bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of high-risk features on disease-free survival (DFS) in patients (pts) with high-risk stage II colon cancer (CC) in ACHIEVE-2 trial as part of the IDEA collaboration.
Authors: Manaka Dai , Shiozawa Manabu , Kotaka Masahito , Gamoh Makio , Shiomi Akio , Makiyama Akitaka , Munemoto Yoshinori , Rikiyama Toshiki , Fukunaga Mutsumi , Ueki Takashi , Shitara Kohei , Shinkai Hiroshi , Tanida Nobuyuki , Oki Eiji , Yamazaki Kentaro , Sunami Eiji , Yamanaka Takeharu , Yoshino Takayuki , Ohtsu Atsushi , Maehara Yoshihiko 
Published: May 2020

4011 Background: The IDEA collaboration for high-risk stage 2 colorectal cancer patients (pts) demonstrated that for CAPOX, 3 months was non-inferior to 6 months treatment, while for FOLFOX, 6 months was superior to 3 months treatment. We investigated the impact of high risk features on disease-free survival (DFS). Methods: ACHIEVE-2, one of the 4 IDEA studies (SCOT, TOSCA, ACHIEVE-2, HORG), was an open-label, multicenter randomized trial for high-risk stage II colon cancer. High risk features are defined as one or more: T4, inadequate nodal harvest < 12, poorly differentiated, clinical sign of obstruction and perforation or vascular invasion. The association of high risk features with DFS were measured by Cox regression analyses. Results: Between 2014 and 2017, ACHIEVE-2 enrolled 525 pts, out of whom 514 pts were the modified ITT (mITT) population; 432 received CAPOX (84.0%) and 82 did mFOLFOX6 (16.0%). High-risk features included 35.8% of T4, 12.8% of inadequate nodal harvest, 11.5% of poorly differentiated, 19.3% of obstruction, 6.4% of perforation and 87.5% of vascular invasion; 47.3% had one features, 35.2% had two, 14.6% had three, and 2.9% had four or more. With a median follow-up of 36.1 months, 3-year DFS rates were 88% in both arms, with a hazard ratio (HR) of 1.12 (95% CI, 0.67-1.87, p=0.67). In multivariate analysis, T4 (HR 3.77 [2.18-6.53], p< 0.0001) and inadequate nodal harvest (HR 2.98 [1.59-5.59], p= 0.0006) remained independent significant negative prognostic factors. The 3-year DFS rates in T4 and Non-T4 diseases were 78% and 94% (p<0.0001), while 3-year DFS rate in pts with inadequate and adequate nodal harvest were 77% and 90% (p=0.0059). No interaction was observed between treatment duration and T4 or inadequate nodal harvest. Conclusions: Our findings indicated the relative impact of high risk features on DFS varies across factors; T4 and inadequate nodal harvest < 12 were more significant than the others. Our results must be interpreted within the combined analysis as well as within the reproducibility of results across the 4 trials. Clinical trial information: 000013036 .
Improving the AJCC/TNM staging classification for colorectal cancer: The prognostic impact of tumor deposits.
Authors: Peacock Oliver , Limvorapitak Thitithep , Hu Chung-Yuan , Bednarski Brian K. , Taggart Melissa , Dasari Arvind , Kopetz Scott , Holliday Emma B. , Das Prajnan , You Y. Nancy , Chang George J. 
Published: May 2020

4012 Background: Identification of tumor deposits (TD) currently plays a limited role in staging for colorectal cancer (CRC) other than for N1c designation. The aim of this study was to determine the prognostic impact, beyond AJCC N1c designation, of TD among primary CRC patients. Methods: Patients with stage 1 to 3 primary CRC diagnosed between 2010 and 2015 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Cancer specific survival (CSS) stratified by TDs and nodal status was calculated, and Kaplan-Meier method and multivariable COX proportional hazards regression analyses were performed. Results: A total of 74,494 patients with primary CRC were identified. Mean age was 66.4 (SD+/-13.2) years, 36,988 (49.7%) were female and 40,651 (54.6%) were right-sided. TDs were present in 4,481 patients (6.0%) and 26,603 (35.7%) had lymph node metastases. The presence of TDs were significantly associated with adverse tumor characteristics including advanced pathological stage, nodal and metastasis status, higher grade and perineural invasion. Incorporating TDs into each nodal status was independently associated with worse CSS and supported reclassification of nodal status to incorporate TDs following multivariable regression analysis as outlined in the table. Following multivariable regression analysis, the proposed AJCC nodal reclassification incorporating TDs, in combination with tumor stage was a strong predictor of CSS, and also represents a new summary staging. Conclusions: TDs are an independent predictor of worse outcome in CRC. The presence of TDs have distinctly different CSS and these data support modification of the current N classification. This study proposes a reclassification of the AJCC system for CRC to incorporate TDs and informs an updated node and summary stage. [Table: see text]
FOxTROT: neoadjuvant FOLFOX chemotherapy with or without panitumumab (Pan) for patients (pts) with locally advanced colon cancer (CC).
Authors: Seligmann Jenny F. ,   FOxTROT Collaborative Group
Published: May 2020

4013 Background: FOxTROT has reported marked down-staging, reduced perioperative morbidity and a trend towards fewer recurrences with 6 wks of oxaliplatin-fluoropyrimidine neoadjuvant chemotherapy (NAC) in CC (Seymour, ASCO 2019 abstract 3504). Using updated data, we investigate the contribution of panitumumab (Pan) and tumour markers to efficacy of NAC. Methods: 1053 pts with radiologically-staged T3-4, N0-2, M0 CC were randomly allocated (2:1) to either 6 wks of NAC and 18 wks of postoperative adjuvant chemotherapy (AC) or 24 wks of AC. 279 pts with RAS-wt tumours were also randomised 1:1 to receive Pan or not with NAC. The primary endpoint was freedom from recurrence or residual disease at 2 years for NAC vs AC, and depth of extramural spread for the Pan randomisation; secondary endpoints include safety, histological downstaging, CC-specific survival and OS. Results: Of 699 allocated pre-and-postoperative chemotherapy, 674 (97%) started and 612 (88%) completed NAC. 684/699 (97.8%) pre-and-postoperative and 349/354 (98.6%) control patients underwent tumour resection. There was marked T- and N-down-staging and tumour regression with NAC (all p<0.001). There were fewer disease recurrences within 2 years in the NAC than AC group: 15.6% (109/698) vs 19.5% (69/354), RR=0.76 (95%CI 0.56-1.02), P=0.07. Response to NAC was significantly (p<0.001) less in MMR-deficient (dMMR) than MMR-proficient (pMMR) tumours: 7%(8/115) vs 23%(128/553) moderate or greater histological tumour regression. Reductions in 2-year recurrence were also seen only in pMMR tumours [RR=0.72 (0.52-1.00), p=0.05], with no apparent benefit in dMMR tumours: RR=0.94 (0.43 to 2.07), p=0.9]. Analyses of panitumumab will be presented. Conclusions: Six weeks of NAC for operable CC can be delivered safely, with marked histopathological down-staging, and may result in better disease control at 2 years in pMMR disease. Clinical trial information: 87163246 .
Pembrolizumab for previously treated advanced anal squamous cell carcinoma: Pooled results from the KEYNOTE-028 and KEYNOTE-158 studies.
Authors: Marabelle Aurelien , Cassier Philippe Alexandre , Fakih Marwan , Kao Steven Chuan-Hao , Nielsen Dorte , Italiano Antoine , Guren Tormod , Dongen Marloes Van , Spencer Kristen Renee , Bariani Giovanni M. , Ascierto Paolo Antonio , Santoro Armando , Hiret Sandrine , Ott Patrick Alexander , Piha-Paul Sarina Anne , Liu Chih-Chin , Leiby Melanie A. , Norwood Kevin , Delord Jean-Pierre 
Published: May 2020

4020 Background: Patients (pts) with anal squamous cell carcinoma (ASCC) have poor outcomes and few treatment options. We report a pooled analysis of pembrolizumab (pembro) antitumor activity and safety in the ASCC cohorts of the multicohort studies KEYNOTE-028 (NCT02054806; phase 1b) and KEYNOTE-158 (NCT02628067; phase 2), providing a robust sample size and longer follow-up. Methods: Eligible pts were aged ≥18 y with histologically/cytologically confirmed metastatic/unresectable ASCC, had prior failure of/intolerance to standard therapy or no standard therapy options, measurable disease (RECIST v1.1), ECOG PS 0/1, and a tissue sample evaluable for PD-L1/biomarkers (KEYNOTE-028 required PD-L1 positivity). Baseline PD-L1 expression was assessed using a prototype IHC assay (QualTek) in KEYNOTE-028 and the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies) in KEYNOTE-158. Pts received pembro 10 mg/kg Q2W (KEYNOTE-028) or 200 mg Q3W (KEYNOTE-158) for 2 y or until PD/unacceptable AEs. The primary endpoint in both studies was ORR (per RECIST v1.1). Secondary endpoints were duration of response (DOR), PFS, OS, and safety. Results: 137 pts with ASCC were treated in KEYNOTE-028 (n = 25) or KEYNOTE-158 (n = 112) and were included in this analysis (median age, 61 y; 83.2% women; 73.0% had PD-L1–positive tumors). Median follow-up was 11.7 mo; 124 pts (90.5%) had discontinued treatment. ORR (95% CI) was 10.9% (6.3%–17.4%). 8 pts had CR and 7 had PR. ORR (95% CI) by PD-L1 status was 14.0% (7.9%–22.4%) in the PD-L1 positive group and 3.3% (0.1%–17.2%) in the PD-L1 negative group. Among all treated pts, median DOR was not reached (range, 6.0+ to 57.5+ mo). By Kaplan-Meier estimation, 84.6% of responders had a DOR ≥24 mo. Median PFS was 2.1 mo (95% CI, 2.0–2.1) and median OS was 11.7 mo (95% CI, 8.8–14.5). The 12-mo PFS and OS rates were 14.5% and 47.4%. 85 pts (62.0%) had +1 treatment-related AE, 24 pts (17.5%) with grade 3–4 events (no grade 5 events). 32 pts (23.4%) had immune-mediated AEs; 2 pts (1.5%) had infusion related reactions. Conclusions: In pts with previously treated advanced ASCC, pembro showed durable antitumor activity, particularly in pts with PD-L1–positive tumors, and manageable toxicity. Clinical trial information: NCT02054806 (KEYNOTE-028), NCT02628067 (KEYNOTE-158) .
Cetuximab/irinotecan/5-FU +/-oxaliplatin or FOLFOXIRI +/- bevacizumab in patients with colorectal cancer and nonresectable liver metastases (AIO CELIM2-study).
Authors: Folprecht Gunnar , Mende Marika , Liersch Torsten , Bechstein Wolf Otto , Kohne Claus-Henning , Stein Alexander , Kunzmann Volker , Ghadimi Michael , Neumann Ulf Peter , Nilsson Sven , Koenig Alexander , Pession Ursula , Troja Achim , Glados Manfred , Kleiss Mathias , Ubbelohde Ulrike , Weitz Juergen 
Published: May 2020

4024 Background: EGFR based combinations and the triplet combination FOLFOXIRI are known to increase response rates compared to doublet combinations. Methods: Patients with colorectal cancer and non-resectable liver metastases were enrolled into the trial. RAS wild type patients were randomised to cetuximab/FOLFIRI or cetuximab/FOLFOXIRI, RAS/BRAF mutant patients were randomised to FOLFOXIRI with or without bevacizumab. The primary endpoint was response. Secondary endpoints included progression free and overall survival. The trial was closed early due to poor recruitment. Results: Between 2014 and 2018, ninety-two pts were enrolled into the study. 54 wild type pts were randomised into cetuximab based treatment with (28 pts) or without (26 pts) oxaliplatin, 38 RAS/BRAF mutant pts were randomised to receive FOLFOXIRI alone (18 pts) or plus bevacizumab (16 pts). Objective response was achieved in 21/26 pts (81 % [95 CI: 61 – 93 %]) with cet/FOLFIRI, 24/28 pts (86 % [95 CI: 67 – 96 %]) with cet / FOLFOXIRI, 13/1 8 pts (72 % [95 CI: 46 – 90 %]) with FOLFOXIRI and 14/20 pts (70 % [95 CI: 46 – 88 %]) with bev/FOLFOXIRI. Two pts with cet/FOLFOXIRI and one pat with FOLFOXIRI achieved CR according to imaging. The median PFS was 12.7 [95 % CI: 7.2 – 18.2], 15.0 [95 % CI: 11.3 – 18.7], 17.5 [95 % CI: 8.0 – 27.1] and 15.0 [95 % CI: 11.4 – 18.5] months with cet/FOLFIRI, cet/FOLFOXIRI, FOLFOXIRI and bev/FOLFOXIRI. The median overall survival was 42 mo. [95 % CI: 28 – 55], 55 [95 % CI:41 – 68], 28 [95 % CI: 22 – 36] and 44 [95 % CI: 0 – 94] months with cet/FOLFIRI, cet/FOLFOXIRI, FOLFOXIRI and bev/FOLFOXIRI. The frequency of grade ≥ 3 toxicity per arm (cet/FOLFIRI, cet/FOLFOXIRI, FOLFOXIRI and bev/FOLFOXIRI) was 29 %, 46 %, 56 %. 45 % for neutropenia/leukopenia, 11 %, 12 %, 28 %, 25 % for diarrhea and 29 %, 19 %, 6 % and 5 % for skin toxicities. Conclusions: High response rates were observed in patients with colorectal liver metastases with all regimens. The numerically highest response rate was observed in RAS wild type patients treated with cetuximab/FOLFOXIRI. Clinical trial information: NCT01802645 .
Fruquintinib combination with sintilimab in refractory metastatic colorectal cancer patients in China.
Authors: Gou Miaomiao , Yan Huan , E Liu Tie , Wang Zhikuan , Si Haiyan , Chen Shiyun , Pan Yuting , Fan Runjia , Qian Niansong , Dai Guanghai 
Published: May 2020

4028 Background: Fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, is a new anti-cancer targeting drug independently developed in China for refractory metastatic colorectal cancer (mCRC). Because Regorafenib combined with nivolumab has a promising future in patients with refractory mCRC, we aim to evaluate the efficiency of combination of Fruquintinib with Sintilimab (a highly selective, fully human monoclonal antibody PD-1 mAb) in these patients. Methods: Fifty-two patients with refractory mCRC were given fruquintinib (3mg orally, once daily for 3 weeks, followed by 1 weeks off in 4 weeks cycles) and sintilimab (200mg intravenously, once every 3 weeks). Before treatment, peripheral blood samples were collected and next-generation sequencing was performed to detect the gene profile of patients. Results: The ORR was 15.38% (8/52), DCR was 57.6% (30/52), and mPFS was 108 days. The patients was divided into two groups according to their PFS: PFS ≥ 90 days and PFS <90 days. PFS was significantly worse in patients with the following mutations: AMER1 ( p=0.0073), DNMT3A ( p=0.0075), ETV5 ( p=0.012), EWSR1 ( p=0.016), FANCA ( p=0.019), IKBKE ( p=0.0073), NOTCH1 ( p=0.015), STAG2 ( p=0.012) and TCF7L2 ( p=0.0073). It was also significantly worse in the patients had the abnormalities of complexity and coagulation cascades ( p = 0.026) and pancreatic cancer pathway ( p = 0.0098). Conclusions: Fruquintinib combined with Sintilimab seemed not resulted in a significant increase in ORR, DCR and OS in refractory mCRC. Certain mutational genes and abnormal pathway caused by some frameshift mutations may affect the efficacy. It is suggested that targeting these mutational genes and signaling pathway may be helpful to improve the efficacy of Fruquintinib combination with Sintilimab.
Genomic aberration of chromatin regulatory BAF complex as predictive biomarker for immunotherapy in gastrointestinal adenocarcinoma.
Authors: QI Changsong , Ge Sai , Peng Zhi , Zhang Xiaotian , Xu Yu , Wang Guoqiang , Bai Yuezong , Shen Lin 
Published: May 2020

4035 Background: SNF/SWI, a large ATP-dependent chromatin remodeling complex, is required for transcriptional activation of genes normally repressed by chromatin, and critical to tumor initiation and progression. Here, we analyzed the predictive utility of the mutations of the SNF/SWI members involved in BAF and PBAF complexes, and sought to explore the potential mechanisms. Methods: Clinical, genomic, transcriptional, and immunohistochemical data from immunotherapeutic cohort (MSKCC, n=185), Cancer Cell Line Encyclopedia (CCLE, n=92), The Cancer Genome Atlas (TCGA, n=925), and 3D Medicines database (3DMed, n=1812) were analyzed to explore the predictive effect of genomic aberration of BAF complex on the benefit from immunotherapy in patients with gastrointestinal adenocarcinoma. Results: In the MSKCC cohort involving 185 patients with gastrointestinal adenocarcinoma, the mutation of any member involved in BAF complex ( ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCD1) was significantly associated with prolonged OS of ICI treatment (HR 0.53, 95%CI 0.31-0.90, P=0.019), instead of the mutations of PBAF members including PBRM1 and ARID2. In addition, BAF mutation was not linked with better prognosis in TCGA database, indicating its predictive, not prognostic efficacy of immunotherapy. BAF-mutated samples exhibited higher tumour mutational burden (TMB, P<0.05, Table), and increased mRNA expression of immune-related genes including chemokines and granzyme A. In the 3DMed cohort where tumour samples received both genomic sequencing and PD-L1 immunohistochemical staining, BAF mutation was associated with higher PD-L1 positive rate in tumour cells (P<0.05, Table). Conclusions: Genomic aberration of members in chromatin regulatory BAF complex may serve as a predictive, not prognostic biomarker of ICI benefit in patients with gastrointestinal adenocarcinoma, partially underlying the mechanisms including higher mutational burden, transcription of immune-related genes, and protein-level PD-L1 expression. [Table: see text]
Pembrolizumab (Pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver oligometastatic MSS/MMR proficient colorectal cancer (CRC).
Authors: Deming Dustin A. , Emmerich Philip , Turk Anita Ahmed , Lubner Sam Joseph , Uboha Nataliya Volodymyrivna , LoConte Noelle K. , Mulkerin Daniel , Kim David H. , Matkowskyj Kristina A. , Weber Sharon M. , Abbott Daniel , Eickhoff Jens C. , Bassetti Michael Frederick 
Published: May 2020

4046 Background: SBRT is used to treat liver metastatic CRC, causing an increase in immunogenic antigen release and influx of responding immune cells. We hypothesize that radiation enhances the immunogenicity of MSS CRC and potentiates the effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients (pts) undergoing resection of their disease. Methods: Eligibility criteria include MSS CRC with resectable liver-confined metastatic disease. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management and adjuvant Pem. The primary objectives are to determine the safety/tolerability of this regimen and the recurrence free survival (RFS) at 1 year following clearance of metastatic disease. Correlative studies examined tumor infiltrating CD8+ T lymphocytes (TILs) and the accumulation and proteolysis of versican (VCAN), an immunoregulatory tumor matrix proteoglycan. Proteolysis of VCAN results in the release of an immunostimulatory fragment, versikine. Cancers with low VCAN and high versikine (VCAN proteolysis predominant (VPP)) are hypothesized to respond better to immunotherapies. Results: 15 pts (median age 58.2 [range 38-69]) have been enrolled. All pts had prior FOLFOX. SBRT median dose was 50 Gy (40-60 Gy) to a single lesion targeted in all pts. No DLTs were observed. AEs included one case of biliary tract injury and biloma, not related to immunotherapy. No grade 3/4 immunotherapy-related AEs have occurred. 10 pts have completed a minimum follow-up of 1 year post resection. In the intention to treat analysis, the 1 year RFS was 70% (historic control 50%). 2 of 3 pts with BRAF V600E mutations have had early recurrences. 2 pts had VCAN high tumors and both recurred prior to 1 year. 4 pts had VPP cancers and all were recurrence free at 1 year. TILs in the radiated lesions were > 2 times as abundant as in the pre-treatment (tx) tissue for 50% of pts. 3 of 4 pts who had non-radiated lesions available for analysis had TILs > 2 times pre-tx in the non-radiated lesions indicating a potential abscopal effect. Conclusions: The combination of SBRT with Pem and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity and preliminary evidence of potential enhanced efficacy. Clinical trial information: NCT02837263 .
Clinical and pathologic factors associated with survival in BRAFV600E colorectal cancers.
Authors: Morris Van K. , Kee Bryan K. , Overman Michael J. , Fogelman David R. , Dasari Arvind , Raghav Kanwal Pratap Singh , Shureiqi Imad , Johnson Benny , Parseghian Christine Megerdichian , Wolff Robert A. , Eng Cathy , Garg Naveen , Kopetz Scott 
Published: May 2020

4047 Background: BRAFV600E mutations occur in fewer than 10% of all patients (pts) with metastatic colorectal cancer (mCRC) and arise from sessile serrated adenomas. Despite efficacy with targeted therapies against MAPK signaling and with immunotherapies in this population, survival outcomes for pts with BRAFV600E mCRC in general are poor. Characteristics distinguishing pts with BRAFV600E mCRC with favorable versus unfavorable outcomes have not been well annotated. Methods: Records of 188 pts with BRAFV600E mCRC evaluated at MD Anderson Cancer Center between 3/2010-1/2020 were reviewed. Pts with the shortest and longest metastatic survival (N = 25 for each group) were compared. Associations between prognostic group and clinical/pathologic features were measured by odds ratio and for median survival by log-rank testing. Results: Median metastatic survival differed between the 2 BRAFV600E mCRC populations (8.6 vs 84 months, p < .0001). Pts with poor survival more commonly had primary tumors arising from the hepatic flexure/proximal transverse colon (44% vs 16%, p = .04) and more frequent hepatic involvement (75% vs 28%, p = .001). Pts with favorable survival were more likely to develop metachronous metastases (52% vs 16%, p = .01), have fewer distant organ involvement (median 1 vs 2, p = .02), and undergo definitive locoregional therapy to metastatic disease (44% vs 0%, p = .01). Microsatellite instability (36% vs 4%, p = .008) and a history of tobacco use (44% vs 16%, p = .04) were associated with a favorable prognosis. Durable responses to MAPK-targeted therapies (5/25) and immunotherapy (3/25) were noted in the favorable group. Conclusions: Pts with BRAFV600E mCRC can achieve excellent long-term survival which belies conventional context and is driven by locoregional and systemic treatment options alike. Anatomic localization of the primary tumor and prior exposures may highlight environmental influences on tumor biology which account for the clinical heterogeneity of pts with BRAFV600E mCRC.