bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early detection of colorectal adenocarcinoma by decoding epigenetic and DNA fragmentation fingerprints of plasma cell-free DNA.
Authors: Suxing Li , Han Tiancheng , Yang Shunli , Liu Dan , Nie Peiyao , Lv Fang , He Shuying , Yang Ying , LI Yulong , Yu Jianing , Hong Yuanyuan , Huang Yu S. , Chen Weizhi , Wen Zhengqi 
Published: June 2022

3550 Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect colorectal adenocarcinoma. Methods: Plasma cfDNA sampels from 215 colorectal adenocarcinoma patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 150 cancer patients and 398 healthy individuals and the independent testing cohort includes 65 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =0.982 in the discovery cohort and AUC =0.9664 in the independent testing cohort. Under a specificity of 94.71% (CI: 90% - 98.82%), sensitivity was 78.46% (CI: 60% - 92.31%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect colorectal adenocarcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
CPGJ602 plus mFOLFOX6 as first-line treatment for patients with KRAS/NRAS/BRAF wild-type metastatic colorectal cancer: A randomized phase II study.
Authors: Xu Jianming , Cao Bangwei , Gu Kangsheng , Bai Yuxian , Li Wei , Zhang Jingdong , Liu Caigang , Niu Zuoxing , Zhang Liangming , Zhong Haijun , Luo SuXia , Zhou Jian-Wei , Liu Tianshu , Gu Yanhong , Lin Jingguan , Deng Yanhong , Chen Chuangqi , Li Yunfeng , Yang Xiuli , Li Bihui 
Published: June 2022

3574 Background: CPGJ602 is a recombinant anti-EGFR human-mouse chimeric monoclonal antibody. CPGJ602 plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) may have efficacy in KRAS/NRAS/BRAF wild-type metastatic colorectal cancer. Methods: In this open-label, randomized trial, patients who had received no previous treatment were randomly assigned (2:2:1) to receive CPGJ60（325mg/m2, q2w) plus mFOLFOX6 (biweekly group), CPGJ602 (400 mg/m 2 initial dose followed by 250 mg/m2 /week thereafter) plus mFOLFOX6 (weekly group) or cetuximab (400 mg/m2 initial dose followed by 250 mg/m2 /week thereafter) plus mFOLFOX6 (cetuximab group). All subjects received treatment up to 16 weeks. The primary endpoint was the best overall response (BOR) at 16 weeks. The second endpoints were DCR, DOR, PFS, safety. Results: As of Dec 30, 2021, 76 patients were enrolled (30 in biweekly group, 32 in weekly group and 14 in control group). The best overall response achieved at 16 weeks was 76.7% (23/30, 95% CI 60.3% - 92.0%),78.1% (25/32, 95% CI 62.5% - 92.5%) and 78.6% (11/14, 95% CI 49.2% - 95.3%) in the biweekly group, weekly group and cetuximab group, respectively. The confirmed overall response rate at 16 weeks was 60%(18/30), 71.9%(23/32) and 57.1%(8/14) in the biweekly group, weekly group and cetuximab group, respectively. The PFS rates at 16 weeks were 81.5% (95% CI 57.7% -92.6%), 96.8% (95% CI 79.2%-99.5%), 81.3% (95% CI 41.5%- 95.2%) in the biweekly group, weekly group and cetuximab group, respectively. The most common adverse events were a decreased neutrophil count (60%，78.1% and 71.4% in the biweekly group, weekly group and cetuximab group respectively), decreased white-cell count (53.3%, 78.1% and 71.4% respectively), decreased platelet count (40.0%, 40.6% and 42.9% respectively), and elevated serum aspartate aminotransferase (43.3%, 37.5% and 35.7% respectively). Conclusions: CPGJ602 plus mFOLFOX6 could be an option for KRAS/NRAS/BRAF wild-type metastatic colorectal cancer. Clinical trial information: NCT04466254.
Codon-specific KRAS mutations predict overall survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.
Authors: van de Haar Joris , Ma Xuhui , Ooft Salo N. , van der Helm Pim W. , Hoes Louisa Rose , Mainardi Sara , Wessels Lodewyk F.A. , Voest Emile E. 
Published: June 2022

3593 Background: Genomics-based precision medicine has greatly improved how patients with cancer are being treated with targeted agents, but clinical-grade genomic biomarkers for chemotherapies are currently lacking. The chemotherapeutic trifluridine/tipiracil (FTD/TPI) is approved for the treatment of late-stage metastatic colorectal cancer (mCRC). We aimed to find genomic biomarkers to improve patient selection for FTD/TPI treatment in mCRC. Methods: In a discovery cohort of FTD/TPI-treated mCRC patients (n = 37), genome-wide somatic variants were tested for association with treatment duration and overall survival (OS). In vitro drug testing on isogenic cell lines and patient-derived mCRC organoids, as well as a re-analysis of the double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800) were performed to support our findings. Results: In the discovery cohort, KRAS codon G12 (KRASG12) mutation status was the only significant genomic determinant of poor outcome of FTD/TPI treatment, which could be replicated in vitro by drug testing on isogenic cell lines and PDOs. In these models, KRASG12 mutations were associated with increased resistance to FTD-induced (geno)toxicity in vitro. KRASG12-based resistance was absent for the closely related chemotherapeutic 5-FU. In the RECOURSE study, KRASG12 mutations were predictive biomarkers for reduced OS benefit of FTD/TPI vs placebo (unadjusted interaction P= 0.0017, adjusted interaction P= 0.017). For patients with KRASG12 mutations, OS was not significantly prolonged with FTD/TPI vs placebo (n = 279; HR, 0.97; 95% CI, 0.73−1.20; P= 0.85). An exploratory analysis showed that the KRASG13 mutant subgroup demonstrated clearly prolonged OS with FTD/TPI vs placebo (n = 60; unadjusted HR, 0.29; 95% CI, 0.15−0.55; P< 0.001; adjusted HR, 0.20; 95% CI, 0.092−0.45; P< 0.001), which was significantly more pronounced as compared to the KRASG12 mutant and KRASWT populations (adjusted interaction P< 0.001 and P= 0.036, respectively). Conclusions: Together, KRASG12 mutations were associated with reduced OS benefit of FTD/TPI treatment, with potential implications for ̃28% of patients with metastatic colorectal cancer now considered for treatment with FTD/TPI. Furthermore, our data show that genomics-based precision medicine may be possible for a subset of chemotherapies.
Effectiveness of nationwide insurance coverage for next-generation sequencing in advanced colorectal cancer: A real-world data study.
Authors: Park Sun-Kyeong , Kang Dong-Won , Yu Ye Lee , Cha Yongjun , Kang Sokbom 
Published: June 2022

3602 Background: Next-generation sequencing (NGS) has been covered by Korean national health insurance since March 2017 for patients with advanced colorectal cancer (CRC). We explored the clinical and socioeconomic impact of NGS compared with that of a single gene test (SGT) alone. Methods: From the nationwide database, we identified patients who 1) are diagnosed with advanced CRC classified as a distant disease using Summary Stage between March 1, 2017, and December 31, 2018; 2) had NGS or SGT within 2 months after diagnosis of advanced CRC. Multivariate logistic regression with covariates including age, sex, Charlson comorbidity index, insurance type, year of diagnosis, and region and type of hospital with the initial diagnosis was conducted to identify factors affecting the performance of NGS. We conducted 1:3 propensity score matching to minimize the impact of confounding factors. The median overall survival and the adjusted hazard ratio (aHR) were estimated using the Kaplan-Meier method and the Cox proportional hazard model, respectively. We calculated the total medical cost, and per patient per year (PPPY) cost adjusted for the survival period. Results: Among 5,029 patients with advanced CRC, 655 patients were identified as NGS group and 1,995 as SGT group after matching. Old age, low household income, rural location, and non-tertiary hospital were all characteristics that reduced the likelihood of obtaining an NGS test. The NGS group showed significantly favorable survival compared to the SGT group (median survival 29.2 vs. 24.9 months, P =.031; adjusted hazard ratio [HR] 0.86, P =.034). The total medical cost was lower in the NGS group ($55,445) than the SGT group ($57,989), and the PPPY cost was also lower in the NGS group ($44,879 and $49,734, respectively). Conclusions: We found that some socioeconomic factors such as age, insurance type, region, and hospital type may hamper the implementation of NGS. Also, lowering the barrier of NGS tests by reimbursing NGS in a specific clinical setting may have survival and cost-benefit in patients with advanced CRC.
Preservation of liver function with local radiation therapy in patients with metastatic intrahepatic cholangiocarcinoma with extrahepatic disease.
Authors: Upadhyay Rituraj , Ludmir Ethan B. , De Brian , Holliday Emma , Smith Grace L. , Taniguchi Cullen M. , Das Prajnan , Minsky Bruce D. , Koong Albert C. , Javle Milind M. , Lee Sunyoung S. , Vauthey Jean-Nicolas , Tzeng Ching-Wei D. , Tran Cao Hop , Koay Eugene Jon 
Published: June 2022

4080 Background: Tumor related liver failure (TRLF) is the most common cause of death in patients with metastatic intrahepatic cholangiocarcinoma (mICC) accounting for up to 72% deaths in patients treated with systemic therapy alone. We present our institutional experience of treating mICC patients with local liver-directed radiation therapy (RT). Methods: ICC patients with extrahepatic metastatic disease who received radiation therapy at our center with a biologically equivalent dose (BED) of at least 50 Gy from January 1, 2011 to March 31, 2021 were included in our study. Patient, tumor and treatment characteristics as well as the survival outcomes were recorded. TRLF was considered the cause of death if the patient died due to liver failure; and freedom from TRLF (FFTRLF) at 1 year and 2 years after RT was calculated. Results: Sixty-seven patients were included in the study. The median age was 63 years (range 29-83 years) and median RT dose was 60 Gy (range, 40-100 Gy). 73.1% patients received a BED > 80.5 Gy. All except 1 patient were treated with upfront induction chemotherapy, followed by RT to the primary lesion in liver with (71.6%) or without (28.4%) concurrent chemotherapy. The most common induction chemotherapy regimen used was gemcitabine and cisplatin (65.7%) followed by gemcitabine, cisplatin and paclitaxel (22.4%), while the most common concurrent systemic therapy was capecitabine. Out of 43 patients with satellitosis, 29 were treated with RT to the dominant liver lesion while 14 received RT to the primary as well as one or more satellites. Overall, 15 patients (22.4%) had local progression of the radiated lesion, 42 patients (62.7%) progressed elsewhere in liver, and 52 patients (77.6%) had a distant progression. TRLF was the cause of death in 28.4% of patients. Median OS from diagnosis was 25 months while median OS after RT was 11.9 months. The 1- and 2-year rates of FFTRLF were 73.1% and 58.2% respectively, which were significantly higher than 1- and 2-year OS after RT (47.1% and 24.7% respectively, p < 0.005). Univariate analysis did not identify significant association of FFTRLF or OS with age, sex, performance status, size of liver lesions, T or N stage, satellitosis, vascular thrombosis, TRLF, timing of metastasis, site of metastasis, RT technique and dose and chemotherapy. Conclusions: Liver directed radiation therapy in patients with mICC with extrahepatic disease appears to have favorable rates of TRLF and survival times, compared to historical data. Future prospective studies are warranted to define the survival benefit in these patients attributable to radiation therapy.
Clinical impact of MAPK pathway alterations in advanced biliary tract cancer (BTC): SCRUM-Japan GOZILA and COLOMATE international collaboration.
Authors: Takahashi Hideaki , Caughey Bennett Adam , Umemoto Kumiko , Green Michelle , Nakamura Yoshiaki , Datto Michael , Ueno Makoto , Walden Daniel , Esaki Taito , Oliver Thomas , Komatsu Yoshito , Mizuno Nobumasa , Oki Eiji , Taniguchi Hiroya , Bando Hideaki , Morizane Chigusa , Yoshino Takayuki , Strickler John H , Ikeda Masafumi , Bekaii-Saab Tanios S. 
Published: June 2022

4086 Background: Abnormalities in the MAPK pathway are potential therapeutic targets in various cancers. However, the clinical impact of alterations in the MAPK pathway in BTC have not been elucidated, especially outside of canonical mutations in KRAS and BRAF. We investigated the clinical outcomes of advanced BTC with MAPK pathway alterations treated with chemotherapy in Japan and the United States. Methods: Patients with advanced BTC who received gemcitabine plus cisplatin as first-line therapy were included from the GOZILA study in Japan and Duke Molecular Registry of Tumors in the US. Genetic abnormalities were detected by Guardant360, a cell-free DNA assay, in Japan and by blood or tissue-based next-generation sequencing (NGS) at Duke University. Two hundred and seven patients with BTC from Japan were included in an exploratory cohort to evaluate the association of MAPK alterations with overall survival (OS) according to MAPK alteration status. One hundred and ten patients with BTC from both Japan and the US harboring oncogenic alterations in the MAPK pathway were included in a biomarker selected cohort to assess the association of specific MAPK alterations with OS. Multivariate analysis was performed using a Cox regression model based on a univariate p-value < 0.2. Results: MAPK pathway-related oncogenic alterations detected in each cohort are shown in the table below. In the exploratory cohort, median OS was shorter for patients with MAPK alterations vs. no MAPK alteration (15.9 m vs. 24.9 m, log-rank p = 0.001). Based on univariate analysis, the following covariates were selected for multivariate analyses: age, prior resection, and MAPK pathway alteration in the exploratory cohort; country, the timing of NGS, distant metastasis, KRAS amplification, and BRAF class 2 mutation in the biomarker selected cohort. In the exploratory cohort, multivariate analysis identified MAPK pathway alterations as an independent predictor of shorter OS with a HR of 1.92 (95% CI = 1.28-2.87, p = 0.001). In the biomarker selected cohort, multivariate analysis identified BRAF class 2 mutations and KRAS amplification as independent predictors of shorter OS with a HR of 16.2 (95% CI = 3.26-80.8, p = 0.001) and 5.97 (95% CI = 1.74-19.3, p = 0.002) respectively. Conclusions: MAPK pathway alterations, especially BRAF class 2 mutation and KRAS amplification, had a significant negative impact on clinical outcomes in BTC receiving first-line chemotherapy. These results are newly confirmed in BTC. [Table: see text]
Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy: A multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study).
Authors: Schwarz Lilian , Bachet Jean-Baptiste , Meurisse Aurelia , Bouché Olivier , Assenat Eric , Piessen Guillaume , Terrebonne Eric , Hammel Pascal , Regenet Nicolas , Turco Célia , Taieb Julien , Mabrut Jean-Yves , Turrini Olivier , Portales Fabienne , Paye Francois , Barbier Louise , Truant Stephanie , Sa Cunha Antonio ,   PANACHE01-PRODIGE48 Authors' Group
Published: June 2022

4134 Background: Despite the limited number of published RCTs, patients with resectable pancreatic adenocarcinoma (rPAC; NCCN criteria) seem to benefit from neoadjuvant (NAT) with regards to R0 resection rate, downstaging and survivals (PREOPANC-1; Preop-02/JSAP-05; NEONAX, SWOG05-15). Few prospective results are currently available concerning the completion of the full therapeutic sequence and oncological results. Methods: In the PANACHE01-PRODIGE48 prospective multicenter controlled non-comparative Phase II trial, 153 patients with rPDAC were randomized 2:2:1 to 4 cycles of NAT chemotherapy (mFOLFIRINOX; Arm1 or FOLFOX; Arm2) or upfront surgery (Ctrl_Arm) in 28 French centers from 02/2017 to 07/2020. Primary objective was to evaluate the safety and efficacy of two regimens of NAT chemotherapy. The main co-primary endpoints were 1y-OS rate after randomization and the rate of patients undergoing the full therapeutic sequence. Event-free survival (EFS) was used to evaluate the time to recurrence between groups. An event being defined as progression before surgery, unresectable or metastatic disease at surgical exploration, recurrence after surgery or death. Results: Of the 153 randomized patients, 146 were available for analysis (Arm1,n=70; Arm2,n=50; Ctrl_arm,n=26). In the Arm1 and 2, completion of the 4 planed cycles was 88.6 and 84%, respectively, with a dose reduction in 52% and 24%. The cumulative rates of grade 3/4/5 toxicity were 56.7 and 57.4%, respectively. The resection rates (RR) were 74, 68 and 81% respectively in Arm1, Arm2 and Ctrl_Arm. Respectively, 88.4, 91 and 85.7% of patients started adjuvant chemo. 1y-OS rates were respectively of 84.1, 71.8 and 80.8% in Arm1, Arm2 and Ctrl_Arm with a median follow-up in each group of 25.6, 33, 30.9 months. Following the intermediate analysis, the Arm2 was stopped for lack of efficacy (rejection of the H0 hypothesis for 1yOS). 1y-Event free survival (EFS) rates were 51.4% in Arm1, 43.1% in Arm2 and 41.7% in Ctrl_Arm, with corresponding median EFS of 12.4, 11 and 9.2 months. Conclusions: The feasibility and efficacy of the mFOLFIRINOX neoadjuvant chemotherapy is confirmed regarding completion of therapeutic sequence and oncological outcomes. These results confirm the rationale for ongoing clinical trials, PREOPANC3 and Alliance AO21806. Clinical trial information: NCT02959879.
Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study.
Authors: Voss Martin H , Powles Thomas , McGregor Bradley Alexander , Porta Camillo , Grünwald Viktor , Merchan Jaime R. , Rolland Frederic , Maroto-Rey Pablo , Goh Jeffrey C. , Xing Dongyuan , Perini Rodolfo F. , McKenzie Jodi , Mody Kalgi , Motzer Robert J. 
Published: June 2022

4514 Background: In the open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS (primary endpoint) and OS (key secondary endpoint) benefits over SUN among pts with aRCC in the 1L setting (Motzer 2021, NEJM). We evaluated PFS on next-line therapy (“PFS2”) and explored the effect of subsequent anticancer therapy on OS in the LEN + PEMBRO and SUN treatment arms of CLEAR. Methods: PFS2 was defined as time from randomization to disease progression (as assessed by investigator) on next-line treatment or death from any cause (whichever occurred first). PFS2 was evaluated in all pts randomly assigned to LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W (n=355) or SUN 50 mg orally QD (4 wks on/2 wks off) (n=357) using Kaplan-Meier estimates, and compared between treatment arms via a log-rank test stratified by geographic region and MSKCC prognostic groups. The HR and corresponding CI were estimated using the Cox regression model with Efron’s method for ties, using the same stratification factors. A post hoc analysis accounting for the effect of subsequent anticancer therapy on OS (time from randomization to death from any cause) in the LEN + PEMBRO and SUN arms using 2-stage estimation was conducted. Results: Among pts who received subsequent anticancer therapy in the LEN + PEMBRO (n=117 pts) and SUN (n=206 pts) arms (Table), median time to next-line therapy was 12.2 mos (range 1.45–37.36) and 6.4 mos (range 0.39–28.52), respectively. Median duration of first subsequent anticancer therapy was 5.2 mos (range 0.10–30.23) in the LEN + PEMBRO arm and 6.8 mos (range 0.03–30.72) in the SUN arm. Among all pts, PFS2 was longer with LEN + PEMBRO than with SUN (median not reached vs 28.7 mos; HR, 0.50; 95% CI 0.39–0.65; nominal P<0.0001); PFS2 rates at 24 and 36 mos are in the Table. The unadjusted OS HR for LEN + PEMBRO vs SUN (from the primary analysis [Motzer 2021, NEJM]) was 0.66 (95% CI 0.49–0.88); the HR for OS adjusted for subsequent therapy was 0.54 (bootstrap 95% CI 0.39–0.72). Conclusions: LEN + PEMBRO had a statistically significant and clinically meaningful benefit over SUN in the CLEAR study. These findings remained consistent after accounting for subsequent therapies, as evidenced by prolonged PFS2 and adjusted OS. Results further support LEN + PEMBRO as a standard of care in 1L aRCC. Clinical trial information: NCT02811861. [Table: see text]