bluuebunny/crossref_metadata_2025_split huggingface dataset:
FOLFIRI versus irinotecan monodrug as second-line treatment in metastatic colorectal cancer patients: An open, multicenter, prospective, randomized controlled phase III clinical study.
Authors: Guo Weijian , Zhang Xiaowei , Wang Yusheng , Zhang Wen , Liu Xin , Shen Wei , He Yifu , Zhu Xiaodong , Chen Zhiyu , Wang Hong Qiang , Huang Mingzhu , Zhang Zhe , Zhao Xiaoying , Qiu Lixin , Wang Chenchen , Sheng Xuedan 
Published: May 2020

4038 Background: The most commonly used treatment methods for metastatic colorectal cancer (mCRC)are systemic chemotherapy, molecular targeted therapy and local treatment. The main chemotherapy drugs for mCRC include Irinotecan, Oxaliplatin and 5-Fu. V308 Research shows that FOLFOX and FOLFIRI can be standard first or second-line of each other in the treatment of metastatic colorectal cancer. However if the first-line treatment regimen containing 5-FU fails, whether it is necessary to re-challenge 5-FU when Irinotecan is applied in the second line is unknown. There is no head-to-head comparative study to answer whether the FOLFIRI regimen is better than the Irinotecan monodrug. Therefore, it is necessary to carry out a comparative study of FOLFIRI Versus Irinotecan monodrug to observe whether adding 5-Fu on the basis of Irinotecan can improve the therapeutic effect. Methods: This was a randomized phase III trial. Patients from 5 centers in China with metastatic colorectal adenocarcinoma, for whom first-line of chemotherapy including oxaliplatin combined with fluorouracil drugs (combined or not combined with targeted therapy) had failed, were enrolled. 172 patients with mCRC were randomly treated with FOLFIRI or Irinotecan monodrug were included in this study. FOLFIRI group: Irinotecan 180mg/m2; Lecovorin 400mg/m2; 5-Fu 400mg/m2; 5-Fu 2400mg/m2 CIV 46h. Irinotecan monodrug group 180mg/m2, The regimen was repeated every 2 weeks. The primary endpoint is PFS, and this clinical trail is a superiority trial. Results: ITT (Intention-To-Treat) analysis: Among 172 patients, 10 had PR, 93 had SD, and 63 had PD, 6 patients have not received efficacy evaluation yet. The ORR was 5.68% VS. 5.95%, and the DCR was 61.36% and 54.76% in FOLFIRI group and Irinotecan monodrug group, respectively. Adverse reactions included neutropenia, stomatitis, diarrhea, fatigue, abnormal liver enzymes, pyrexia, arrhythmia, nausea and most of these were grade 1-2. The dose reduction rate induced by drug tocixity of was 13.64% and 7.14% in FOLFIRI group and Irinotecan monodrug group, respectively. Conclusions: These data show that Irinotecan monodrug has the similar ORR and DCR with FOLFIRI regimen in second-line treatment of mCRC. Irinotecan monodrug has lower adverse effect. Clinical trial information: NCT02935764 .
Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).
Authors: Kopetz Scott , Grothey Axel , Van Cutsem Eric , Yaeger Rona , Wasan Harpreet Singh , Yoshino Takayuki , Desai Jayesh , Ciardiello Fortunato , Loupakis Fotios , Hong Yong Sang , Steeghs Neeltje , Guren Tormod Kyrre , Arkenau Hendrik-Tobias , Garcia-Alfonso Pilar , Gollerkeri Ashwin , Maharry Kati , Christy-Bittel Janna , Keir Christopher Hunt , Pickard Michael D , Tabernero Josep 
Published: May 2020

4039 Background: In the BEACON CRC study, the triplet regimen of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) significantly improved overall survival (OS, HR:0.52, P < 0.0001) and objective response rates (ORR, 26% vs 2%, P < 0.0001) in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) compared with current standard of care. This analysis focuses on the patient-reported quality of life (QOL) assessments from this study. Methods: The BEACON CRC study was a randomized, open-label, 3-arm, phase 3 global study which evaluated triplet (ENCO+BINI+CETUX) or doublet (ENCO+CETUX) vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in pts with BRAFV600E mCRC. QOL assessments (secondary endpoints in the trial) included the EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The primary assessment for the QOL variables was the time to definitive 10% deterioration. The study is ongoing. Results: 665 pts were randomly assigned to receive either triplet (n = 224), doublet (n = 220), or control (n = 221). Reduction in the risk of QOL deterioration was an estimated 45% (HR 0.55, 95% CI: 0.43, 0.70) and 52% (HR 0., 9485% CI: 0.38, 0.62) in EORTC QLQ C30 and FACT C assessments, respectively, in favor of the triplet regimen over control. For the doublet vs. control, reduction in risk of QOL deterioration was an estimated 46% (HR 0.54, 95% CI: 0.43, 0.69) and 54% (HR 0.46, 95% CI: 0.36, 0.59) in EORTC QLQ C30 and FACT C, respectively in favor of the doublet. Similar results were observed in EuroQol 5D 5L and PGIC assessments. There were no overall differences in QOL between triplet and doublet across the 4 instruments. Conclusions: In BEACON CRC, triplet and doublet demonstrated substantial improvement in patient-reported QOL assessments over the current standard of care in pts with BRAFV600E-mutant metastatic CRC whose disease had progressed after 1 or 2 prior regimens. Clinical trial information: NCT02928224 .
Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Two-year clinical update.
Authors: Lenz Heinz-Josef , Lonardi Sara , Zagonel Vittorina , Van Cutsem Eric , Limon M. Luisa , Wong Mark , Hendlisz Alain , Aglietta Massimo , Garcia-Alfonso Pilar , Neyns Bart , Gelsomino Fabio , Cardin Dana Backlund , Dragovich Tomislav , Shah Usman , Yang Jing , Ledeine Jean-Marie , Overman Michael J. 
Published: May 2020

4040 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI had robust, durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (median follow-up 13.8 months [mo; range, 9–19]; Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up is presented here. Methods: Patients (pts) with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + low-dose IPI 1 mg/kg Q6W until disease progression or discontinuation. The primary endpoint was investigator-assessed (INV) objective response rate (ORR) per RECIST v1.1. Results: In 45 pts with median follow-up of 29.0 mo, ORR (95% CI) increased to 69% (53–82) (Table) from 60% (44.3–74.3); complete response (CR) rate increased to 13% from 7%. The concordance rate of INV and blinded independent central review was 89%. Median duration of response (DOR) was not reached (Table). Median progression-free survival (PFS) and overall survival (OS) were not reached, and 24-mo rates were 74% and 79%, respectively (Table). Nineteen pts discontinued study treatment without subsequent therapy. An analysis of tumor response post discontinuation will be presented. Ten (22%) pts had grade 3–4 treatment-related adverse events (TRAEs); 3 (7%) had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + low-dose IPI continued to show robust, durable clinical benefit with a deepening of response, and was well tolerated with no new safety signals identified with longer follow-up. NIVO + low-dose IPI may represent a new 1L therapy option for pts with MSI-H/dMMR mCRC. Clinical trial information: NTC02060188 . [Table: see text]
Recurrence after surgery for concurrent metastatic colorectal cancer: The perspective of bioinformatics and machine learning.
Authors: Luo Zhiwen , Bi Xinyu 
Published: May 2020

4043 Background: Recurrence of concurrent metastatic colorectal cancers (mCRCs) after surgery is still a challenge. But mCRCs’ outcomes are heterogeneous, and no clinicopathological methods can predict its recurrence and guide postoperative treatment from an intrinsic cell activities and extrinsic immune microenvironment perspective. We aimed to identify such gene models. Methods: Gene expression analysis on CRCs. Based on metastasis-related genes, a metastatic evaluation model (MEM) was developed, dividing mCRCs into high and low recurrence risk clusters. Machine learning tested MEM’s importance to predict recurrence. Further investigating MEM’s two clusters made an immune prognostic model (IPM) with immune genes differentially expressed between MEM clusters. The predictive performance of MEM and IPM on prognosis was comprehensively analyzed and validated. The mechanism of IPM on the immune microenvironment and response to immuno/chemotherapy was analyzed extensively. Results: RNA data of 998 CRCs were analyzed. High postoperative recurrence risk in mCRCs was owing to immune response’s down-regulation, which was influenced by 3 MEM genes ( BAMBI, F13A1, LCN2) and their related 3 IPM genes ( SLIT2, CDKN2A, CLU). MEM and IPM were developed and validated on 239 mCRCs to differentiate a low and high recurrence risk (AUCs > 0.7). Functional enrichment analysis showed immune response and immune system diseases pathway represented the major function and pathway related to IPM gene. IPM high-risk group (IPM-high) had higher fractions of Tregs ( P= 0.04), lower fractions of resisting memory CD4+ T cells ( P= 0.02) than IPM-low. And stroma and immune cells in IPM-high samples were scant ( P= 0.0002, 0.001, respectively). In IPM-high, MHC class II molecules all down-expressed, and DNA methylation disordered. TIDE algorithm and GDSC analysis discovered IPM-low was more promising to respond to both anti-CTLA4 therapy ( P= 0.005) and common FDA targeted drugs ( P< 0.05), while IPM-high had nonresponse to both of them. But anti-CDKN2A agent with activation of MHC class II response might reverse the dilemma of this refractory mCRCs subgroup. Conclusions: Postoperative recurrence of mCRC is strongly related to immune microenvironment. Our two relative gene models could identify subgroups of mCRC with different recurrence risk, and stratify mCRCs sensitive to immune/chemotherapy, even highlight the ignored importance of MHC class II molecules on immunotherapy in mCRCs for the first time.
Prospective study of biomarkers in squamous cell carcinoma of the anal canal (SCCAC) and their influence on treatment outcomes: Five-year long-term results.
Authors: Moniz Camila Motta Venchiarutti , Riechelmann Rachel Pimenta , Braghiroli Maria Ignez , Ribeiro Suilane Coelho , Rivelli Thomás Giollo , Bariani Giovanni M. , Chen Andre Tsin Chih , Nahas Caio , Bonadio Renata Colombo , Ortega Cinthia , Franco Rejane , Meireles Sibele , Pereira Allan Andresson Lima , Sabbaga Jorge , Coudry Renata A. , Hoff Paulo Marcelo 
Published: May 2020

4053 Background: Chemoradiation (CRT) is a curative treatment for SCCAC. However, some patients (pts) present primary CRT resistance. As a rare tumor, there is a lack of prospective studies of prognostic factors in this setting. Methods: This prospective cohort study was aimed to evaluate predictive biomarkers (Ki-67, PD-L1, Human papillomavirus (HPV), HIV status, and tumor DNA mutations) in SCCAC. We published the 6 months (m) response rate (RR) of this cohort showing that HIV- were 5.7 times more likely to achieve response 6m post CRT (OR 5.72, CI 95% 2.5-13.0, P < 0.001). Now we report the long-term follow-up results of 5-year progression-free survival (PFS) and overall survival (OS). Eligible pts had T2-4/N0-3/M0 disease and were candidates to standard CRT. DNA mutations were analyzed by next-generation sequencing (NGS). HPV positivity was tested by PapilloCheck Test. KI-67 and PD-L1 were evaluated by immunohistochemistry. Results: 78 pts were recruited from Jan/2011 to Dec/2015. 75 were evaluable for PFS and OS. The median age was 57 years; 49 (65%) were stage III, and 9 (12%) were HIV+. HPV was evaluated in 67 and found in 47 (70.1%); HPV16 was the most common. PD-L1 was tested in 61; 10 (16.4%) had positive expression > 1%. Ki-67 was performed in 65, with a median of 50% (range 1-90%). The median follow up is 66m. 5-year PFS and OS rates were 63.3% (95% CI 51.2-73.2%) and 76.4% (95% CI 64.8-84.6%), respectively. In a multivariate analysis, age (HR 1.06, P = 0.022, IC 95% 1.01-1.11) and absence of complete response at 6m (HR 3.36, P = 0.007, IC 95% 1.39-8.09) was associated with inferior OS. The OS rate was 62.5% in HIV+ group (95% CI 22.9-86%) in comparison with 78% (95% CI 65.7-86.3%) among HIV- pts, although this difference was not statistically significant (P = 0.400). A tendency to inferior OS was observed among pts with p53 codon 72 polymorphism (HR 2.83, P = 0.181, 95% CI 0.61-13.02). Other tumor mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS. Conclusions: HIV- pts were 5.7 times more likely to achieve response 6m post CRT. The absence of complete response at 6m was the main factor associated with poor 5-year OS. New strategies of follow up and complementary treatment should be studied in late responders and HIV+ pts to ensure the success of curative treatment. Clinical trial information: 36211 .
17-year incidence trends of anal squamous cell carcinoma.
Authors: Jhaveri Khushali , Surani Salim , Shah Shailja , Talati Shailesh S. , Shah Maya 
Published: May 2020

4058 Background: Anal Cancer is a rare neoplasm with 9 out of 10 cases being Anal Squamous Cell Carcinoma (SCCA). We did a population-based analysis to assess the incidence trends in patients with SCCA and identify any significant change in the direction of trends using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Data was extracted from SEER database for the years 2000-2016 for the US population, across all gender, ages, and races. Joinpoint regression models of SCCA incidence were fitted to identify any discrete joints (year) that represent statistically significant changes in the direction of the trend. The average annual percentage change (APC) in the age-adjusted incidence rate in the pre- and post-joinpoint era were measured. Subgroup analysis for gender, ages, and races was also done. Results: 27,721 new adult cases of SCCA were identified from 2000 to 2016. The incidence was higher amongst females (62.44%) compared to males (37.56%) with the white population contributing 85.41% to incidence compared to black (11.84%) and other (2.75%) population. The age-based incidence rate for different groups has been mentioned in Table. A significant jointpoint for SCCA incidence was observed in 2009. The APC was 4.6% (3.5-5.6 95% CI) in 2000-2009 which reduced to 2.1% (0.7-3.4 95% CI) in 2009-2016 indicating a 54% relative reduction in the average annual APC in the US population after 2009. Subgroup analysis revealed significant joinpoints for incidence decrease in Ages 40-59, 80 and above and females of all ages. No significant changes in APC were seen when stratified by race (Refer to Table). Conclusions: Our study, in our knowledge, is the first study assessing incidence trends of SCCA over 17-years. The overall incidence of SCCA is increasing but a statistically significant trend towards decreasing rate of growth in incidence was observed in 2009 and later. Further studies are needed to analyze the causality of such changes in the trend of SCCA. [Table: see text]
The role of fibroblast growth factor receptor 4 (FGFR4) signaling in anti-EGFR resistance in colon cancer.
Authors: Cho Sang Hee , Kim Jo-Heon , Hong Chang-Soo , Sun Eun-Gene , Ryu Kyung-Hyun , Hwang Jun Eul , Bae Woo Kyun , Chung Ik-Joo , Bang Hyun-Jin 
Published: May 2020

4060 Background: Anti-EGFR therapy has been used as a standard treatment for metastatic colon cancer, but the innate resistance is still issues of increasing significance. Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cell proliferation, invasion and anti-apoptosis, through the pathway of MAPK-ERK and PI3K-AKT. We investigated potential crosstalk between FGFR4 and EGFR signaling to identify new resistant mechanism of anti-EGFR therapy and how to overcome it in colon cancer. Methods: RNA-Seq was used to identify the associated signal pathway and down targets induced by FGFR4. Molecular studies including RTK array, RT-qPCR, western blotting were performed to validate the interaction between FGFR4 and EGFR signaling in vitro and in vivo. Next, the effect of FGFR4 in cetuximab resistance was investigated in vitro and in colon cancer patients. Results: FGFR4 overexpression in colon cancer cells activates downstream signaling, such as, PI3K/Akt and RAS/RAF/Erk pathway. Gene Ontology (GO) analysis from RNA-seq revealed that differentially expressed genes (DEGs) altered by expression of FGFR4 were related to biological functions, including cell proliferation, epidermal growth factor receptor signaling, NIK/NF-kB signaling, interferon-gamma signaling, wound healing. RT–qRCR showed that FGFR4 promotes the EGFR and ErbB3 by inducing the expression of EGFR ligands such as AREG, BTC, EREG, HBEGF. In vivo tumorigenesis, we found that FGFR4 promotes tumor growth and high expression of AREG in xenograft tumors. FGFR4 expression reduced the sensitivity to cetuximab in colon cancer cells and synergistic effect was shown when treated with FGFR4 inhibitor with cetuximab. A positive correlation between FGFR4 and AREG expression was observed in cancer, but not in normal tissues and high FGFR4 or AREG expression showed significantly inferior overall survival than low expression in patients treated with cetuximab for metastatic colon cancer. Conclusions: We demonstrated a pivotal mechanism of FGFR4 in colon cancer progression and cetuximab resistance through inducing AREG. Our data point to FGFR4 as a new biomarker to predict cetuximab response and dual targeting of FGFR4 and EGFR may be a promising treatment modality for colon cancer.
Initial correlative studies from a trial of cetuximab and pembrolizumab in metastatic colorectal cancer (mCRC).
Authors: Boland Patrick M , Muhitch Jason , Abrams Scott I , Maguire Orla , Minderman Hans , Bajor David Lawrence , Saltzman Joel N. , Wang Katy , Hutson Alan , Mukherjee Sarbajit , Iyer Renuka V. , Kalinski Pawel , Fountzilas Christos 
Published: May 2020

4062 Background: Cetuximab is an EGFR-targeting IgG1 mAb. Pre-clinical data suggests cetuximab induces CD8+ cytotoxic T-cell (CTL) infiltration of tumors. We hypothesized that augmentation of CTLs in the tumor microenvironment (TME) may provide the proper milieu for effective PD-1 inhibition in metastatic colorectal cancer (mCRC). We conducted a phase Ib/II study of cetuximab with the PD-1 antibody, pembrolizumab, in mCRC. Correlative blood and tissue samples were collected to assess the impact of this treatment on CTLs, as well as potential compensatory alterations in regulatory T-cells (Tregs) and suppressive MDSCs (NCT02713373). Methods: 3 week treatment cycles included pembrolizumab at 200 mg on day 1 and cetuximab 250 mg/m2 following the 400 mg/m2 loading dose. Tumor biopsies were obtained at baseline and at c4d1 (Day 64). Peripheral blood (PB) was drawn at baseline, c2d1 (day 22) and c4d1 (Day 64). Flow cytometry was performed within 24 hours with additional samples stored for future analysis. In the present analysis, we assessed changes in levels of the cellular populations of interest between cycle 4 and cycle 1. Results: Forty-two RAS-wt patients were enrolled through October 2019. Paired tumor tissues were successfully analyzed for 16 patients and PB for 38. Intratumoral CTLs (CD3+CD8+) increased significantly (+47%, p < .05). In PB, there was a slight overall decrease in PB CTLs (-5%, p = NS) and a significant decrease in CD8+CD45RO+PD1+ cells (-42%, p < .05). We saw simultaneous decreases in PD-1+ CTLs in the tumor and PB. There was a trend for increase in Tregs (CD4+ Cd25+ FoxP3+) in PB (+11%, p = NS), but an overall increase in the Teff:Treg ratio (+30%, p = NS). CD4+CTLA4+ cells significantly increased (+37%, p < .05). Granulocytic MDSCs (CD11b+CD14−CD33+HLADR−) in PB decreased significantly on-treatment (-30%, p < 0.5). The sample size and tissue limitations prohibited meaningful evaluation of tissue Tregs and MDSCs via the present methods. Conclusions: Cetuximab and pembrolizumab induced dynamic changes in the TME and PB. The treatment associated increase in intratumoral CTLs was particularly pronounced, consistent with their local expansion and/or influx. This was accompanied by a decrease in PB CTLs. Decreases in multiple PD-1+ lymphoid populations were observed in both tumor and PB, notably PD-1+ CTLs. Of note, we saw a synchronous increase in immunosuppressive CD4+CTLA4+ T-cells in PB. Patient outcomes are pending maturation. Further analyses are planned, coupled with integration of clinical data. Clinical trial information: NCT02713373 .
The landscape of DNA damage response (DDR) pathway in colorectal cancer (CRC).
Authors: Arai Hiroyuki , Elliott Andrew , Wang Jingyuan , Battaglin Francesca , Soni Shivani , Zhang Wu , Sohal Davendra , Goldberg Richard M. , Hall Michael J. , Scott Aaron James , Khushman Mohd , Hwang Jimmy J. , Lou Emil , Weinberg Benjamin A. , Marshall John , Lockhart Albert Craig , Stafford Phillip , Zhang Jian , Korn W. Michael , Lenz Heinz-Josef 
Published: May 2020

4064 Background: Abnormal DDR is a hallmark of cancer, relating to genome instability, anti-tumor immunity, and sensitivity to chemotherapeutic agents and radiation. We conducted a large-scale investigation to clarify the alteration of DDR pathway in CRC. Methods: Tumor samples from 9321 CRC patients were retrospectively reviewed. Next-Generation Sequencing (NGS) on a custom-designed panel enriching 592 gene targets was performed. Samples with mutations detected in any of 29 DDR-related genes were deemed DDR-mutant (DDR-MT); the rest DDR-wild type (DDR-WT). Microsatellite instability (MSI) status was tested with a combination of immunohistochemistry (IHC), fragment analysis and NGS. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. PD-L1 was tested by IHC (SP142). Consensus molecular subtype (CMS) was developed using RNA sequencing data. Results: Of 9321 cases, 1290 (13.8%) were DDR-MT. DDR-MT frequency was higher in right vs. left sided (20.9% vs 10.8%, p < 0.001) and MSI-H vs. MSS (76.4% vs 9.5%, p < 0.001) cases. In the MSS cases, right-sided had marginally higher frequency of DDR-MT than left-sided (10.6% vs 9.1%, p = 0.055), with much higher frequency of Fanconi anemia pathway alteration in right-sided (1.5% vs 0.7%, p < 0.01). CMS1 subtype had the highest frequency of DDR-MT (34.8%); CMS2 had the lowest (7.1%). DDR-MT cases (vs. DDR-WT) had higher mutation rate of ARID1A (55.0% vs 19.1%, p < 0.0001), PIK3CA (22.6% vs 15.8%, p < 0.0001) and BRAF (20.4% vs 7.3%, p < 0.0001), and lower mutation rate of TP53 (48.2% vs 76.1%, p < 0.0001), APC (60.5% vs 74.5%, p < 0.0001) and KRAS (44.0% vs 49.8%, p < 0.001). Mean TMB was much greater in DDR-MT than DDR-WT (All: 20.9/Mb vs 7.7/Mb, p < 0.0001; MSS: 13.7/Mb vs 7.6/Mb, p < 0.05). PD-L1 positivity was also higher in DDR-MT compared to DDR-WT (All: 10.1% vs 2.7%, p < 0.0001; MSS: 4.8% vs 2.4%, p < 0.0001). Conclusions: Alteration of the DDR pathway was strongly associated with MSI status in CRC. The primary tumor sidedness might also be related, as DDR-MT was more prevalent in right-sided tumors. Elevated TMB and PD-L1 expression in DDR-MT CRC indicate more activated anti-tumor immune profiles compared to DDR-WT, regardless of MSI status, suggesting possible therapeutic benefit from immune checkpoint inhibitors in DDR-MT CRC.