Dataset Information

Prognostic role of ERBB2, MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies.

ABSTRACT: High amplification of epiregulin (EREG) and amphireglin (AREG) in tumour tissues has been previously reported to be associated with better outcome in metastatic colorectal cancer (mCRC) patients who were treated with anti-EGFR antibodies. Here we investigated associations between the expression of other candidate prognostic biomarkers and outcome in mCRC patients receiving similar treatment.The relative mRNA levels of seven genes including ERBB2, MET, VEGFA, EREG, AREG, PTEN and ERCC1 between tumour (T) and non-tumour (NT) tissue sections were analysed by quantitative real-time PCR. Relative mRNA values, that is, T/NT ratios, of target genes were calculated and hazard ratios (HRs) for each gene of interest were adjusted for age, gender, performance status, minor RAS mutations and other clinicopathological variables which exhibited P-values<0.1 on the basis of univariate analysis.Among 108 cases who received anti-EGFR antibodies, there were 96 cases of KRAS exon2 wild-type patients enroled in this study. When the cutoff values for relative mRNA levels were set to the upper 25th percentile of all patients, there were statistically significant differences in overall survival (OS) between the patients with high and low levels of EREG (HR: 0.326, 95% CI: 0.136-0.772, P=0.011), ERBB2 (HR: 1.31, 95% CI: 1.084-1.652, P=0.040), MET (HR: 2.48, 95% CI: 1.356-5.463, P=0.026), and VEGF-A (HR: 1.29, 95% CI: 1.036-1.606, P=0.046). In addition, patients with high ERBB2 had shorter progression-free survival (PFS) compared with low ERBB2 (HR: 1.98, 95% CI: 1.062-3.850). There were no significant differences in PFS and OS with respect to relative expression levels of PTEN and ERCC1. The prognostic role of AREG was evaluated in only T sections, as the mRNA expression level of this gene was mostly (91% cases) undetectable in NT sections. Patients with high AREG had longer OS compared with low AREG (HR: 0.227, 95% CI: 0.095-0.808).Our study has shown that higher T/NT ratios of ERBB2, MET and VEGFA mRNA were associated with worse OS in mCRC patients treated with anti-EGFR antibodies, with higher EREG and AREG were associated with better prognosis in the same setting. These findings will contribute the further understanding and management of anti-EGFR antibody treatment in mCRC patients.

SUBMITTER: Takahashi N

PROVIDER: S-EPMC4984915 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Prognostic role of ERBB2, MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies.

Takahashi Naoki N Iwasa Satoru S Taniguchi Hirokazu H Sasaki Yusuke Y Shoji Hirokazu H Honma Yoshitaka Y Takashima Atsuo A Okita Natsuko N Kato Ken K Hamaguchi Tetsuya T Shimada Yasuhiro Y Yamada Yasuhide Y

British journal of cancer 20160322 9

<h4>Background</h4>High amplification of epiregulin (EREG) and amphireglin (AREG) in tumour tissues has been previously reported to be associated with better outcome in metastatic colorectal cancer (mCRC) patients who were treated with anti-EGFR antibodies. Here we investigated associations between the expression of other candidate prognostic biomarkers and outcome in mCRC patients receiving similar treatment.<h4>Methods</h4>The relative mRNA levels of seven genes including ERBB2, MET, VEGFA, ER ...[more]

PMID: 27002940

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Project description:BACKGROUND: BRAF mutation has been investigated as a prognostic factor in metastatic colorectal cancer (mCRC) undergoing anti-EGFR monoclonal antibodies (moAbs), but current results are still inconclusive. The aim of this meta-analysis was to evaluate the relationship between BRAF mutation status and the prognosis of mCRC patients treated with moAbs. METHODS: Eligible studies were identified by systematically searching Pubmed, the Cochrane Library, Web of Knowledge, and OVID. Risk ratio (RR) for overall response rate (ORR), Hazard ratios (HRs) for Progression free survival (PFS) and Overall survival (OS) were extracted or calculated. Prespecified subgroup analyses were conducted in KRAS wild-type and in different study types. The source of between-trial variation was explored by sensitivity analyses. Quality assessment was conducted by the Hayden's criteria. RESULTS: A total of twenty one trials including 5229 patients were identified for the meta-analysis. 343 patients displayed BRAF mutations of 4616 (7.4%) patients with known BRAF status. Patients with BRAF wild-type (WT) showed decreased risks of progression and death with an improved PFS(HR 0.38, 95% confidence intervals 0.29-0.51) and an improved OS (HR 0.35 [0.29-0.42]), compared to BRAF mutant. In KRAS WT population, there were even larger PFS benefit (HR 0.29[0.19,0.43]) and larger OS benefit (HR 0.26 [0.20,0.35]) in BRAF WT. A response benefit for BRAF WT was observed (RR 0.31[0.18,0.53]) in KRAS WT patients, but not observed in unselected patients (RR 0.76 [0.43-1.33]). The results were consistent in the subgroup analysis of different study types. Heterogeneity between trials decreased in the subgroup and explained by sensitivity analysis. No publication bias of ORR, PFS and OS were detected. CONCLUSIONS: The results indicate that BRAF mutant is a predictive biomarker for poor prognosis in mCRC patients undergoing anti-EGFR MoAbs therapy, especially in KRAS WT patients. Additional large prospective trials are required to confirm the predictive role of BRAF status.

Project description:BackgroundEpidermal growth factor receptor gene copy number (EGFR GCN) has been heavily investigated as a potential predictive biomarker for the treatment of metastatic colorectal cancer (mCRC) with anti-EGFR monoclonal antibodies (MAbs). The objective of this study was to systematically review current evidences on this issue.MethodsPubMed, EMBASE, The Cochrane Library, Chinese Biomedical Literature Database, Wanfang Data, and the conference abstracts of American Society of Clinical Oncology and European Society of Medical Oncology were comprehensively searched. Studies that reported the objective response rate (ORR), progression-free survival, and/or overall survival of mCRC patients treated with anti-EGFR MAbs, stratified by EGFR GCN status, were included. The effect measures for binary outcome (response) and time-to-event outcomes (progression-free survival and overall survival) were risk difference and hazard ratio, respectively. Statistical heterogeneity among the studies was assessed by the Cochran's Q-test and the I2 statistic. If appropriate, a quantitative synthesis of data from different studies would be conducted with a random-effects model.ResultsNineteen eligible studies were identified. The criteria for increased EGFR GCN (GCN+) were highly inconsistent across different studies. The prevalence of GCN?+?ranged from 6.9% to 88.9%, and the difference in ORR between patients with GCN?+?and those with non-increased EGFR GCN (GCN-) varied from -28% to 84%. Because of the significant heterogeneity, no quantitative synthesis of data was performed. There was a general trend towards higher ORR in patients with GCN+. The difference in ORRs between patients with GCN?+?and those with GCN- was even greater in KRAS wild-type patients, while in KRAS mutated patients the difference often did not exist. Almost all patients with EGFR amplification responded to the treatment. However, the prevalence of EGFR amplification was generally low. Incomplete data on progression-free survival and overall survival seemingly supported the findings on ORR.ConclusionsAlthough increased EGFR GCN is generally associated with a better outcome of anti-EGFR MAbs treatment, especially among patients with wild-type KRAS, the clinical utility of this biomarker for selecting recipients of anti-EGFR MAbs would be severely limited by the heterogeneous scoring system and the poor reproducibility of EGFR GCN enumeration due to technical reasons.

Project description:Background:There is increasing evidence that metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and that tumours arising from different sides of the colon (left versus right) have different clinical outcomes. Furthermore, previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type (wt) or RAS wt mCRC suggest that primary tumour location (side), might be both prognostic and predictive for clinical outcome. Methods:This retrospective analysis investigated the prognostic and predictive influence of the localization of the primary tumour in patients with unresectable RAS wt mCRC included in six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus EGFR antibody therapy (experimental arm) with chemotherapy or chemotherapy and bevacizumab (control arms). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) for patients with left-sided versus right-sided tumours, and odds ratios (ORs) for objective response rate (ORR) were estimated by pooling individual study HRs/ORs. The predictive value was evaluated by pooling study interaction between treatment effect and tumour side. Results:Primary tumour location and RAS mutation status were available for 2159 of the 5760 patients (37.5%) randomized across the 6 trials, 515 right-sided and 1644 left-sided. A significantly worse prognosis was observed for patients with right-sided tumours compared with those with left-sided tumours in both the pooled control and experimental arms for OS [HRs?=?2.03 (95% CI: 1.69-2.42) and 1.38 (1.17-1.63), respectively], PFS [HRs?=?1.59 (1.34-1.88) and 1.25 (1.06-1.47)], and ORR [ORs?=?0.38 (0.28-0.50) and 0.56 (0.43-0.73)]. In terms of a predictive effect, a significant benefit for chemotherapy plus EGFR antibody therapy was observed in patients with left-sided tumours [HRs?=?0.75 (0.67-0.84) and 0.78 (0.70-0.87) for OS and PFS, respectively] compared with no significant benefit for those with right-sided tumours [HRs?=?1.12 (0.87-1.45) and 1.12 (0.87-1.44) for OS and PFS, respectively; P value for interaction?<0.001 and 0.002, respectively]. For ORR, there was a trend (P value for interaction?=?0.07) towards a greater benefit for chemotherapy plus EGFR antibody therapy in the patients with left-sided tumours [OR?=?2.12 (1.77-2.55)] compared with those with right-sided tumours [OR?=?1.47 (0.94-2.29)]. Exclusion of the unique phase II trial or the unique second-line trial had no impact on the results. The predictive effect on PFS may depend of the type of EGFR antibody therapy and on the presence or absence of bevacizumab in the control arm. Conclusion:This pooled analysis showed a worse prognosis for OS, PFS and ORR for patients with right-sided tumours compared with those with left-sided tumours in patients with RAS wt mCRC and a predictive effect of tumour side, with a greater effect of chemotherapy plus EGFR antibody therapy compared with chemotherapy or chemotherapy and bevacizumab, the effect being greatest in patients with left-sided tumours. These predictive results should be interpreted with caution due to the retrospective nature of the analysis, which was carried out on subpopulations of patients included in these trials, and because none of these studies contemplated a full treatment sequence strategy.

Dataset Information

Prognostic role of ERBB2, MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies.

Publications

Prognostic role of ERBB2, MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies.

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