Molecular determinants of capecitabine efficacy in colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3606-3606
Author(s):  
D. Vallbohmer ◽  
H. Kuramochi ◽  
D. Shimizu ◽  
K. D. Danenberg ◽  
J. N. Nielsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Single Agent ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Expression Levels ◽  
Cox 2 ◽  
Gene Expression Levels

3606 Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text]

cMET expression in HER2+ MBC patients with first-line lapatinib (L) treatment

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1073-1073
Author(s):  
Y. Liu ◽  
L. Liu ◽  
H. Shi ◽  
J. G. Greger ◽  
K. D. Jackson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Los Angeles ◽  
Clinical Outcome ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Expression Levels ◽  
Combination Study ◽  
Her 2

1073 Background: Overexpression of MET correlates with poor prognosis in breast cancer (Garcia et al., 2007) and is a factor associated with decreased sensitivity to L in HER2+ breast tumor cell lines in vitro (Liu et al., submitted). To test whether MET expression was associated with resistance to L in the clinic we evaluated baseline tumor MET expression levels and clinical outcome to L in 64 patients who participated in the EGF20009 trial of monotherapy L as first-line treatment in HER2+ advanced or MBC. Methods: RNA was extracted from FFPE tumors and MET and HER-2 gene expression was measured by qRT-PCR (Response Genetics, Inc., Los Angeles, CA). The correlation between expression levels of MET, HER2, and clinical outcome (overall response and progression free survival) was performed using JMP software. Results: A trend towards an association with increased MET expression and decreased response (p < 0.054) was observed.. Patients with high HER2 and low MET gene expression had the longest PFS (median difference = ∼9 weeks) compared to patients with low HER2 and high MET gene expression (p < 0.0038). Conclusions: These data support investigating a combination study of L and GSK1363089, a multi-kinase MET inhibitor, in HER2+ BC patients with high MET gene expression. [Table: see text]

EGFR, Cox-2, and EGF polymorphisms associated with progression-free survival of EGFR-expressing metastatic colorectal cancer patients treated with single-agent cetuximab (IMCL-0144)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4129-4129 ◽  
Author(s):  
F. Nagashima ◽  
W. Zhang ◽  
M. Gordon ◽  
H. M. Chang ◽  
G. Lurje ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Markers ◽  
Clinical Outcome ◽  
Response Rate ◽  
Phase Ii Study ◽  
Single Agent ◽  
Progression Free Survival ◽  
Tissue Samples ◽  
Free Survival ◽  
Cox 2

4129 Background: A phase II study of cetuximab (IMCL-0144) has shown response rate of 12 % in patients with EGFR expressing metastatic colorectal cancer (mCRC). Recently, we reported that polymorphisms in the EGFR pathway may be useful molecular markers to predict clinical outcome. In this larger study, we tested whether polymorphisms in genes involved in the EGFR and angiogenesis pathway will be associated with clinical outcome. Methods: We analyzed 136 tissue samples from 346 mCRC pts enrolled in the phase II study of cetuximab (IMCL-0144), 133 cases were informative. The response rate in these 133 pts was 10% with a median progression-free survival (PFS) of 1.3 months (95% CI, 1.2 to 1.5) and an overall survival time (OS) of 5.5 months (95% CI, 4.1 to 7.5). Gr3–4 toxicity was observed in 56%. Gene polymorphisms of EGFR, Cox-2, EGF, cyclin D1, fragment c γ receptor 2A (FCGR2A), FCGR3A, VEGF, IL-8 were assessed from gDNA extracted from tissue samples by using PCR-based RFLP technique. Univariate analysis (Fisher’s exact test for response; log-rank test for PFS and OS) was performed to examine associations between polymorphisms and clinical outcome. A classification and regression tree (CART) analysis was used to identify subgroups of patients who were more likely to benefit from cetuximab. Results: Pts with EGFR G497C GA, Cox-2 G-765C CC, EGF A61G GG genotype showed better PFS (p=0.02, 1.8mo. vs. 1.2mo.; p=0.03, 6.9mo. vs. 1.3mo.; p=0.04, 1.4mo. vs. 1.2mo.), respectively. We found trends in associations between Cox-2 and tumor response (p=0.09), between EGF and Gr3–4 toxixity (p=0.06). CART analyses indicated that germline polymorphisms in EGFR, EGF, Cox-2, Cyclin D1, IL-8, FCGR2A and FCGR3A genes could be used to identify patients who benefit most likely of cetuximab therapy. Conclusions: Our data suggest that the polymorphisms of EGFR, Cox-2, and EGF may be useful molecular markers to predict clinical outcome in mCRC pts treated with single-agent cetuximab. And prospective studies will need to be done to confirm these preliminary findings. [Table: see text]

Molecular Determinants of Cetuximab Efficacy

2005 ◽  
Vol 23 (15) ◽  
pp. 3536-3544 ◽  
Author(s):  
Daniel Vallböhmer ◽  
Wu Zhang ◽  
Michael Gordon ◽  
Dong Yun Yang ◽  
Jim Yun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Growth Factor ◽  
Clinical Outcome ◽  
Single Agent ◽  
Rank Test ◽  
Expression Levels ◽  
Log Rank Test ◽  
Cox 2 ◽  
Gene Expression Levels

Purpose To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab. Patients and Methods Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction. Results There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment. Conclusion This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment.

Molecular markers associated with response and clinical outcome to cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer (BOND2)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4113-4113 ◽  
Author(s):  
M. Azuma ◽  
D. Yang ◽  
M. Carpanu ◽  
E. Hollywood ◽  
M. Lue-Yat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Molecular Markers ◽  
Clinical Outcome ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Free Survival ◽  
Expression Levels ◽  
Cart Analysis ◽  
Group I

4113 Background: Phase II (BOND2) trial of Cetuximab/Bevacizumab/Irinotecan (CBI) vs Cetuximab/Bevacizumab (CB) has shown that bevacizumab added to the efficacy of cetuximab and cetuximab/irinotecan in irinotecan-refractory bevacizumab-naïve CRC patients. We tested whether expression levels of genes involved in angiogenesis (VEGF, IL-8), the EGFR pathway (EGFR, COX2) and DNA repair (ERCC1) are associated with clinical outcome. Patients and Methods: This randomized phase II trial enrolled 81 patients. Treatment plan as: Arm A received IRI at the same dose and schedule as last received prior to study, plus Cetuximab 400 mg/m2 loading dose, then weekly at 250 mg/m2, plus Bevacizumab 5 mg/kg given every other week. Arm B received the same as arm A, but without IRI. FFPE samples for 35 out of 81 patients (M:W 24:11, median age 56 (29–80) enrolled in the BOND2 study were tested. Patients received either with CBI (n=18, Arm A) or with CB (n=17, Arm B). FFPE tissues were dissected using laser-captured microdissection and analyzed EGFR, ERCC1, VEGFA, VEGFR2, COX2, Cyclin D1, IL-8, and NRP1 mRNA expression using a quantitative real-time RT-PCR. Gene expression values are expressed as ratios between the target gene and internal reference gene. Results: All eight genes and treatment arm were considered in the CART analysis. The classification tree for response, progression-free survival, and overall survival are evaluated. The expression levels of VEGFR2 and NRP1 classified patients in 3 response groups with response rate range from 61% to 0%. Patients who were classified as responders (Group I; VEGFR2=0.65 and NRP1<2.285) were at a lower risk for progression, compared with patients who were classified as non- responders (Group II; VEGFR2=0.65 and NRP1=2.285 and Group III; VEGFR2<0.65). The expression levels of NRP1 and ERCC1, and EGFR and VEGFR2 were chosen to classify patients into 3 groups with distinct risk of progression-free survival and overall survival, respectively. Conclusion: These data suggest that gene expression levels may be molecular markers of response for patients with mCRC treated with CBI or CB. Prospective studies are needed to validate these preliminary findings. No significant financial relationships to disclose.

Wt Kras and gene expression levels of VEGFR2, EGFR, and ERCC-1 associated with progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line 5-FU or capecitabine with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4056-4056
Author(s):  
A. B. El-Khoueiry ◽  
A. Pohl ◽  
K. Danenberg ◽  
J. Cooc ◽  
W. Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kras Mutation ◽  
Chemokine Receptors ◽  
Progression Free Survival ◽  
Vegf Receptor ◽  
First Line ◽  
Tissue Samples ◽  
Expression Levels ◽  
Kras Status ◽  
Gene Expression Levels

4056 Background: While wild type (wt) Kras is associated with improved outcome to anti-EGFR therapy in pts with mCRC, there are no identified predictors of outcome for FOLFOX/BV. We evaluated Kras status and expression of genes involved in angiogenesis, DNA repair and 5-FU metabolism in 68 patients treated with FOLFOX/BV or XELOX/BV. These genes included VEGF, VEGF-receptor 2 (KDR), Cox-2, IL 6 and 8, chemokine-receptors 1 & 2, EGFR and ERCC-1. Methods: Tissue samples from 68 patients with mCRC were analyzed. mRNA was extracted from laser-capture-microdissected tumor tissue. cDNA was prepared by reverse transcription and quantitation of the candidate genes was performed using a fluorescence- based real-time detection method (TaqMan). Allele specific RT-PCR was performed to determine Kras mutation status in codons 12 and 13. Results: There were 68 pts (38 males, 30 females), median age: 56 years (range 29–81). All received first line 5FU, oxaliplatin and BV (28 FOLFOX/BV, 40 XELOX/BV). Radiologic response: 1 CR, 39/68 (57%) PR, 27/68 (40%) SD, and 1 PD. Median OS is not reached. At a median follow-up of 32.0 months (mo) (range: 2.3–47.8 mo), the median PFS was 12.4 mo (95% CI: 9.8–15.2). Kras mutation was identified in 39 pts (57%). RR was 64% in pts with wt Kras and 52% in pts with mutant Kras (p=0.33). PFS was significantly longer for pts with wt kras compared to pts with mutant kras (13.7 mo [95% CI: 6.9–13.2] versus 8.3 mo [95%CI: 6.9–13.2], P=0.039). High EGFR (median PFS: 15.2 mo; 95% CI 11.7–16.5 mo), high VEGFR2 (median PFS: 13.9 mo; 95% CI 11.0–16.5 mo), and low ERCC1 (median PFS: 12.4 mo; 95% CI 10.9–16.4 mo) were associated with longer PFS compared to low EGFR (median PFS: 7.9 mo; 95% CI 6.9–11.0 mo, P=0.040), low VEGFR2 (median PFS: 7.2 mo; 95% CI 6.5–8.1 mo, P=0.032), and high ERCC1 (median PFS: 9.6 mo; 95% CI 5.8–15.2 mo, P=0.045). Conclusions: To our knowledge, this is the first report of a potential association between Kras status as well as gene expression levels of VEGFR2, ERCC-1 and EGFR and clinical outcome to FOLFOX/BV therapy in pts with mCRC. Prospective clinical trials are needed to validate these results. [Table: see text]

scholarly journals Molecular subtype-specific efficacy of anti-EGFR therapy in colorectal cancer is dependent on the chemotherapy backbone

2021 ◽  
Author(s):  
Sanne ten Hoorn ◽  
Dirkje W. Sommeijer ◽  
Faye Elliott ◽  
David Fisher ◽  
Tim R. de Back ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Primary Tumour ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Tumour Location ◽  
Selection For

Abstract Background Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location. Methods Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively. Results When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26–0.75, P = 0.003 and HR 0.12, 95% CI 0.04–0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04–0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36–0.96, P = 0.034). Conclusions The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.

Efficacy and prognostic significance of triflurodine/tipiracil beyond oxaliplatin and irinotecan based chemotherapy in patients with refractory metastatic colorectal cancer: An observational multicenter study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15586-e15586
Author(s):  
Mohamed Alghamdi ◽  
Shouki Bazarbashi ◽  
Elsamany Shereef ◽  
Mervat Mahrous ◽  
Omar Al shaer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Saudi Arabia ◽  
Neutrophil Count ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
P Value ◽  
Second Line ◽  
First Line ◽  
Free Survival

e15586 Background: In Saudi Arabia, the incidence of colorectal cancer has been increased over the past few years. The optimal treatment beyond the second line is not fully understood. To the best of our knowledge, the efficacy and disease outcomes of triflurodine/tipiracil in Saudi patients with refractory metastatic colorectal cancer(mCRC) has not been studied yet. Our study is a real-life practice evaluation of the efficacy of triflurodine/tipiracil in patients with refractory mCRC. Moreover, the prognosis and the prognostic significance of the different clinical variables have been analyzed. Methods: A retrospective, multi-centers ( 5 centers representative of Saudi Arabia )observational study in patients with mCRC who have received triflurodine/tipiracil beyond oxaliplatin & Irinotecan-based chemotherapy between December 2018-December 2020.We aimed to assess the response to triflurodine/tipiracil, to evaluate the progression-free survival (PFS ), the overall survival (OS), and the associated factors of prognostic significance. Results:The data of 100 patients with refractory mCRC who has received triflurodine/tipiracil have been analyzed. The mean age was 55.2 +11.8 years. Forty-two patients were (42%) females and 58 (58%) were male patients. Sigmoid was the most common primary site of cancer in 35 (35%) patients, followed by rectum 29 (29%). Peritoneal metastasis was present in 17 (23.3%) patients ,liver in 51(56.6%) and lung in 39 (50.7%). Metastatic sites were ≥ 2 in 45 (45%) patients. Metastatic lesions were ≥ 5 in 65 (65%) patients. Xelox chemotherapy regimen was the most commonly used first-line chemotherapy which represents 43%, while Folfiri or Xeliri combination was the most used second line in 57 (60%). For the third line, Folfox or Xelox was used in 81 (83.5%) patients. The fourth line was given to 49 (67.1%). For first-line biological agents, Cetuximab was used most frequently 31 (46.3%).Evaluation of the response to treatment with triflurodine/tipiracil revealed one patient (1%) with a complete response,3 patients (3%) with partial response, 28 (28%) patients with stable disease, and 66 (66%) showed progressive disease. The estimated median progression-free survival was 5 months ( 3.839 - 6.161) and the median overall survival was 12 months (9.732-14.268). The log-rank analysis showed that the baseline neutrophils ≤ 75 % ( P-value= 0.0092) and low hemoglobin level (P-value= 0.0245) were strongly associated with a higher survival. By multivariate Cox regression analysis, the neutrophil count ≤ 75 % was the only independent predictor for survival. Conclusions: Trifluridine/tipiracil is effective in patients with refractory mCRC. The low neutrophil count might predict a better overall survival.

scholarly journals Protocol of the EFFORT study: a prospective study of FOLFIRI plus aflibercept as second-line treatment after progression on FOLFOXIRI plus bevacizumab or during maintenance treatment in patients with unresectable/metastatic colorectal cancer

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Hironaga Satake ◽  
Koji Ando ◽  
Eiji Oki ◽  
Mototsugu Shimokawa ◽  
Akitaka Makiyama ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy

Abstract Background FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Methods EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer. Discussion This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered. Trial registration Japan Registry of Clinical Trials jRCTs071190003. Registered April 18, 2019.

Pharmacogenetic Assessment of Toxicity and Outcome in Patients With Metastatic Colorectal Cancer Treated With LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05

2010 ◽  
Vol 28 (15) ◽  
pp. 2556-2564 ◽  
Author(s):  
Valérie Boige ◽  
Jean Mendiboure ◽  
Jean-Pierre Pignon ◽  
Marie-Anne Loriot ◽  
Marine Castaing ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Response ◽  
Progression Free Survival ◽  
Hematologic Toxicity ◽  
First Line ◽  
Free Survival ◽  
Increased Risk ◽  
Grade 3 ◽  
Cancérologie Digestive

Purpose The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). Patients and Methods Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. Results The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5′UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5′UTR genotypes, respectively. Conversely, patients with the TS-5′UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). Conclusion A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.

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