patients with localized PDAC. The patients were staged using previously published criteria as follows: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR–C (comorbidities requiring medical optimization), and LA. The 99 patients (PR/BR/LA: 45/14/40) were treated with Gem/nab-P. Clinical staging showed that 20 patients had PR or BR-A disease, whereas 39 patients had BR-B or BR-C disease. The BR-B+C cases included one or more of the following: age of 80 years or older (13%), Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more (13%), moderate to severe comorbidities (55%), CA19-9 of 1000 or higher (28%), and suspicion for metastases (21%). The majority of the patients received biweekly Gem/nab-P dosing, which was well tolerated. Pancreatectomy was performed for 12 (60%) of 20 patients with PR+BR-A, 2 (5%) of 39 patients with BR-B+C, and 1 (3%) of 40 patients with LA disease. During a median follow-up period of 26 months, the median overall survival (OS) period was 18 months (95% confidence interval [CI], 15.6–20.5 months) for all the patients, 17 months (95% CI, 14.6–19.5 months) for the unresected patients, and not reached for the resected patients (p = 0.028 for resected vs unresected patients). A significant number of patients with radiographically resectable PDAC albeit aggressive biology (BR-B), medically inoperable conditions (BR-C), or both received biweekly first-line Gem/nab-P. The resection rates were lower for the BR-B/BR-C patients than for the PR/BR-A patients (hazard ratio [HR], 0.43; 95% CI, 0.19–1.00; p = 0.05).

// Robert A. Wolff 1,* , Andrea Wang-Gillam 2,* , Hector Alvarez 8,* , Herve Tiriac 3,* , Dannielle Engle 3,* , Shurong Hou 4,* , Abigail F. Groff 6,* , Anthony San Lucas 9 , Vincent Bernard 10 , Kelvin Allenson 11 , Jonathan Castillo 8 , Dong Kim 8 , Feven Mulu 8 , Jonathan Huang 8 , Bret Stephens 8 , Ignacio I. Wistuba 9 , Matthew Katz 11 , Gauri Varadhachary 1 , YoungKyu Park 3 , James Hicks 3 , Arul Chinnaiyan 5 , Louis Scampavia 4 , Timothy Spicer 4 , Chiara Gerhardinger 6 , Anirban Maitra 8 , David Tuveson 3 , John Rinn 6,13 , Gregory Lizee 12 , Cassian Yee 12 and Arnold J. Levine 7 1 Department of Gastrointestinal (GI) Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA 2 Division of Oncology, Washington University, St. Louis, MO, USA 3 Cold Spring Harbor Laboratory, New York, NY, USA 4 Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA 5 Center for Translational Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA 6 Department of Molecular and Cellular Biology, Harvard University, The Broad Institute, Cambridge, MA, USA 7 Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA 8 Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA 9 Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA 10 Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA 11 Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA 12 Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA 13 Current address: University of Colorado Boulder, BioFrontiers Institute, Boulder, CO, USA * These authors have contributed equally to this paper Correspondence to: Arnold J. Levine, email: // Keywords : pancreatic cancer; genomic instability; organoids; epithelial-mesenchymal transition Received : December 20, 2017 Accepted : February 01, 2018 Epub: February 13, 2018 Published: March 13, 2018 Abstract This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient’s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment.

Since the advent of modern surgery for pancreatic cancer, clinicians have recognized this cancer's propensity to recur locally, metastasize, and cause death. Despite significant efforts to improve patient outcomes with better adjuvant therapy, only modest gains in survival have been observed. An alternative strategy of neoadjuvant therapy followed by surgery has the potential to improve patient selection and survival, and expand the pool of patients eligible for curative surgery. This article summarizes large, randomized trials of adjuvant therapy, explains the limitations imposed by up-front surgery, and suggests neoadjuvant therapy as a rational alternative to initial surgery and adjuvant therapy.

Background The assessment of pancreatic ductal adenocarcinoma (PDAC) response to therapy remains challenging. The objective of this study was to investigate whether changes in the tumor/parenchyma interface are associated with response. Methods Computed tomography (CT) scans before and after therapy were reviewed in 4 cohorts: cohort 1 (99 patients with stage I/II PDAC who received neoadjuvant chemoradiation and surgery); cohort 2 (86 patients with stage IV PDAC who received chemotherapy), cohort 3 (94 patients with stage I/II PDAC who received protocol-based neoadjuvant gemcitabine chemoradiation), and cohort 4 (47 patients with stage I/II PDAC who received neoadjuvant chemoradiation and were prospectively followed in a registry). The tumor/parenchyma interface was visually classified as either a type I response (the interface remained or became well defined) or a type II response (the interface became poorly defined) after therapy. Consensus (cohorts 1-3) and individual (cohort 4) visual scoring was performed. Changes in enhancement at the interface were quantified using a proprietary platform. Results In cohort 1, type I responders had a greater probability of achieving a complete or near-complete pathologic response (21% vs 0%; P = .01). For cohorts 1, 2, and 3, type I responders had significantly longer disease-free and overall survival, independent of traditional covariates of outcomes and of baseline and normalized cancer antigen 19-9 levels. In cohort 4, 2 senior radiologists achieved a κ value of 0.8, and the interface score was associated with overall survival. The quantitative method revealed high specificity and sensitivity in classifying patients as type I or type II responders (with an area under the receiver operating curve of 0.92 in cohort 1, 0.96 in cohort 2, and 0.89 in cohort 3). Conclusions Changes at the PDAC/parenchyma interface may serve as an early predictor of response to therapy. Cancer 2018;124:1701-9. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Background Detection of circulating tumor DNA can be limited due to their relative scarcity in circulation, particularly while patients are actively undergoing therapy. Exosomes provide a vehicle through which cancer-specific material can be enriched from the compendium of circulating non-neoplastic tissue-derived nucleic acids. We carried out a comprehensive profiling of the pancreatic ductal adenocarcinoma (PDAC) exosomal ‘surfaceome' in order to identify surface proteins that will render liquid biopsies amenable to cancer-derived exosome enrichment for downstream molecular profiling. Patients and methods Surface exosomal proteins were profiled in 13 human PDAC and 2 non-neoplastic cell lines by liquid chromatography–mass spectrometry. A total of 173 prospectively collected blood samples from 103 PDAC patients underwent exosome isolation. Droplet digital PCR was used on 74 patients (136 total exosome samples) to determine baseline KRAS mutation call rates while patients were on therapy. PDAC-specific exosome capture was then carried out on additional 29 patients (37 samples) using an antibody cocktail directed against selected proteins, followed by droplet digital PCR analysis. Exosomal DNA in a PDAC patient resistant to therapy were profiled using a molecular barcoded, targeted sequencing panel to determine the utility of enriched nucleic acid material for comprehensive molecular analysis. Results Proteomic analysis of the exosome ‘surfaceome' revealed multiple PDAC-specific biomarker candidates: CLDN4, EPCAM, CD151, LGALS3BP, HIST2H2BE, and HIST2H2BF. KRAS mutations in total exosomes were detected in 44.1% of patients undergoing active therapy compared with 73.0% following exosome capture using the selected biomarkers. Enrichment of exosomal cargo was amenable to molecular profiling, elucidating a putative mechanism of resistance to PARP inhibitor therapy in a patient harboring a BRCA2 mutation. Conclusion Exosomes provide unique opportunities in the context of liquid biopsies for enrichment of tumor-specific material in circulation. We present a comprehensive surfaceome characterization of PDAC exosomes which allows for capture and molecular profiling of tumor-derived DNA.

Currently, treatment of small bowel adenocarcinoma (SBA) mirrors that of colorectal cancer (CRC). Recent genomic data have demonstrated SBA to be a genetically unique entity, suggesting that therapies not traditionally utilized in CRC should be explored. In order to further characterize the activity of taxanes in this rare cancer, we completed a single-center retrospective study. Twenty patients were found to have been treated with taxane-based regimens (monotherapy in 3, combination therapy in 17). Median time to progression was 3.8 months (95% confidence interval [CI] 2.9–4.6), and median overall survival was 10.7 months (95% CI: 3.1–18.3). The results of this study demonstrate clinical activity from taxane-based therapy in advanced SBA and support further clinical trial investigation.

BackgroundPancreatic cancer (PaC) is immune-quiescent and resistant to single-agent checkpoint inhibitor (CPI). NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 that can increase T-cell infiltration in the tumor microenvironment (TME) and may enhance tumor responsiveness to CPI therapy. We hypothesize that the combination of NT-I7 and pembrolizumab may result in enhanced efficacy in CPI-naïve advanced PaC.MethodsThis is an open-label, phase 2a, study in subjects with relapsed/refractory (R/R) tumors, including CPI-naïve R/R PaC. Subjects received NT-I7 intramuscularly at 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously Q3W. Antitumor activity based on Overall Response Rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Biomarker analyses of peripheral blood and tumor biopsies were performed.ResultsAs of 15-July-2021, 26 subjects were enrolled in the CPI naïve R/R PaC cohort. Median age 69 years [31–81], ECOG PS 0 (35%), 1 (65%). Twenty-one (81%) subjects had ≥ 2 prior therapies All subjects had metastatic or locally advanced disease at enrollment. The median duration of follow-up was 3.3 months. Among 10 subjects with at least 1 post-treatment tumor assessment, the RECIST1.1-based ORR and disease-control rate (DCR) were 10% and 50%, respectively. One subject with MSS and TMB of 1, achieved a confirmed partial response (cPR) with 65% tumor reduction and drastically improving CA19-9. Treatment-related adverse events (AEs) occurred in 14 (53.8%) subjects, 9 (34.6%) G1–2, 3 (11.5%) G3; 2 (7.7%) G4; no G5 AEs were reported. No subjects discontinued from treatment due to AE. NT-I7 + pembro elicited a significant increase in the peripheral absolute lymphocyte count that peaked at week 3 (>3X from baseline, p15X, pConclusionsThe chemo-free combination of NT-I7 + pembro was well tolerated and showed promising anti-tumor activity in subjects with CPI-naïve R/R PaC. Increased TSCM and CD8+ T-cell infiltration within TME may be the underlying mechanisms of action for the observed efficacy. These results support continued evaluation of NT-I7 + pembro in subjects with CPI-naïve R/R PaC.AcknowledgementsThe authors thank ICON for their partnership in conducting this trial.Trial RegistrationNCT04332653Ethics ApprovalThe trial was approved by MD Anderson IRB (#2020–0008_MOD001), Mary Crowley IRB (#20–13) and Advarra IRB (#Pro00042639)All participant gave informed consent prior to study enrollment.

PURPOSE/OBJECTIVE(S) The role of RT remains controversial in treating BRPC and LAPC following Alliance A021501 and LAP07. These studies shifted our institutional practice to more selective use of RT, whereas in the past, we most often consolidated with RT after chemotherapy (chemo). We reviewed our experience using modern multi-agent chemo with or without RT. MATERIALS/METHODS We utilized a retrospective registry to analyze 454 pts (240 M, 214 F, median age 65 [28 - 89]) who were diagnosed with BRPC (n = 172) or LAPC (n = 282) between 2011 to 2019 and who underwent chemo alone (n = 167) or chemo then RT (n = 287). For those pts who received RT, the median dose and fractionation was 50 Gy (30 - 98 Gy) and 15 fractions (4 - 28). Median biological effective dose was 60 Gy (33 - 132 Gy). All pts received FOLFIRINOX (n = 274) or gemcitabine/nab-paclitaxel (GnP, n = 180). Associations between chemo regimen (FOLFIRINOX vs. GnP), resection (surgery vs. no surgery), CA19-9 response (normalized vs. not vs. not applicable [N/A]), and other demographic characteristics were tested using the likelihood-ratio. CA19-9 normalizers were defined by the minimum CA19-9 value between the start of chemo and 6 mos post-chemo start that was < 40 U/mL. Pts were classified as N/A if the pt either had an abnormal bilirubin level or a CA19-9 < 40 U/mL at baseline, or were missing CA19-9 data. Kaplan-Meier and Cox proportional hazards tests were used for survival analyses. RESULTS For all pts, median overall survival (OS) was 17.5 mos and median distant metastasis free survival (DMFS) was 11.5 mos. The chemo then RT group had a greater proportion of pts who received FOLFIRINOX than the chemo only group (64% vs 54%, P = 0.03). The chemo then RT group also had a greater percentage of pts who went to surgery than the chemo alone group (33% vs 16%, P < 0.0001). Pts with BRPC were more likely to receive surgery than pts with LAPC (48% vs. 14%, P < 0.0001). Univariate analyses showed that baseline stage (BRPC vs LAPC), surgery, CA19-9 response, and receipt of chemo then RT were associated with both OS and DMFS. Chemo regimen was associated with OS but not DMFS on univariate analysis. Multivariate analysis identified that surgery, CA19-9 response, and receipt of chemo then RT were independent prognostic factors for both OS and DMFS (Table). Multivariate analysis of only LAPC showed the same associations with OS and DMFS as with all pts. CONCLUSION RT following chemo was associated with better OS and DMFS compared with chemo alone in a modern retrospective BRPC and LAPC cohort. Additional studies are needed to clarify the role of RT.

BackgroundGemcitabine/nab-Paclitaxel (GnP) is a standard of care regimen for first-line metastatic pancreatic ductal adenocarcinoma (PDAC) and has a 1-year overall survival (OS) rate of approximately 35%. There is an urgent need for novel therapeutics and precision medicine approaches in PDAC. PRINCE, a randomized phase 2 trial, reported an increased 1-year OS relative to historical data, for patients treated with nivolumab (nivo)/GnP (57.3%, p = 0.007, n=34) and sotigalimab (sotiga) (APX005M; CD40 agonist)/GnP (48.1%, p = 0.062, n= 36).MethodsTo investigate immune modulatory and pharmacodynamic (PD) effects of nivo or sotiga in combination with GnP we used several orthogonal minimally invasive, blood-based biomarker technologies. Immune population profiles were evaluated by CyTOF and features of T cell phenotype and function by multicolor flow cytometry. Soluble proteins were evaluated with predefined panels using the Olink platform (Immuno-oncology (IO) and Immune Response) along with an unbiased mass spectrometry proteomic approach (Biognosys) that identified circulating soluble proteins of significance.ResultsRelative to baseline, patients who received nivo/GnP had numerically increased frequencies of proliferating, activated CD8+ and CD4+ effector memory T cells in circulation across multiple timepoints. These patients also had significantly increased levels of soluble proteins associated with type II interferon responses and immune cell migration and T cell activation, as well as significantly decreased levels of immunomodulatory proteins.Patients who received sotiga/GnP had increased expression of the co-stimulatory molecule CD86 on conventional dendritic cells. These patients also had significantly increased concentrations of soluble proteins associated with mature antigen presenting cells, and the activation of helper CD4+ T cells, B cells, and monocytes. Significant increases in soluble proteins associated with type-1 cell-mediated effector immunity and decreases in immunosuppressive factors were observed in both arms. Significant proteins were defined as p ≤ 0.05, log2 expression fold change ≥ 0.5 (Olink) and Sparse PLS discriminant analysis was used with zero as a threshold (Biognosys).ConclusionsThis study is a first to use multiomic minimally invasive biomarker approaches in PDAC to demonstrate PD effects and immune modulation with immunotherapy/chemotherapy combinations. Orthogonal assays demonstrate that nivo/GnP and sotiga/GnP elicit unique immune responses and the observed effects are consistent with their distinct mechanisms of action. These data suggest that multiomic biomarker signatures may identify subsets of patients who may benefit from an immunotherapy/chemo approach in PDAC. Moreover, results from these analyses will support early phase clinical study development decisions.AcknowledgementsWe extend our gratitude to the patients, their families, the clinical investigators, and their site staff members who are making this trial possible. We would also like to thank Sultan Nawabi at Parker Institute for Cancer Immunotherapy (PICI) for operations leadership of the trial. We thank Bristol Myers Squibb (BMS) and Apexigen for collaboration and study drugs. The study was funded by Cancer Research Institute, BMS and PICI.Trial RegistrationNCT03214250Ethics ApprovalThis study was approved by University of Pennsylvania Institutional Review Board; Federalwide assurance #00004028.

Background Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Due to its rarity, high-quality data are lacking to guide treatment. This retrospective analysis was conducted to help characterize the treatment options for patients with metastatic SBA while providing clinically meaningful prognostic information. Patients and methods In total, 437 patients who initially presented with or developed metastatic SBA between September 1977 and September 2019 were identified from the MD Anderson Tumor Registry. Clinical data were collected from review of the medical record. Overall response rates (ORR), time to progression (TTP), and overall survival (OS) were assessed across various treatments and treatment lines. Results The median OS from diagnosis of metastatic disease was 15.9 months [95% confidence interval (CI): 14.3-17.9]. Seventy-five patients (17.1%) underwent metastasectomy, which was associated with a median OS of 34.5 versus 17.1 months among patients who received chemotherapy alone (P < 0.001). Fluoropyrimidine plus platinum (n = 164) was the most common first-line chemotherapy, associated with an ORR of 59% and TTP of 8.1 months. Irinotecan with 5-FU (n = 101) was the most common second-line therapy associated with an ORR of 31% and TTP of 4.0 months. Twenty-two patients received immunotherapy; 5 of 6 patients with deficient mismatch repair (dMMR) responded, while 0 of 16 with proficient mismatch repair (pMMR) responded. Taxane-based chemotherapy was given to 34 patients with an ORR of 21% and a median TTP of 2.4 months. Among 11 patients who received anti-epidermal-growth-factor-receptor (EGFR) monotherapy, the best response was stable disease (SD) in 1 patient. Conclusions In well-selected patients with SBA, metastasectomy appears to be associated with improved OS. This improvement was seen across metastasectomy sites, including liver, lung and peritoneal. Anti-programmed cell death protein 1 (PD-1) based immunotherapy was active for dMMR SBA but not pMMR SBA. While taxane-based chemotherapy demonstrates therapeutic activity, the activity of anti-EGFR therapy was limited., Highlights • Metastasectomy for well-selected metastatic SBA patients was associated with improved OS. • Anti-PD1-based immunotherapy was active for dMMR SBA but not pMMR SBA. • Taxane-based chemotherapy demonstrated clinical activity in refractory SBA. • Anti-EGFR therapy demonstrated minimal activity in SBA.