bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity and tolerance of biweekly CapeOx-cetuximab in 1st line therapy of metastatic colorectal cancer (mCRC): Relation to K-ras mutation status
Authors: Yuan Y. , Ma H. , Cohen D. J. , Ryan T. , Choi H. , Love‘ E. , Awad M. , Khambata-Ford S. , Mauro D. , Hochster H. 
Published: August 2020

e15018 Background: This novel q2w schedule trial combined oxaliplatin (Ox), flat dose capecitabine (Cape) and cetuximab(C) in first line therapy of mCRC. C was given weekly initially and then q2w. We report the response rate, toxicity and influence of K-ras mutation status in first-line patients treated with biweekly CapeOx-C in this phase II trial. Methods: Pts with previously untreated, histologically confirmed, metastatic colon adenocarcinoma, ECOG PS 0–1, and adequate organ function were eligible. Pts were treated with C (initially 250mg/m2 q week and later amended to 500mg/m2 q2w) and Ox (85mg/m2) combined with flat dose Cape (2500mg po bid x 7days) q2w. Endpoints included response (RECIST), toxicity (CTCAE v3) and relationship to K-ras mutation status as determined in codons 12/13 of exon 2 in genomic tumor DNA by PCR, blinded to clinical data. Results: Between 8/04 and 8/08, 27 pts were enrolled. One pt failed screening, 1 withdrew prior to rx and 2 too early for assessment. 25 pts were treated: M/F (15/10), PS 0/1 (13/12), median age 65 yrs (37–80). 12 pts were treated weekly with C and 13 q2w. 23 pts were eligible for both toxicity and efficacy analysis. The most common grade 3/4 toxicities (N=23) were diarrhea (26%), thrombosis (22%), neuropathy (17%), rash (13%), hand-foot syndrome (9%), hypersensitivity reaction (9%), stomatitis (9%). Toxicity profiles between the two C schedules were comparable. Of 23 pts evaluable for response, there were 2 CR, 12 PR, and 3 SD (ORR 61%; disease control rate (DCR) 74%). K-ras status was determined in 18 pts: 9 were K-ras wild-type (WT) and 9 mutant (MT) with ORR and DCR = 66%, 89% for WT vs. 44%, 44% MT. Time on study was 6 mon for WT vs 3 mon for MT (p<0.05). Grade 0–1 vs. 2–3 skin rash was 33% vs. 67% for WT and. 89% vs. 11% in MT pts. Conclusions: The novel combination of biweekly CapeOx-C, with flat dose Cape was well tolerated and very active (regardless of K-ras status) as first line treatment in mCRC. C 500 mg/m2 q2w appears equal to weekly dosing. Analysis of the K-ras mutation status showed a trend toward increased benefit by response rate and time on study, with more cutaneous toxicity in K-ras WT pts. [Supported in part by grant from BMS.] [Table: see text]
Relation between long-term blood pharmacokinetics (PK), pharmacogenomics (PG), and severe neurotoxicity in patients undergoing an oxaliplatin (O)-based regimen
Authors: Bastian G. , Chibaudel B. , Maindrault-Goebel F. , Garcia-Hejl C. , Bonnetain F. , Rebischung C. , Hebbar M. , Yataghene Y. , de Gramont A. 
Published: August 2020

e15024 The aim of the study was to investigate the residual blood level of O before each cycle of various oxaliplatin (O)-based protocols, and to explore its predictive value for potential occurrence of a severe neurotoxicity. Methods: Between 11/2005 and 06/2008, 220 Pts were included in a prospective cohort, in 7 French centers. Patients received a minimum of 7 cycles of O. Blood samples were taken before each cycle with a maximum of 12 cycles. In parallel neurotoxicity was assessed by the modified Levi score (grade 0 to 3) and by the Von Frey filament exam. Saliva was collected before the first cycle for genomics analysis. The O concentration was obtained by Atomic Absorption Spectrometry assay. Polymorphism of different targets were investigated (carrier proteins: MRP2, OCT1, OCT2, GSTP1, adducts repair system: ERCC1, ERCC2). Time to first severe neurotoxicity occurrence (TTSN Events: Grade 2 or3) was estimated using Kaplan-Meier. Predictive value of severe neurotoxicity was explored using univariate and multivariate logistic or Cox regressions. Harrel C index was produced. Results: 206 pts with gastro-intestinal cancer had, at the time of analysis, completed follow-up and 171 pts were eligible. 84% received FOLFOX regimen (85mg/m2every 2 weeks), the others GEMOX or XELOX (100mg/m2 every 3 weeks). After cycle 1, 2 and 10, median residual level of O was respectively 0.23 mg/L, 0.40 mg/L and 0.58 mg/L. The maximal concentration was obtained between cycle 5 and cycle 9. Respectively 83 Pts (40%) and 15 pts (7%) had a Gr2 and a Gr3 neurotoxicity. Median time TTSN was 141 days (95% CI: 132 - 161). O concentration before 2nd (HR = 1.39, p = 0.34, C =0.53) or 3rd cycle (HR = 1.00, p = 0.99, C =0.54) were not associated with TTSN. Multivariate logistic and Cox analyses confirmed these results. Conclusions: Despite a trend, which needs to be confirmed, the residual blood level of O is not predictive of a Gr 2 or Gr 3 neurotoxicity in patients with an O based-regimen. With updated data, further statistical analyses will be done to be presented at the next ASCO meeting. They will take into account more precise data as the cycle delay or the dose-intensity of O received by the patients. [Table: see text]
Dose escalating study of 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) and cetuximab in first-line therapy of patients with metastatic colorectal cancer
Authors: Trarbach T. , Schuette K. , Stoehlmacher J. , Goekkurt E. , Guenther H. , Ubbelohde U. , Stroszczynski C. , Ehninger G. , Folprecht G. 
Published: August 2020

e15025 Background: Highly active chemotherapy schedules are necessary in several clinical situations, i.e. for conversional chemotherapy in order to resect liver metastases. Adding oxaliplatin or cetuximab to 5-FU / FA / irinotecan was shown to increase the efficacy of chemotherapy in patients with metastatic colorectal cancer (Falcone et al, JCO 2007, Van Cutsem et al, ASCO 2008). Methods: We performed a phase I study in patients (pts) with metastatic colorectal cancer, WHO PS 0–1 who had not been pretreated for metastatic disease. They received cetuximab (500 mg/m2, 2h), oxaliplatin (85 mg/m2, 2h), folinic acid (400 mg/m2, 2h), irinotecan (95, 125, or 165 mg/m2, 1h), 5-FU (3200 mg/m2, 46 h), each on day 1 in biweekly cycles. Dose was escalated if dose limiting toxicities (DLT) were absent in the first three pts per cohort, or if <2 DLTs in six pts. Non-evaluable pts were replaced. Pts were not selected for EGFR IHC or KRAS status. Results: Twenty-one pts were enrolled into the study between Jan 2007 and June 2008, six evaluable pts per each cohort. Two pts who had adverse events deemed unrelated to study during the first cycle (morphine overdosing, mechanical ileus) were replaced, one patient (port dysfunction during first dose) was excluded from analysis. Patient characteristics were as follows: median age 59 (33–72) years, 16 pts WHO PS 0, 15 pts male, 10 pts rectal cancer primary, 3 pts previous adjuvant chemotherapy. In the first two cohorts, 95 and 125 mg/m2 irinotecan, one DLT occurred per dose level (neutropenia gr. 4 and diarrhea gr. 3). In the 165 mg/m2 cohort, 2 DLTs were observed (neutropenia grade 4). Most common grade ≥ 3 toxicities were neutropenia (40%), diarrhea (25%), skin toxicities (15%), thrombopenia (10%) and infections (15%). One patient had a confirmed complete response, 14 pts had confirmed partial response (ORR 75%, 95% CI: 51–91%), 5 pts stable disease. Median progression free survival has not yet been reached. Conclusions: With the combination of FOLFOXIRI/cetuximab, the recommended dose of irinotecan is 125 mg/m2 for further investigation in clinical trials in patients with good performance status. The observed response rate of 75% is very promising. [Table: see text]
Phase I trial of zalutumumab and irinotecan in metastatic colorectal cancer patients who have failed irinotecan- and cetuximab-based therapy
Authors: Mano M. , Hendlisz A. , Machiels J. , Ehrnrooth E. , Aladdin H. , Van Laethem J. 
Published: August 2020

e15028 Background: Zalutumumab is a novel human IgG1 anti-EGFR mAb. We investigated the safety of zalutumumab and irinotecan in heavily pretreated mCRC patients. Methods: Metastatic CRC patients with documented progression (PD) during or within 6 months of stopping cetuximab and irinotecan based therapy were eligible. No prior treatment with anti-EGFR antibodies other than cetuximab was allowed. Patients received weekly doses of zalutumumab 8mg/kg and 16 mg/kg respectively in combination with irinotecan (180 mg/m2) every second week until PD or unacceptable toxicity. Results: The maximum tolerated dose was not reached and no patients experienced any dose limiting toxicity. At data cut-off (18-Dec-08) 4 patients had died (no cases of death were considered related to zalutumumab), 4 were off study due to PD and 1 was still ongoing ( Table 1 ). In total, 6 patients experienced one or more grade 3/4 toxicities (diarrhea 2; neutropenia 2; leucopenia 1; abdominal pain 1; pulmonary embolism 1; alopecia 1). Conclusions: Zalutumumab can be safely administrated in doses up to 16mg/kg in combination with irinotecan in mCRC patients failing cetuximab and irinotecan based therapy. Zalutumumab and irinotecan resulted in durable stable disease warranting further investigation of this regimen. [Table: see text] [Table: see text]
Neoadjuvant cetuximab, capecitabine, and radiotherapy (RT) in locally advanced resectable rectal cancer: results of a phase II trial
Authors: Velenik V. , Ocvirk J. , Oblak I. , Anderluh F. 
Published: August 2020

e15029 Background: Preoperative chemoradiotherapy (CRT) with capecitabine is a treatment of choice for locally advanced rectal cancer. The radiosensitizing effect of cetuximab, an EGFR-targeting monoclonal antibody, may further enhance the tumor response. The aim of this prospective, nonrandomized, open-label phase II study was to establish the efficacy and safety profile of cetuximab combined with capecitabine and concurrent RT for locally advanced resectable rectal cancer. Methods: Patients (pts) with stage II or III rectal cancer confirmed by MRI were treated with capecitabine 1250 mg/m2 twice daily for 2 weeks. Cetuximab 400mg/m2 was intravenously administered on week 3, followed by cetuximab 250mg/m2/week and capecitabine 825 mg/m2 bid including weekends during RT. The RT dose was 45 Gy (25×1.8 Gy, 3D conformal technique), starting on week 4. Total mesorectal excision was scheduled 4–6 weeks after completion of CRT. Tumor regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was complete pathologic response (pCR). Results: Thirty-seven pts were eligible for safety and efficacy analyses. Median age was 55 (range: 33–72) years, 81% of pts were male. Three pts (8.1%) had T3N0 tumors, 1 pt (2.7%) T2N1, 13 pts (35%) T3N1, 1 pt (2.7%) T2N2, 15 pts (40.5%) T3N2 and 4 pts (11%) T4N2. The median tumor distance from anal verge was 6 (range: 1–11) cm. All pts received 45 Gy RT. Dose reduction/treatment interruption was necessary for 9/37 (24.3%) pts owing to hypersensitivity reaction (n=4), hepatotoxicity grade 3 (n=1) or diarrhea grade 3 (n=4). Other grade 3 toxicities included dermatitis (n=6, 16.2%), anorexia (n=1, 2.7%) and infection (n=1, 2.7%). TRG 4 (pCR) was recorded in 3 pts (8.1%) and TRG 3 in 7 pts (18.9%). T-, N- and overall downstaging rates were 56.8%, 81.1% and 73.0%, respectively. The total sphincter preservation rate was 75.7%; in 17 pts whose tumors were located ≤5 cm of the anal verge, the rate was 53%. Conclusions: Preoperative CRT with cetuximab and capecitabine is safe and feasible. A high pathologic downstaging rate was achieved, although the pCR rate appeared to be in the range previously reported for CRT with capecitabine. No significant financial relationships to disclose.
Functional and prognostic influence of receptor polymorphisms in the vascular endothelial growth factor system in colorectal cancer
Authors: Hansen T. , Spindler K. G. , Olsen D. A. , Andersen R. F. , Lindebjerg J. , Brandslund I. , Jakobsen A. 
Published: August 2020

e15032 Background: The vascular endothelial growth factor (VEGF) system plays a key role in the angiogenic process ensuring a sufficient blood supply to the growth of malignant tumours. The clinical importance of single nucleotide polymorphisms (SNP's) in the VEGF receptors is still unknown. The aim of this study was to investigate the functional and prognostic influence of the V297I C/T and the -604 T/C SNP's in the VEGFR-2 gene, in tumour and normal tissue from colorectal cancer patients. Methods: Blood samples and tissue were collected from 110 patients, surgically resected for colorectal cancer. Genomic DNA was isolated from whole blood, and SNP's were analysed by PCR. Gene expression analysis was performed by RT-PCR and protein analysis was performed by ELISA. Progression free survival according to genotypes was compared using the Kaplan-Meier method and the logrank test. Results: Median gene expression according to the CC genotype of the -604 T/C SNP, were significantly higher than the median gene expression of the TT genotype (p = 0.045) and the TC genotype (p = 0.033) in CRC tissue. Regarding the V297I C/T SNP, median protein concentration according to the CT genotype was significantly higher than the median protein concentration of the CC genotype, p = 0.005. The CC genotype held prognostic information compared to CT and TT genotypes for both SNP's, p<0.05. Conclusions: The V297I C/T SNP seems to have a functional influence on the VEGFR-2 protein level, and the -604 T/C SNP on the gene expression level in CRC patients. The results furthermore indicate a prognostic influence of both SNP's on progression-free survival. No significant financial relationships to disclose.
Evaluation of stool melting curve analysis of methylated CpG island promoters as an alternative for early noninvasive diagnosis of colorectal tumors
Authors: Azuara D. , Rodriguez-Moranta F. , Soriano-Izquierdo A. , Guardiola J. , de Oca J. , Biondo S. , Blanco I. , Esteller M. , Capella G. 
Published: August 2020

e15036 Background: Previous studies have shown that assessment of promoter hypermethylation of a limited number of genes in tumor biopsies may identify all colorectal tumors analyzed. The aim of the present study was to assess the clinical usefulness of a panel of methylation biomarkers in stool DNA in the diagnosis of colorectal tumors using Methylation Curve (MC) analyses, a technique that simultaneously analyze all CpG residues within a promoter. Methods: Promoter methylation status of 5 tumor-related genes (RARB2, p16INK4a, MGMT, p14ARF and APC) was analyzed in DNA stool samples and corresponding tissues in an initial set of 12 newly diagnosed patients with primary colorectal carcinomas and 20 with colorectal adenomas using Methylation-specific PCR (MSP). Results were validated in a set of 88 patients (20 healthy subjects, 17 inflammatory bowel disease, 23 adenomas, 28 carcinomas) using MC analyses. Median age for every group was 63, 51, 66 and 67 y respectively. Results: In the initial set, the majority [10 of 12 (83%) carcinomas and 18 of 20 (90%) adenomas] of biopsies were positive for at least one marker. In stool DNA prevalence was 75% for carcinomas (9 of 12) and 60% for adenomas (12 of 20) with no false positive in stools. In the validation set MC was used. Analytical sensitivity of MC was 5% of methylated alleles for p16INK4a, p14ARF, RARB2 and APC and 10% for MGMT. In the validation set MC analyses of biopsies showed that at least one marker was positive in 22 of 28 (79%) carcinomas and 16 of 23 (70%) adenomas. In stool DNA, these percentages were 64% (18 of 28) for carcinomas and 42% (9 of 23) for adenomas. No aberrant methylation was observed in healthy subjects and in 2 of 15 (13%) of IBD patients aberrant RARB2 methylation was detected. Conclusions: Melting Curve analysis of a panel of methylation markers in stool DNA is a good alternative for the early non-invasive diagnosis of colorectal tumors. [Table: see text]
18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) as a prognostic and predictive biomarker in metastatic colorectal cancer (mCRC)
Authors: Philip P. A. , Gupta S. , Heilbrun L. , Smith D. , El-Rayes B. , Shields A. 
Published: August 2020

e15037 Background: Information on the prognostic and predictive role of FDG-PET in the management of patients (pts) with mCRC is limited. The growing complexity of current therapies and the increasing number of agents to be tested in this disease warrants better understanding of the role of FDG-PET in earlier treatment decisions. Methods: Consecutive pts with 2 or more serial FDG-PET scans at baseline and during the treatment course were studied. Tumor standardized uptake value (SUV) and its percentage change (%ΔSUV) were each studied for their potential association with time to progression (TTP) via univariate Cox models to estimate the hazard ratio (HR) for progression. Results: 27 pts (median age 58.2 yrs) with mCRC were studied. 85% of pts were treated in the first line setting. 44% had received prior adjuvant therapy. 63%, 26% and 11% received oxaliplatin based, irinotecan based and fluropyrimidine only regimens, respectively. 85% received concurrent bevacizumab. Median pretreatment SUV was 9.0 (range 1.7 - 46.0); Median post treatment SUV was 3.4 (0–13.5); median %ΔSUV was -77.2 (range -10% to -100%). Mean interval between scans was 4.1 months. Ten (37%) patients had no tumor uptake on post treatment scans. 56% and 37% of pts had partial response and stable disease (RECIST criteria), respectively. Median TTP was 13.0 months (90% CI: 10.9 - 16.3 mos), with a median follow-up time for progression of 7.8 months. The HRs for baseline SUV and %ΔSUV were 0.972 (90% CI: 0.901 - 1.048, p=0.534) and 1.018 (90% CI: 1.003 - 1.033, p=0.049), respectively. The median TTP of patients whose post-treatment SUV reached zero was 13.8 months vs. 10.9 months (p=0.17) for pts whose post-treatment SUV did not reach zero. Conclusions: Systemic therapy significantly decreased the SUV on follow up PET scans in pts treated for mCRC. However, no significant association was seen between either baseline SUV or %ΔSUV and TTP. There may be a very weak statistical association of decreasing SUV with decreasing risk of progression. Further work is needed to optimize and standardize evaluation of tumor response in mCRC patients with FDG-PET. No significant financial relationships to disclose.
EGFR gene copy number, KRAS and BRAF status, PTEN and AKT expression analysis in patients with metastatic colon cancer treated with anti-EGFR monoclonal antibodies ± chemotherapy
Authors: Bengala C. , Bettelli S. , Fontana A. , Bertolini F. , Sartori G. , Malavasi N. , Losi L. , Del Giovane C. , Luppi G. , Conte P. 
Published: August 2020

e15055 Background: Cetuximab and panitumumab have proven to be effective in metastatic colon cancer (mCRC). KRAS mutation has been demonstrated to be a biomarker of resistance to both monoclonal antibodies. However the status and expression of other biomarkers of the RAS-RAF-MAPK signalling pathway can have a crucial role in sensitivity to anti-EGFR monoclonal antibodies. Methods: We have retrospectively analyzed tumor tissue biomarkers including EGFR gene copy number (GCN) by FISH, KRAS and BRAF status by PCR-based sequencing, PTEN and AKT expression by IHC in patients with mCRC treated with cetuximab and panitumumab ±chemotherapy. Response to treatment, TTP and OS were evaluated. Results: Sixty-three patients (pts) have been analyzed. Median age was 59 years (34–80); 53 pts had received cetuximab and 10 pts panitunumab. Concomitatnt chemotherapy was FOLFIRI, CPT-11, FOLFOX4 and Xeliri in 35, 13, 6 and 4 pts respectively. Five pts had received monoclonal antibodies only. Twenty- one pts were treated in 1st-2nd line and 42 pts in 3rd-4th line. So far EGFR GCN is available on 55 pts, KRAS and BRAF on 63 pts, PTEN in primary tumor (PT) on 36 pts and in metastatic (MTS) site on 24 pts, AKT on 19 pts. EGFR/nuclei ratio was > 2.9 in 31 % of the pts, KRAS and BRAF were mutated in 36.5 % and 3 % of the pts respectively; PTEN was positive in 42 % and 79 % in PT and MTS respectively. Moreover 21.8 % of the pts had EGFR/nuclei > 2.9 and CEP7 Polisomy > 50 %. Four pts achieved a partial remission (6.3 %). Partial response rate was 17 % vs. 2.6 % in pts with high and low EGFR GCN respectively (p: 0.007) and 13 % vs. 2.5 % in pts with WT and mutated KRAS respectively (p: 0.048). Median TTP was 3 months (0.83–32.9). It was 4.2 vs. 2.3 mos in pts with WT and mutated KRAS respectively (p: 0.001). Median OS was 9.7 mos (2.03–49.0) and no statistically significant differences were observed according to the biomarkers status. However a trend was observed for pts with KRAS WT 10.6 vs. 7.8 mos and for PTEN positive in PT: 9.0 vs. 5.67 mos. Conclusions: Our data confirm the predictive role of EGFR gene copy number and KRAS status on the response and survival. Complete biomarker characterization is ongoing and an analysis for interaction will be performed. No significant financial relationships to disclose.
Involvement of ppGalNAc-T6, a new colon cancer marker, in the molecular basis of simple mucin-type O-glycosylated antigen expression
Authors: Ubillos L. , Berois N. , Mazal D. , Braña V. , Yacoel C. , Masllorens A. , Berriel E. , Rondan M. , Carriquiry L. , Osinaga E. 
Published: August 2020

e15060 Background: Abnormal O-glycosylation is one of the most common changes during colon carcinogenesis, leading to the expression of short truncated O-glycan antigens (such as Tn, sialyl-Tn, Tk, and core 6). These structures which are related with the malignant behavior are actively investigated as immunotherapeutic targets. The ppGalNAc-T family enzymes regulate the initial step of mucin O-glycosylation and could be responsible for the altered glycosylation observed in cancer. The objective of this work was to describe the abnormal expression of ppGalNAc-Ts in colon cancer comparing its relationship with incomplete O- glycosylated antigens. Methods: We studied the gene expression of ppGalNAc-Ts in colon cell lines by RT-PCR assays. Using immunohistochemistry we determined ppGalNAc-T6, Tn, sialyl-Tn, Tk, and core 6 expression in 64 colon cancer samples and in 10 normal colon tissues. Results: We found that ppGalNAc-T6 (an enzyme usually restricted to normal placenta, trachea, brain, and pancreas) is expressed by colon cancer cell lines. Using immunohistochemistry we detected ppGalNAc-T6 in 70.3% of cancer samples with no staining in normal colon tissues. Staining pattern was predominantly cytoplasmatic. Staining of Tn, STn, core 6 and Tk antigens was observed in 87,5%, 79,6%, 76,5% and 68.7% of tumors, respectively. We observed a statistically significant relationship between the enzyme expression and Tn antigen (p=0.009) and core 6 (p=0.001). No relationship was observed between the enzyme expression and sialyl-Tn (p = 0.406) and Tk (p= 0.18) antigens. Conclusions: ppGalNac-T6 is a new tumor marker for colon cancer and its expression is related with the accumulation of two O-glycosylated antigens such as Tn and core 6. This is the first evidence in human tissues suggesting that the abnormal expression of a ppGalNac transferase could be in the molecular basis of aberrant O-glycosylated antigens accumulation in cancer. No significant financial relationships to disclose.