bluuebunny/crossref_metadata_2025_split huggingface dataset:
REGOMUNE: A phase II study of regorafenib plus avelumab in solid tumors—Results of the non-MSI-H metastatic colorectal cancer (mCRC) cohort.
Authors: Cousin Sophie , Bellera Carine A. , Guégan Jean Philippe , Gomez-Roca Carlos A. , Metges Jean-Philippe , Adenis Antoine , Pernot Simon , Cantarel Coralie , Kind Michèle , Toulmonde Maud , Bourcier Kevin , Soubeyran Isabelle , Bessede Alban , Italiano Antoine 
Published: May 2020

4019 Background: Regorafenib (R) has been shown to modulate anti-tumor immunity by different mechanisms including reduction of tumor-associated macrophages (TAMs). Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical models. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of R (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in non MSI-H mCRC patients (pts). The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline and C2D1. Results: Between Nov. 2018 and Oct. 2019, 48 pts were enrolled in 4 centers. Median age was 61.8 (range: 26.3-78.7). Median follow-up was: 7.2 months. Median number of previous treatment lines was: 3 (range: 1-7). 41 (87.2%) pts experienced at least 1 dose modification or treatment interruption. The most common grade 3/4 adverse events were palmar-plantar erythro-dysesthesia syndrome (29.8%), hypertension (23.4%) and diarrhea (12.8%). No death was related to the treatment. Among 40 pts who had at least one imaging tumor assessment, 12 (30%) had reduction in tumor burden. Best response was stable disease for 23 pts (57.5%) and progressive disease for 17 pts (42.5%). The median PFS and OS were 3.6 months (CI95%: [1.8 – 5.4]) and 10.8 months (CI95%: [5.9 – NA]) respectively. Baseline tumor samples and paired biopsies were available for 24 and 15 pts respectively. High infiltration by TAMs at baseline was significantly associated with adverse outcome (PFS: 1.9 vs 3.7 months, p=0.045; OS: 4.8 months vs NR, p=0.027). Increased tumor infiltration by CD8+ at C2D1 compared to baseline was significantly associated with better PFS (p=0.011). Combining low TAMs infiltration and low tumor cells to CD8+ T cells distance enabled the identification of a subgroup of pts (n= 6/24, 25%) more likely to benefit from R+A combination: median PFS: 5.3 vs 1.9 months (p=0.037); median OS: NR vs 5.3 months (p=0.02). Conclusions: The R+A combination achieved PFS and OS that compared favourably with historical data of R alone in this clinical setting. High-resolution analysis of tumor samples identified a composite score based on TAMs infiltration and tumor cell to CD8+ T cells distance which could be used as a biomarker in further studies investigating this approach in mCRC pts. Clinical trial information: NCT03475953 .
Sex differences in efficacy and toxicity of first-line treatment of metastatic colorectal cancer (CRC): An analysis of 18,399 patients in the ARCAD database.
Authors: Wagner Anna Dorothea , Rakez Manel , Chibaudel Benoist , Adams Richard , Zalcberg John Raymond , Saltz Leonard B. , Venook Alan P. , Schmoll Hans-Joachim , Douillard Jean-Yves , Tournigand Christophe , Heinemann Volker , Goldberg Richard M. , Hecht J. Randolph , Cremolini Chiara , Diaz-Rubio Eduardo , Grothey Axel , Shi Qian , De Gramont Aimery 
Published: May 2020

4029 Background: The clearance of 5-FU differs significantly between men (M) and women (W). Adjuvant chemotherapy (CT) for CRC has a higher toxicity in W. The impact of sex on efficacy and toxicity in first-line trials of metastatic CRC (mCRC) is unknown. Methods: We analyzed patient (pt) and tumor characteristics, toxicities (nausea (AE1), vomiting (AE2), diarrhea, neutropenia (AE3)) and efficacy (overall survival (OS), progression-free survival (PFS)) according to sex in the following treatment groups: A: CT alone, B: CT + bevacizumab, C: CT + EGFR-antibodies, with subgroup analyses in the CT alone group for single-agent, doublets and triplets, as well as irinotecan- and oxaliplatin-based regimens. Pts from trials with treatments still used today and all relevant data available were eligible. OS and PFS were assessed using Kaplan-Meier and Cox models adjusted for primary tumor location and performance status (PS). Results: We included 28 trials with 18.399 pts (11.352 M and 7.047 W). W were younger (61 vs. 63 years), had more often a PS of 1 (49 vs 45%), BRAF mutations (10 vs. 7%), right-sided tumors (42 vs. 35%) and less often rectal tumors (26 vs. 32%). Significant differences in toxicity are reported in table. Rates of diarrhea were similar. There was no sex disparity in OS in the predefined subgroups except for pts receiving triplets where OS was better in M (HRadj=1.39 (1.05 - 1.85)). Median (interquartile range) OS in months for M and W was 16.7 (9.2-27.4) and 16.2 (8.9-27.2) in group 1, 21.9 (12.7-37.5) and 22.3 (12.9 – 39.0) in group 2, and 26.8 (14.6-45.3) and 24.8 (12.3-49.2) in group 3. HRsadj (W vs M) (95% CI), p values for OS were 1.02 (0.96-1.09), .557, 0.92 (0.83-1.03), .142, 0.99 (0.85-1.14), .866. Conclusions: M and W with mCRC differ significantly regarding patient and tumor characteristics. The significant higher toxicity in W does not translate in a higher treatment efficacy. Apart from known sex differences in pharmacokinetics of 5-FU, differences in pharmacodynamics must be postulated. [Table: see text]
Inpatient outcomes and predictors of mortality in patients with gastrointestinal malignancies presenting with sepsis: A nationwide analysis.
Authors: Desai Parth , Vohra Ishaan , Attar Bashar , Katiyar Vatsala , Lingamaneni Prasanth , Moturi Krishna Rekha , Malapati Sindhu Janarthanam , Singh Sunny R K , Zia Maryam , Batra Kunnal , Gupta Shweta 
Published: May 2020

4045 Background: Sepsis is a frequent cause of morbidity and mortality in patients with malignancy. However, there is paucity of literature on mortality, hospital charges and overall healthcare utilization among patients with GI malignancy, which we hope to characterize in this study. Methods: We queried retrospective data from the Nationwide Inpatient Sample (NIS) database for the year 2016. Sepsis (Dx1) was identified using ICD-10 code as primary diagnosis in patients with known GI malignancies (Dx2). Univariate and multivariate Poisson regression analysis was done to study outcomes. Propensity score matching was done to minimize confounding factors. Primary outcome was inpatient mortality. Secondary outcomes were Length of Stay (LOS), Total Charge (TOTCHG) and ICU admission. Results: A total of 43,240 patients with GI malignancy were admitted in 2016 with sepsis. Two most common GI malignancies admitted with sepsis were colorectal (35%) and hepato-cellular cancer (HCC) (28.2%). Overall mortality in GI cancer was 19.8% vs 10.2% in all cancers (p<0.01). There was male (59%) and Caucasian (63%) preponderance. Out of all hospital admissions for GI malignancy, 41.4% were secondary to sepsis. E. coli (31%) infection and gram-negative bacteremia (15%) were the most common causes of sepsis. Sepsis with GI malignancy was associated with length of stay of 7.4 days vs 5.4 days (coef 2.44, 95% CI 2.3-6.7 p=0.04) and a mean hospital charge of $88,728 vs $ 54, 668 (coef 34,140, 95% CI 44,264-90,646, p<0.01) as compared to without sepsis. After adjusting for demographic and patient related variables, independent predictors of mortality were old age, uninsured, African Americans, septic shock requiring pressor support, AKI, inpatient hemodialysis, metabolic encephalopathy and acute respiratory failure. Conclusions: Sepsis poses a substantial healthcare burden in patients with GI malignancy and is a major cause of mortality. Early antibiotic treatment is necessary for sepsis control in patients with GI malignancy. [Table: see text]
Sequencing of treatment matters in synchronous liver or lung only metastatic colon cancer.
Authors: Parasramka Saurabh , Jacob Aasems , Chen Quan , Huang Bin , Hao Zhonglin 
Published: May 2020

4049 Background: Per SEER database, approximately 21% of patients have synchronous metastatic disease at presentation with a median 5 year survival of 14%. Liver is by far the most common site of metastatic disease followed by lung. Metastatectomy of appropriate lesions have achieved a 5 year survival ranged between 40%-70% depending on the extent of the metastasis. For liver or lung only metastatic disease, practice varies from surgery followed by adjuvant chemotherapy to perioperative chemotherapy. Benefit of one approach versus the other has not been demonstrated. We decided to study this using the National Cancer Database (NCDB) database available from the 2010-2015 period. Methods: Adults > 20 years with primary colon cancer (excluding rectal and recto sigmoid junction) with single organ metastatic disease to liver and/or lung at diagnosis were identified. All patients had received surgery to the primary site, resection of the distant site and chemotherapy in the neoadjuvant setting (NAC) or adjuvant setting (AC) within 1 year of diagnosis. Histology except for adenocarcinoma and variants were excluded. Patients who died within 90 days of surgery were excluded. Descriptive analysis, Kaplan-Meier plots, Log-Rank tests for univariate and proportional hazards models for multivariate survival analyses were performed. To reduce biases, a sensitive analysis was also performed based on the intention to treat principle by including additional surgery only and chemotherapy only cases. Results: A total of 3175 colon cancer patients with liver or lung only metastatic disease were identified. 2487 (78%) had AC and 688 (22%) had NAC. Approximately 54% were males with 90% less than 75 years of age. More patients had private insurance and were treated in academic centers in the NC group (62 Vs 51%) and (58 Vs 42%) respectively. Both groups had similar Charlson comorbidity index. NC approach had better OS with HR of 0.75 (CI 0.65-0.85; p < 0.0001) on univariate analysis and 0.86 (0.74-0.98; P < 0.0281) on multivariate analysis. On multivariate analysis, age group > 75 years, black race, treatment outside academic research program had worse survival (p < 0.0001, 0.0139, 0.0001) respectively. The sensitive analysis showed the similar effects. Conclusions: Within the limitations of database review, our analysis suggests survival advantage of neoadjuvant chemotherapy approach over surgery first.
Development of drug resistance in colon cancer patients following chemotherapy, a contributing factor in the failure of oxaliplatin-based HIPEC to improve survival in the Prodige 7 trial.
Authors: Nagourney Robert Alan , Evans Steven Scott , Bernard Paula J , Nagourney Adam , Tran Peter , Francisco Federico , Sugarbaker Paul H. 
Published: May 2020

4063 Background: Numerous studies suggest benefit for heated intra-peritoneal chemotherapy (HIPEC) in colon cancer but the Prodige 7 trial in 265 colon cancer patients randomized to HIPEC or observation after neo-adjuvant chemotherapy (NACT) didn't confirm benefit with median OS of 41.7 vs. 41.2 mos. (p = 0.99) (Proc. ASCO, 2018). One concern is that prior drug exposure selects for drug resistance blunting HIPEC effect. To test the hypothesis we examined the impact of prior chemotherapy on drug resistance in human tumor organoids isolated from colon cancer patients. Methods: Data query identified 111 colorectal cancers (87 colon & 24 rectal) tested for Oxaliplatin sensitivity by ex vivo analysis of programmed cell death (EVA/PCD), a primary culture platform that examines drug induced cell death (apoptotic & non-apoptotic) by morphology, metabolism & histology. Five-point dose response curves interpolated to provide lethal concentration 50% (LC50) were compared by Z score to distribute Oxaliplatin LC50 values around the mean using standard deviation units as the metric of sensitivity or resistance. Of 87 colon 54(62%) were untreated and 33 (38%) treated with 21/33 (64%) having received FOLFOX. To approximate Prodige 7, treated patients were separated by having received FOLFOX < 2 > months before EVA/PCD analysis and also compared Mitomycin (14 vs 41), Irinotecan (18 vs 47) & 5-FU (19 vs. 52) activity to assess cross-resistance. Results: Compared to chemo-naïve, FOLFOX-treated patients were significantly more resistant to Oxaliplatin (P < 0.01) with the degree of resistance increasing significantly for patients who received treatment < 2 months prior to EVA/PCD compared to those with chemotherapy > 2 months prior to EVA/PCD (P < 0.01). Activity for Mitomycin & Irinotecan was not significantly different for chemo-naïve vs. treated patients, but 5 FU was more resistant (P = 0.048) in previously treated. Conclusions: The failure of Prodige 7 to improve survival with HIPEC following NACT may reflect diminished Oxaliplatin activity in patients whose residual disease has been selected for Oxaliplatin & 5FU resistance. Resistance was not observed for Mitomycin or Irinotecan. This suggests that those using HIPEC may i) examine other classes of drugs or drug combinations for IP administration ii) improve the selection of candidates for HIPEC administration or iii) consider HIPEC administration earlier in the course of therapy when chemotherapy-induced drug resistance may be less evident.
Duration of FOLFOX adjuvant chemotherapy in high-risk stage II and stage III colon cancer with deficient DNA mismatch repair.
Authors: Wu Zehua , Hu Huabin , Wang Chao , Huang Yan , Deng Yanhong 
Published: May 2020

4075 Background: In the IDEA collaboration, noninferiority was not confirmed for 3 months versus 6 months of FOLFOX adjuvant chemotherapy among patients with high-risk stage II and stage III colon cancer (CC). Patients with deficient DNA mismatch repair (dMMR) have a good prognosis, but for whom, whether limiting the duration of adjuvant therapy will compromise oncologic outcomes remains undefined. We evaluated the impact of 3 months of FOLFOX adjuvant chemotherapy or surgery alone in comparison with 6 months of FOLFOX on disease-free survival (DFS) in dMMR CC patients. Methods: This retrospective study included all consecutive patients who underwent curative surgical resection for high-risk stage II or III dMMR CC between May, 2011 and July, 2019. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Results: A total of 242 dMMR CC patients were included (43.4% high-risk stage II, 56.6% stage III). The patients received 6 months of FOLFOX adjuvant chemotherapy (n = 66; median cycles [rang] = 12 [10-12]), 3 months of FOLFOX (n = 87; median cycles [rang] = 6 [4-8]), or surgery alone (n = 89). Three groups were generally well balanced, although more patients with stage III were in the 6-month therapy group (74.2%), compared with the 3-month therapy group (57.5%) and the surgery alone group (42.7%). As compared with 6 months of FOLFOX adjuvant chemotherapy in the overall population, 3 months therapy reduced DFS in multivariable analysis (HR, 2.78; 95CI, 1.18 to 6.47; P = 0.02), similar to surgery alone (HR, 2.30; 95CI, 0.99 to 5.38; P = 0.05). In the subgroup analysis, a therapy duration of 6 months was statistically superior to a duration of 3 months only in the patients with stage III, with a 3-year rate of DFS of 86.2% versus 70.8% (HR, 3.06; 95% CI, 1.14 to 8.19; P = 0.026). Conclusions: This study supports the 6-month duration of FOLFOX adjuvant chemotherapy in stage III dMMR CC.
Mutation of DNA damage repair genes confers an immune-privileged tumor microenvironment in colorectal cancer with a prognostic value.
Authors: Liang Dandan , Chen Huan , Yang Ying , Zhang Guanxiong , Zhang Jiao , Zhang Henghui 
Published: May 2020

4080 Background: Microsatellite instability high (MSI-H)/mismatch-repair-deficient (dMMR) has been proved as a validated biomarker in solid tumors receiving immune checkpoint inhibitors (ICIs). Recently, mutational status of the DNA damage repair (DDR) genes has been linked to anti-tumor immune response in bladder cancer. Therefore, it would be of great interest to unravel the implications of DDR in shaping the immune responsiveness in CRC. Methods: The genomic correlates were examined in a publicly available cohort from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To explore the associations between DDR mutation and immune features, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was analyzed. Further, we determined DDR mutation and MSI status in a Chinese CRC cohort via a 543-gene panel sequencing. Results: First, we observed that DDR pathway was commonly mutated (21.79%) in the multi-cancer MSK ICI cohort, with the highest frequency of 36.36% in CRCs. Second, survival analysis revealed that the median overall survival (mOS) in patients with DDR mutations was significantly longer than that in the DDR wild-type subgroup, in both pan-cancer (P = 0.0008; mOS 31 vs 16 months) and CRC patients (P = 0.016; mOS 34 vs 13 months) in the MSK ICI cohort. However, in the TCGA COADREAD dataset, there was no significant difference in OS or progression free survival (PFS) between DDR mutant and DDR wild-type subgroups. These observation indicated a specific prognostic value for DDR mutation in patients with ICI treatment while not conventional treatment. Third, in the TCGA COADREAD dataset, DDR mutations were associated with increased TMB, enrichment of immune cell infiltration and immune checkpoint molecule expression, suggesting an improvement of various steps of the cancer immunity cycles in DDR mutant CRCs. Lastly, we investigated the DDR mutational pattern, and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation account for 5.7% and 13.4% respectively, suggesting that DDR may identify a higher proportion of potential responders than MSI-H. Conclusions: Our data suggest that DDR mutation is a potential prognostic biomarker for ICI-treated CRCs. Functional analysis in TCGA dataset revealed that DDR mutation might be an indication of enhanced cancer immunity. The higher incidence of DDR mutation in Chinese CRCs emphasized the future utility of panel-based DDR evaluation in guiding ICI treatment.
Consensus molecular subtype (CMS) as a novel integral biomarker in colorectal cancer: A phase II trial of bintrafusp alfa in CMS4 metastatic CRC.
Authors: Mehrvarz Sarshekeh Amir , Lam Michael , Zorrilla Isabel R. , Holliday Emma Brey , Das Prajnan , Kee Bryan K. , Overman Michael J. , Parseghian Christine Megerdichian , Shen John Paul Y.C. , Tam Alda , Parra Cuentas Edwin Roger , Zhang Liren , Wang Xuemei , Duose Dzifa Yawa , Luthra Rajyalakshmi , Reddy Neelima , Maru Dipen M. , Kopetz Scott , Morris Van K. 
Published: May 2020

4084 Background: Consensus Molecular Subtype 4 (CMS4) colorectal cancer (CRC) features increased TGFβ signaling, which may account for de novo resistance to immunotherapy for patients (pts) with microsatellite stable mCRC. To date, no prior trial has incorporated CMS status as an integral biomarker. Bintrafusp alfa (M7824) is a dual PD-L1 antibody/TGFβ trap with acceptable safety. Methods: Primary tumors from pts with metastatic CRC underwent CMS testing in a CLIA setting. In this Simon two-stage phase II trial (Ho: p < .05; Ha: p≥.25) for CMS4 mCRC, pts received bintrafusp alfa 1200mg IV every 14 days. RT (8Gy/day x 3 days) to a single metastatic lesion with abscopal intent was administered between doses 2 and 3. The primary objective was to estimate response rate (RR) per iRECIST. Correlative studies including RNA sequencing were performed on pre- and on-treatment biopsies. Results: 53 of 137 tested pts (39%) between June 2018-December 2019 had CMS4 mCRC. 13 of 15 treated pts received the agent with RT. All pts were evaluable for toxicity, and 13 for response. Median number of doses was 3 (IQR, 2-4). There was one grade 3 immune-related adverse event (colitis) requiring study discontinuation. There were 2 pts with stable disease and 11 with progressive disease as best response (RR 0%, 95% CI 0-22%). Enrollment was stopped after first stage for futility. Median PFS and OS were 1.6 months and 5.0 months, respectively. In paired samples, treatment with bintrafusp alfa resulted in an increase in the expression of IFNγ signature in nonirradiated metastatic lesions ( p< .001, q< .001). Updated results will be presented. Conclusions: This is the first reported clinical trial to utilize CMS status as an integral biomarker for pts with metastatic CRC and capitalizes on treating CRC subpopulations with targeted agents based upon validated RNA-based signatures. Although the efficacy for bintrafusp alfa and RT is low, changes in IFNγ signature provides a potential signal for refining therapeutic strategies based upon TGFβ enrichment in pts with mCRC. Clinical trial information: NCT03436563 .
Treatment effects (TEs) of EGFR monoclonal antibodies (mAbs) in metastatic colorectal cancer (mCRC) patients (pts) with KRAS, NRAS, and BRAF mutation (MT) status: Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database.
Authors: Karapetis Christos Stelios , Liu Heshan , Sorich Michael , Fiskum Jack , Grothey Axel , Van Cutsem Eric , Maughan Tim , Douillard Jean-Yves , Jonker Derek J. , Bokemeyer Carsten , Sobrero Alberto F. , Chibaudel Benoist , Zalcberg John Raymond , Adams Richard , Buyse Marc E. , De Gramont Aimery , Shi Qian 
Published: May 2020

4090 Background: EGFR mAbs have become incorporated into clinical practice for the management of mCRC over the last decade. KRAS and NRAS mutations are used as predictive biomarkers and BRAF V600E mutations are associated with an adverse prognosis. The observed TE within biomarker subpopulations has varied between studies. Methods: IPD from randomized trials with head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or BSC) in mCRC, across all lines of therapy (first, second and later), were pooled. Biomarker subpopulations are defined in the table. Overall survival (OS) and progression-free survival (PFS) were compared between groups by Cox model, stratified by studies and adjusted by age, gender, and performance status. TEs were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). Within each biomarker subgroup, EGFR mAb efficacy was explored according to multiple exploratory factors, including line of therapy, type of backbone chemo, gender, sidedness and site of metastasis. Interaction tests were performed. P-values < 0.01 were considered statistically significant to account for multiple comparisons. Results: 5729 pts from 8 studies with data available for ≥ 1 biomarker were analysed. PFS benefits (median 9.2 mos in EGFR mAbs, 8.0 mos in no EGFR mAbs) were confirmed in triple-WT pts, but not for OS (refer to table). No OS/PFS benefits were observed for pts with any of the MT tumors. Exploratory analyses showed a potential detrimental TE of EGFR mAbs in KRAS MT mCRC with liver metastasis (OS: HRadj 1.22, p = .003, pinteraction .0056; PFS: HRadj 1.24, p = .0009, pinteraction .0008). These results were confirmed within the subgroup of pts with all 3 biomarkers available. Conclusions: This is the largest IPD analysis to explore the predictive value of RAS/BRAF biomarkers in mCRC. Our findings demonstrate that there is no evidence of efficacy of EGFR mAbs in KRAS, BRAF and/or NRAS MT mCRC. EGFR mAbs might have a detrimental effect in KRAS MT mCRC with liver metastases. [Table: see text]