bluuebunny/crossref_metadata_2025_split huggingface dataset:
Germline polymorphisms in genes maintaining replication fork to predict the efficacy of oxaliplatin and irinotecan in metastatic colorectal cancer (mCRC) patients enrolled in MAVERICC trial.
Authors: Arai Hiroyuki , Xiao Yi , Wang Jingyuan , Battaglin Francesca , Kawanishi Natsuko , Jayachandran Priya , Soni Shivani , Wu Zhang , Mancao Christoph , Salhia Bodour , Mumenthaler Shannon M. , Millstein Joshua , Lenz Heinz-Josef 
Published: June 2021

3139 Background: Protection of replication forks is critical for the survival of cancer cells. Chemotherapeutic drugs such as oxaliplatin and irinotecan can impede the progression of replication forks by inducing DNA lesions, which cause fork collapse and generate double-strand breaks. We hypothesized that functional genetic variants in genes involved in the maintenance of replication forks may predict the efficacy of cytotoxic drugs in mCRC patients. Methods: We analyzed genomic and clinical data from MAVERICC, a phase II trial which compared mFOLFOX6 and FOLFIRI in combination with bevacizumab in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped using an OncoArray (Illumina, Inc., San Diego, CA, USA). Candidate six missense single nucleotide polymorphisms (SNPs) ( SLFN11 rs9898983, SLFN11 rs12453150, RPA1 rs5030749, MCM3 rs2230240, TIMELESS rs2291739, and TIMELESS rs774047) were tested for association with progression-free survival (PFS) and overall survival (OS), using Cox proportional hazards model. To confirm the predictive value, the treatment-by-SNP interaction was tested. Results: A total of 324 patients were available for the SNP analyses (mFOLFOX6 plus bevacizumab arm [OHP arm]: n = 161; FOLFIRI plus bevacizumab arm [IRI arm]: n = 163). In the OHP arm, univariable analysis showed a significantly better PFS in patients with G/G genotype of TIMELESS rs2291739 compared to those with any A allele, and in patients with T/T genotype of TIMELESS rs774047 compared to those with any C allele. However, neither of these SNP’s associations were confirmed by multivariable analysis: TIMELESS rs2291739 (any A allele vs G/G, hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.31–1.17, p = 0.12) and TIMELESS rs774047 (any C allele vs T/T, HR = 0.74, 95% CI = 0.41–1.36, p = 0.33). In the IRI arm, univariable analysis showed a significantly worse OS in patients with G/G genotype of TIMELESS rs2291739 compared to those with any A allele, and in patients with T/T genotype of TIMELESS rs774047 compared to those with any C allele. Multivariable analysis confirmed the significant associations in these SNPs: TIMELESS rs2291739 (any A allele vs G/G, HR = 3.06, 95% CI = 1.49–6.25, p < 0.01) and TIMELESS rs774047 (any C allele vs T/T, HR = 2.95, 95% CI = 1.43–6.08, p < 0.01). Treatment-by-SNP interaction test confirmed the significant predictive value of both SNPs, both on PFS and OS. Conclusions: Germline polymorphisms in the TIMELESS gene involved in the protection of replication forks may predict efficacy of oxaliplatin and irinotecan in mCRC patients. Our novel findings warrant further validation studies.
Maintenance therapy with 5-fluoruracil/leucovorin (5FU/LV) plus panitumumab (pmab) or 5FU/LV alone in RAS wildtype (WT) metastatic colorectal cancer (mCRC) - the PANAMA trial (AIO KRK 0212).
Authors: Modest Dominik Paul , Karthaus Meinolf , Frühauf Stefan , Graeven Ullrich , Müller Lothar , Koenig Alexander , Von Weikersthal Ludwig Fischer , Caca Karel , Kretzschmar Albrecht , Goekkurt Eray , Haas Siegfried , Kurreck Annika , Stahler Arndt , Heinemann Volker , Held Swantje , Jarosch Armin , Horst David , Kasper Stefan , Stintzing Sebastian , Trarbach Tanja 
Published: June 2021

3503 Background: Planned discontinuation or stop-and-go use of oxaliplatin are established strategies in the systemic therapy of mCRC. Consequently, and irrespective of antibody use, 5FU/LV represents the standard backbone of most maintenance strategies. Unlike VEGF-targeted substances, there is limited evidence that EGFR-antibodies add efficacy to 5FU/LV maintenance in RAS wildtype ( RAS WT) mCRC patients. Methods: Following induction therapy with six cycles of 5FU/LV, oxaliplatin (FOLFOX) and pmab, the trial randomized maintenance therapy with 5FU/LV plus pmab vs. 5FU/LV alone in a 1:1 fashion in patients (pts) with RAS WT mCRC. The primary endpoint was PFS (progression-free survival: time from randomization until progression or death). With 218 events needed for PFS, the trial was designed to demonstrate superiority of the 5FU/LV+ pmab arm vs. 5FU/LV alone with a hazard ratio (HR) of 0.75, power of 80% and a significance level of 10%. Secondary endpoints included overall survival (OS), objective response to induction- and maintenance therapy as well as quality of life. The trial is registered with ClinicalTrials.gov, NCT01991873. Results: The full analysis set consists of 248 pts (125 pts 5FU/LV + pmab and 123 pts 5FU/LV) who were randomized and received maintenance therapy. Median age was 66 vs. 65 years, male patients were 69.6% vs. 63.4%, ECOG 0 was 56.8% vs. 60.2% in the respective trial arms (5FU/LV+ pmab vs. 5FU/LV). At data cut-off, with 218 events, PFS of maintenance therapy was improved with 5FU/LV+ pmab vs. 5FU/LV alone (8.8 (80% CI 7.6-10.2) months vs. 5.7 (80% CI 5.6-6.0) months, HR 0.72 (80%CI 0.60-0.85), p = 0.014). OS (event rate 54.4%) numerically favoured the 5FU/LV+ pmab arm (28.7 (95% CI 25.4-39.1) months) as compared to 5FU/LV alone (25.7 (95% CI 22.2-28.2) months), HR 0.84 (95% CI 0.60-1.18). Conclusion: In RAS WT mCRC, maintenance therapy with 5FU/LV+ pmab appears to be superior to 5FU/LV alone and should be regarded as standard of care maintenance regimen following induction therapy with FOLFOX plus pmab. Clinical trial information: NCT01991873.
Phase II trial of neoadjuvant mFOLFOX 6 with panitumumab (P) in T3 rectal cancer with clear mesorectal fascia (MRF) and KRAS, NRAS, BRAF, PI3KCA wild type (4WT). GEMCAD 1601 PIER trial.
Authors: Fernandez-Martos Carlos , Pericay Carles , Maurel Joan , Virgili Ana , Capdevila Jaume , Gallego Javier , Vera Ruth , Rodriguez-Salas Nuria , Losa Ferran , Valladares Manuel , Vivancos Ana , Ayuso Juan , Maas Monique , Martínez Fernando , Melian Marcos , García de Albéniz Xabier 
Published: June 2021

3512 Background: Patients with advanced colorectal cancer with 4WT tumors achieve increased response rates with chemotherapy and anti-EGFR therapy as compared with chemotherapy alone. In clinically staged (c) T3 rectal cancer neoadjuvant oxaliplatin/fluoropyrimidine combination has shown to induce encouraging pathological complete response (pCR). We hypothesize that combining FOLFOX and P could improve outcomes in 4WT tumors. Methods: PIER was an investigator-initiated phase II, single-arm, multicentre clinical trial to evaluate the safety and efficacy of neoadjuvant mFOLFOX6 with P in pts < 75-y, with 4WT rectal cancer of the middle third staged as T3 by centrally-reviewed magnetic resonance imaging (MRI) and clear MRF, who were candidate for a R0 resection with sphincter preservation surgery. Pts received 6 cycles and underwent re-staging with MRI and sigmoidoscopy. Pts without progression underwent total mesorectal excision 4 weeks after the last cycle. Patients with progression were treated with pre-op chemoradiotherapy. The primary endpoint was pCR. The study followed a 2-Stage Simon’s MiniMax design (P0 of 16%, P1 of 35%, alpha and beta of 0.1). The target sample size was 35 patients and if 9 or more achieved a pCR, the results would be compatible with efficacy. We present primary and early secondary endpoints. Results: Between 9/2017 and 6/2020, 90 patients were screened (56 excluded; 42 were excluded due to mutations, 12 were excluded due to discrepancies with central review of radiology) of whom 34 were enrolled. In the ITT population a pCR was observed in 11 pts (32.3%; [95% CI 17.39-50.53]) and a near-complete pathological response (Mandard 1+2) was observed 17 pts (52.9%). Clinical complete or near complete response was achieved in 50% and there were no progressions. R0 resection rate and pathological circumferential resection margin neg- were 100%. Full compliance with induction was 88%. Neoadjuvant G3/4 toxicity occurred in 54% and was consistent with FOLFOX/P safety profile. G3/4 postoperative related toxicity was 19% with one reoperation. Conclusions: The study met the threshold for efficacy. mFOLFOX6 with P as neoadjuvant therapy can be effective and safe without unexpected toxicities in mrT3, clear MRF and 4WT rectal cancer and resulted in a higher rate of pCR compared with our previous series (GEMCAD 0801; The Oncologist 2014) in a similar molecular-unselected population. This study was funded by Amgen S.A. Clinical trial information: NCT03000374.
Use of circulating tumor DNA in colorectal cancer patients to assess tumor burden and response to therapy: An observational study.
Authors: Symonds Erin L. , Pedersen Susanne Kartin , Yeo Bernita Hui Li , Al Naji Hiba , Byrne Susan E. , Roy Amitesh Chandra , Young Graeme P. 
Published: June 2021

3528 Background: Residual disease after treatment for colorectal cancer (CRC) poses a risk for recurrence but imaging and CEA are limited in their capacity to detect residual disease. A simple test is needed for assessing treatment response. This study determined whether levels of methylated BCAT1/IKZF1 DNA in blood correlate with tumor burden and whether post-treatment levels inform efficacy of different treatments for CRC. Methods: Patients with primary CRC had blood collected prior to treatment (n = 282, 59.9% males, median age 68.5y). Cell free DNA (cfDNA) was extracted from plasma and assayed for methylation in BCAT1 and IKZF1. Detection of methylation in either gene deemed a sample positive; levels were expressed as %methylation (average methylation/average cfDNA). Positive patients had additional samples collected post-treatment for early stage CRC (surgery, n = 31), advanced/metastatic CRC (surgery + adjuvant chemotherapy, n = 15), and rectal cancer (neoadjuvant therapy, surgery +/- chemotherapy, n = 6), or following mid-therapy suspension of treatment in advanced CRC (n = 24). Tumor size was expressed as the maximum diameter of the primary (assessed surgically or by MRI). Results: Pretreatment results increased with CRC stage. Positivity by stage was: I, 23.7% (14/59); II, 62.1% (54/87); III, 68.6% (70/102); IV, 85.3% (29/34). Level by stage: I, 0.0%; II, 0.06%; III, 0.07%; IV, 4.07%, p < 0.001). Pretreatment levels correlated significantly with tumor size (r = 0.372, p < 0.001). Post-treatment blood was collected a median 2.4mo (IQR 1.7-3.9) after therapy completion. Positivity decreased after completing treatment (Table), with 88.4% of cases (46/52) becoming ctDNA negative. All cases with complete treatment had a reduction in biomarker levels, whereas in those with incomplete therapy, 54.5% (12/22) remained positive and the pre- and post-treatment levels were not significantly different. Of those positive after treatment, 13 had a further blood sample: 8 had become ctDNA negative and all but one remained disease free. Five remained positive and all had further suspected or confirmed disease. Conclusions: Levels of methylated BCAT1 and IKZF1 DNA in blood correlated with tumor burden; levels became undetectable in the majority of patients following completion of planned curative intent treatment. The methylated ctDNA blood test aids monitoring of responses to therapy and identification of those cases with residual cancer who might benefit from ongoing therapy.[Table: see text]
The impact of colorectal cancer screening on incidence and stage IV disease in the Netherlands.
Authors: Krul Myrtle F , Elferink Marloes AG , Kok Niels FM , Dekker Evelien , Lansdorp-Vogelaar Iris , Meijer Gerrit A. , Nagtegaal Iris D , Ruers Theo JM , van Leerdam Monique E , Kuhlmann Koert FD 
Published: June 2021

3531 Background: Population-based screening for colorectal cancer (CRC) aims to decrease incidence and mortality due to precancerous polyp removal, early detection and early treatment of CRC. In the Netherlands, phased introduction of a biennial fecal immunochemical hemoglobin test started in 2014 for individuals aged 55-75. This evaluation of the national data focuses on the initial effect of CRC screening on incidence and stage distribution and the impact on stage IV disease. Methods: All CRC patients diagnosed in the Netherlands between 2009 and 2018 were selected from the Netherlands Cancer Registry (NCR). Patients were linked to the Dutch national pathology registry (PALGA) to identify screen-detected tumors. Results: The NCR identified 137,717 CRC patients between 2009 and 2018. The incidence within screening age (55-75 yr) of all CRC stages showed an initial peak after introduction of screening in 2014, followed by a continuous decrease for all stages. CRC incidence outside the screening age did not show these explicit changes between 2009 and 2018. In 2018, the incidence of stage IV CRC within screening age was lower than the level at the start of the screening program. Stage distribution within screening age shifted towards earlier stages in the screening period (2014-2018) compared to the period before screening (2009-2012) (stage I: 31% vs. 18%, stage II: 22% vs. 26%, stage III: 29% vs. 31%, Stage IV: 18% vs. 25%, respectively). In the period 2014-2018 and within screening age, the ratio of screen-detected and symptom-detected tumors was highest in stage I (47%:53%) and lowest in stage IV (9%:91%). Screen-detected compared to symptom-detected stage IV patients diagnosed in the period 2014-2018 and within screening age had more frequently single organ metastases (74.5% vs 57.4%, p < 0.001), higher resection rate of the primary tumor (57.5% vs. 41.3%; p < 0.001) and higher local treatment rate of metastases (40.0% vs. 23.4% p < 0.001). The median overall survival of screen-detected stage IV patients was significantly longer than that of symptom-detected stage IV patients (31.0 months (95% CI: 27.7 – 34.3) vs. 15.0 months (95% CI: 14.5 – 15.5), p < 0.001). Conclusions: The initial results of the introduction of CRC screening in the Netherlands showed a favorable trend on CRC incidence and stage distribution. Screen-detected patients with stage IV disease had less extensive disease, resulting in better treatment options and improved survival.
A model combing an immune-related genes signature and an extracellular matrix-related genes signature in predicting prognosis of left- and right-sided colon cancer.
Authors: Zhong Min-Er , Cai Du , Fan Dejun , Wang Wei , Li Cheng-Hang , Huang Ze-Ping , Zhu Qiqi , Lv Min-Yi , Hu Chuling , Wu Xiaojian , Gao Feng 
Published: June 2021

3533 Background: Primary tumor sidedness has been found to be prognostic in colorectal cancer (CRC), with right-sided colon cancer (RCC) having a worse survival than left-sided tumors (LCC), even after controlling for known negative prognostic factors. Our previous proteomic study identified differences in protein profiles between LCC and RCC. Immune-related proteins were found to be up-regulated in LCC while the differentially expressed proteins in RCC were mainly enriched in extracellular matrix-related proteins. Herein we aim to construct a prognostic prediction model for LCC and RCC patients by using immune-related genes (IRGs) and extracellular matrix-related genes (ECMGs). Methods: A total of 1,868 CRC patients with complete follow-up data from 1 training cohort (n = 562) and 3 independent validation cohorts (n = 622, n = 403, n = 281, respectively) were enrolled in our study. Tumors located in the splenic flexure, descending colon, sigmoid colon, and rectum are defined as LCC. In contrast, tumors located in the region from the hepatic flexure to the cecum are defined as RCC. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was used to construct the multi-gene signatures. Univariate and multivariate analyses were used to test the prognostic value of these models. Results: Our biomarker discovery effort identified a 9-gene IRGs signature that significantly associated with poor DFS for LCC (HR = 3.46, 95%CI = 2.38-5.01, P < 0.001) and a 21-gene ECMGs signature associated with prognosis for RCC (HR = 4.53, 95%CI = 2.84-7.22, P < 0.001). For LCC, the IRGs signature was significantly correlated with worse prognosis in three independent validation cohort (Validation-1 cohort: HR = 2.08, 95%CI = 1.41-3.09, P < 0.001; Validation-2 cohort: HR = 2.19, 95%CI = 1.26-3.81, P = 0.004; Validation-3 cohort: HR = 2.94, 95%CI = 1.53-5.63, P < 0.001). Similarly, the ECMGs signature also robustly predicted survival for RCC in three independent validation (Validation-1 cohort: HR = 1.86, 95%CI = 1.22-2.83, P = 0.003; Validation-2 cohort: HR = 1.96, 95%CI = 1.18-3.26, P = 0.008; Validation-3 cohort: HR = 2.8, 95%CI = 1.27-6.17, P = 0.007). When compared with Oncotype DX, we found IRGs achieved an improved survival correlation in LCC (C-index, validation-3 cohort: 0.75 vs 0.64) and ECMGs got a better survival correlation in RCC (C-index, validation-3 cohort: 0.74 vs 0.58). Conclusions: Combing a 9-gene IRGs signature for LCC and a 21-gene ECMGs signature for RCC, we established a prognostic model that can robustly stratify CRC patients into high- and low- risk groups of tumor recurrence and predict prognosis.
Genetic variants involved in the cGAS-STING pathway to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and TRIBE trials.
Authors: Wang Jingyuan , Xiao Yi , Loupakis Fotios , Stintzing Sebastian , Arai Hiroyuki , Battaglin Francesca , Kawanishi Natsuko , Jayachandran Priya , Soni Shivani , Zhang Wu , Mancao Christoph , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz-Josef 
Published: June 2021

3535 Background: The intracellular DNA sensor stimulator of interferon genes (STING) plays a vital role in anti-tumor immune responses by recognition of self-DNA from tumors and by-products of genomic instability. Activation of STING was reported to enhance cetuximab mediated natural killer cell activation and dendritic cell maturation. Previous reports suggested that polymorphisms of cGAS-STING can affect innate immune response. Therefore, we hypothesized that genetic variants in the cGAS-STING pathway may predict first-line treatment outcome in mCRC pts treated with bevacizumab/cetuximab-based chemotherapy. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, FIRE-3 (cetuximab arm, n = 129; bevacizumab arm, n = 107) and TRIBE (bevacizumab arm, n = 215), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 7 selected SNPs in 3 genes involved in the STING pathway (cGAS, STING, IFNB1) was analyzed. Results: In the Cetuximab cohort, pts with STING rs1131769 any T allele (N = 29) showed significantly shorter overall survival (36.3 vs 56.07 months) compared to carriers of C/C (N = 95) in both univariate (hazard ratio [HR] = 2.08; 95% confidence interval [CI]: 1.06-4.07; p = 0.003) and multivariate (HR = 2.98; 95%CI 1.35-6.6; p = 0.00848) analysis; Pts carrying IFNB1 rs1051922 any A allele (N = 68) showed significant shorter progression-free survival (10.23 vs 14.1 months) than carriers of G/G (n = 59) in both univariate (HR = 1.87; 95%CI 1.26-2.78; p = 0.00163) and multivariate (HR = 2.03; 95%CI 1.25-3.3; p = 0.004) analysis. No association were observed in the bevacizumab cohort of TRIBE and FIRE-3. Conclusions: Our study demonstrates for the first time that STING and IFNB1 polymorphisms could predict outcomes of Cetuximab-based treatment in mCRC patients; These finding may provide insight for the combination of STING agonist and anti-EGFR treatment in mCRC patients.
The effect of primary tumor location on second- or later-line treatment with anti-EGFR antibodies in patients with metastatic colorectal cancer: A single-center cohort study.
Authors: Archwamety Anita , Poungvarin Naravat , Akewanlop Charuwan , Korphaisarn Krittiya 
Published: June 2021

3541 Background: The guideline recommends anti-EGFR monoclonal antibodies (anti-EGFR Ab) as first-line treatment only for patients with left-sided RAS wild type (RASwt) metastatic colorectal cancer (mCRC). However, there are no recommendations on tumor sidedness in subsequent lines. This study aimed to evaluate the effect of primary tumor location on second- or later-line treatment outcomes in patients with KRASwt mCRC. Methods: Medical records of patients diagnosed with mCRC at Siriraj Hospital between 2008 and 2019 were retrospectively reviewed. Patients with KRASwt who received anti-EGFR Ab in second- or later-line treatment were included. The impact of tumor sidedness on progression-free survival (PFS) was determined using the Kaplan-Meier method and compared using the log-rank test. Results: Of 671 patients who had data on KRAS analysis, 396 patients (59%) had KRASwt. Of these, 210 patients received anti-EGFR Ab in second- or later-line treatment. Twenty-nine percent of patients (60 out of 210) had extended RAS analysis. Thirty patients (14%) had right-sided tumors, while 180 patients (86%) had left-sided tumors. Sixty-nine percent of patients (146 of 210) were treated in the third line, while 19% and 12% were treated in the second and the fourth line, respectively. Single-agent irinotecan was the most commonly used chemotherapy backbone (92%). Patients with right-sided tumors had non-significantly inferior PFS compared with patients with left-sided tumors (median PFS was 4.7 months, 95% CI 0.8–8.7 vs. 6 months, 95% CI 4.6–7.3; p = 0.55). Subgroup analysis on the impact of primary tumor location showed no difference in PFS when stratified by treatment lines. Conclusions: This study demonstrated that tumor sidedness has no impact on treatment outcomes in patients treated with anti-EGFR Ab in second- or later-line treatment. Therefore, there is not enough evidence to use tumor sidedness for treatment selection in these settings. A multi-center retrospective study is ongoing.