bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic signatures of MSI-high metastatic colorectal cancer to predict efficacy of immune checkpoint inhibitors.
Authors: Gallois Claire , Landi Matteo , Taieb Julien , Lonardi Sara , Bergamo Francesca , Intini Rossana , Maddalena Giulia , Pietrantonio Filippo , Corti Francesca , Ambrosini Margherita , Martinetti Antonia , Germani Marco Maria , Boccaccio Chiara , Vetere Guglielmo , Mouillet-Richard Sophie , de Reynies Aurélien , Laurent Puig Pierre , Cremolini Chiara 
Published: June 2023

3570 Background: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10-40% of patients with MSI mCRC will experience a primary resistance to ICI. Methods: In a cohort of 103 patients with MSI mCRC treated with ICI, 3’RNAseq was performed from primary tumors resected before the beginning of ICI. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analysed. Results: The unsupervised clustering of this cohort allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A (“stromalHIGH-proliferationLOW”), cluster B (“stromalHIGH-proliferationMED”), and cluster C (“stromalLOW-proliferationHIGH”), with an enrichment of patients progressing at first disease assessment under ICI in the cluster A (30% vs 12% in cluster B and 8.1% in cluster C, p = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared to clusters B or C (p < 0.001) with 2-year PFS rates of 33.5%, 80.5% and 78.3%, respectively. Similar results were observed for overall survival (OS).In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B (HR: 0.26 95%CI 0.11-0.58, p = 0.001) and cluster C (HR: 0.35 95%CI 0.16-0.78, p = 0.01), compared to patients belonging to cluster A (Table). No association of identified clusters with PFS during non-ICI-based regimens was identified. Conclusions: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The “stromalHIGH-proliferationLOW” cluster is associated with a lower efficacy of ICI. [Table: see text]
Real-world comparison of triplet- versus doublet-chemotherapy with bevacizumab in patients with newly diagnosed metastatic colorectal cancer (mCRC).
Authors: Chapin William Joseph , Hwang Wei-Ting , Mamtani Ronac , O'Hara Mark H. 
Published: June 2023

3574 Background: Meta-analysis of five randomized intensification trials in mCRC demonstrated an overall survival (OS) benefit of triplet chemotherapy (5FU/leucovorin, oxaliplatin, irinotecan) plus bevacizumab (Triplet/Bev) compared to doublet chemotherapy plus bevacizumab (Doublet/Bev) (HR 0.81). Guidelines recommend first-line Triplet/Bev for patients with excellent performance status and normal organ function who can withstand increased toxicity, but such patients are less represented in the real world. In this retrospective cohort study, we examine the real-world effectiveness of Triplet/Bev compared to Doublet/Bev in the U.S. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data curated via technology-enabled abstraction from ~ 280 cancer clinics. Included were mCRC patients treated with first-line Triplet/Bev or Doublet/Bev between 10/23/14 and 10/31/22. OS by treatment was assessed using the Kaplan Meier method and adjustment for confounding variables was performed using Cox proportional hazards modeling with stabilized inverse probability of treatment weighting (IPTW). Pre-specified confounding variables included age, gender, race/ethnicity, year of metastatic diagnosis, health insurance, practice setting, KRAS/NRAS/BRAF mutation status, MMR/MSI status, synchronous/metachronous metastases, primary tumor sidedness, CEA, renal dysfunction, hepatic dysfunction, and ECOG performance status. Missing data were imputed using multiple imputation with chained equations. Results: Among 10,016 patients, 391 (3.9%) received Triplet/Bev and 9,625 (96.1%) received Doublet/Bev. Patients who received Triplet/Bev were younger (median age 52 vs 63 years) and were more likely to be treated at academic practices (27% vs 8%), to have synchronous metastatic disease (83% vs 65%), and to have KRAS/NRAS/BRAF wild-type disease (30% vs 17%). In the univariate analysis, median OS was 30.0 months (95% CI 24.7 – 34.7) in the Triplet/Bev cohort versus 23.4 months (95% CI 22.8 – 24.1) in the Doublet/Bev cohort (HR 0.73; 95% CI 0.62 – 0.85; p < 0.001). In Cox proportional hazards modeling with IPTW, there was no significant difference in hazard of death between Triplet/Bev and Doublet/Bev (HR 0.92; 95% CI 0.75 – 1.12; p = 0.4). Conclusions: In this large, national, real-world population of patients with mCRC, first-line treatment with Triplet/Bev was not associated with improved survival compared to Doublet/Bev after accounting for differences in baseline patient characteristics. The benefit to Triplet/Bev observed in randomized trials does not translate well to a more heterogeneous, real-world population. Sub-group analyses including by age, tumor sidedness, KRAS/NRAS/BRAF status, and baseline CEA level will be performed.
Efficacy and safety of IBI351 (GFH925) monotherapy in metastatic colorectal cancer harboring KRASG12C mutation: Preliminary results from a pooled analysis of two phase I studies.
Authors: Yuan Ying , Deng Yanhong , Jin Yongdong , Pan Yueyin , Wang Cunji , Wang Zhiwu , Zhang Zhiye , Meng Xiangjiao , Hu Yi , Zhao Mingfang , Wang Huijuan , Yang Nong , Wu Dongde , Dong Xiaorong , Huang Dingzhi , Sun Meili , Liu Lian , Hua Dong , Guo Zengqing , Ding Ke-Feng 
Published: June 2023

3586 Background: IBI351 (GFH925) is an irreversibly covalent inhibitor of KRASG12C and has demonstrated promising anti-tumor activity with acceptable safety in advanced solid tumors. Here, we report a pooled analysis of two phase I studies (NCT05005234, NCT05497336) evaluating the efficacy and safety of IBI351 (GFH925) monotherapy for metastatic colorectal cancer (CRC) harboring KRASG12C mutation. Methods: Eligible metastatic CRC patients (pts) with KRASG12C mutation were included. Pts received IBI351 (GFH925) orally at dose levels of 700mg once daily (QD), or 450/600/750mg twice daily (BID). The primary endpoint was objective response rate (ORR) assessed by investigator per RECIST v1.1. Data cutoff for the analyses was November 30, 2022 unless otherwise specified. Results: A total of 45 pts were enrolled (median age: 58.0 years; male: 57.8%; ECOG PS 1: 71.1%; pts with ≥2 prior lines of treatment: 66.7%), including 3, 4, 37, and 1 pts in 700mg QD, 450mg BID, 600mg BID, and 750mg BID cohorts, respectively. The median exposure to therapy was 84 days (range, 7-286), and 36 pts (80.0%) were still on treatment including one patient at 450mg BID with treatment exposure for 286 days. As of December 15, 2022, ORR was 47.5% (19/40, 95% CI: 31.5%-63.9%) and disease control rate (DCR) was 85.0% (95% CI: 70.2%-94.3%) for the efficacy-evaluable pts across all dose levels. The median duration of response (DOR) was not reached. For 32 efficacy-evaluable patients at 600mg BID, ORR and DCR were 43.8% (14/32) and 87.5%, respectively. Treatment-related adverse events (TRAEs) occurred in 40 (88.9%) pts, with the most common being anaemia, white blood cell count decreased, alanine aminotransferase increased, and pruritus. Grade ≥ 3 TRAEs occurred in 9 (20.0%) pts. No drug-related adverse events leading to treatment discontinuation or death occurred. Conclusions: IBI351 (GFH925) monotherapy demonstrated promising anti-tumor activity with manageable safety profile in metastatic CRC patients harboring KRASG12C mutation. These two studies are still ongoing and longer follow-up will provide more solid evidence. Updated data will be presented at the meeting. Clinical trial information: NCT05005234 , NCT05497336 .
Phase II study of biweekly TAS-102, irinotecan and bevacizumab in pre-treated metastatic colorectal cancer (TABAsCO).
Authors: Boland Patrick M , Mukherjee Sarbajit , Imanirad Iman , Vijayvergia Namrata , Cohen Seth D. , Gupta Medhavi , Iyer Renuka V. , Chatley Sarah , Cahill Beth , Vadehra Deepak , Attwood Kristopher , Hochster Howard S. , Fountzilas Christos 
Published: June 2023

3590 Background: The efficacy of 2nd line FOLFIRI plus VEGF inhibition (VEGFi) is limited for metastatic colorectal cancer (mCRC). TAS-102 is a novel oral anti-metabolite approved for pts with mCRC following standard treatment with FP, oxaliplatin and irinotecan. TAS-102 has a distinct mechanism of action from 5-FU and overcomes 5-FU resistance in preclinical models, and in the clinic. We hypothesized that the combination of TAS-102 with irinotecan (TAS-IRI) and bevacizumab (BEV) would prove superior to FOLFIRI/VEGFi. Methods: Phase II, single-arm study of TAS-IRI and BEV in 2nd-line mCRC. Eligible patients had received prior treatment with a fluoropyrimidine and oxaliplatin in the advanced setting or experienced recurrence within 12 mos of this regimen in the adjuvant setting. Adequate organ function, ECOG PS 0-1, measurable disease (RECIST 1.1), no prior irinotecan or TAS-102 exposure and candidacy for BEV were required. Pts were treated with BEV 5 mg/kg IV, irinotecan 180 mg/m2 IV (day 1 and 15), and TAS-102 25 mg/m2 orally bid (days 2-6 and 16-20) in 4-week cycles (PMID: 31924737). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS). Assuming a median PFS for historic control (FOLFIRI/VEGFi) of 6 mos vs. 9 mos for TAS-IRI plus BEV (HR: 0.67), treatment of 36 evaluable pts would achieve 80.5% power (at α = 0.1) to detect such an effect. Results: Forty-nine patients were enrolled; 42 were eligible and 38 had at least one disease assessment (median age 59 yr, 47% male, 74% colon primary, tumor KRAS/NRAS mutated in 55%/21%). The median PFS was 8.7 mos (range: 6.7-11.8 mos, p = 0.009), meeting the primary endpoint. The most common reason for study treatment discontinuation was progressive disease (53%). The objective response rate was 16% (90% CI: 8.0-27.3%); the median OS was 16.5 mo (range: 11.8-25.3). Twenty-eight pts (67%) had a treatment-related adverse event (TRAE) G3 or higher (Table). The most common TRAEs were gastrointestinal and hematologic. Grade 3/4 neutropenia occurred in 34%, with only 1 episode of febile neutropenia, though G-CSF use was frequently needed to maintain dose density/intensity. Conclusions: TAS-IRI plus BEV is an effective 2nd line therapy for patients with mCRC. The median PFS appears higher compared to historical controls (FOLFIRI/VEGFi). Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted. (Clinical trial registration ClinicalTrials.gov NCT04109924). Clinical trial information: NCT04109924 . [Table: see text]
Preoperative assessment in lung-limited metastatic patients with colorectal cancer: The Meta-Lung Score.
Authors: Ziranu Pina , Ferrari Paolo Albino , Guerrera Francesco , Bertoglio Pietro , Tamburrini Alessandro , Lyberis Paraskevas , Pretta Andrea , Grimaldi Giulia , Lai Eleonora , Santoru Massimiliano , Dubois Marco , Riva Laura , Bardanzellu Fabio , Alzetani Aiman , Luzzi Luca , Solli Piergiorgio , Paladini Piero , Ruffini Enrico , Cherchi Roberto , Scartozzi Mario 
Published: June 2023

3598 Background: Due to the inconsistent data on curative resection of isolated lung metastases (LM) from colorectal cancer (CRC) and the lack of specific recommendations, the therapeutic approaches for metastatic liver disease are mostly applied to LM treatment, despite differences in their biological behavior. Like Fong's criteria in CRC liver metastases, our study proposed a score associated with clinical outcomes in patients (pts) undergoing CRC lung metastasectomy, aiming to better pts' selection for surgery and the most appropriate therapeutic strategy. Methods: We retrospectively collected data from 260 pts (aged 18-85) who underwent CRC lung metastasectomy with curative intent from December 2002 to January 2022 at four Italian Centers: the Division of Thoracic Surgery at “A. Businco Cancer Center” in Cagliari, the Division of Thoracic Surgery at “Città della Salute e della Scienza” in Tourin, the Department of Thoracic Surgery at “IRCCS Azienda Ospedaliero-Universitaria” in Boulogne, and the Medical Oncology Unit of the University Hospital of Cagliari. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; association between categorical variables: Fisher's exact test). Results: We analyzed the impact of different clinicopathological features on overall survival (OS). At the univariate analysis: higher baseline CEA levels (p = 0.0001), disease-free survival less than or equal to 12 months (m) (p = 0.0043), LM size larger than 2 cm (p = 0.0187), multiple resectable nodules (p = 0.0083), and positive nodal status of the primary tumor (p = 0.0011) were associated with poorer prognosis. In a Cox regression model, these five characteristics retained their independent role for OS (p < 0.0001) and were chosen as criteria to be assigned one point each for clinical risk score. The 5-year survival rate in pts with 0 points was 88%, while no pts with a 5-points score survived at 2 years. Based on the 0-2 versus 3-5 score range, we obtained a significant difference in median OS: 101.7 m (95%CI 64.6 - 101.7) vs. 39.5 m (95%CI 27.3 - 87.5) respectively (p < 0.0001) stratifying pts into good and poor prognosis. Conclusions: The Meta-Lung Score appeared to be an exciting prognostic tool in selecting CRC pts’ candidates for radical surgical treatment when LM were diagnosed. Whether early surgery should be considered in pts with a score 0-2, the same choice should be taken with caution in pts with a score 3-5, for whom early chemotherapy would allow better assessment of tumor biology and appropriate selection for surgery.[Table: see text]
Targeting EZH2 to overcome the resistance to immunotherapy in microsatellite stable colorectal cancer: Results from the CAIRE study.
Authors: Palmieri Lola Jade , Cousin Sophie , Spalato Mariella , Guégan Jean Philippe , Bessede Alban , Pernot Simon , Italiano Antoine 
Published: June 2023

3599 Background: Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. Targeting EZH2 can enhance anti-tumor immunity by reshaping the tumor microenvironment (TME). The CAIRE study is first study investigating the impact of EZH2 inhibition in combination with immune checkpoint inhibitor in solid tumors. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of tazemetostat (800 mg BID) combined with durvalumab (1120 mg every 3 weeks) in patients with advanced microsatellite stable colorectal cancer. The primary endpoint was the disease control rate within 24 weeks after treatment onset defined as the proportion of patients with at least a tumor assessment showing connfirmed or unconfirmed complete response, confirmed or unconfirmed partial response or stable disease 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. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 47 pts were enrolled at Institut Bergonié (Bordeaux, Centre). Median age was 67.7 (range 39.6 – 84.0). Median number of previous treatment lines was 4: (range 1 – 6). The most common treatment related adverse events were grade 1/2 asthenia, nausea. No death was related to the treatment. Among the 34 pts for whom blinded central review of imaging was available for at least one imaging tumor assessment, best tumor response was confirmed partial response, stable disease and progressive disease in 1 (2.9%), 11 (32.3%) and 22 (64.7%) patients respectively. The disease control rate was 35.3% (95%CI 19.7 – 53.5). Conclusions: The CAIRE study met its first endpoint for disease control rate in patients with advanced colorectal cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT04705818 .
Cost-effectiveness analysis of later-line therapies for metastatic colorectal cancer (mCRC) based on a novel methodology of network meta-analysis (NMA) of survival curves.
Authors: Obeng-Kusi Mavis , Roe Denise , Erstad Brian L , Abraham Ivo 
Published: June 2023

3605 Background: With advances in the management of mCRC, survival outcomes of patients have improved. While some patients still progress after first and second lines of treatment, there remain options for third or later-line treatment. This study aimed to determine the cost-effectiveness of later-line (>3) treatments for patients with mCRC in the US, based on a NMA of survival curves. Unlike conventional NMA using constant hazard ratios, this method is not constrained by the proportional hazard assumption and uses parametric fitting that incorporates the shape and scale parameters to provide time-varying treatment effects. Methods: The NMA compared the efficacy of 6 treatments, atezolizumab+/-cobimetinib (ATE+/-COB), fruquintinib (FRU), regorafenib (REG), TAS-102+/-bevacizumab (TAS+/-BEV), including biosimilar, to placebo (PBO). The study used a 3-state partitioned survival model over a 5-year time horizon incorporating drug acquisition, administration, adverse events, monitoring, and end of life costs, and utilities sourced from literature. Total costs, life-years (LY) and quality-adjusted LYs (QALY) for each treatment were determined. Incremental cost-effectiveness (ICER) and incremental cost-utility ratios (ICUR) were estimated using PBO as a common comparator. Results: Over the 5-year period and across the 6 therapies, survival ranged from 0.62 LYs for PBO to 1.15 LYs for TAS+BEV, translating to QALYs ranging from 0.44 for PBO to 0.85 for TAS+BEV. Total costs of treatment ranged from 278,877 for PBO to 417,495 for TAS+BEV (405,002 with biosimilar). TAS+BEV yielded the lowest ICER of an additional 261,421 (237,860 with biosimilar)/LY gained (g) and ICUR of an additional 343,458 (312,504 with biosimilar)/QALYg; while ATE presented the least favorable ICER and ICUR of an additional $522,602/LYg and $701,381/QALYg, respectively (Table). Conclusions: Among the 6 treatments evaluated, TAS+BEV emerged as the most cost-effective later-line treatment for mCRC while atezolizumab was the least cost-effective. Additionally, replacing BEV with a biosimilar reduces costs and enhances cost-effectiveness, improving access for patients. [Table: see text]
Efficacy and safety of mFOLFOX6 with apatinib as postoperative adjuvant chemotherapy in stage IIIB or IIIC colorectal cancer.
Authors: Gu Xiaodong , Zhou Minwei , Wang Zihao , Li Zhenyang , Yang Yi , Zang Yiwen , Zhou Yiming , Xiang Jianbin , Chen Zongyou 
Published: June 2023

3613 Background: Antiangiogenic therapy has shown benefit in metastatic colorectal cancer. However, the role of apatinib in adjuvant treatment of stage IIIB and IIIC colorectal cancer remains unclear. Methods: Patients received modified FOLFOX6 once every 2 weeks for a 6-month period (control group) or modified FOLFOX6 for 6 months plus apatinib (500mg) once a day for a 12-month period (experimental group). Progression free survival (PFS), overal survival (OS) and treatment-related adverse events were evaluated in two groups. Results: 63 patients have been enrolled in this study. This trial reported a 3-year PFS of 74.2% for modified FOLFOX6 plus apatinib vs. 61.5% for modified FOLFOX6 ( P< 0.05). 5-year OS was significantly improved in the experimental group compared with the control group (86.3% vs. 72.5%; P< 0.05). The most common grade 3 adverse events were hypertension and hand–foot syndrome. No treatment-related grade 4 adverse events or treatment-related deaths were observed. Conclusions: Apatinib can prolong PFS and OS when added to adjuvant chemotherapy in resected stage IIIB and IIIC colorectal cancer. The toxicities associated with apatinib were generally acceptable. Clinical trial information: NCT03365765 .
Mismatch Repair system protein deficiency as a factor of resistance to chemo-radiotherapy treatment in patients with locally advanced rectal adenocarcinoma and its influence on disease-free survival.
Authors: Pretta Andrea , Ziranu Pina , Giampieri Riccardo , Donisi Clelia , Pinna Giovanna , Randon Giovanni , Loi Francesco , Deias Giulia , Palmas Enrico , Morano Federica , Solinas Cinzia , Lai Eleonora , Pusceddu Valeria , Puzzoni Marco , Zorcolo Luigi , Barbara Raffaele , Faa Gavino , Berardi Rossana , Pietrantonio Filippo , Scartozzi Mario 
Published: June 2023

3615 Background: Available data on Mismatch Repair system deficit and microsatellite instability are conflicting and are generally derived from a small number of patients due to the rarity of this condition in rectal cancer. Our study aimed to evaluate the frequency and therapeutic implications of Mismatch Repair proteins (MMR) status in patients with locally advanced rectal cancer (LARC). Methods: We retrospectively collected data from 318 patients affected by LARC adenocarcinoma (cT3-4 +/- N1-2) treated at the Medical Oncology Unit of the University Hospital of Cagliari, Italy, the Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and at the Medical Oncology Unit, AOU Ospedali Riuniti, Ancona. Italy. All patients included in the study underwent neoadjuvant concurrent capecitabine and long-course radiotherapy (RT) (total dose of Gy 50.4), afterwards a total mesorectal excision (TME) was performed. MMR expression was evaluated through immunohistochemistry. The primary objective was major TRG (0-1 Ryan’s score) while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). Results: 160 patients (148 pMMR and 12 dMMR) were included in exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in validation cohort. A major TRG has been shown in 64/148 (42,6%) and 63/146 (43,1%) patients with pMMR in exploratory cohort and validation cohort, respectively; while no major TRG have been shown in dMMR patients in exploratory cohort nor in validation cohort. Both exploratory and validation cohorts showed a statistically significant higher median DFS in pMMR patients compared to dMMR ones: NR vs 14 months in exploratory cohort ( p = 0,003) and NR vs 17 months in validation cohort ( p = 0,02). Conclusions: Our retrospective study indicated an association between dMMR and poor or no response to preoperative chemoradiotherapy. These results are consistent with the role of MMR as a predictor of poor-response to chemoradiotherapy and represent a hypothesis-generating study for the selection of these patients for immunotherapy in the neoadjuvant setting, in which the available data are immature.