Association of TLR9 polymorphism with overall survival in metastatic colorectal cancer patients treated with FOLFIRI plus bevacizumab enrolled in FIRE3.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 498-498 ◽  
Author(s):  
Satoshi Okazaki ◽  
Sebastian Stintzing ◽  
Volker Heinemann ◽  
Shu Cao ◽  
Wu Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Clinical Outcome ◽  
Metastatic Colorectal Cancer ◽  
Direct Sequencing ◽  
Statistical Significance ◽  
Nucleotide Polymorphisms ◽  
Mutant Type ◽  
Tlr9 Gene

498 Background: Toll-like receptors (TLRs) play crucial roles in carcinogenesis and evolution of the tumor microenvironment. TLR9 dependent stimulation is known to cause antitumor activity not only by activating anti-tumor immunity but also by interfering with angiogenesis. We tested the hypothesis that genetic variations in TLR9 will be associated with clinical outcome in metastatic colorectal cancer (mCRC) patients treated with bevacizumab based chemotherapy. Methods: Genomic DNA was isolated from tissue samples from 301 mCRC patients enrolled in the FIRE3 trial and treated in first-line with FOLFIRI plus bevacizumab. Three single nucleotide polymorphisms (SNPs) in the TLR9 gene, rs187084 A/G, rs352140 C/T, and rs5743836 T/C, were analyzed by PCR-based direct sequencing. These SNPs were tested for the association with tumor response, progression free survival (PFS), and overall survival (OS). Subgroup analyses by gender, tumor location, and Kras status were also analyzed. Results: The patients carrying variant genotype (T/C or C/C) for rs5743836 showed a strong trend toward shorter OS compared to those with a wild-type T/T genotype (median: 21.2 vs. 24.8 months, HR: 1.35, P = 0.069). This difference remained statistically significant in the multivariate analysis (HR: 1.53, 95%CI: 1.09-2.15, P = 0.014). In the subgroup of Kras-mutant type, the variants (T/C and C/C) were significantly associated with worse PFS (8.1 vs. 11.3 months, HR 2.06, p = 0.043) and OS (16.4 vs. 25.1 months, HR: 2.44, p = 0.012), which retained statistical significance in the multivariate analysis. No association with clinical outcome was observed for rs187084 and rs352140. Conclusions: Our findings suggest that TLR9 polymorphism of rs5743836 is a prognostic marker of mCRC patients, especially of those with Kras-mutant type, who were treated with FOLFIRI plus bevacizumab.

Predictive value of VEGF gene polymorphisms in metastatic colorectal cancer patients treated with a bevacizumab-based chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14512-e14512
Author(s):  
Paola Ulivi ◽  
Giorgia Marisi ◽  
Emanuela Scarpi ◽  
Alessandro Passardi ◽  
Angela Ragazzini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Direct Sequencing ◽  
Statistical Significance ◽  
Objective Response ◽  
Case Series ◽  
Predictive Marker ◽  
Treated Group ◽  
Phase Iii ◽  
Nucleotide Polymorphisms

e14512 Background: Bevacizumab (B) + chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of B efficacy have still not been identified. In this study we verified the role of specific VEGF polymorphisms as predictive markers of the efficacy of B in mCRC patients. Methods: One hundred and forty-nine patients enrolled onto the phase III prospective multicentric randomized “Italian Trial in Advanced Colorectal Cancer (ITACa)” trial were considered for this study. Seventy-four patients received FOLFIRI or FOLFOX plus B and 75 patients received only CT. A peripheral blood sample was collected from each patients and submitted to genomic DNA extraction. Five single nucleotide polymorphisms (SNPs) were analyzed by direct sequencing: VEGF -2578 C/A, -1498 C/T, -1154 G/A, -634 G/C, +936 C/T. All candidate genotypes were evaluated for a potential correlation with objective response rate (ORR) (Chi-square test). Results: In the B-treated group, the presence of VEGF -2578 AA, -634 GG or -1498 CC polymorphisms was associated with a better ORR compared to the other genotypes. In particular, of the 17 patients carrying the VEGF -2578 AA genotype, 14 (82.4%) showed a response, whereas only 30 (54.6%) of the 55 patients carrying -2578 CC or CA responded to therapy (p=0.05). Similarly, of 30 patients with VEGF -634 GG, 23 (76.7%) responded to therapy, whereas only 21 (50%) of the 42 patients with VEGF -634 GC or CC were responders (p=0.03). Moreover, 13 (81.3%) of the 16 patients carrying VEGF -1498 CC were responders, whereas of the 56 patients with VEGF -1498 CT or TT, only 31 (55.4%) showed a response (p=0.07). No differences in terms of ORR were observed in patients receiving only chemotherapy. However, as a result of the low power of the interaction test, the relation between ORR and treatment was very close to statistical significance for VEGF -2578 only (p=0.07). Conclusions: VEGF -2578 C/A seems to be a potential predictive marker for B-based CT in mCRC patients. Further studies on larger case series are now needed to confirm this finding.

Polymorphism of the chemokine CXCR4 to predict treatment benefit of first-line bevacizumab-based chemotherapy in patients with metastatic colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 635-635
Author(s):  
Satoshi Matsusaka ◽  
Fotios Loupakis ◽  
Wu Zhang ◽  
Shu Cao ◽  
Dongyun Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Metastatic Colorectal Cancer ◽  
Tumor Cells ◽  
Direct Sequencing ◽  
Univariate Analysis ◽  
Candidate Snps ◽  
First Line ◽  
Significant Difference

635 Background: The chemokine receptor CXCR4 and its ligand CXCL12 promote angiogenesis and the migration of tumor cells into the metastatic sites in many cancers. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor. Therefore, we analyzed the association between CXCR4/CXCL12 polymorphisms and prognosis in metastatic colorectal cancer (mCRC) patients underwent bevacizumab-based chemotherapy. Methods: This study included 144 Japanese patients (pts) for evaluation set and 424 patients from two clinical trials (204 of TRIBE arm A and 220 of PROVETTA) for validation set, with mCRC treated with bevacizumab-based chemotherapy as first line. A total of 144 Japanese pts with (male/female; 81/63, median age 61 years, median follow-up 4.2 years) and 424 pts (male/female; 252/172, median age 62 years; median follow-up time; 2.8 years) were enrolled in a pharmacogenomics translational study. Genomic DNA was extracted from the pts’ blood or tissue. One CXCR4 single nucleotide polymorphisms (SNP) (rs2228014) and two CXCL12 SNPs (rs1801157, rs3740085) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with the clinical outcome. Results: In univariate analysis, CXCR4 rs2228014 showed a significant difference in PFS [(G/G 15.3 months, any A allele 13.7 months, HR (95% CI) 1.64 (1.01-2.68), p=0.036)]. After multivariate analysis, CXCR4 rs2228014 remained to be a significant for PFS [HR (95% CI) 1.67 (1.01-2.78), p =0.046]. However, this polymorphism was not associated with tumor response and survival. In the validation cohort, pts with GG genotype had significantly longer PFS compared to those with any A allele (10.5 vs 9.6 months, HR (95% CI) 1.40 (1.02-1.93), p =0.035). CXCL12 polymorphisms were not associated with the clinical outcome. Conclusions: This study shows for the first time that CXCR4 rs2228014 may serve as a predictive marker in patients with mCRC treated with bevacizumab-based chemotherapy.

Gene polymorphisms of CCL3, CCL4, CCL5, and CCR5 network in metastatic colorectal cancer patients treated with regorafenib.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 199-199
Author(s):  
Mitsukuni Suenaga ◽  
Wu Zhang ◽  
Tetsuo Mashima ◽  
Marta Schirripa ◽  
Shu Cao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Gene Polymorphisms ◽  
Direct Sequencing ◽  
Rank Test ◽  
Alternative Mechanism ◽  
Nucleotide Polymorphisms ◽  
Positive Correlation ◽  
Colorectal Cancer Patients

199 Background: We previously reported that genetic variant in the CCL5/CCR5 pathway predict efficacy of regorafenib in metastatic colorectal cancer patients (mCRC). CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with longer overall survival (OS) and severe skin toxicity due to low VEGF-A production via endothelial progenitor cell (EPC). CCL4 rs1634517 G allele and CCL3 rs1130371 C allele correlated with longer Progression-free survival (PFS) and OS. We investigated the biological role of CCL4 and CCL3 gene polymorphisms. Methods: We analyzed genomic DNA extracted from 79 samples of a Japanese cohort receiving regorafenib. Single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Blood samples were obtained from 57 patients at baseline (BL), day 21 and progressive disease (PD), and serum CCR5, CCR5 ligands (CCL3, CCL4, CCL5) and VEGF-A levels were measured using ELISA. PFS and OS were analyzed using Kaplan-Meier curves and log-rank test. Results: Increased CCL3 levels at PD were associated with longer OS than decreased (12.6 vs 4.8 mos, P = 0.003). Patients with decreased CCL4 levels at day 21 had a trend toward longer PFS and tumor shrinkage. Positive correlation was observed between CCL3 and CCR5 throughout the treatment independent of other ligands (change at day 21: r = 0.426, P = 0.009). There was no significant correlation of CCL3 and CCL4 levels with VEGF-A levels. Patients with the G/G variant in CCL3 rs1130371 had increased CCL3, CCR5 and CCL5 levels at day 21 than any A allele. Similarly, patients with the C/C variant had increased CCL3, CCR5 and CCL5 levels at day 21 compared with those with any A allele. In contrast, both CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with increased CCL3 levels and decreased CCL4 levels at day 21 (P = 0.006, P = 0.043; P = 0.006, P = 0.043). Conclusions: Positive correlation of CCL3, CCR5 and CCL5 impact similarly on CCL3 and CCL4 SNPs, while different manner between CCL3 and CCL4 was found in CCL5 SNPs. This suggests an alternative mechanism of action in the network of CCR5 and the ligands except CCL5-VEGF-A signaling via EPC in mCRC patients receiving regorafenib.

scholarly journals KRAS Mutant Allele-Specific Imbalance (MASI) assessment in routine samples of patients with metastatic colorectal cancer

2015 ◽  
Vol 68 (4) ◽  
pp. 265-269 ◽  
Author(s):  
Umberto Malapelle ◽  
Roberta Sgariglia ◽  
Alfonso De Stefano ◽  
Claudio Bellevicine ◽  
Elena Vigliar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Spatial Distribution ◽  
Tissue Distribution ◽  
Mutant Allele ◽  
Direct Sequencing ◽  
Statistical Significance ◽  
Wild Type ◽  
Exon 2 ◽  
Allele Specific

AimsPatients with colorectal cancer harbouring KRAS mutations do not respond to antiepidermal growth factor receptor (anti-EGFR) therapy. Community screening for KRAS mutation selects patients for treatment. When a KRAS mutation is identified by direct sequencing, mutant and wild type alleles are seen on the sequencing electropherograms. KRAS mutant allele-specific imbalance (MASI) occurs when the mutant allele peak is higher than the wild type one. The aims of this study were to verify the rate and tissue distribution of KRAS MASI as well as its clinical relevance.MethodsA total of 437 sequencing electropherograms showing KRAS exon 2 mutation was reviewed and in 30 cases next generation sequencing (NGS) was also carried out. Five primary tumours were extensively laser capture microdissected to investigated KRAS MASI tissue spatial distribution. KRAS MASI influence on the overall survival was evaluated in 58 patients. In vitro response to anti-EGFR therapy in relation to different G13D KRAS MASI status was also evaluated.ResultsOn the overall, KRAS MASI occurred in 58/436 cases (12.8%), being more frequently associated with G13D mutation (p=0.05) and having a heterogeneous tissue distribution. KRAS MASI detection by Sanger Sequencing and NGS showed 94% (28/30) concordance. The longer overall survival of KRAS MASI negative patients did not reach statistical significance (p=0.08). In cell line model G13D KRAS MASI conferred resistance to cetuximab treatment.ConclusionsKRAS MASI is a significant event in colorectal cancer, specifically associated with G13D mutation, and featuring a heterogeneous spatial distribution, that may have a role to predict the response to EGFR inhibitors. The foreseen implementation of NGS in community KRAS testing may help to define KRAS MASI prognostic and predictive significance.

scholarly journals Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms

2020 ◽  
Author(s):  
Xunwei Deng ◽  
Jingyuan Hou ◽  
Qiaoting Deng ◽  
Zhixiong Zhong
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Direct Sequencing ◽  
Dihydropyrimidine Dehydrogenase ◽  
Severe Toxicity ◽  
Nucleotide Polymorphisms ◽  
Mutant Type ◽  
Severe Vomiting ◽  
Significant Difference ◽  
The Impact

Abstract Background: Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to Chemotherapy-related adverse events. In the present study, we purposed to assess the impact of DPYD and GSTP1 variants on the toxicity of adjuvant chemotherapy risk among the Hakka population, minimize adverse events, and to maximize therapy outcome for individualized treatment.Methods: Genotyping was examined in 104 patients diagnosed with CRC cases and receiving fluoropyrimidine and platinum drugs based chemotherapy regimen by direct sequencing of DPYD and GSTP1 polymorphisms. Three DPYD variants including *2A, *5A, *9A, and GSTP1 c.313A>G were analyzed and clinical outcomes were assessed.Results: The data suggest that the incidence of DPYD*5A, DPYD*9A, and GSTP1 c.313A>G variants were 38.4%, 24%, and 32.7%, respectively. DPYD*2A variant was not found. A total of 23 patients (22.1%) suffered severe vomiting and 19 patients (18.3%) suffered severe anemia. DPYD*5A polymorphism was found significantly associated with grade 3/4 ulceration (p = 0.001). GSTP1 was determined to be an independent risk factor for severe vomiting and skin ulceration (p = 0.042 and p = 0.018, respectively). Patients with GSTP1 c. 313A>G mutant type contributed to a higher risk for grade severe toxicity compared with wild genotype (p = 0.027). Nevertheless, no significant difference was found between patients with DPYD*2A, *5A, *9A for chemotherapeutic toxicity.Conclusions: The results demonstrated that GSTP1 polymorphisms were useful predictors of severe events. Screening of single nucleotide polymorphisms of GSTP1 in colorectal cancer patients before chemotherapy may help to realize personalized therapy.

scholarly journals VEGF-A and ICAM-1 Gene Polymorphisms as Predictors of Clinical Outcome to First-Line Bevacizumab-Based Treatment in Metastatic Colorectal Cancer

2019 ◽  
Vol 20 (22) ◽  
pp. 5791 ◽  
Author(s):  
Apostolos Papachristos ◽  
Polychronis Kemos ◽  
Theodora Katsila ◽  
Eirini Panoilia ◽  
George P. Patrinos ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Metastatic Colorectal Cancer ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Progression Free Survival ◽  
Nucleotide Polymorphisms ◽  
First Line ◽  
Intracellular Signaling Pathways

Bevacizumab is used to treat metastatic colorectal cancer (mCRC). However, there are still no available predictors of clinical outcomes. We investigated selected single nucleotide polymorphisms (SNPs) in the genes involved in VEGF-dependent and -independent angiogenesis pathways and other major intracellular signaling pathways involved in the pathogenesis of mCRC as an attempt to find predictors of clinical outcome. Forty-six patients treated with first-line bevacizumab-based chemotherapy were included in this study with a 5 year follow up. Genomic DNA was isolated from whole blood for the analysis of VEGF-A (rs2010963, 1570360, rs699947), ICAM-1 (rs5498, rs1799969) SNPs and from tumor tissue for the detection of genomic variants in KRAS, NRAS, BRAF genes. PCR and next generation sequencing were used for the analysis. The endpoints of the study were progression-free survival (PFS) and overall survival (OS). The VEGF-A rs699947 A/A allele was associated with increased PFS (p = 0.006) and OS (p = 0.043). The ICAM-1 rs1799969 G/A allele was associated with prolonged OS (p = 0.036). Finally, BRAF wild type was associated with increased OS (p = 0.027). We identified VEGF-A and ICAM-1 variants in angiogenesis and other major intracellular signaling pathways, such as BRAF, that can predict clinical outcome upon bevacizumab administration. These identified biomarkers could be used to select patients with mCRC who may achieve long-term responses and benefit from bevacizumab-based therapies.

scholarly journals Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5715
Author(s):  
Davide Ciardiello ◽  
Vincenzo Famiglietti ◽  
Stefania Napolitano ◽  
Lucia Esposito ◽  
Nicola Normanno ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Multivariate Analysis ◽  
Metastatic Colorectal Cancer ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Circulating Tumor Dna ◽  
Wild Type ◽  
Line Of Therapy

The single-arm phase II CAVE mCRC trial evaluated the combination of cetuximab plus avelumab as rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients, with clinical response to first-line anti-EGFR-based chemotherapy, who progressed and received a subsequent line of therapy. The correlation of skin toxicity (ST) and different clinico-molecular variables with overall survival (OS), progression-free survival (PFS) and response rate (RR) was assessed at univariate and multivariate analysis. A total of 33/77 (42.9%) patients experienced grade 2–3 ST and displayed median OS (mOS) of 17.8 months (CI 95%, 14.9–20.6); whereas 44/77 (57.1%) patients with grade 0–1 ST exhibited mOS of 8.2 months (CI 95%, 5.5–10.9), (hazard ratio (HR), 0.51; CI 95%, 0.29–0.89; p = 0.019). Median PFS (mPFS) was 4.6 months (CI 95%, 3.4–5.7) in patients with grade 2–3 ST, compared to patients with grade 0–1 ST with mPFS of 3.4 months (CI 95%, 2.7–4.1; HR, 0.49; CI 95%, 0.3–0.8; p = 0.004). Grade 2–3 ST (HR, 0.51; CI 95%, 0.29–0.89; p = 0.019) and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA) (HR, 0.50; CI 95%, 0.27–0.9; p = 0.019) had a statistically significant effect on OS at univariate analysis. At the multivariate analysis, RAS/BRAF/EGFR WT ctDNA status maintained statistical significance (HR, 0.49; CI 95%, 0.27–0.9; p = 0.023), whereas there was a trend towards ST grade 2–3 (HR, 0.54; CI 95%, 0.29–1.01; p = 0.054). Skin toxicity is a promising biomarker to identify patients with mCRC that could benefit of anti-EGFR rechallenge.

Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study

2008 ◽  
Vol 26 (12) ◽  
pp. 2013-2019 ◽  
Author(s):  
Leonard B. Saltz ◽  
Stephen Clarke ◽  
Eduardo Díaz-Rubio ◽  
Werner Scheithauer ◽  
Arie Figer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Placebo Group ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Statistical Significance ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Free Survival

PurposeTo evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC).Patients and MethodsPatients with MCRC were randomly assigned, in a 2 × 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS).ResultsA total of 1,401 patients were randomly assigned in this 2 × 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials.ConclusionThe addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.

NOTCH1 as a potential prognostic biomarker for anti-VEGF therapy in patients with metastatic colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11038-11038
Author(s):  
Tadeu Ferreira Paiva ◽  
Alexandre Andre Balieiro Anastacio da Costa ◽  
Flavio Augusto Ismael Pinto ◽  
Victor Hugo Fonseca Jesus ◽  
Raul A. Marques ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Lymph Node ◽  
Liver Metastasis ◽  
Lymph Node Metastasis ◽  
Metastatic Colorectal Cancer ◽  
Response Rate ◽  
High Expression ◽  
Node Metastasis

11038 Background: There are no validated biomarkers for clinical response or survival benefit in patients treated with bevacizumab (Bv) in advanced metastatic colorectal cancer (mCRC). The aim of this study was to evaluate the predictive value of putative biomarkers in mCRC. Methods: One hundred and five mCRC patients who received Bv combined with FOLFOX or FOLFIRI were retrospectively evaluated for clinical and pathological characteristics. VEGFR1, VEGFR2, VEGFR3, PlGF, DLL4 and NOTCH1 expression were assessed by immunohistochemistry on formalin-fixed, paraffin-embedded neoplastic tissue of either primary or metastatic tissue in a tissue microarray. High levels of expression were defined as less than or equal to or more than the median. Survival curves were calculated by the Kaplan-Meier method and compared by the log-rank test. For multivariate analysis the Cox proportional hazards model was used. Results: Grade 1 or 2 (p=0.01), non-mucin-producing histology (p=0.04) and presence of liver metastasis (p=0.001) were associated with a higher response rate. There was no difference between the expression of markers and the response rate. ECOG 0 or 1 (p=0.002), grade 1 or 2 (p=0.02), liver metastasis (p=0.003), no lymph node metastasis (p=0.01) no peritoneal metastasis (p=0.02) and resection of metastasis (p<0.001) were correlated with higher progression-free survival (PFS). There was also a strong correlation between ECOG 0 or 1 (p=0.001), grade 1 or 2 (p=0.006), no lymph node metastasis (p=0.004), liver metastasis (p<0.001) and resection of metastasis (p<0.0001) with better overall survival. There was a trend between high expression of NOTCH1 (p=0.06) and worst PFS.High expression of VEGFR2 (p=0.07) was slightly associated with a better overall survival, while high expression of NOTCH1 was associated with a worse overall survival (p=0.01). Using multivariate analysis, NOTCH1 proved to be an independent variable for adverse overall survival (HR 2.01, IC 1.07 – 3.77, p=0.02). Conclusions: High NOTCH1 expression assessed by immunohistochemistry is capable of predicting poor survival in advanced colorectal cancer patients treated with bevacizumab.

Third line chemotherapy in metastatic colorectal cancer: A single institution experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14706-e14706
Author(s):  
Wilver Federico Carbonel Luyo ◽  
Zoila Elizabeth Carranza Montenegro ◽  
Antia Cousillas Castineiras ◽  
Manuel Constenla Figueiras ◽  
Francisco Ramon Garcia Arroyo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Statistical Significance ◽  
Performance Status ◽  
Descriptive Analysis ◽  
Rank Test ◽  
Male Predominance ◽  
Third Line ◽  
Line Chemotherapy

e14706 Background: The median overall survival for metastatic colorectal cancer (mCRC) has been increasing over the past two decades and is very common to see longer survivals with a good performance status. They may benefit from treatment after progression to second line chemotherapy. In this context, raltitrexed is an active and simple-administration drug that appears to be a convenient treatment. Our objetive was to determine if there is benefit in patient retreated with oxaliplatin based chemotherapy (OBCT), CPT 11 based-chemotherapy (CBCT) or raltitrexed every 21 days in a third line chemotherapy (3L CT) setting. Methods: We conducted an analytical epidemiological study, using descriptive analysis and Long Rank test. Between 2009 and 2012, were treated 28 mCRC with a 3L CT and 11 of which recieved adyuvant chemotherapy. All were treated previously with OBCT and CBCT. Treatment consisted in OBCT, CBCT or raltitrexed in monotherapy. Results: Male predominance in proportion of cases (67.9%) with a median of 62 years old (range 27-79 and 90% between 45-75) and 78.6% had aceptable clinical condition (ECOG 0-1). Median CEA level before 3L CT was 61.1 ng/dL. Sixteen patient had rectal cáncer, mostly male (75%). In our sample, the mCRC overall survival was 30.4 months (95% confidence interval(CI), 14.3 to 46.4) . Patients retreated with OBCT or CBCT had the same survival than treated with a particular sequence that includes OBCT, CBCT and raltitrexed in monotherapy (7.5 months (CI, 5.81 to 9.2) vs 7.4 months (CI, 2.5 to 12.3); p<,598). Raltitrexed in monotherapy tends to have better survival in comparison with OBCT or CBCT, no reaching statistical significance (14.3 months (CI, 3.6 to 24.9) vs 7.5 months (CI, 5.9 to 9.1) vs 7.4 months (CI, 0.0 to 18.1); p<,755). The most common toxicity with raltitrexed was asthenia grade 1 (32,1%), with OBCT was neurotoxicity grade 1 (75%) and with CBCT was abdominal pain grade 1 (55.5%). Conclusions: In our serie, there was a male predominance and median mCRC survival is better than reported in the literature. There is a trend for a better survival with raltitrexed in monotherapy with a good toxicity profile in a 3L CT setting. Future studies are needed to verify these findings.

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