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Purpose Guanylyl cyclase C (GCC) is highly expressed in several gastrointestinal malignancies and preclinical studies suggest that it is a promising target for antibody-based therapeutics. This phase I trial assessed the safety and tolerability of TAK-164, an investigational, anti-GCC antibody–drug conjugate (NCT03449030). Methods Thirty-one patients with GCC-positive, advanced gastrointestinal cancers received intravenous TAK-164 on day 1 of 21-day cycles. Dose escalation proceeded based on cycle 1 safety data via a Bayesian model. Results Median age was 58 years (range 32–72), 25 patients (80.6%) had colorectal carcinoma, and median number of prior therapies was four. No dose-limiting toxicities (DLTs) were reported during cycle 1 DLT evaluation period. After cycle 2 dosing, 3 patients reported dose-limiting treatment-emergent adverse events (TEAEs): grade 3 pyrexia and grade 5 hepatic failure (0.19 mg/kg), grade 4 hepatic failure and platelet count decreased (0.25 mg/kg), grade 3 nausea, grade 4 platelet and neutrophil count decreased (0.25 mg/kg). The recommended phase II dose (RP2D) was 0.064 mg/kg. Common TAK-164-related TEAEs included platelet count decreased (58.1%), fatigue (38.7%), and anemia (32.3%). There was a dose-dependent increase in TAK-164 exposure over the range, 0.032–0.25 mg/kg. TAK-164 half-life ranged from 63.5 to 159 h. One patient (0.008 mg/kg) with high baseline GCC expression had an unconfirmed partial response. Conclusions TAK-164 appeared to have a manageable safety profile at 0.064 mg/kg. Hepatic toxicity was identified as a potential risk. The RP2D of 0.064 mg/kg was considered insufficient to derive clinical benefit; there are no plans for further clinical development. Clinical Trial Registration NCT03449030.

Purpose We conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze® technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02 + patients with advanced/metastatic HPV16 + cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8 + cells, and demonstrated antitumor activity. Methods Administration of SQZ-PBMC-HPV was every 3 weeks. Enrollment followed a modified 3 + 3 design with primary objectives to define safety, tolerability, and the recommended Phase 2 dose. Secondary and exploratory objectives were antitumor activity, manufacturing feasibility, and pharmacodynamic evaluation of immune responses. Results Eighteen patients were enrolled at doses ranging from 0.5 × 106to 5.0 × 106live cells/kg. Manufacture proved feasible and required 6live cells/kg with double priming was chosen as the recommended Phase 2 dose. Multiple participants exhibited pharmacodynamic changes consistent with immune responses supporting the proposed mechanism of action for SQZ-PBMC-HPV, including patients previously refractory to checkpoint inhibitors.

Background Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly. Methods This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70–74, 75 or more years) and respective treatment outcomes were compared. Results The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70–74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70–74 years, and 12 of 34 aged 75 years or more; P Conclusion The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years.

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. Despite excellent prognosis for early stage disease, 5-year survival rates in metastatic disease remain low. A small subset of CRC is defined by a deficiency in mismatch repair (dMMR) resulting in high levels of microsatellite instability and are responsive to immunotherapy. Immune checkpoint inhibitors (ICIs) targeting the programmed death 1 (PD-1)/programmed death ligand 1 axis and cytotoxic T-lymphocyte antigen 4 have been explored and show robust clinical outcomes with prolonged progression-free survivals in nonrandomized single-arm clinical trials. On the basis of these data, single-agent therapy with pembrolizumab and nivolumab and combination therapy with nivolumab/ipilimumab have been approved by the US Food and Drug Administration for metastatic CRC that has progressed after treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Ongoing clinical trials are exploring the use of these agents in earlier lines of therapy such as first-line metastatic therapy and adjuvant therapy for stage III CRC. However, resistance to ICIs does occur in a subset of patients and ongoing clinical trials are exploring novel approaches in these PD-1-refractory patients. The aim of this review is to outline the development and decision-making of ICIs in the treatment of dMMR CRC and to discuss ongoing clinical trials in this therapeutic space.

Background AZD0156 is an oral inhibitor of ATM, a serine threonine kinase that plays a key role in DNA damage response (DDR) associated with double-strand breaks. Topoisomerase-I inhibitor irinotecan is used clinically to treat colorectal cancer (CRC), often in combination with 5-fluorouracil (5FU). AZD0156 in combination with irinotecan and 5FU was evaluated in preclinical models of CRC to determine whether low doses of AZD0156 enhance the cytotoxicity of irinotecan in chemotherapy regimens used in the clinic. Methods Anti-proliferative effects of single-agent AZD0156, the active metabolite of irinotecan (SN38), and combination therapy were evaluated in 12 CRC cell lines. Additional assessment with clonogenic assay, cell cycle analysis, and immunoblotting were performed in 4 selected cell lines. Four colorectal cancer patient derived xenograft (PDX) models were treated with AZD0156, irinotecan, or 5FU alone and in combination for assessment of tumor growth inhibition (TGI). Immunofluorescence was performed on tumor tissues. The DDR mutation profile was compared across in vitro and in vivo models. Results Enhanced effects on cellular proliferation and regrowth were observed with the combination of AZD0156 and SN38 in select models. In cell cycle analysis of these models, increased G2/M arrest was observed with combination treatment over either single agent. Immunoblotting results suggest an increase in DDR associated with irinotecan therapy, with a reduced effect noted when combined with AZD0156, which is more pronounced in some models. Increased TGI was observed with the combination of AZD0156 and irinotecan as compared to single-agent therapy in some PDX models. The DDR mutation profile was variable across models. Conclusions AZD0156 and irinotecan provide a rational and active combination in preclinical colorectal cancer models. Variability across in vivo and in vitro results may be related to the variable DDR mutation profiles of the models evaluated. Further understanding of the implications of individual DDR mutation profiles may help better identify patients more likely to benefit from treatment with the combination of AZD0156 and irinotecan in the clinical setting.

Introduction: The impact of radiation prescription dose on postoperative complications during standard of care trimodality therapy for operable stage II-III esophageal and gastroesophageal junction cancers has not been established.Methods: We retrospectively reviewed 82 patients with esophageal or gastroesophageal junction cancers treated between 2004 and 2016 with neoadjuvant chemoradiation followed by resection at a single institution. Post-operative complications within 30 days were reviewed and scored using the Comprehensive Complication Index (CCI). Results were compared between patients treated with Results: Twenty-nine patients were treated with Conclusions: In selected esophageal and gastroesophageal junction cancer patients, radiation doses ≥ 50 Gy do not appear to increase 30 day post-operative complication rates. These findings suggest that the use of definitive doses of radiotherapy (50–50.4 Gy) in the neoadjuvant setting may not increase post-operative complications.

Background: We examined characteristics of early-onset colorectal cancer (CRC) patients to identified factors, which may lead to earlier diagnosis. Materials & methods: This is a retrospective study with inclusion criteria: CRC diagnosed between 2012 and 2018 and age at diagnosis

Pancreatic adenocarcinoma is one of the deadliest malignancies worldwide and its incidence is rising in the United States. The only potential curative treatment for this disease is surgical resection, however, due to the lack of an effective screening strategy, the majority of patients present with advanced or metastatic disease which preclude resectability. Further, the best clinical outcomes occur in those patients that receive multimodality treatment with surgical resection combined with chemotherapy with or without the addition of radiation therapy. Despite decades of innovation in treatment modalities, including chemotherapy, radiation therapy and advancements in surgical techniques, the long term outcomes for this disease remain poor with high rates of both local and distant recurrence despite curative intent treatment. The dismal outcomes of this disease highlight the dire need for more effective treatment strategies and therapeutics. This review focuses on the treatment of localized pancreatic adenocarcinoma with an in depth review of the literature to support the use of chemotherapy in the adjuvant and neoadjuvant setting in this disease and exploration and discussion of the growing paradigm shift to neoadjuvant treatment. Further, this review highlights the ongoing and planned clinical trials evaluating neoadjuvant treatment strategies and novel therapeutics in localized pancreatic adenocarcinoma.

BackgroundTreatment-related toxicity can vary substantially between chemotherapy regimens. In this study we evaluated the frequency of outpatient office visits among a cohort of early stage breast cancer survivors after completion of 4 different adjuvant chemotherapy regimens to better understand how differences in toxicities between regimens might affect health care use.Materials and methodsWe analyzed administrative claims data from a US commercial insurance database (OptumLabs) to identify women who received adjuvant doxorubicin/cyclophosphamide (AC), AC followed or preceded by docetaxel or paclitaxel (AC-T), AC concurrent with docetaxel or paclitaxel (TAC), or docetaxel/cyclophosphamide (TC) between 2008 and 2014. We compared mean numbers of visits per patient (adjusted for age, race/ethnicity, region, year, surgery type, radiation, chronic conditions, and previous hospitalizations) across the different regimens (TC= reference) for 12 months, starting 4 months after the end of chemotherapy.ResultsIn 6247 eligible patients, the mean adjusted number of outpatient visits per patient was significantly higher in patients who received AC-T (8.1) or TAC (7.3) than TC (6.5) or AC (6.0; P< .001 for comparisons of AC-T and TAC with TC), primarily because of differences in Medical Oncology visits. Approximately 40% did not see a primary care provider at all during this time frame.ConclusionsAC-T and TAC are associated with more subsequent outpatient visits than TC. Visits to primary care providers are infrequent during the year after completion of chemotherapy.

Purpose: Prevention of chemotherapy-induced nausea and vomiting is essential to preserve quality of life in patients with cancer receiving highly emetogenic chemotherapy (HEC). Recently, new drugs (eg, fosaprepitant, and the newer neurokinin-1 receptor antagonists [NK1RAs] rolapitant and netupitant) and updated antiemetic guidelines have emerged. However, trends in real-world antiemetic use are understudied. Methods: We identified patients treated with an initial dose of HEC (either cisplatin or doxorubicin/cyclophosphamide) from January 2006 to June 2016 using administrative claims data from a US commercial insurance database (OptumLabs). Antiemetic use was determined by identifying intravenous/oral/transdermal administration within ±1 day of the chemotherapy dose and/or prescription fill from 14 days before to 7 days after chemotherapy. We used descriptive statistics to present patient demographics, chemotherapy drugs administered, presence/absence of a central intravenous access device, and antiemetics used. Results: A total of 23,030 patients (67.3%) received doxorubicin/cyclophosphamide and 11,206 (32.7%) received cisplatin. Dexamethasone and 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) were consistently used by 85% to 95% of patients, consistent with guideline recommendations. NK1RAs were underused early on, but use increased to approximately 80% in the most recently evaluated year. Fosaprepitant use increased precipitously starting in 2009, preceding a sharp decrease in aprepitant use beginning in 2011. Receipt of olanzapine, rolapitant, and netupitant was minimal throughout the study period. Conclusions: Dexamethasone and 5-HT3RAs were used by most patients receiving HEC, in accordance with guideline recommendations. NK1RA use was less adherent with guidelines.

Purpose: Prevention of chemotherapy-induced nausea and vomiting (CINV) is essential to preserve quality of life in cancer patients receiving highly emetogenic chemotherapy (HEC) such as doxorubicin-cyclophosphamide (AC) or cisplatin. Recently, new drugs (e.g. fosaprepitant and newer neurokinin 1 receptor antagonists [NK1RAs], rolapitant and netupitant) and updated guidelines for antiemetic use (e.g. adding olanzapine) have emerged. However, trends in real world antiemetic use are understudied. Methods: We performed a retrospective study using the OptumLabs Data Warehouse (OLDW), which includes administrative claims for privately insured and Medicare Advantage enrollees in the U.S. We identified 34,236 patients age 18 years or older treated with either AC or cisplatin between January 2006 and June 2016. Data collected included baseline demographics (age, gender, census region and race), chemotherapy administered, and presence/absence of a central intravenous access device. Trends of anti-emetic use were presented overall and separately for 5-HT receptor antagonists (5HT3RAs) and NK1RAs. Results: 23,030 patients (67.3%) received an anthracycline-based regimen (AC with or without docetaxel or paclitaxel), and 11,206 (32.7%) patients received cisplatin. Approximately two thirds of patients were female (n= 23,392). Dexamethasone use was stable over the decade (used by 85-90% in all years). Use of 5HT3RAs, primarily palonosetron and ondansetron, occurred in at least 95% of patients in all study years, consistent with guideline recommendations. NK1RAs were underutilized early on compared with guideline recommendations, but use increased to approximately 80% in the most recently evaluated year. Fosaprepitant use rose precipitously starting in 2009, preceding a sharp fall in aprepitant use beginning in 2011. The use of olanzapine, rolapitant and netupitant was minimal throughout the study period. Conclusions: Dexamethasone and 5-HT3RAs were used in the vast majority of patients receiving HEC, in accordance with guideline recommendations. Less compliance with guidelines was seen with NK1RA use. Citation Format: O'Sullivan CC, Van Houten HK, Sangaralingham L, Leal AD, Shinde S, Liu H, Ettinger D, Loprinzi CL, Ruddy KJ. Ten year trends in antiemetic prescribing in cancer patients receiving highly emetogenic chemotherapy (HEC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-11-18.

Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer (CRC). Expanded mutational testing, such as next-generation sequencing (NGS), often identifies mutations with unclear clinical or prognostic implications. One such example is BRAF mutations that occur outside of codon 600 (non-V600 BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of non-V600 BRAF mutations in metastatic CRC. We pooled patients in whom non-V600 BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories. Results A total of 9,643 patients with metastatic CRC underwent NGS testing. We identified 208 patients with non-V600 BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with non-V600 BRAF mutations, compared with cancers with V600E BRAF (V600E BRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, non-V600 BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P < .001). Conclusion Non-V600 BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.

Background Performance status (PS) is a measurement of a patient’s functional capabilities and has been validated as a prognostic indicator in patients with cancer. This study was conducted to compare patient and physician-rated Eastern Cooperative Oncology Group (ECOG) PS to determine the incidence of inter-observer variability and identify determinants of PS disagreement among a cohort of patients with hematologic malignancy. Methods Newly diagnosed patients with leukemia and lymphoma were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002-2008. At diagnosis, patients and their physicians were asked to independently rate ECOG PS. Those who reported PS within 1 month of diagnosis were included in this analysis. Chi-squared and Wilcoxon rank-sum tests were used to assess the association between PS disagreement and prognostic or demographic factors; Cox proportional hazards models and c-statistics were used to evaluate the association between PS and overall survival. Results 1269 patients were included with a median age of 61 years (range 18-91). Of these, 58% were male; 275 had chronic lymphocytic leukemia (CLL), 127 had Hodgkin lymphoma (HL), and 867 had non-Hodgkin lymphoma (NHL). Overall, 829 (65%) patients and physicians rated PS the same. Age greater than 60 was a significant predictor of disagreement overall (p Patient and physician-rated PS were both significant predictors of overall survival in univariate models and also adjusted for subtype and subtype specific risk score. The prognostic ability for PS was similar for both patient rated and physician-rated assessment overall (c-statistic=0.76 for both patient and physician rated PS) and in those with HL (c-statistic=0.85 for both patient and physician rated PS) and NHL (c-statistic=0.76 for both patient and physician rated PS). However, patient-rated PS was better for prognostication in CLL (c-statistic=0.75; p Conclusions Patients with hematological malignancies and their physicians do not always rate PS the same, particularly in patients who are older or have more advanced or aggressive disease. These findings suggest the need for physicians to communicate with patients when determining PS, as PS is a strong predictor of survival. Disclosures: No relevant conflicts of interest to declare.

3050 Background: TAK-164 is a second-generation ADC comprising a human IgG1 monoclonal antibody targeting GCC conjugated to a DNA-damaging alkylating agent by a peptide linker. TAK-164 demonstrated cytotoxic and antitumor activity in GCC-expressing cells and xenograft mouse models. This first-in-human study investigated the safety, pharmacokinetics (PK), and preliminary efficacy of TAK-164. Methods: Adult pts with GCC-positive, advanced/metastatic GI cancers received TAK-164 intravenously on day 1 of a 21-day cycle (Q3W). Dose escalation proceeded based on cycle 1 safety data via a Bayesian model of modified toxicity probability interval starting at 0.004 mg/kg. Results: Thirty-one pts were enrolled. Median age was 58 years (range 32–72), 58.1% of pts were female and 64.5% had colon carcinoma. The median number of prior lines of therapy was 4 (range 2–9). TAK-164 was given at 0.004 (n = 1), 0.008 (n = 1), 0.016 (n = 1), 0.032 (n = 5), 0.064 (n = 7), 0.12 (n = 7), 0.16 (n = 2), 0.19 (n = 3), 0.25 (n = 3) and 0.32 mg/kg (n = 1). No pts had dose-limiting toxicities (DLT) in cycle 1 up to 0.32 mg/kg. Three pts had adverse events (AEs) after cycle 1 considered to be DLTs: 1 pt receiving 0.19 mg/kg (grade 3 pyrexia and grade 5 hepatic failure) and 2 pts receiving 0.25 mg/kg (1 pt had grade 3 nausea, and grade 4 platelet count decrease and neutrophil count decrease; 1 pt had grade 4 hepatic failure and grade 4 platelet count decrease). Dosing was capped at 0.19 mg/kg due to hepatic toxicity and the recommended phase 2 dose (RP2D) was determined as 0.064 mg/kg based on safety and tolerability beyond cycle 1. Overall, pts received a median of 2 (range 1–8) treatment cycles. TAK-164-related treatment-emergent AEs (TEAEs) reported in 77.4% of pts included platelet count decrease (58.1%), fatigue (38.7%), and anemia (32.3%). TAK-164-related grade ≥3 TEAEs reported in 32.3% of pts included platelet count decrease (12.9%), alanine aminotransferase increase, aspartate aminotransferase increase, fatigue, and anemia (all 9.7%). Three pts discontinued due to TAK-164-related TEAEs. There was a dose-dependent increase in TAK-164 maximum plasma concentration and exposure over the range 0.016–0.32 mg/kg, with no meaningful accumulation in PK with repeat Q3W dosing. One pt receiving TAK-164 0.19 mg/kg showed γH2AX induction via immunohistochemistry in a post-treatment biopsy, demonstrating target engagement. One pt with low baseline GCC expression who received 5 cycles of TAK-164 0.008 mg/kg had an unconfirmed partial response at cycle 4; 11 of 25 (44.0%) evaluable pts had a best overall response of stable disease. Conclusions: TAK-164 appeared to have a manageable safety profile up to 0.064 mg/kg in pts with advanced GI cancers; hepatic toxicity was identified as a potential risk. The RP2D was determined as 0.064 mg/kg but was considered insufficient to derive significant clinical benefit. Clinical trial information: NCT03449030.

e14559 Background: While TMB is very dependent on methodology, tissue TMB-H (≥10 mutations/megabase) may predict benefit with ICIs. Pembrolizumab received tissue-agnostic approval for TMB-H unresectable cancers in 2020, but little is known about TMB as a predictive biomarker in mGI cancers. We hypothesized that tissue TMB will correlate with efficacy of ICIs in mGI cancers. Methods: A retrospective chart review identified patients with mGI cancers who received an anti-PD-(L)1 drug and had known TMB at a single academic center from 2012 to 2020. The association of TMB with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was analyzed using the Fisher’s exact and Log-rank tests. Survival curves were generated using the Kaplan-Meier method. Cox proportional hazard and logistic regression models were used to adjust for microsatellite status. Significance was prespecified at 0.05. Results: 83 patients were identified and included. The most common cancer types were colorectal adenocarcinoma (AC, n = 29), esophageal/gastric AC (n = 21) and SCC (n = 4), cholangiocarcinoma (n = 11), anal SCC (n = 7), and pancreas AC (n = 7). Average age was 61, average number of lines of prior systemic therapy for advanced disease was 1.3 (range 0-4), and 37% of patients were treated on a clinical study. All patients received an anti-PD-(L)1 drug; 6%, 2%, and 36% also received ipilimumab, cytotoxic chemotherapy, and other combinations, respectively. Among those with esophageal/gastric cancer, 76% had known PD-L1 CPS (84% ≥1, 63% ≥5, 42% ≥10). TMB was primarily determined by Foundation One CDx (87%). TMB ranged from 0 to 54; n = 22 (27%) were TMB-H (of these, n = 10 were microsatellite instability-high (MSI-H)), and n = 61 were TMB-L ( < 10 mutations/megabase; of these, n = 2 were MSI-H). The prevalence of TMB-H and microsatellite stable (MSS) was 14.4%. TMB-L, compared to TMB-H, was associated with inferior ORR (3.5% vs 55.6%; odds ratio (OR) 0.045; p < 0.001) and PFS (median 12.7 vs 29.3 weeks; hazard ratio (HR) 2.70; p = 0.001), but not OS (HR 1.20; p = 0.60). In patients with MSS disease, TMB-L, compared to TMB-H, was associated with inferior ORR (OR 0.13; p = 0.04) but not PFS (HR 1.76; p = 0.07) or OS (HR 0.89; p = 0.79). In subgroup analyses, ORR was not significantly associated to tumor type in all or MSS patients. TMB as a continuous variable, in patients with MSS disease, was positively correlated with ORR (p = 0.02) and PFS (p = 0.04), but not OS (p = 0.59). Among all patients, PFS and OS data is immature (median follow-up 13 and 31 weeks). Conclusions: In a single center retrospective study of patients with mGI cancers treated with ICIs, TMB-H was associated with improved ORR and PFS compared to TMB-L. In patients with MSS disease, ORR remained significant. PFS and OS data are immature. TMB as a biomarker of efficacy with ICIs in mGI cancers warrants further study to guide clinical use.

e16276 Background: Appendiceal adenocarcinoma is relatively rare and often diagnosed incidentally during operations for acute appendicitis. It is commonly associated, either at time of initial presentation or upon recurrence, with peritoneal metastases. A typical treatment strategy for patients with peritoneal disease includes cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Extrapolating largely from literature in colorectal cancer, chemotherapy is frequently given before and/or after CRS/HIPEC though high-level evidence to support this is lacking. We sought to evaluate the effect of systemic chemotherapy on survival. Methods: Utilizing a database of CRS/HIPEC procedures at University of Colorado Hospital from 2008 to present we retrospectively reviewed cases of appendiceal adenocarcinoma. Data collected included staging, histologic grade, chemotherapy given, surgical outcomes, and time to disease recurrence. Patients without adequate information regarding treatment, or without at least 1 year of clinical follow-up, were excluded. Associations between administration of chemotherapy or histologic grade and 1-year DFS were analyzed using Fisher’s exact test, and logistic regression was used to assess whether 1-year DFS were different in chemotherapy-treated patients when adjusted for histologic grade. Results: In total, 117 cases reviewed indicated an appendiceal pathology. Of these, 54 cases in a total of 51 patients met the specified criteria for pathology and completeness and length of follow-up information. The average age was 58 years (range 26-81 years). Adenocarcinoma was graded as low in 15 (28%) cases, intermediate in 18 (33%) cases, and high in 21 (39%) cases. 23 (43%) patients received no chemotherapy while 31 (57%) received chemotherapy before and/or after surgery. In the overall population, there was no significant effect of chemotherapy on survival, with 1-year DFS demonstrated in 74.2% of patients receiving some chemotherapy and 70% in patients not receiving chemotherapy (p = 0.765). One-year DFS was achieved in 86% of low-grade cases, 61% of intermediate-grade cases, and 71% of high-grade cases, though this was also not statistically significant (p = 0.254). Furthermore, when 1-year DFS between chemotherapy and non-chemotherapy patients was adjusted for grade, there was again no significant interaction (odds ratio = 0.48, 95% C.I. (0.13-1.64), p = 0.763). Conclusions: In this small, single-institution experience of patients with peritoneal appendiceal adenocarcinoma, there was no significant effect of chemotherapy administration on 1-year DFS. These findings are likely affected by significant confounding with the small sample size and retrospective nature of the data. Further investigation on a larger scale is warranted.

64 Background: The management of locally advanced rectal cancer has historically included preoperative chemoradiation followed by surgery and then adjuvant chemotherapy. Recently there has been an increasing utilization of preoperative chemotherapy in addition to standard chemoradiation, a strategy known as total neoadjuvant therapy (TNT). TNT has been offered to patients at the University of Colorado Cancer Center since 2015. Methods: Records of all patients presenting to the University of Colorado colorectal multidisciplinary clinic since 2015 were screened for treatment with TNT. Data collected on these patients included demographic information, diagnosis and initial staging, preoperative treatment received, and surgical outcomes including treatment response and pathological stage. TNT included preoperative chemotherapy with oxaliplatin combined with either 5-FU (FOLFOX) or capecitabine (CAPOX) as well as chemoradiation, generally given with concurrent capecitabine. Patients then underwent surgical resection; if a complete clinical response was achieved with TNT, non-operative management (NOM) was offered. Results: A total of 81 patients thus far have undergone TNT followed by resection or, if complete clinical response and preferred by the patient, NOM. The mean age of patients was 56 years, ranging from 23 to 87, and 60% of patients were male. The majority of patients (67) had stage III disease at presentation while 1 had stage 1 (T2N0) disease, 11 had stage II disease and 2 patients had oligometastatic disease. Ultimately 13 patients (16%) opted for non-operative management after being found to have a complete clinical response following TNT. Of the 68 patients who underwent surgical resection, 21 (31%) had a pathological complete response, with another 14 (21%) with near-complete response. 28 patients (41%) had a partial treatment response and 5 (7%) had no treatment response. In total, the rate of complete clinical or pathologic response was 42%. Treatment was overall well-tolerated with 90% of patients receiving the full planned dose of radiation and 98% of patients completing all planned cycles of chemotherapy, though most of them with typical dose reductions needed. Of the patients who underwent surgery, 49 (72%) had low anterior resection and 19 (28%) had an abdominoperineal resection. Of patients with temporary ileostomies, 85% of them had their ileostomy reversed within 10 weeks of surgery. Conclusions: Treatment of locally advanced rectal cancer by a total neoadjuvant approach is well-tolerated and results in a high rate of clinical and pathological complete response.

Background: Hormonal and reproductive history has been associated with risk of some hematologic malignancies, but their role in myeloproliferative neoplasms (MPN) is largely unknown. Methods: Using a population-based cohort study, we evaluated the association of these factors with risk of MPN overall, and for essential thrombocythemia (ET) and polycythemia vera (PV) specifically. Incident MPN cases from 1993 to 2004 were identified via linkage to Medicare. RR and 95% confidence intervals (CI) were estimated utilizing Cox proportional hazard regression. Results: After >250,000 person-years of follow-up, 257 cases of MPN were identified (172 ET, 64 PV). Ever use of hormone therapy (HT) was associated with an increased risk of ET (RR = 1.63; 95% CI, 1.19–2.23) but a decreased risk of PV (RR = 0.58; 95% CI, 0.34–0.98). There were no statistically significant associations of oral contraceptives or reproductive factors with MPN risk overall, or by MPN subtype. Bilateral oophorectomy was associated with increased risk of ET (RR = 1.58; 95% CI, 1.11–2.25) and decreased risk of PV (RR = 0.32; 95% CI, 0.12–0.88). There was no association of ovulatory years with ET risk; however, there was increased risk of PV (RR = 1.68 for >36.8 compared with ≤27.6 years; P trend = 0.045). Adjustment for potential confounding factors did not alter these associations. Conclusions: HT use and bilateral oophorectomy had opposite associations for ET and PV. Except for ovulatory years and PV risk, reproductive history did not appear to play a role in the etiology of MPN. Impact: This study suggests different mechanistic impacts of estrogen, and perhaps distinct etiologies, for the two major MPN subtypes. Cancer Epidemiol Biomarkers Prev; 25(1); 151–7. ©2015 AACR.

Immunotherapies that target immune regulatory checkpoints such as CTLA-4 and PD-1 are widely used among many cancer types and have shown positive results in CRC with high microsatellite instability. However, in microsatellite stable (MSS) CRC there is a dismal response rate of 0%. The limited efficacy has shown to be partially due to the lack of T-cells in the tumor microenvironment and/or no activation/regulation of paramount cells in the immune system. The Wnt pathway is the most commonly altered pathway in CRC and is highly involved in driving tumor initiation and progression. Recent evidence also demonstrates the Wnt pathway is involved in T-lymphocyte development, maturation/activation of CD8+ effector T cells and recruitment of dendritic cells. Therefore, targeting the Wnt pathway utilizing a Porcupine (PORCN) inhibitor (ETC-159) in MSS CRC may be a promising strategy to sensitize tumors to immune checkpoint inhibition. Human Immune System BRGS (BALB/c, Rag2−/−, IL2RγC−/−, NODSIRPα) mice were engrafted with MSS CRC PDX (hPDX). The hPDX were randomized according to human chimerism into the following drug treatments groups: Vehicle, ETC-159, nivolumab, and the combination. Treatments began when tumors reached 100-300mm3 and tumors were measured twice weekly. At the end of study, sera, lymph nodes, spleen, and tumor tissue were collected for immunohistochemistry, single cell suspensions, and flow cytometry analysis. Combination therapy resulted in a significant decrease in tumor volume compared to both single agents and vehicle. Flow cytometric analysis demonstrated an increase in human immune cells, in particular human CD4 and CD8 cells in the combination compared to the vehicle and nivolumab treated groups. Additionally, these T-cells showed increased signs of activation and effector function, as indicated by increased CD69+ expression, effector memory subsets, and granzyme B+ cells in the TILs, with a further reduction in Treg populations, suggesting an overall increase in inflammation. An increase in MHC II expression on tumor cells was observed in the ETC-159 single agent with a statistically significant increase in the combination treated tumors demonstrating enhanced antigen presentation. Furthermore, PD-1 expression was upregulated on CD4+ T-cells in the ETC-159 single agent. Lastly, VECTRA analysis corroborates the flow cytometry data showing a changing tumor immune landscape through an increase in CD4+ and CD8+ T cells in the tumor and surrounding stroma. Our data demonstrates the combination treatment of ETC-159 + nivolumab in MSS CRC hPDX show increased tumor infiltration of human immune cells. Further preclinical data is compulsory but these results support further development of this combination in clinical trials. Citation Format: Stacey M. Bagby, Sarah J. Hartman, Natalie M. Navarro, Betelehem W. Yacob, Jeremy Shulman, Jessica Barkow, Christopher H. Lieu, S. Lindsey Davis, Alexis D. Leal, Wells A. Messersmith, Angela Minic, Kimberly R. Jordan, Julie Lang, Todd M. Pitts. Sensitizing microsatellite stable colorectal cancer to immune checkpoint therapy utilizing Wnt pathway inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6647.

Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer deaths with more than 56,000 new cases estimated to be diagnosed in 2019. Current treatment options for PDAC include radiation and chemotherapeutic regimens, however these targeted therapies are ineffective for patients with advanced disease progression. Additionally, the dense stromal nature of PDAC tumors create challenges to target the cancer cells resulting in incomplete cell killing and eventual drug resistance. Recent evidence has shown that CPT1A, an enzyme that regulates the entry of lipids into mitochondria for β-oxidation, is strongly expressed in several cancers. CPT1A is located on the mitochondrial membrane and potentially interacts with BCL-2, an anti-apoptotic protein that promotes tumor maintenance and metastasis. Metabolic stress can activate the anti-apoptotic effects of BCL-2, reprograming metabolism to use fat oxidation for cancer survival. Therefore, a co-inhibition using the selective BCL-2 inhibitor, venetoclax, with agents that inhibit CPT1A and β-oxidation, could be a novel strategy for PDAC. There are few studies considering CPT1A as a therapeutic target for PDAC. Current available drugs to target these pathways include the anti-anginal ranolazine, and CPT1A inhibitors etomoxir and perhexiline. Previous studies have shown that expression of BCL-2 by tumor cells is necessary for BCL-2 inhibitors to be effective. We initially wanted to determine the expression of BCL-2 and CPT1A in PDAC cells utilizing western blot and rtPCR, and to confirm their proximity using a proximity ligation assay (PLA). PDAC cells were then plated in 96 well plates and Cell Titer-Glo assays were performed to determine effective concentrations of single agent venetoclax, etomoxir, and perhexiline. The effects of these drugs in combination were then evaluated using a clonogenic assay, which was analyzed using the ImageJ colony area plugin. PDAC cells were then exposed to the combinations and western blots were performed to evaluate changes downstream effectors. We have confirmed the expression of BCL-2 and CPT1A on the mitochondrial membrane using Westerns, rtPCR, and a PLA on several PDAC lines. Though single agent drugs had little effect on cell viability, the combination of venetoclax with CPT1A and β-oxidation inhibitors decreased colony formation in some PDAC cell lines. Western blot analysis revealed the drug combinations affected the phosphorylation of AKT and 4E-BP1 and expression of the pro-apoptotic protein BID. These data suggest that co-targeting BCL-2 and CPT1A have potential for anti-tumor effects in PDAC. Additional research into the role of CPT1A in PDAC biology will elucidate the optimal dosing concentrations and mechanisms for further studies. Citation Format: Sarah J. Hartman, Nathalie Nadales, Stacey M. Bagby, Betelehem W. Yacob, Brian L. Gittleman, Adriana Estrada-Bernal, Anh T. Le, Christopher H. Lieu, S. Lindsey Davis, Alexis D. Leal, Jennifer R. Diamond, Wells A. Messersmith, Isabel R. Schlaepfer, Todd M. Pitts. Therapeutic targeting of lipid oxidation and apoptosis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6387.

4031 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition and VEGF inhibition have immunomodulatory effects (upregulation of tumor major histocompatibility complex-I expression, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors) supporting clinical evaluation of combined MEKi (B), anti–PD-1 (P), and anti-VEGF (BV) in pts with mCRC. We hypothesize that the combination of binimetinib, pembrolizumab, and bevacizumab (BPBV) will result in greater clinical benefit than pembrolizumab alone. Methods: Patients with chemotherapy-refractory mCRC were evaluated (20 planned in the safety lead-in and 50 planned for total accrual). B was dosed at 45mg PO BID, P was administered at 200mg IV Q21 days, and BV was administered at 7.5mg/kg IV Q21 days. Primary objectives were safety, tolerability, and investigator-assessed ORR by RECIST 1.1. Clinical benefit rate (CR+PR+SD) and progression-free survival were secondary endpoints. Descriptive statistics were used to summarize safety and clinical activity. Results: As of January 9, 2020, 21 pts (10 KRAS/NRASmt, 11 RASwt, 21 MSS) were enrolled into the safety lead-in and were evaluable. The median number of prior therapies was 6. The BPBV combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 38%, respectively. The most frequent related Gr 3-4 AEs were aceniform rash, diarrhea, and hypertension (19%, 14%, 14% respectively). No treatment-related Gr 5 AEs occurred. A total of 17 patients were evaluable for response. Confirmed PR was observed in 2 pts (12%). SD was noted in 14 patients (82%) leading to a clinical benefit rate of 94%. 1 patient had PD as the best response to treatment. Median PFS was 6.4 months (95% CI 4.2-8.9). Molecular determinants, immune biomarkers, and updated tumor assessments of response will be presented. Conclusions: B + P + BV demonstrated a tolerable safety profile and improvements in ORR and clinical benefit rate compared to those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts were durable, suggesting benefit of this novel combination in a patient population refractory to immune therapies. Clinical trial information: NCT03475004 .

The success of single-agent checkpoint inhibitors has been unfortunately limited to a subset of cancers. For colorectal (CRC) cancers, anti-PD1 therapies have proven to be successful in the clinic for microsatellite instable (MSI-high) tumors but have no efficacy in the majority of CRC patients who have microsatellite stable (MSS) cancers. The tumor antigen burden as well as the tumor microenvironment are two key important features that distinguish “hot,” or immunogenic, from “cold” tumors. Cabozantinib is a small-molecule tyrosine kinase inhibitor that has received FDA approval as a cancer treatment in renal cell, medullary thyroid, and hepatocellular carcinoma. Using humanized mice, we tested the ability of cabozantinib to “prime” the tumors and the human immune system to enhance the potency of nivolumab (anti-PD1). In four independent experiments, we implanted distinct MSS CRC patient-derived xenografts (PDXs) into the flanks of humanized BRGS (BALB/c, Rag2-/-, IL2RγC-/-, NODSIRPα) mice that had been engrafted with human hematopoietic stem cells at birth. For each PDX, humanized mice cohorts were treated with vehicle, nivolumab, cabozantinib, or a combination of nivolumab plus cabozantinib. In three out of the four models, the combination had a better survival experience versus the nivolumab-treated group. The fourth model demonstrated an equal survival experience in the combination versus nivolumab treated. Furthermore, the human immune system in the immune organs and tumors was interrogated by flow cytometry to assess changes in the cellular composition and the activation state of the immune system as a result of treatments. In addition, the expression of immune-related molecules was assessed on the tumor cells themselves. Over the four experiments, we found consistent changes in some immune parameters within treatment arms, including increases in CD4+ T cells as a result of cabozantinib treatment alone or CD8+ T cells with nivolumab alone. Similar to reports from mouse and human immunotherapy trials, we also observed increases in IFNγ-producing T cells in the tumors of combination-treated mice. Notably, inhibitory receptors, such as TIM-3 and PD-L1, were shown to be increased on both the human T cells and the tumors themselves as a result of cabozantinib alone or in combination with nivolumab. Furthermore, we also observed upregulation of other IFNγ-responsive genes including antigen-presenting molecules, MHC Class I and II, on the tumor cells from mice treated with both drugs. Thus, our data from humanized mice bearing CRC MSS xenografts show reduced tumor growth that correlates with activation of human T cells and increased “immunogenicity” of the tumors themselves following treatment with cabozantinib and nivolumab. These preclinical in vivo data warrant translation to testing in human trials for patients with MSS CRC. Citation Format: Julie Lang, Alexis D. Leal, Sarah J. Hartmann, Juan Marin-Jimenez, Jeremy Shulman, Anna Capasso, Stacey M. Bagby, Bethlehem W. Yacob, Patrick J. Blanchford, Christopher H. Lieu, Wells A. Messersmith, Todd M. Pitts. Cabozantinib sensitizes microsatellite stable colorectal cancer to immune checkpoint inhibition by immune modulation in humanized mouse models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A109.

258 Background: Patients with clinical stage II or III locally advanced rectal cancer may be treated with the total neoadjuvant therapy (TNT) approach; chemotherapy with 4 mths of FOLFOX followed by chemoradiation (chemo/XRT) with capecitabine for 5 wks administered before surgery. We hypothesized that full dose intensity is not necessary for treatment benefit. Methods: A retrospective chart review was conducted on patients with newly diagnosed rectal cancer recommended to receive TNT by the multidisciplinary (multiD) colorectal cancer tumor board at the University of Colorado Cancer Center (UCCC). The primary objective was to evaluate dose intensity of TNT and its impact on response assessed by biopsy and/or imaging (MRI). Results: Between January 31, 2016 and January 31, 2019, 80 patients were recommended the TNT approach for cancer management by the multiD team. Of those, 48 completed their neoadjuvant treatment at UCCC and were included in the analysis. The average age was 55 years (range 23-80) and 61% were male. Thirty-one patients had an ECOG of 0 and 17 had an ECOG of 1. Overall responses were 44% complete response (CR, n = 21), 15% near complete response (nCR, n = 7), 35% partial response (PR, n = 17), and 6% no response (NR, n = 3). See Table for responses seen by dose intensity for chemotherapy. Two patients did not receive their full planned XRT course, and 9 patients had their capecitabine doses held/decreased during chemoradiation. Conclusions: This single center retrospective analysis of patients receiving the TNT approach for rectal cancer provides data supporting that achieving full dose intensity is not necessary to achieve treatment benefit. [Table: see text]

685 Background: For borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC), neoadjuvant (NAT) FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP) are standard treatment options and these regimens have shown a survival advantage over single-agent gemcitabine. However, the role of these modern therapeutic regimens in elderly patients is debatable. In this analysis, we evaluated the outcomes of neoadjuvant treatment (NAT) with combination chemotherapy in elderly patients. Methods: 230 consecutive patients who underwent neoadjuvant treatment for BRPC/LAPC discussed and planned for NAT at the University of Colorado Cancer Center from January 2011 to March 2019 were reviewed. 214 patients who received FOLFIRINOX (n = 143) or GnP (n = 71) were eligible for analysis. We divided all patients into three groups ( < 70, 70-74, ≥75 years) and compared the short-term and long-term outcomes. Results: Of 214 patients, patients < 70 (n = 147) received FOLFIRINOX more frequently than the other groups (p < 0.001): FOLFIRINOX: 115 cases, GnP: 32 cases, 70-74 years (n = 33): FOLFIRINOX: 15 cases, GnP: 18 cases, and ≥75 years (n = 34): FOLFIRINOX: 13 cases, GnP: 21 cases. Resection rates were not statistically different between three groups ( < 70: 62%, 70-74: 70%, ≥75 years: 56%, p = 0.504). There was a slight trend towards worse survival in the two older groups (Median Survival Time [MST]: < 70: 23.2 mo., 70-74: 19.5 mo., ≥75 years: 17.6 mo., p = 0.075) The FOLFIRINOX group was superior to GnP group in all three groups (MST: < 70: 25.6 vs 18.2 mo., p = 0.017; 70-74: 33.2 vs 16.1mo., p = 0.029; ≥75 years: not reached vs 16.1 mo., p = 0.135). There were no toxic deaths or 30 day mortality after pancreatectomy in the study population. Conclusions: Neoadjuvant combination chemotherapy regimens were safe and feasible for elderly patients. Neoadjuvant therapy with FOLFIRINOX was associated with a survival advantage vs GnP and is an good option for fit and elderly patients ≥75 years.

Antibody drug conjugates (ADCs) represent a developing class of anticancer therapeutics which are designed to selectively deliver a cytotoxic payload to tumors, while limiting systemic toxicity to healthy tissues. There are several ADCs which are currently in various stages of clinical development for the treatment of gastrointestinal malignancies.We discuss the biologic rationale and review the clinical experience with ADCs in the treatment of gastrointestinal malignancies, summarizing the pre-clinical and phase I/II clinical trial data that have been completed or are ongoing.While there have been significant advances in the development of ADCs since they were first introduced, several challenges remain. These challenges include (i) the selection of an ideal antigen target which is tumor specific and internalized upon binding, (ii) selection of an antibody which has high affinity for its antigen target and low immunogenicity, (iii) selection of a potent payload which is cytotoxic at sub-nanomolar concentrations, and (iv) optimal design of a linker to confer ADC stability with limited off-site toxicity. Efforts are ongoing to address these issues and innovate the ADC technology to improve the safety and efficacy of these agents.

The treatment of colon cancer has evolved significantly since the discovery of 5-fluorouracil, and with continued innovation, it will continue to advance for the foreseeable future. In this review, we identify and discuss novel adjuvant trial designs which are currently being employed and that are forthcoming in the treatment of colon cancer. Novel approaches include investigation into whether a shorter duration of adjuvant therapy is as effective as the current standard, whether there is benefit of neoadjuvant chemotherapy in the treatment of nonmetastatic colon cancer, the role of circulating tumor cells and cell-free DNA on clinical decision making and their impact on long-term outcomes, identification, and individualized treatment of molecular subgroups of colon cancer (i.e., HER2 amplified, microsatellite instable, BRAF V600E mutated, etc.) and the efficacy of targeting cancer stem cells.

Young patients with triple-negative breast cancer tend to present with aggressive, advanced disease at diagnosis. Young patients with breast cancer can face unique challenges, including delays in diagnosis, higher rates of germline mutations, diminished fertility, and other treatment-associated long-term toxicities. All these issues must be addressed as part of their oncology care to ensure the best health and psychosocial outcomes after treatment. In this chapter, we discuss the distinctive issues faced by young women with triple-negative breast cancer.

There are few studies examining complementary and alternative medicine (CAM) use and beliefs among nonHodgkin lymphoma (NHL) survivors. Seven hundred and nineteen patients with NHL from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource who completed the 3-year post-diagnosis questionnaire were included in this study. Altogether 636 (89%) reported ever using CAM, with 78% utilizing vitamins, 54% alternative therapies and 45% herbals. Female gender was associated with increased overall CAM use ( p 0.0001) as well as use of vitamins ( p 0.0001), herbals ( p 0.006) and alternative therapy ( p 0.0002) for cancer. Older age ( 60) was associated with increased vitamin use ( p 0.005) and decreased herbal use ( p 0.008). Among users, 143 (20%) believed CAM assists healing, 123 (17%) believed CAM relieves symptoms, 122 (17%) believed CAM gives a feeling of control, 110 (15%) believed CAM assists other treatments, 108 (15%) believed CAM boosts immunity, 26 (4%) believed CAM cures cancer and 36 (5%) believed CAM prevents the spread of cancer.

Fosaprepitant is an antiemetic used for chemotherapy-induced nausea and vomiting. We recently reported increased infusion site adverse events (ISAE) in a cohort of breast cancer patients receiving chemotherapy with doxorubicin and cyclophosphamide (AC). In this current study, we evaluated the venous toxicity of fosaprepitant use with non-anthracycline platinum-based antineoplastic regimens.A retrospective review was conducted of the first 81 patients initiated on fosaprepitant among patients receiving highly emetogenic chemotherapy, on or after January 1, 2011 at Mayo Clinic Rochester. None of these regimens included an anthracycline. Data collected included baseline demographics, chemotherapy regimen, type of intravenous access and type, and severity of ISAE. Data from these patients were compared to previously collected data from patients who had received AC. Statistical analysis using χ 2 and univariate logistic regression was used to evaluate the association between treatment regimen, fosaprepitant, and risk of ISAE.Among these 81 patients, the incidence of ISAE was 7.4% in the non-anthracycline platinum group. The most commonly reported ISAE were swelling (3%), extravasation (3%), and phlebitis (3%). When stratified by regimen, fosaprepitant was associated with a statistically significant increased risk of ISAE in the anthracycline group (OR 8.1; 95% CI 2.0-31.9) compared to the platinum group.Fosaprepitant antiemetic therapy causes significant ISAE that are appreciably higher than previous reports. Patients receiving platinum-based chemotherapy appear to have less significant ISAE than do patients who receive anthracycline-based regimens.

BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of taxane and platinum-based chemotherapy. Several studies have supported the potential benefit of glutathione for the prevention of platinum-induced CIPN. The current trial was designed to determine whether glutathione would prevent CIPN as a result of carboplatin/paclitaxel therapy. METHODS In total, 185 patients who received treatment with paclitaxel and carboplatin were accrued between December 4, 2009 and December 19, 2011. Patients were randomized to receive either placebo (n = 91) or 1.5 g/m2 glutathione (n = 94) over 15 minutes immediately before chemotherapy. CIPN was assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life (EORTC-QLQ) 20-item, CIPN-specific (CIPN20) sensory subscale and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. RESULTS There were no statistically significant differences between the 2 study arms with regard to: 1) peripheral neurotoxicity, as assessed using both the EORTC-QLQ-CIPN20 (P = .21) and the CTCAE scales (P = .449 for grade ≥2 neurotoxicity; P = .039 for time to development of grade ≥2 neuropathy, in favor of the placebo); 2) the degree of paclitaxel acute pain syndrome (P = .30 for patients who received paclitaxel every 3-4 weeks and P = .002, in favor of the placebo, for patients who received weekly paclitaxel); 3) the time to disease progression (P = .63); or 4) apparent toxicities. Subgroup analyses did not reveal any evidence of benefit in any particular subgroup. CONCLUSIONS The results from this study do not support the use of glutathione for the prevention of paclitaxel/carboplatin-induced CIPN. Cancer 2014;120:1890–1897. © 2014 American Cancer Society.

Introduction: Pancreatic adenocarcinoma remains a devastating disease, with a predicted 5-year survival at the time of diagnosis of less than 10%, and likely the number 2 cause of U.S. cancer deaths in the next decade. The lack of effective therapies and resistance to cytotoxic agents contribute to the poor outcomes in this patient population. Aldehyde dehydrogenases (ALDHs) are a family of enzymes that play important biological and metabolic roles in the human body. ALDH activity has been identified in many human malignancies as a marker of tumor initiating cells. In pancreatic cancer, ALDH1A1 has been shown to be upregulated in cancer stem cells (CSCs) and has been attributed to tumorigenesis and chemotherapeutic resistance. Methods: Six novel ALDH1A1 inhibitor drugs from the National Center for Advancing Translational Sciences (NCATS) were screened on human pancreatic cancer cell lines using the Cell Titer-Glo Assay. Proliferation assays were also performed with the three best performing inhibitors on a total of eight human pancreatic cancer cell lines. The best performing ALDH1A1 inhibitor drug were chosen and tested in combination with gemcitabine and paclitaxel on patient-derived tumor organoids (PDTOs). The combination effects were assessed over a 7-day period using the IncuCyte ZOOM live cell imager and CellTiter-Glo 3D Assay. Results: We assessed the anti-proliferative effects of 6 novel ALDH1A1 inhibitors on 4 pancreatic cancer cell lines. Two out of 4 pancreatic cell lines showed moderate treatment effects to 3 ALDH1A1 inhibitors. Further evaluation of one of the ALDH1A1 inhibitor on 8 additional pancreatic cancer cell lines revealed similar results. While several pancreatic cell lines showed some moderate activity at higher levels of drug exposure, most of the pancreatic cancer cell lines treated were more resistant. We next investigated the treatment effects of ALDH1A1 inhibitor in combination with gemcitabine or paclitaxel on PDTO 269 and 272. A combination effect with the ALDH1A1 inhibitor and paclitaxel was observed after 72 hours of drug exposure in both PDTO 269 and 272. In contrast, treatment with the ALDH1A1 inhibitor with gemcitabine did not further decrease growth when compared to single agent ALDH1A1 and gemcitabine. Conclusions: Although single agent activity of novel ALDH1A1 inhibitors is limited at significantly reducing cellular proliferation, inhibition of ALDH1A1 in combination with paclitaxel appears to have potent anti-tumor activity in PDTOs. These findings support further investigation of this combinational therapy for the treatment of pancreatic cancer. Additional studies are currently underway to evaluate this combinational activity in more preclinical pancreatic cancer models and to elucidate the underlying mechanisms whereby the inhibition of ALDH1A1 enhances the anti-tumor potential of paclitaxel. Citation Format: Betelehem W. Yacob, John J. Arcaroli, Maraake Taddese, Todd M. Pitts, Stacey M. Bagby, Sarah J. Hartman, S.Lindsey Davis, Christopher H. Lieu, Alexis D. Leal, Wells A. Messersmith. Preclinical investigation of novel ALDH1A1 inhibitors in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3855.

Introduction: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death and has a 5-year survival rate of less than 7%. The poor prognosis associated with PDA is related in part to a lack of screening tests to promote early detection and ineffective systemic targeted therapies. Adavosertib (AZD1775, MK1775) is a selective Wee1 inhibitor with promising preclinical activity in PDA and synergy with cytotoxic chemotherapy in other cancer types. Wee1 is a tyrosine kinase that activates in the G2M cell cycle checkpoint in response to DNA damage. Inhibition of Wee1 with adavosertib prevents the phosphorylation of CDC2, thus allowing unrepaired DNA to enter mitosis and ultimately succumb to mitotic catastrophe. The purpose of this study was to investigate adavosertib in combination with standard chemotherapy and other targeted agents in preclinical models of PDA. Methods: Athymic nude mice were implanted with PDA PDX models on the right and left flanks. When the average tumor volume reached 100-300 mm3, mice were randomized into one of the following treatments: vehicle, adavosertib, irinotecan, navitoclax, capecitabine, adavosertib + irinotecan, or adavosertib + navitoclax, adavosertib + capecitabine. Tumor volume was calculated using the following equation: volume = (length × width) × 0.52. Four pancreatic cancer cell lines were plated in 96-well plates and Cell Titer-Glo proliferation assays were performed to determine the most effective combination doses of irinotecan, 5FU, or navitoclax with adavosertib in vitro. Combination effects were analyzed using CalcuSyn software. The most effective doses within each cell line were selected and used for Caspase 3/7 apoptosis assays and cell cycle analyses by flow cytometry. Western blots were performed to evaluate changes in downstream effectors. Results: In vivo, the combination of adavosertib with either irinotecan or navitoclax resulted in decreased tumor growth compared to the respective single agents. The combination of adavosertib with irinotecan, 5FU, or navitoclax in vitro resulted in greater antiproliferative effects in all cell lines, and the several combinations were synergistic in all cell lines as determined by CI values less than 1. Navitoclax increased apoptosis in several cell lines both as a single agent and was enhanced in combination with adavosertib. Irinotecan proved to be more cell cycle dependent and significantly altered the cell cycle in all cell lines. Irinotecan increased phospho-CDC2 and decreased PHH3, while adavosertib increased gamma-H2AX as a single agent and in combination. Conclusions: The combination of adavosertib with either irinotecan, 5FU, or navitoclax in vivo decreased tumor growth and had enhanced antiproliferative effects in vitro. These data support future studies with adavosertib in combination with standard therapies or navitoclax to treat PDA. Citation Format: Sarah J. Hartman, Stacey M. Bagby, Betelehem W. Yacob, Dennis M. Simmons, Tonia E. Tse, Christopher H. Lieu, S. Lindsey Davis, Alexis D. Leal, Jennifer R. Diamond, Wells A. Messersmith, Todd M. Pitts. Combination of Wee1 inhibition with targeted and standard chemotherapy in preclinical models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1315.

Background: AZD0156 is an oral inhibitor of ATM, a serine threonine kinase that plays a key role in DNA damage response associated with DNA double strand breaks. Topoisomerase-I inhibitors like irinotecan induce single-strand DNA breaks, which are converted to double-strand breaks during DNA replication. Thus the combination of AZD0156 and irinotecan is a rational combination for clinical use. Irinotecan is used clinically to treat a variety of malignancies, including colorectal cancer (CRC), usually in combination with 5-fluorouracil (5FU) as FOLFIRI. An ongoing phase 1 clinical trial is evaluating AZD0156 in combination with single-agent irinotecan and FOLFIRI in patients with refractory cancers (NCT02588105). The purpose of this study is to evaluate AZD0156 in combination with irinotecan and 5FU in preclinical models of CRC to help inform clinical use. Methods: Anti-proliferative effects of single-agent AZD0156 and combination therapy with SN38 (active metabolite of irinotecan) and 5FU were evaluated in CRC cell lines using the Cell-Titer Glo assay. Immunoblotting and cell cycle analysis were performed to determine the mechanism of enhanced combination effects. Four CRC patient derived xenograft (PDX) models were treated with AZD0156, irinotecan, and 5FU alone and in combination for assessment of tumor growth inhibition (TGI). Results: An enhanced antiproliferative effect was observed with the combination treatment over either single agent. A more significant synergistic effect was demonstrated with the combination of AZD0156 and SN38 as compared with the combination of AZD0156 and 5FU. Cell cycle data demonstrated enhanced cell cycle arrest with combination therapy as compared to single agents. Immunoblotting results suggest a decrease in phosphorylated gamma-H2AX in cell lines treated with combination therapies. Increased TGI was observed in CRC PDX models treated with the combination of AZD0156 and irinotecan as compared to single-agent therapy in 3 of 4 models. There was not a significant change in TGI with the addition of 5FU for triplet therapy in the majority of models. Conclusions: The combination of AZD0156 with irinotecan is synergistic in in vitro models and is associated with increased TGI in CRC PDX in vivo models. The addition of 5FU to AZD0156 and irinotecan did not result in increased TGI as compared to doublet therapy in CRC PDX models, though did not decrease the AZD0156/irinotecan combination effect. An ongoing clinical trial is evaluating this combination in patients with cancers refractory to standard treatments (NCT02588105). Citation Format: S. Lindsey Davis, Marina I. Schlaepfer, Stacey M. Bagby, Sarah J. Hartman, Betelehem W. Yacob, Tonia Tse, Dennis M. Simmons, Jennifer R. Diamond, Christopher H. Lieu, Alexis D. Leal, Elaine B. Cadogan, Gareth D. Hughes, Stephen T. Durant, Wells A. Messersmith, Todd M. Pitts. Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD0156 in combination with 5-fluorouracil and irinotecan in preclinical models of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4720.

3576 Background: In contrast to the older population, the incidence of colorectal cancer (CRC) in younger patients (aged < 50 years) has been increasing in the last three decades. Younger patients tend to present with more advanced disease, thought to be in part related to lack of routine screening colonoscopies. The goal of this study was to examine characteristics of young-onset CRC and potentially identify factors that may aid in earlier diagnosis and treatment. Methods: We collected data for patients available through the University of Colorado Cancer Center Cancer Registry. Inclusion criteria included: 1) Diagnosis of colon or rectal cancer between the years 2012-2018 and 2) age at diagnosis of less than 50 years. Pertinent data including baseline characteristics, clinical presentation, family history, pathology, molecular testing, staging, and treatment were collected. Results: 211 patients with young-onset CRC were available for review. Mean age at diagnosis was 42.4 years and 55.5% were males. A total of 42.1% had rectal cancer and a majority of the colon cancer diagnoses had left-sided tumors (66%). Regarding clinical presentation, 52.2% presented with rectal bleeding prior to diagnosis. Of those who presented with rectal bleeding, the average time from the onset of bleeding to diagnosis was 271.17 days. 42.9% of young-onset CRC were stage IV at the time of initial diagnosis. Evaluation of the pathology specimens showed that 89.6% were adenocarcinomas and 63.5% were grade 2 or higher. At diagnosis, the mean BMI was 26.6 and the mean CEA was 135.5. A total of 72.5% of young-onset patients had a positive family history of any cancer. KRAS or NRAS mutations were present in 49.6% of patients, BRAF V600E mutations were present in 3.8%, and 10.8% were MSI-H. Conclusions: Prolonged rectal bleeding history prior to diagnosis was noted in a significant proportion of young-onset patients with colorectal cancer. Patients and primary care physicians should be made aware of this finding in order to facilitate timely referral for colonoscopy which may lead to earlier diagnosis, less advanced disease at diagnosis, and improved outcomes.

119 Background: Neoadjuvant chemoradiation (nCRT) followed by resection is standard of care for operable stage II-III EC and GEJC; however, it can be associated with significant risk of postoperative complications (POC). The CROSS study group reported no increase in POC severity with nCRT using 41.4 Gy compared to surgery alone as defined by the Comprehensive Complication Index (CCI). We applied the CCI metric to evaluate the impact of nCRT radiation dose of < 50 Gy vs. ≥ 50 Gy on POC rates and compared to the CROSS rates. Methods: We retrospectively reviewed 82 pts (2004-2016) with EC or GEJC treated with nCRT followed by resection at our institution. 29 (35%) pts were treated with < 50 Gy (range 39.6-46.8 Gy) and 53 (65%) were treated with ≥ 50 Gy (range 50.0-52.5 Gy) delivered using IMRT/VMAT (41%), 3D-CRT (46%), or tomotherapy IMRT (12%). Concurrent chemotherapy were carboplatin/paclitaxel (59%), cisplatin/5-FU (17%), or other (24%). Resection was performed by Ivor Lewis esophagectomy (67%), esophagogastrectomy (14%), or trans-hiatal approach (11%). POC within 30 days were graded using the Clavien-Dindo scale and CCI scores were computed and compared between the two dose groups and with the CROSS nCRT group. Results: CCI scores and complication rates between our < 50 Gy and ≥ 50 Gy groups were not significantly different. Assuming a normal distribution of the CROSS CCI scores, there was no significant difference in CCI scores between the CROSS study nCRT, < 50 Gy, or ≥ 50 Gy groups. Rates of pulmonary complications were greater in the CROSS study. Conclusions: In highly selected EC and GEJC pts, definitive nCRT radiation doses do not appear to increase POC rates. Thus, 50 Gy can likely be delivered without increasing toxicity while also achieving a definitive dose for pts not able or willing to undergo subsequent surgery. [Table: see text]

370 Background: Management for borderline resectable pancreas cancer (BRPC) and locally advanced pancreas cancer (LAPC) is controversial. Multiagent chemotherapy (CT) followed by SBRT may allow for tumor downstaging and the ability to perform an R0 resection. Methods: We retrospectively evaluated BRPC and LAPC patients (pts) treated on our multidisciplinary treatment pathway. Pts underwent 2-3 months of CT. Pts without systemic progression received five fractions of SBRT, delivered every other day, to a dose of 30-33 Gy. After restaging, pts underwent surgery if resectable. Overall survival (OS), distant metastasis free survival (DMFS) and local progression free survival (LPFS) were estimated and compared by Kaplan-Meier and log-rank methods. Results: We identified 80 pts with BRPC (65) or LAPC (15) treated with neoadjuvant CT + SBRT between 2011-2017. Median follow up was 20 months. CT primarily included FOLFIRINOX (65%) and gemcitabine/nab-paclitaxel (30%). Of pts completing CT + SBRT, 67 (84%) went to surgery and 53 (79%) of those pts underwent definitive surgery including seven LAPC patients. The remaining 14 pts underwent palliative or exploratory surgery due to intraoperative metastases (43%) or vascular involvement (57%). Of pts undergoing definitive surgery, 51 had R0 resection (96%) and 5 (9%) had a complete pathologic response (PR) to CT + SBRT. The R0 resection rate of the cohort was 64%. OS was 24.5 months. Pts with a complete or marked (14%) PR had significantly better OS than those with a moderate (40%) PR (41.3 vs 30 months, p = 0.04) and pts unable to undergo definitive surgery (18.2 months, p < 0.001). Zero of 11 pts who had a marked or complete PR had local progression, significant compared to those with moderate PR (p = 0.012). DMFS between these two groups was not statistically significantly different. Conclusions: Neoadjuvant CT + SBRT are associated with favorable PR rates and R0 resection rates. Marked or complete PR was associated with improved LPFS and OS compared to moderate PR and pts who did not undergo definitive surgery. DMFS was not significantly different between complete and marked PR compared to those with moderate PR.

Myeloproliferative neoplasms (MPN), previously called myeloproliferative disorders (MPD), are a collective group of hematopoietic malignancies, which are categorized by a clonal expansion of terminally differentiated myeloid cells within the peripheral blood. Within this group of malignancies, essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) are collectively classified as classical MPN. These malignancies arise from a single mutated progenitor cell, with the most common mutation being a gain-of-function mutation within the Janus kinase 2 (JAK2) gene.1 Epidemiological studies have found JAK2 mutations to be present in nearly all cases of PV and approximately half of all cases of ET and MF.1, 2 There have been numerous additional studies that have discovered other mutations within patients with MPN that may play a role in their development, although the underlying pathogenesis of these malignancies is largely unknown. Although there is growing knowledge regarding the role that these mutations have in MPN, there are few data available regarding other risk factors that may be involved in their development. Ashkenazi Jewish descent was associated with higher risk of MPN3 and PV,4 and a family history of MPN is also a risk factor.4–7 The role of occupation and chemical exposure has been evaluated, with a few studies suggesting benzene as a possible risk factor for MPN development.8, 9 There are only limited data available regarding lifestyle and medical factors that may play a role in MPN development. In a large cohort of study of 1.3 million middle-aged women in the U.K., Kroll et al10 found that frequent smokers (defined as ≥15 cigarettes per day) were at increased risk of myeloproliferative/myelodysplastic disease combined, while there was no association with alcohol use; results specific to MPN were not reported. Kristinsson et al11 conducted a large record linkage study of 11,039 population-based cases of MPN, and found that prior history of an autoimmune disease was associated with an increased risk for MPN development. In contrast, Anderson et al12 conducted a case-control study consisting of 13,846 myeloid malignancy patients (1,017 of which had chronic myeloproliferative disease (MPD)) and found that overall, autoimmune conditions were not associated with risk of MPD. Given the limited data on risk factors for MPN, we investigated the role of medical, lifestyle and anthropometric factors in the development of MPN in a large, prospective cohort of Iowa women. In a secondary analysis, we also evaluated etiologic heterogeneity for the two most common MPN subtypes, ET and PV.

TPS3623Background: After primary therapy for rectal cancer (chemotherapy, surgery, and/or radiotherapy), 7-10% of patients will develop locally recurrent disease. Re-irradiation +/- resection of re...

3554 Background: There is considerable variability in the outcomes between second line (SL) trials in mCRC. The aim of this analysis is to compare the outcomes of patients (pts) with mCRC treated either on SAFL, with protocol defined SL treatment, or DSLT. Methods: Individual pt data was available on pts with mCRC enrolled in 1 of 10 trials (7 DSLT, 3 SAFL) in the ARCAD database. Regimens included FOLFIRI, FOLFOX, and irinotecan (IRI), since pts did not receive biologic agents in SL on SAFL. For pts on a SAFL, PFS and OS were defined as time from initiation of SL treatment to second progression (SP)/death and death, respectively. Descriptive statistics and multivariable Cox models were used to assess differences in PFS and OS. Results: 5,076 pts were included; 63% were male; median age was 62. See Table for treatment details. Pts treated on SAFL had shorter OS (0.7-1.5 months (mos>) shorter) and PFS (0.6-2.6 mos shorter), compared to those treated on DSLT. These findings were statistically significant and differences in OS did not attenuate after adjustment for age, gender, and prior treatment. PFS differences in FOLFOX became insignificant after multivariable adjustment. Conclusions: There are modest differences in both PFS and OS between pts with mCRC treated on SAFL and those on DSLT, suggesting differences in these pt populations. Caution is needed when applying these data to pts, as we were unable to control for potential confounders (ECOG PS, number and sites of metastases) at initiation of SL in SAFL, which may impact outcomes. [Table: see text]

3558 Background: Anti-programmed death-1 (PD-1) antibodies have been shown to be effective in the treatment of dMMR CRC. We describe an updated analysis from a cohort of 19 patients (pts) with dMMR CRC treated with pembrolizumab. Methods: Pts were identified through review of the Mayo Clinic electronic medical record (EMR) and chemotherapy administration records from May 2015 through January 2017. All pts with dMMR CRC who received treatment with pembrolizumab were included. The EMR was reviewed to identify demographic, clinical, pathologic and treatment details. Overall survival (OS), progression free survival (PFS) and disease control rate (DCR = CR+PR+SD) are reported. Time to event analysis was calculated using the Kaplan-Meier method. Results: Nineteen pts were included in this analysis; median age at diagnosis was 48.6 years (range 25-93); 53% were female. Most primary tumors were right sided (n = 12; 63%), 6 (32%) were left sided and 1 (5%) was a tumor of unknown primary within the bowel. Twelve (63%) pts received ≥2 lines of therapy prior to pembrolizumab (range 1-4). Five pts received 2 mg/kg every 3 weeks, 11 received 200 mg/day every 3 weeks and 2 pts received 10 mg/kg (1 every 2 weeks, the other every 3 weeks). The most common alterations identified were loss of MLH1 (11/15) and PMS2 (12/15); 4 pts had germline mutations (mut) identified. KRAS mut was identified in 6/16 pts and 2 pts had BRAF mut. Three pts had MLH1 hypermethylation. Median number of cycles of pembrolizumab was 8 (range 1-35+), with 13 (68%) pts receiving ≥6 cycles. DCR at first assessment was 68%, with 5% CR, 47% PR and 16% SD. Median follow-up from diagnosis was 29 months (95% CI 18-42). Median OS was 103 months (95% CI 85-103); 12-month OS was 89%. Median OS from PD-1 therapy was 16.1 months (95% CI 16-NR); 12-month OS from PD-1 therapy was 79%. Median PFS was NR (95% CI 5-NR); 12-month PFS was 54%. At time of analysis, 9 pts remain on PD-1 therapy; 5 pts have died; 3 have received subsequent therapy. Conclusions: Anti-PD1 blockade with pembrolizumab can provide long lasting benefit in dMMR mCRC, even in heavily pretreated pts.

757 Background: Progression free survival (PFS) and overall survival (OS) appear to differ across trials, even when pts receive the same regimen (REG). This analysis aimed to benchmark the clinical outcomes in the 2nd line treatment of metastatic colorectal cancer (mCRC). Methods: Individual patient (pt) data was available on 6,462 pts with mCRC enrolled in 7 2ndline clinical trials (8 REGs) in the ARCAD database. Regimens used in at least two trials included FOLFIRI +/- an EGFR inhibitor (EGFRi), FOLFOX +/- a VEGF inhibitor (VEGFi), and irinotecan (IRI). Descriptive statistics were used to describe pt demographics. Multivariable Cox models were used to assess differences (DIFFs) in PFS and OS, while p-value

714 Background: Mismatch repair deficient (dMMR) colorectal cancer (CRC) has been shown to be responsive to blockade with anti-programmed death-1 (PD-1) antibodies. We describe a cohort of 17 patients with dMMR mCRC receiving treatment with pembrolizumab. Methods: Patients were identified through review of the Mayo Clinic electronic medical record (EMR) and chemotherapy administration records from May 2015 through September 2016. All patients with dMMR mCRC who received treatment with pembrolizumab were included. The EMR was reviewed to identify demographic, clinical, pathologic and treatment details. Overall survival (OS), progression free survival (PFS) and disease control rate (DCR=CR+PR+SD) are reported. Time to event analysis was calculated using the Kaplan-Meier method. Results: A total of 17 patients were included in this analysis; median age at diagnosis was 48.5 years (range 25-93); 59% were female. Most primary tumors were right sided (n=12; 71%), 4 (24%) were left sided and 1 (5%) was a tumor of unknown primary within the bowel. Thirteen (75%) patients received 2 or more lines of therapy prior to pembrolizumab (range 1-4). All patients received 2 mg/kg every 3 weeks, with the exception of two patients on a clinical trial; one who received 200 mg every 3 weeks, the other received 10 mg/kg every 2 weeks. The most common mutations (mut) identified were loss of MLH1 (9/12) and PMS2 (10/12), 4 patients had germline mut. KRAS mut was identified in 6/15 patients and only 1 patient had BRAF mut. Number of cycles of pembrolizumab ranged from 1 to 35, with 10 (59%) patients receiving 6 or more cycles. DCR at first assessment was 57%, with 7% CR and 50% PR. Median follow-up was 28 months (95% CI 18-55). Median OS was 103 months (95% CI NR-NR); 12-month OS was 88% and 24-month OS was 81%. Median OS post-PD-1 therapy was NR (95% CI 2-NR). Median PFS was 19 months (95% CI 5-19); 12-month PFS was 64% and 24-month PFS was 0%. At time of analysis, 11 patients remain on PD-1 therapy; 4 patients have died. Conclusions: Anti-PD1 blockade with pembrolizumab can provide long lasting benefit in dMMR mCRC, even in heavily pretreated patients.

Classical myeloproliferative neoplasms (MPNs) are composed of essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), the etiology of which is largely unknown. We investigated the role of anthropometric, medical and lifestyle factors with risk of MPN in a prospective cohort of 27,370 women aged 55-69 years at enrollment. After250,000 person-years of follow-up, 257 cases of MPN were identified (172 ET, 64 PV, 21 MF). Risk factor profiles were mostly unique for the two most common types, ET and PV. ET was associated with energy balance factors including body mass index (RR = 1.52 for29.3 vs.23.4 kg/m(2) ; p-trend = 0.042), physical activity (RR = 0.66 for high vs. low; p-trend = 0.04) and adult onset diabetes (RR = 1.82; p = 0.009), while PV was not. PV was associated with current smoking (RR = 2.83; p-trend = 0.016), while ET was not. Regular use of aspirin was associated with lower risk of ET (RR = 0.68; p = 0.017). These results broadly held in multivariate models. Our results suggest distinct etiologies for these MPN subtypes and raise mechanistic hypotheses related to obesity-related inflammatory pathways for ET and smoking-related carcinogenic pathways for PV. Regular aspirin use may lower risk for ET.