bluuebunny/crossref_metadata_2025_split huggingface dataset:
VEGF, EGF, HGF, and PDGF levels during chemotherapy in patients with metastatic colorectal cancer
Authors: Er O. , Inanc M. , Dikilitas M. , Ozkan M. , Karaca H. , Saraymen R. , Elmali F. 
Published: August 2020

4057 Background: Colon cancer is the third most common type of cancer in USA. Angiogenesis is necessary for the growth and metastasis of tumors in colorectal cancer (CRC). Increased angiogenesis in the primary tumor has been associated with poor prognosis and relapse of the disease. The aim of the present study was to measure plasma levels of the angiogenic factors in metastatic CRC patients before and after chemotherapy and to correlate with prognosis, in order to estimate the possible predictive value of angiogenic factor levels. Methods: Thirty-eight patients with metastatic CRC were recruited to the study and blood samples were taken to measure VEGF, EGF, HGF and PDGF before chemotherapy. All patients received XELOX (Capecitabine+Oxaliplatin) and response was assessed according to their clinical and radiologic evaluation after three cycles of XELOX. Angiogenic factors were measured after third cycle of chemotherapy. Statistical analysis was performed by SPSS 15.0 package program. Kolmogorov-Smirnov, Wilcoxon and 2 sample T test were used. Results: Eighteen patients (47.3%) achieved partial response (PR), 10 (26.3%) stable disease (SD), and 10 (26.3%) progressive disease (PD). VEGF, EGF, HGF and PDGF levels at baseline and after three cycles of chemotherapy are summarized in table . After 3 cycles of XELOX therapy VEGF, EGF, HGF and PDGF levels significantly decreased respectively, (p<0.0001, p=0.011, p=0.049, p<0.0001), in PR group. PDGF levels significantly decreased in SD group (p<0.0001). However, other angiogenic factors were not influenced. Serum HGF levels significantly increased (p<0.046) after 3 cycles of chemotherapy, however, VEGF, EGF, and PDGF levels were not significantly different in patients with PD. Conclusions: Significant decrease in VEGF, EGF, HGF and PDGF levels correlate with PR and indicate good prognosis in patients with advanced CRC. However, increased HGF level is associated with PD. [Table: see text] No significant financial relationships to disclose.
EGFR polymorphism and KRAS mutational status as predictors of resistance to anti-EGFR therapy in advanced colorectal cancer (ACRC): A GEMCAD study
Authors: Maurel J. , Alonso-Espinaco V. , Alonso V. , Escudero P. , Jimeno M. , Garcia-Albeniz X. , Muñoz J. , Fernandez- Martos C. , Carcereny E. , Castellví-Bel S. 
Published: August 2020

4060 Background: Single nucleotide polymorphism (SNP) in codon R497K of EGFR by reducing EGFR activity has been associated to resistance to anti-EGFR monoclonal antibodies in ACRC (Carcereny, ASCO2008). Methods: We retrospectively investigated the role of EGFR R497K and KRAS mutational status in primary CRC or metastases, in predicting response rate (RR), progression free survival (PFS) and overall survival (OS) of cetuximab or panitumumab in second or third line therapy in patients (pts) with ACRC. EGFR R497K was detected by real-time PCR using the TaqMan technology and KRAS mutation status in codons 12/13 was determined by sequencing. CT scans were done every 6–8 weeks (w) until progressive disease. Results: A total of 117 pts with available tissue out of 168 pts treated with anti-EGFR therapy in 6 Spanish Institutions, were analysed for EGFR R497K and KRAS mutational status. There were no differences in RR (18.8 vs.16.8%), PFS (13.2 vs. 12 w) and OS (31 vs. 28 w) between the whole and the selected cohort. We found no significant differences on RR (9/59;15.2 vs. 9/52; 17.3%), PFS (13.5 vs. 13.2 w) and OS (33 vs. 26.8 w) according to EGFR R497K (GG vs. GA/AA). Pts with wild-type (WT) KRAS had better response (20.7% vs. 8.1%;p=0.07) and PFS (14.4 vs. 11.7 w; p=0.006) compared with mutant KRAS. Interestingly, a significant increment on RR (30 vs. 0%, p=0.003), PFS (14.4 vs. 7.4 w, p=0.002) and OS (34.1 vs. 20 w, p=0.03) was observed only in those patients with WT KRAS and >1x upper limit of normal (ULN) lactate dehydrogenase (LDH) levels compared with mutant KRAS, but these differences were not found in pts with WT KRAS and <1xULN levels of LDH: [RR (14 vs. 14%, p=NS), PFS (14.4 vs. 13.1 w, p=NS) and OS (31 vs. 31 w; p=NS)]. Conclusions: EGFR R497K is not a predictive marker of efficacy to EGFR-inhibitors. Our study suggest that pts with WT KRAS and >1xULN levels of LDH, have major benefit to anti-EGFR therapy in second-third line therapy. No significant financial relationships to disclose.
DUSPs as markers of MEK/Erk activation in primary colorectal cancer
Authors: De Roock W. , Janssens M. , Biesmans B. , Jacobs B. , De Schutter J. , Fieuws S. , Van Cutsem E. , Tejpar S. 
Published: August 2020

4064 Background: DUSPs dephosphorylate P-MAPK and are activated as a negative feedback loop upon RTK signaling. Higher expression of DUSP 4 & 6 is also found in cells with constitutive Erk activation like KRAS mutant (MUT) cells (Bild et al. Nature 2005). We correlated DUSP1, 4, 6 (isoforms a & b) & 8 mRNA expression level in FFPE primary colorectal cancer (CRC) of 186 chemorefractory patients treated with cetuximab (CTX) with KRAS MUT state and progression-free survival (PFS) and overall survival (OS). Methods: KRAS codon 12,13, 61&146, BRAF V600E and NRAS codon 12&13 MUT were analyzed with the Sequenom MALDI TOF MassArray system. The DUSPs and 3 housekeeping genes were quantified by qRT-PCR. TwoStep cluster analysis was performed. PFS and OS were estimated by the Kaplan-Meier method. Results: KRAS MUT was associated with increased DUSP4 (MWU;p=.0006) & 6a (p=.0067). DUSP6a dephosphorylates P-Erk, DUSP4 also dephosphorylates P-JNK & P-p38. DUSP1 & 8 primarily dephosphorylate P-JNK & P-p38 and were not associated with KRAS MUT. KRAS MUT clustered into 3 groups according to DUSP4 expression: 32 high, 38 median & 13 low (t- test;p<.0001). The low MUT expression was comparable to wild-type (WT) expression. KRAS WT clustered into 2 groups: 69 low & 24 high DUSP4 (ANOVA;p<.0001). 7/24 of high expressors were found to have a BRAF or NRAS MUT. The 32 MUT high expressors had a longer median PFS (log-rank;p=.015) and OS (p=.065) after CTX. The 17 KRAS/BRAF/NRAS WT high expressors had a shorter median OS (p=.026), but not PFS (p=.745). Conclusions: There is a significantly higher DUSP4 & 6a mRNA expression in the KRAS MUT compared to WT primary CRC. However, this is not a black and white observation. In the KRAS MUT there are 3 distinct clusters of DUSP4 expression. The high expressors (= supposed attenuated Erk signaling) have a longer PFS and OS after CTX. Adaptation to constitutive KRAS signaling with differential levels of MEK/Erk activation needs to be further investigated and will be of help in selecting patients for therapy with MEK inhibitors. It suggests not all KRAS MUT will be good candidates for MEK inhibitors. In the cluster of high DUSP4 expressing KRAS WT 30% are BRAF or NRAS MUT. This suggests DUSP expression of FFPE samples could be a more sensitive marker of MEK/Erk activation and resistance to EGFR inhibitors than KRAS MUT analysis alone. [Table: see text]
Prospective pharmacogenetic analysis in advanced colorectal cancer (CRC) patients receiving first-line cetuximab-UFT-irinotecan therapy: Importance of gene polymorphisms related to antibody-dependent cellular cytotoxicity (ADCC)
Authors: Etienne-Grimaldi M. , Bennouna J. , Formento J. , Douillard J. , Francoual M. , François E. , Faroux R. , El Hannani C. , Jacob J. , Milano G. 
Published: August 2020

4069 Background: Our purpose was to test the predictive value of germinal gene polymorphisms potentially linked to cetuximab, fluoropyrimidine and irinotecan pharmacodynamics on toxicity, clinical response, time to progression (TTP) and overall survival (OS). Methods: 52 patients with advanced CRC were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial (33 men, 19 women, mean age 63, range 36–84, PS 0–1). Treatment consisted in cetuximab (day 1-day 8-day 15, 250 mg/m2/week following a 400 mg/m2 loading dose) associated with irinotecan (day 1, 250 mg/m2) and UFT-folinic acid (day 1 to day 14, 250 mg/m2/day UFT, 90 mg/day folinic acid). Median number of administered cycles was 7 (range 1–8). The following gene polymorphisms were analyzed on blood genomic DNA: EGFR (CA repeats in intron 1, - 216G>T, -191C>A), EGF (61A>G), FCGR2A (131Arg>His), FCGR3A (158Phe>Val), UGT1A1 (TA repeats), TYMS (28 bp repeats including the G>C mutation on the 3R allele, 6 bp deletion in 3’ UTR), MTHFR (677C>T, 1298A>C). Results: Grade 3–4 toxicity was recorded in 59.6 % of patients. The toxicity score (sum of maximum grade for each toxicity pattern) was significantly linked to the FCGR2A genotype (median score 9, 9.5 and 13 in Arg/Arg, Arg/His and His/His patients, respectively, p = 0.035) and to the EGFR -191 genotype (median score 11 in CC patients versus 8.5 in CA patients, p = 0.040). Response rate was 49% (3 CR and 21 PR over 49 assessable patients) and was significantly higher in patients bearing the FCGR3A Val allele (62.1 % in Val/Val or Val/Phe versus 26.3 % in Phe/Phe, p = 0.020) or the TYMS 3RG allele (65.0 % versus 28.6 % in patients with no 3RG allele, p = 0.029). Gene polymorphisms did not influence TTP. A multivariate Cox analysis including gene polymorphisms and PS showed that overall survival was improved in patients bearing the FCGR3A Val allele (relative risk of death was 2.25 in Phe/Phe patients relative to Val-containing genotypes, 95% CI 1.03–4.91, p = 0.041). Conclusions: Present data suggest the importance of ADCC in cetuximab pharmacodynamics, as outlined by the role of FCGR gene polymorphisms on toxicity, responsiveness and survival. No significant financial relationships to disclose.
Safety and efficacy of AMG 655 plus modified FOLFOX6 (mFOLFOX6) and bevacizumab (B) for the first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Saltz L. , Infante J. , Schwartzberg L. , Stephenson J. , Rocha-Lima C. , Galimi F. , Dillingham K. , Hsu M. , Wiezorek J. , Fuchs C. 
Published: August 2020

4079 Background: AMG 655 is an investigational fully human monoclonal antibody (IgG1) agonist of human death receptor 5 (DR5). AMG 655 activates caspases and induces apoptosis in sensitive tumor cells. The primary objective of this phase 1b study was to determine the maximum tolerated dose (up to a target dose of 10 mg/kg IV every 2 weeks) of AMG 655 that can be safely administered in combination with mFOLFOX6-B to mCRC pts. Methods: Eligible pts were ≥ 18 years old with previously untreated mCRC, ECOG PS of 0 or 1, and adequate hematologic, hepatic, and renal function. Pts were enrolled into sequential cohorts of 3- or 10-mg/kg AMG 655 + mFOLFOX6-B administered on day 1 of each 14-day cycle. Study endpoints included incidence of dose-limiting toxicities (DLT), adverse events (AE), pharmacokinetic (PK) parameters of AMG 655, and objective response rate (by modified RECIST). Results: As of 09/08, 12 pts (6 per cohort) were enrolled and received ≥ 1 cycle of treatment; 8 were female. Median (range) age was 54 (37–75), median (range) time on AMG 655 treatment was 6.9 (1.6 to 11.4+) months; 8 pts continue on study treatment. There were no DLTs in the first 28 days of treatment. Eight pts had grade 3–4 AE; the most common were diarrhea, febrile neutropenia, peripheral neuropathy, neutropenia, DVT, and pulmonary embolism (2 pts each). Post baseline laboratory parameters grade ≥ 3: no ALT and AST; 1 grade 3 bilirubin (due to disease progression), and 3 grade 3 lipase (asymptomatic). No anti-AMG 655 antibodies were detected. AMG 655 PK values (Cmax, Cmin) were similar to those observed with single-agent AMG 655 (LoRusso JCO 2007; 25: abstract 3534). AMG 655 did not appear to affect PK of oxaliplatin or bevacizumab. Best overall tumor response: 5 partial responses (2 unconfirmed, both underwent resection); 6 stable disease; 1 pt had non-measurable disease at baseline. Time to disease progression (3 patients): 8, 42, and 44 weeks. Conclusions: The addition of AMG 655 does not appear to substantially alter the safety profile of mFOLFOX6-B. The randomized phase 2 part of the trial (mFOLFOX6-B ± AMG 655) is in progress. [Table: see text]
Phase II efficacy results using an oncolytic herpes simplex virus (NV1020) in patients with colorectal cancer metastatic to liver (mCRC)
Authors: Geevarghese S. K. , Chen A. , Geller D. A. , de Haan H. A. , Iagaru A. , Knoll A. , Nemunaitis J. , Reid T. R. , Sze D. Y. , Tanabe K. 
Published: August 2020

4089 Background: NV1020 is a genetically engineered oncolytic Herpes virus. Published Phase 1 dose-ranging results reported no significant related toxicity except for a mild (<24 hr) viral syndrome. Initial Phase 2 tumor response data using the optimal biological dose (OBD) are now presented. Methods: Patients with heavily pretreated, progressing liver mCRC received 4 doses of NV1020 (1 X108 pfu) by weekly hepatic artery infusion followed by two cycles of conventional chemotherapy. Follow-up (≥1 year) evaluation included 4 X 3-monthly scans, then telephone contact to determine survival. Blinded, independent radiologists interpreted CT (modified RECIST) and FDG PET (EORTC) scans. Results: All 22 patients had prior 5FU-based treatment: 77% and 58% also had oxaliplatin or irinotecan, respectively (50% both agents); 86% had one targeted therapy (24% ≥2 such agents); 29% had radiofrequency ablation. Mean time from primary resection was 95 weeks, mean CEA was 182 ng/mL, and 55% had pulmonary lesions. Two patients received only 2 NV1020 infusions due to rapidly progressing disease. Virus tolerability was unchanged from Phase 1 and no related, serious or Grade 4 toxicity was found. NV1020 neutralizing antibodies rose in all patients but no NV1020 was shed (saliva, skin). After NV1020 alone, 10/22 (45%) and 8/20 (40%) on CT and PET, respectively, showed stable disease. 21 patients subsequently received chemotherapy, 45% with drugs to which they were previously refractory and 36% with only one new drug. 14% refused both planned cycles. Best response observed with CT was 55% (1 CR, 1 PR, 10 SD) and 59% (5 PR, 8 SD) with PET. Despite intrahepatic delivery, some remote responses were observed. Response did not correlate with initial tumor size, SUV, or CEA, with time since primary resection, pre- or post NV1020 chemotherapy type. Nine (41%) remain alive > 1 year. Kaplan-Meier median time to progression is 28 weeks (95% CI [9–37]); median survival probability is 52 weeks (95% CI [36–90]). Conclusions: NV1020 stabilizes liver metastases in highly advanced mCRC and may sensitize tumors to salvage chemotherapy resulting in extended overall survival. A controlled Phase 2/3 trial is justified. [Table: see text]
Preoperative hepatic and regional arterial chemotherapy in the prevention of liver metastasis after colorectal cancer surgery
Authors: Xu J. , Zhong Y. , Niu W. , Qin X. , Wei Y. , Ren L. , Wang J. , Chen J. , Qian S. 
Published: August 2020

4090 Background: To investigate whether preoperative hepatic and regional arterial chemotherapy are able to prevent liver metastasis and improve overall survival in patients receiving curative colorectal cancer resection. Methods: Patients with Stage II or Stage III colorectal cancer (CRC) were randomly assigned to receive preoperative hepatic and regional arterial chemotherapy (PHRAC group, n=256) or surgery alone (control group, n=253). The primary endpoint was disease-free survival, whereas the secondary endpoints included liver metastasis-free survival and overall survival. Results: There were no significant differences in overall morbidity between PHRAC and Control groups. During the follow-up period (median, 42 months), the median liver metastasis time for patients with stage III CRC was significantly longer in the PHRAC group (16±3 months v.s. 8±1 months, P=0.01). In stage III patients, there was also significant difference between the two groups with regard to the incidence of liver metastasis (18.9% vs 27.3%, P=0.01), 5-year disease-free survival (70.2% vs 52.0%, P=0.0076), 5-year overall survival (80.3% vs 69.5%, P=0.020) and the median survival time (40.1± 4.6 months vs 36.3 ± 3.2 months, P=0.03). In the PHRAC arm, the risk ratio of recurrence was 0.63 (95% CI, 0.51–0.79, P=0.0001), of death was 0.50(95% CI, 0.32–0.67; P=0.005), and of liver metastasis was 0.70 (95% CI, 0.52–0.86; p=0.01). In contrast, PHRAC seemed to be no benefit for stage II patients. Toxicities, such as hepatic toxicity and leucocyte decreasing, were mild and could be cured with medicine. Conclusions: Preoperative hepatic and regional arterial chemotherapy, in combination with surgical resection, could be able to reduce and delay the occurrence of liver metastasis and therefore improve survival rate in patients with stage III colorectal cancer. No significant financial relationships to disclose.
A phase I/II study of bevacizumab (beva), erlotinib (erl), and 5-fluorouracil (5-FU) with concurrent external beam radiation therapy (RT) in locally advanced rectal cancer (LARC)
Authors: Blaszkowsky L. S. , Hong T. S. , Zhu A. X. , Kwak E. L. , Mamon H. J. , Shellito P. C. , Cusack J. C. , Berger D. , Horgan K. , Ryan D. P. 
Published: August 2020

4106 Background: The German Rectal Cancer Study Group established neoadjuvant therapy as a standard of care in patients with T3/T4 rectal cancer. Beva, a vascular endothelial growth factor (VEGF) inhibitor with demonstrated activity in colorectal cancer, and erl, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor may both serve as radiation sensitizers. Methods: Twenty one pts with LARC, defined as T3 or T4 disease by MRI or endorectal ultrasound, were enrolled from May 2006-December 2008. Pts had adequate hepatic, renal and hematopoietic function, and an ECOG performance status of ≤2. Treatment consisted of 5-FU 225 mg/M2/day by continuous infusion for the duration of radiation (50.4 Gy). Beva 5 mg/kg was administered on days 1, 15 and 29. The first cohort received erl 50 mg, the second cohort 100 mg, and third cohort 150 mg daily until completion of radiation. Pts underwent surgery 6–9 weeks following the radiation. The primary endpoints were determination of the maximally tolerated dose (MTD) and pathologic complete response (pCR). Secondary endpoints included toxicity (TOX), local control (LC), progression free survival and median survival. A total of 25 pts will be treated at the MTD. Results: Twenty-one pts began study therapy: 2 withdrew consent prior to completing study therapy, and 2 pts were removed prior to completion for clostridium difficile colitis and cardiac ischemia. No dose limiting toxicities were achieved. Erl 100 mg was chosen as the MTD. Two pts have not yet completed study treatment. Fifteen pts have completed study therapy and have undergone surgery, of whom 7 (47%) have demonstrated a pCR. At a median follow-up of 7 months, there have been no local recurrences in patients who completed study therapy. Grade 3–4 treatment related TOX included: lymphopenia 6 (59%), diarrhea 4 (24%), rash 2(12%), cardiac ischemia 1(6%), transaminitis 1(6%), mucositis 1(6%). One pt developed an anastomotic leak. Conclusions: Beva and erl in combination with infusional 5-FU and RT appears to be a highly active preoperative regimen for locally advanced rectal cancer. [Table: see text]
Neutropenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOX
Authors: Shitara K. , Matsuo K. , Takahari D. , Yokota T. , Ura T. , Muro K. 
Published: August 2020

4115 Background: FOLFOX combined with bevacizumab is established as standard first-line chemotherapy for metastatic colorectal cancer (MCRC), and neutropenia is one of the most common of its side effects. Neutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several type of cancers, although there are no reports in MCRC. We aimed to assess whether neutropenia during chemotherapy could be a marker of improved survival of patients with MCRC. Methods: Patients with MCRC who received FOLFOX with or without bevacizumab as first-line chemotherapy were retrospectively analyzed to assess whether neutropenia during chemotherapy is associated with improved survival. Several background characteristics and chemotherapy features (grade of neutropenia, use of bevacizumab, use of irinotecan, reintroduction of oxaliplatin, and tumor progression) as time-varying covariates (TVCs) were analyzed as potential prognostic factors. Results: Of 153 patients, mild neutropenia (grade 1–2) occurred in 60 patients (39%) and severe neutropenia (grade 3–4) occurred in 46 patients (30%). The other 47 patients (31%) did not experience neutropenia. In 106 patients experiencing neutropenia, 66% of patients experienced their highest grade within 4 cycles. According to a multivariate Cox model with TVCs, hazard ratios of death were 0.55 (95% CI, 0.31–0.98; P = 0.044) for patients with mild neutropenia and 0.35 (95% CI, 0.18–0.66; P = 0.002) for those with severe neutropenia. If the analysis of neutropenia was limited to 4 cycles of FOLFOX, mild or severe neutropenia remained a significant prognostic factor according to survival analysis with TVCs. Conclusions: Both mild and severe neutropenia during chemotherapy are associated with improved survival in patients with MCRC. Prospective trials are required to assess whether dosing adjustments based on neutropenia may improve chemotherapy efficacy. No significant financial relationships to disclose.
Metastatic colorectal cancer (mCRC): Recent patterns of chemotherapy and monoclonal antibody (MoAb) therapy in clinical practice
Authors: Hess G. P. , Wang P. F. , Quach D. , Barber B. 
Published: August 2020

4120 Background: New systemic chemotherapies, particularly the MoAbs, bevacizumab (BMab), cetuximab (CMab), and panitumumab (PMab) have advanced therapy for mCRC. However, the optimal combination and sequencing of these and other chemotherapies are not established, and little is known about their patterns of use in clinical practice. We examined the frequency, patterns of use, and dosing changes of MoAbs across lines of therapy. Methods: The dataset consists of Varian and Impac electronic medical records for 304,654 cancer patients from 91 practice sites across 19 states. Inclusion/exclusion criteria were applied: ≥18 years old, newly diagnosed with mCRC or developed metastases during 1/1/2004 - 1/31/2008, and could be observed ≥3 months beyond their dates of metastases. Patients on a clinical trial at any time during the analysis were excluded. Results: The study sample included 1,655 patients (52% male, mean age 61.9 years). 11% received all five therapeutic classes: fluoropyrimidines, irinotecan, oxaliplatin, EGFR MoAbs (PMab and CMab), and VEGF MoAb (BMab). 19% received at least 3 treatment classes. BMab, fluorouracil, leucovorin, oxaliplatin (BMab+FOLFOX) was the most frequently observed 1st line regimen in 26% of patients. Across the study period more patients received BMab than PMab or CMab (69%, 7%, and 22%, respectively, for any exposure); 55% received BMab for 1st-line therapy. A BMab dose increase within a line of therapy was recorded in 22% of patients for 1st-line, 21% for 2nd-line, and 15% for 3rd-line. Among patients who continued BMab from 1st to 2nd line (N=239) and 2nd to 3rd line (N=88), 44% and 39%, respectively had a dose increase (mean/month 890mg to 1078mg, and 844mg to 1053mg). Conclusions: The most frequent 1st-line chemo regimen was FOLFOX. BMab was the most commonly administrated MoAb. Trends toward dose-escalation of BMab were observed both within lines of therapy and across lines of therapy. [Table: see text]