Dataset Information

Changes of TCR repertoire diversity in colorectal cancer after Erbitux (cetuximab) in combination with chemotherapy.

ABSTRACT: We have previous found a positive correlation between post-therapy TCR repertoire normalization and remission of colorectal cancer (CRC) patients following fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or Rh-endostatin therapy. To further define the TCR repertoire diversity changes following treatment in CRC patients, and confirm its potential prognostic value, the present study extended the sample size of follow-up and used an alternative therapy regime to investigate changes of TCR repertoires following Erbitux plus FOLFIRI therapy. Inclusion and exclusion criteria have been established to screen out 26 patients to receive Erbitux plus FOLFIRI therapy. Efficacy and toxicity assessment have been made for them after 3 months' treatment as well as the TCR repertoire diversity has been determined. A CDR3 complex scoring system was used to quantify the diversity of TCR repertoire. The results showing that the diversity of CD4(+) T cells in PR group was significantly higher than that of SD and PD groups, and the difference was enlargement after treatment. The diversity of CD8(+) T cells in PR group has no difference before and after treatment, but significant decrease in SD and PD group after treatment. In conclusion, analysis the diversity of T cell repertoire has an important prognosis value for CRC patients.

SUBMITTER: Luo W

PROVIDER: S-EPMC4266724 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Changes of TCR repertoire diversity in colorectal cancer after Erbitux (cetuximab) in combination with chemotherapy.

Luo Wei W He Wen-Ting WT Wen Qian Q Chen Shu S Wu Jing J Chen Xiang-Ping XP Ma Li L

American journal of cancer research 20141119 6

We have previous found a positive correlation between post-therapy TCR repertoire normalization and remission of colorectal cancer (CRC) patients following fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or Rh-endostatin therapy. To further define the TCR repertoire diversity changes following treatment in CRC patients, and confirm its potential prognostic value, the present study extended the sample size of follow-up and used an alternative therapy regime to investigate chan ...[more]

PMID: 25520880

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Project description:BackgroundIn the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.MethodsIn this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.Findings1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3-29·2] in the control group vs 17·0 months [9·4-30·1] in the cetuximab group; HR 1·04, 95% CI 0·87-1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0-12·5] in the control group vs 8·6 months [5·1-13·8] in the cetuximab group; HR 0·96, 0·82-1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5-27·4); KRAS mutant, 14·4 months (8·5-24·0); all wild-type, 20·1 months (11·5-31·7).InterpretationThis trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.FundingCancer Research UK, Cancer Research Wales, UK Medical Research Council, Merck KGgA.

Dataset Information

Changes of TCR repertoire diversity in colorectal cancer after Erbitux (cetuximab) in combination with chemotherapy.

Publications

Changes of TCR repertoire diversity in colorectal cancer after Erbitux (cetuximab) in combination with chemotherapy.

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