bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of age and gender on the efficacy and safety of panitumumab plus fluorouracil and folinic acid versus fluorouracil and folinic acid alone as maintenance therapy in RAS WT metastatic colorectal cancer (mCRC): Subgroup analysis of the PANAMA-study (AIO-KRK-0212).
Authors: Heinrich Kathrin , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Müller Lothar , Koenig Alexander , von Weikersthal Ludwig , Caca Karel , Kretzschmar Albrecht , Goekkurt Eray , Haas Siegfried , Alig Annabel Helga Sophie , Kurreck Annika , Stahler Arndt , Held Swantje , Reinacher-Schick Anke C. , Heinemann Volker , Stintzing Sebastian , Trarbach Tanja , Modest Dominik Paul 
Published: June 2022

3567 Background: Clinical trials in mCRC are usually conducted irrespective of gender and mostly also irrespective of age. However, gender- and age-associated differences relating to safety and efficacy in the treatment of mCRC are of presently moving into the focus of interest. We investigated the effect of gender and age on efficacy and safety in the PANAMA trial. Methods: PANAMA investigated the efficacy of panitumumab (Pmab) plus fluorouracil and folinic acid (FU/FA) versus FU/FA alone after first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab in patients with RAS wild-type metastatic colorectal cancer. In this post-hoc analysis, the study population was stratified for age (≤ 65 years versus > 65 years) and gender (male versus female). Evaluated efficacy endpoints were progression-free survival (PFS), overall survival (OS) of maintenance therapy and objective response rate (ORR) during maintenance therapy. Safety endpoints were rates of any grade and grade 3/4 adverse events (AEs). Results: In total, 165 male and 83 female patients were randomized and treated. Male patients had a significant benefit from the addition of Pmab to maintenance treatment with regard to PFS (HR 0.63; 95% CI 0.45-0.88; p = 0.006) and demonstrated a strong trend towards better ORR during maintenance therapy (Odds ratio 1.92; 95%CI 1.02-3.70, p = 0.053). In female patients, no difference regarding PFS was seen between treatment arms (HR 0.85; 95% CI 0.53-1.35, p = 0.491), while a trend towards better ORR with Pmab (Odds ratio 2.50; 95% CI 0.99-6.25; p = 0.063) was observed. Gender had no significant impact on OS, nor did age categories affect survival endpoints. Adverse events grade ≥ 3 occurring during maintenance therapy were comparable between male and female patients (12.9% vs 13.5%; p = 0.791) and in different age categories (p = 0.393). Conclusions: In the Panama trial, addition of Pmab to maintenance treatment with FU/FA improved outcome in RAS wild-type mCRC. This effect is irrespective of age and is pronounced in male patients. Our results support the relevance of gender in mCRC. Clinical trial information: NCT01991873. [Table: see text]
Trifluridine/tipiracil plus bevacizumab (FTD/TPI + BEV) and trifluridine/tipiracil (FTD/TPI) monotherapy in metastatic colorectal cancer (mCRC): Results of a meta-analysis.
Authors: Yoshino Takayuki , Taieb Julien , Andre Thierry , Kuboki Yasutoshi , Pfeiffer Per , Kumar Amit , Hochster Howard S. 
Published: June 2022

3568 Background: FTD/TPI is approved for patients (pts) with refractory mCRC. FTD/TPI + BEV has been evaluated in refractory mCRC in phase 1 and 2 trials and shown efficacy and tolerability, but few head-to-head studies compare FTD/TPI + BEV with FTD/TPI. We therefore conducted this meta-analysis to evaluate outcomes with FTD/TPI + BEV and FTD/TPI monotherapy in mCRC. Methods: We searched MEDLINE, Embase, and Cochrane Library databases; ASCO, ESMO, and AACR proceedings (past 3 years); Clinicaltrials.gov and UMIN registries; systematic review bibliographies; gray literature; and guidelines through June 2021 for studies involving pts with mCRC treated with FTD/TPI + BEV or FTD/TPI. Only randomized controlled trials (RCTs), non-RCTs, and prospective observational studies of previously treated pts with mCRC were evaluated. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse event (AE) rates, and AE-related discontinuation rates. Fixed and random effects models based on inverse-variance weighting were used to estimate relative effects and pooled absolute outcomes for ORR, DCR, AE rates, and AE-related discontinuation rates. PFS and OS were estimated from pooled Kaplan–Meier curves using Guyot’s algorithm. Results: Twenty-nine of 875 screened publications were selected, which included a total of 10,285 pts and reported on 5 RCTs, 11 non-RCTs, and 10 prospective observational studies. In an RCT (n = 93; Pfeiffer et al. Lancet Oncol. 2020), FTD/TPI + BEV was associated with significant reductions in risks for progression and death versus FTD/TPI. Pooled efficacy outcomes were higher with FTD/TPI + BEV than FTD/TPI (Table). Pooled rates for grade ≥3 febrile neutropenia, asthenia/fatigue, diarrhea, nausea, and vomiting were similar with FTD/TPI + BEV and FTD/TPI, although grade ≥3 neutropenia occurred more frequently with FTD/TPI + BEV than FTD/TPI (43% vs 29%). AE-related discontinuation rates were similar (Table). Conclusions: This meta-analysis suggests that FTD/TPI + BEV provides benefits over FTD/TPI in pts with refractory mCRC and has a similar safety profile, but it is associated with a higher rate of grade ≥3 neutropenia. Limitations of the analysis include study design heterogeneity. Data from RCTs (eg, phase 3 SUNLIGHT trial [NCT04737187]) are required to confirm these findings. [Table: see text]
Response to epithelial growth factor receptor inhibitor (EGFRi) treatment in patients with early-onset, treatment-naïve metastatic colorectal cancer (mCRC): An ARCAD database analysis.
Authors: Jin Zhaohui , Dixon Jesse G. , Hubbard Joleen M. , Eng Cathy , Lieu Christopher Hanyoung , Douillard Jean-Yves , Adams Richard , Maughan Timothy S. , Van Cutsem Eric , Venook Alan P. , Lenz Heinz-Josef , Heinemann Volker , Stintzing Sebastian , Kaplan Richard S. , Bokemeyer Carsten , Chibaudel Benoist , Zalcberg John Raymond , Yoshino Takayuki , De Gramont Aimery , Shi Qian 
Published: June 2022

3572 Background: Early onset colorectal cancer (eoCRC: disease diagnosed < 50) has been increasing over the past 2 decades. Currently, standard treatment recommendations for eoCRC patients (pts) with metastatic disease does not differ from late-onset CRC (loCRC) pts although outcomes data in eoCRC pts is limited. Methods: Individual patient data on 5,761 treatment-naive metastatic eoCRC pts was pooled from 8 phase II and III randomized EGFRi studies (2000 - 2012) from the ARCAD mCRC database. The distribution of demographics, clinicopathological features, and biomarkers were summarized by age groups. Progression-free survival (PFS) was compared between age groups by stratified Cox models, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables based on a subset of trials with concurrent randomizations between regimens with and without EGFRi Results: eoCRC (n=756) were more evenly distributed between gender, had improved performance status (PS), increased likelihood of metastatic resection, and distant lymph node metastasis, but were less likely to have lung metastasis or KRAS mutation compared to loCRC (n=5,005, table 1). eoCRC and loCRC patients had similar distribution of primary tumor sidedness, primary resection, liver and/or peritoneal involvement, number of metastatic sites involved, and BRAF mutations (MT). No difference in PFS for eoCRC versus loCRC pts was noted (7.8 vs. 7.9 months [M], adjusted hazard ratio [HRadj], 1.02, 95% confidence interval [CI], 0.93-1.11). Among pts with KRAS wild type (WT) and left sided primary tumors, univariable analysis of EGFRi demonstrated improved mPFS in loCRC (9.9 vs 8.5M, HR = 0.74, p<0.001), but this benefit was not seen in eoCRC (8.3 vs 8.9 months, HR 1.20, p=0.36). The same pattern was observed upon multivariable analysis (Table). Conclusions: In our pooled analysis, EGFRi + chemotherapy significantly improved PFS in treatment-naïve loCRC patients but not in left sided, KRAS WT, eoCRC patients. Further validation in an independent cohort is warranted. [Table: see text]
Predictive and prognostic value of carcinoembryonic antigen (CEA) on maintenance therapy with 5-fluoruracil/leucovorin plus panitumumab or 5-fluoruracil/leucovorin alone in RAS wildtype metastatic colorectal cancer: Evaluation of the phase II PanaMa trial (AIO KRK 0212).
Authors: Kurreck Annika , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Mueller Lothar , Koenig Alexander , von Weikersthal Ludwig , Goekkurt Eray , Haas Siegfried , Stahler Arndt , Heinemann Volker , Held Swantje , Alig Annabel Helga Sophie , Hoppe Beeke , Kind Andreas Jay , Kasper Stefan , Stintzing Sebastian , Trarbach Tanja , Modest Dominik Paul 
Published: June 2022

3587 Background: Carcinoembryonic antigen (CEA) may reflect response to antitumor treatment in metastatic colorectal cancer (mCRC). The predictive value of CEA has not yet been proven for subsequent maintenance therapy. This analysis aims to evaluate the predictive and prognostic value of pre- and post-induction treatment CEA on maintenance with 5-fluoruracil/leucovorin (FU/FA) plus panitumumab (pmab) [arm A] or FU/FA alone [arm B] in RAS wildtype mCRC patients treated within the PanaMa trial. Methods: Patients with CEA measurements (pre- and post-induction therapy) were grouped as normal (both measurements ≤5 ug/l), stable (between +25% and -25%), decreasing (<-25%), and increasing (>+25%) CEA. Survival parameters (overall survival (OS), progression-free survival (PFS) from initiation of maintenance therapy) were expressed by the Kaplan-Meier method and compared by log-rank testing, and Cox regression. The objective response (OR) to maintenance therapy was analyzed by chi-square testing. Results: Out of 248 patients in the in the full analysis set, 245 patients were eligible for CEA analysis. Normal CEA occurred in 58 (23.7%), stable CEA in 16 (6.5%), decreasing CEA in 161 (65.7%), and increasing CEA in 10 (4.1%) patients. In the subgroup of decreasing CEA, there was a significant difference in the prediction of OR between both treatment arms with a better positive predictive value for the pmab-containing maintenance (44.0% vs. 27.5%, p=0.032). Increasing compared to decreasing CEA was associated with unfavourable survival outcome of maintenance irrespective of treatment arm (Table). Conclusions: CEA kinetics during induction therapy appears to have a predictive value for subsequent maintenance, notably pmab-based. Besides that, CEA levels had a significant impact on survival parameters of maintenance irrespective of the addition of pmab to FU/FA. This analysis is limited by the small number of patients in the subgroup of increasing CEA. Clinical trial information: NCT01991873. [Table: see text]
Metastasis patterns and racial disparities in gastrointestinal cancers: A SEER database population study 2010–2018.
Authors: Al Armashi Abdul Rahman , Hammad Faris , Elantably Dina , Patell Kanchi , Somoza-Cano Francisco , Al Zubaidi Anas , Ravakhah Keyvan , Alkrekshi Akram 
Published: June 2022

3597 Background: Metastatic disease at the time of diagnosis of gastrointestinal (GI) malignancies is a strong predictor of poor outcomes. Differences in metastatic patterns among Caucasians (C) and African-Americans (AA) needs further elucidation. In this study, we analyzed the patterns of metastasis in C and AA in colorectal cancer (CRC), pancreatic cancer (PC), gastric cancer (GC), and liver cancer (LC). Methods: We identified patients with CRC, PC, GC, and LC from the Surveillance, Epidemiology, and End Results Program (SEER) database from 2010-2018. We obtained metastasis data to lungs, liver, bone, and brain at the time of diagnosis. We calculated the relative risk (RR), confidence interval (CI), and standard error with the use of SPSS software, 28.0 (IBM). Results: The most common metastasis site was the liver being highest at 39% in AA with PC. Brain metastasis was the least common. Significant racial disparities were noted. In CRC, AA had a 35-37% increased risk of metastasis to the liver, lung, or bone. AA had a higher risk of liver metastasis in PC and GC, whereas C had a higher risk of lung metastasis. Table 1 summarizes the data findings. Conclusions: This study illustrates the disparities of metastasis from GI cancers among AA and C. While a delay in screening, earlier onset of CRC in AA and socioeconomic factors may explain the disparities witnessed in CRC. However, these factors will fail to explain the difference in metastasis pattern in PC and GC in that AA had a higher risk of liver metastasis, and C had a higher risk of lung metastasis. Moreover, In GC, the brain metastasis rate in C was double that of AA. Further studies of possible biological and other risk factors are needed. [Table: see text]
Using T stage to predict outcomes of adjuvant oxaliplatin (OX)-based chemotherapy (CT) in stage III colon cancer (CC): An ACCENT pooled analysis.
Authors: Cohen Romain , Raeisi Morteza , Yothers Greg , Schmoll Hans-Joachim , Haller Daniel G. , Bachet Jean-Baptiste , Chibaudel Benoist , Wolmark Norman , Yoshino Takayuki , Goldberg Richard M. , Kerr Rachel , Lonardi Sara , George Thomas J. , Shmueli Einat Shacham , Sharara Lama , Andre Thierry , Shi Qian , De Gramont Aimery 
Published: June 2022

3606 Background: Standard adjuvant CT for stage III CC are FOLFOX and CAPOX. Recently, IDEA study separated stage III patients (pts) into low risk (T1 to 3, N1) and high risk (T4 or N2). We recently confirmed benefit of OX in both risk groups. However, we observed a difference in the two high-risk subgroups, with benefit in N2 but not in T4 (Margalit O et al; Clin Colorectal Cancer 2021). This prompted us to compare outcomes (OS/TTR) between treatment with OX vs. without OX within sub-stage III CC groups defined by T and N. Methods: We pooled 4941 stage III CC pts from the three studies evaluating 6 months of CT with fluoropyrimidine (FP) ± OX: MOSAIC, C-07 and XELOXA. Baseline characteristics were compared using χ2 and t-test. OS was compared between OX and no OX in T and N subgroups. Kaplan-Meier analyses, adjusted and unadjusted Cox models stratified by study were used. Sub-groups classification was done according to OX benefit and verified by interaction test (Int) considered as significant with a P<0.1. We considered for recommendation of using OX-based adjuvant CT, 1) significant benefit in OS, 2) significant Int between substage and adjuvant therapy, and 3) the three individual trials showing similar results (benefit or non-benefit of OX). Results: In stage III population, T3 pts were 74.9%, T1-2 12.4%, T4 13.1%, while N stage was N1 64.7% and N2 35.3%. Population was well balanced according to treatment allocation in most subgroups. A significant benefit of OX was only observed in T3N1 and T3N2 (OS HR 0.76). Whatever N stage, there was no significant benefit of OX in the T1-2 and T4 subgroups. The effect of OX+FP vs FP alone in OS of the three studies differed between T3 and T1-2 subgroups (P = 0.047). Interaction was borderline between T3 and T4 subgroups (P = 0.10) but there was no interaction between T1-2 and T4 subgroups (P = 0.429). A benefit of OX in TTR remained in the T4 population. Discrepancy between advantage in time to relapse (TTR) and no advantage in OS was not explained by survival post relapse. Conclusions: Our analysis suggested that pts with T1-2N1-2 and T4N1-2 disease had no OS benefit of addition of OX to FP. The good survival achieved with FP alone in T1-2N1-2 pts (5-yr OS 89%) question the addition of OX. In the T4 population our results suggested that benefit of OX was limited and that further studies should assess this issue or at least stratify pts on T stage in the future adjuvant trials in CC. [Table: see text]
Genetic ancestry differences in tumor mutation in early and average-onset colorectal cancer.
Authors: Rhead Brooke , Hein David , Pouliot Yannick , Guinney Justin , De La Vega Francisco , Sanford Nina Niu 
Published: June 2022

3620 Background: The incidence and mortality of early onset colorectal cancer (EOCRC), defined as CRC diagnosed prior to age 50, are rising, in contrast to declining rates of average onset CRC (AOCRC). Epidemiologic trends for CRC appear to differ by race/ethnicity, which could be related in part to underlying differences in tumor mutation and gene expression. Previous research has used self-reported race/ethnicity categories, which has been shown to be missing or inaccurate, particularly in highly admixed groups such as Black and Hispanic patients. Hence, we examined tumor profiles of EOCRC and AOCRC using genetic ancestry. Methods: Genetic ancestry was inferred from de-identified data of 1,443 and 3,315 patients with EOCRC and AOCRC, respectively, who underwent tumor profiling with the Tempus xT NGS 648-gene panel and targeted RNAseq. Ancestry informative markers were used to estimate likelihoods for the five continental groups defined in the 1000 Genomes Project: Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS). We assessed the association of genetic ancestry proportions (per 10% increase in each ancestry proportion) with presence of protein altering somatic mutations in key driver genes in CRC. We also assessed interactions between onset age (EOCRC vs. AOCRC) and genetic ancestry in somatic mutations. Results: Across all ages, African ancestry was associated with higher odds of mutations in APC and KRAS and lower odds of BRAF mutations (Table). East Asian ancestry was associated with higher odds of mutations in NTRK3 and TP53. For EOCRC, the association between KRAS and African ancestry remained significant (OR 1.07, p=0.04). Furthermore, there was an interaction (p=0.031) between onset age and race/ethnicity such that the association between African ancestry and APC mutation was significant in AOCRC (OR=1.09) but not EOCRC (OR=1.00). Conclusions: The use of genetic ancestry instead of categorical race/ethnicity provides a more quantitative and precise profile of shared genetic background that can underlie biological race differences in CRC cancer etiology and outcomes. [Table: see text]
The impact of African ancestry on colorectal cancer disparity.
Authors: Joung Yoo Jin , Lee Michelle Jeung-Eun , Jain Sanjay R. 
Published: June 2022

3621 Background: Colorectal cancer is the second leading cause of cancer deaths in the world to affect both men and women. Racial disparities have been known to affect the disease diagnosis and progression, and proliferative genomic studies have been undertaken to elucidate their relationship. In this study, we investigate the tumor mutation profile in colorectal adenocarcinoma (COAD) based on genetic ancestry using The Cancer Genetic Ancestry Atlas (TCGAA). Methods: 59 AA (African American) individuals in TCGAA COAD dataset were identified. To account for and eliminate the biases introduced by self-identification of races, we utilized TCGAA genomic analysis to accurately estimate the ancestral genomic composition of each individual. For each individual, percentages of European (EA), West African (WA), East Asian (EAA), and Native American (NA) ancestry were identified based on Local Ancestry in adMixed Populations (LAMP). Individuals were screened for dominant WA ancestry (≥50% based on LAMP) and assigned to three groups, ≥90%, 80-89%, and 50-79%. Differences in gene mutation frequency and overall survival were compared among the three subgroups of individuals with WA ancestry. Results: Based on genomic ancestry analysis, 58 individuals with dominant WA ancestry (Range 53%-100%) were identified. We classified them into three groups based on percentage of WA ancestry: ≥90% (n = 17), 80-89% (n = 26), and 50-79% (n = 15). APC was the most frequently mutated gene in all groups except ≥90% WA ancestry, which had the most mutation frequency in TP53. ≥90% WA ancestry showed the highest rate of mutation of 81.3% in TP53 compared to 70.8% (80-90% WA ancestry) and 40.0% (50-79% WA ancestry). Interestingly, ≥90% WA ancestry had the highest average rate of mutation (33%) for 7 tumor suppressor genes ( AMER1, APC, ARID1, FBXW7, TCF7L2, TGFBR2, and TP53), compared to 29% and 22% in 80-89% WA ancestry and 50-79% WA ancestry, respectively. In addition, ≥90% WA ancestry had a lower rate (19%) of mutation in 6 oncogenes ( BRAF, NRAS, KRAS, PIK3CA, SMAD4, and SOX9) compared to 24% in both 80-89% and 50-79% WA ancestry. Although not statistically significant, a higher percentage of WA ancestry in an individual was correlated with a downward trend in the overall survival rate (median survival 56.3 months in ≥90% WA ancestry vs 61.8 months in 80-89% WA ancestry). Conclusions: In this study, we analyzed different gene mutations correlated with African ancestry and their potential relationship to the etiology, progression, and prognosis of COAD. The mutation profile of these genes will allow us to investigate altered pathways associated with African ancestry and draw insight into colon cancer pathogenesis in various ancestry groups. Further studies are warranted to elucidate the role of genetic ancestry in tumorigenesis and disease progression and to identify potential therapeutic targets specific to groups disproportionately affected by cancer.
Radical versus local surgical excision for early rectal cancer: A systematic review and meta-analysis.
Authors: El-Nakeep Sarah , Madala Samragnyi , Chidharla Anusha , Martin Benjamin , Kasi Anup 
Published: June 2022

3622 Background: Colorectal cancer is the third common cancer worldwide. Radical excision (RE) as total mesorectal excision for rectal cancer carries a higher risk of mortality and morbidity, while local excision (LE) could decrease these postoperative risks. However, the long-term oncologic outcomes of LE are still debatable. We aim to study the effect of LE versus RE in T1 and T2 rectal cancer. Methods: We conducted a systematic review and meta-analysis. We searched PubMed and CENTRAL databases, using an optimized search-strategy from inception until 15 June 2021, without restriction on publication date or status. We included only cohort and randomized controlled trials (RCTs). Two authors independently screened the title, abstracts, and full-text manuscripts for inclusion and data extraction. All included trials contained at least one of the primary outcomes. We used RevMan 5.4 tool for data analysis. We calculated both hazards ratio (HR) and risk ratio (RR) for the 5-years survival analyses, with their 95% confidence intervals (CI). We assessed both clinical and statistical heterogeneity of the studies; I2 >75% was considered highly heterogeneous. We used random effect model (REM). We used standardized mean difference (SMD) for hospitalization days. We conducted a subgroup analysis of patients with T1-only without adjuvant chemo/radiotherapy (CRT). Results: We retrieved from the search a total of 1243 reports. A total of 18 studies were included for final meta-analysis (4 RCTs and 14 retrospective cohorts). Nine studies were multi-central while ten were unicentral studies. We did not find any difference in risk ratio (RR) between overall survival (OVS) and disease-free survival (DFS). But there were higher HRs in OVS and DFS with LE as compared to RE. A higher recurrence rate was also seen with LE. Six studies showed absent 30-days postoperative mortality in both groups so we used peto-odds ratio. Postoperative mortality and morbidity were lower with LE rather than RE. Conclusions: LE for early stage rectal cancer has a higher risk of decreased 5-year OVS and DFS than RE, with higher local recurrence rate. However, LE is associated with lower early postoperative mortality, morbidity, and hospitalization days, as compared to RE. Patient selection is key to balance these risks for the optimal outcome. [Table: see text]