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Tumor Sidedness and Enriched Gene Groups for Efficacy of First-line Cetuximab Treatment in Metastatic Colorectal Cancer.

ABSTRACT: Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with KRAS exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Biomarker Panel. Univariate Cox regression analysis using log2 values of counts per million (CPM) was conducted in each sidedness to assess associations with clinical outcomes, and to define the optimal cut-off point for clinically significant genes. In addition, a gene set enrichment analysis (GSEA) was performed to identify significant gene pathways in each sidedness. Sixty-nine patients were assessable for gene expression data. Overexpression of BECN1 [log2(CPM) ? 6.8] was associated with favorable survival, regardless of tumor sidedness. High expression of NOTCH1 [log2(CPM) ? 7.5] predicted significantly longer progression-free survival (PFS; median 14.7 vs. 11.1 months, HR 0.43, P = 0.01) and overall survival (OS; median 42.8 vs. 26.5 months, HR 0.35, P = 0.01) in left side but not in right side. The GSEA showed that regulation of DNA replication gene set correlated with favorable survival in the left, whereas the subcellular component and leukocyte migration gene sets were associated with good survival in the right. In conclusion, genes contributing to the efficacy of cetuximab treatment may differ according to the sidedness in mCRC. NOTCH1 may potentially discriminate favorable responders to cetuximab in patients with left-sided tumors.

SUBMITTER: Sunakawa Y

PROVIDER: S-EPMC7497846 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Tumor Sidedness and Enriched Gene Groups for Efficacy of First-line Cetuximab Treatment in Metastatic Colorectal Cancer.

Sunakawa Yu Y Mogushi Kaoru K Lenz Heinz-Josef HJ Zhang Wu W Tsuji Akihito A Takahashi Takehiro T Denda Tadamichi T Shimada Ken K Kochi Mitsugu M Nakamura Masato M Kotaka Masahito M Segawa Yoshihiko Y Tanioka Hiroaki H Negoro Yuji Y Moran Miriana M Astrow Stephanie H SH Hsiang Jack J Stephens Craig C Fujii Masashi M Ichikawa Wataru W

Molecular cancer therapeutics 20181001 12

Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with <i>KRAS</i> exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Bi ...[more]

PMID: 30275242

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Project description:Background:Previous studies have reported the prognostic impact of primary tumor sidedness in metastatic colorectal cancer (mCRC) and its influence on cetuximab efficacy. The present retrospective analysis of two panitumumab trials investigated a possible association between tumor sidedness and treatment efficacy in first-line mCRC patients with RAS wild-type (WT) primary tumors. Materials and methods:Data from two randomized first-line panitumumab trials were analyzed for treatment outcomes by primary tumor sidedness for RAS WT patients. PRIME (phase 3; NCT00364013) compared panitumumab plus FOLFOX versus FOLFOX alone; PEAK (phase 2; NCT00819780) compared panitumumab plus FOLFOX versus bevacizumab plus FOLFOX. Primary tumors located in the cecum to transverse colon were coded as right-sided, while tumors located from the splenic flexure to rectum were considered left-sided. Results:Tumor sidedness ascertainment (RAS WT population) was 83% (n?=?559/675); 78% of patients (n?=?435) had left-sided and 22% (n?=?124) had right-sided tumors. Patients with right-sided tumors did worse for all efficacy parameters compared with patients with left-sided disease in the RAS WT population and also in the RAS/BRAF WT subgroup. In patients with left-sided tumors, panitumumab provided better outcomes than the comparator treatment, including on median overall survival (PRIME: 30.3 versus 23.6?months, adjusted hazard ratio?=?0.73, P?=?0.0112; PEAK: 43.4 versus 32.0?months, adjusted hazard ratio?=?0.77, P?=?0.3125). Conclusion:The results of these retrospective analyses confirm that in RAS WT patients, right-sided primary tumors are associated with worse prognosis than left-sided tumors, regardless of first-line treatment received. RAS WT patients with left-sided tumors derive greater benefit from panitumumab-containing treatment than chemotherapy alone or combined with bevacizumab, including an overall survival advantage (treatment difference: PRIME 6.7?months; PEAK 11.4?months). No final conclusions regarding optimal treatment could be drawn for RAS WT patients with right-sided mCRC due to the relatively low number of paxtients. Further research in this field is warranted. Trial registration (Clinicaltrials.gov):PRIME (NCT00364013), PEAK (NCT00819780).

Project description:Background: Colorectal cancer (CRC) has been reconsidered as a heterogeneous disease. Among advances of genomic analysis in CRC, the sidedness of tumors (left-sided colon vs. right-sided colon) and microsatellite instability (MSI)-high (H) tumors have been highlighted. Methods: We analyzed 153 CRC patients who were available for evaluation of MSI status and had been treated with cetuximab-containing chemotherapy between April 2008 and January 2013. KRAS mutational status was available in all 153 patients, but BRAF mutational status was only available in 72 patients (47.1%). We evaluated the impact of microsatellite instability status and location of the primary colon tumor on the effect of cetuximab-containing chemotherapy in patients with metastatic colorectal cancer. Results: MSI-H was detected in 3.9% of analyzed patients. Characteristics of patients, with the exception of BRAF mutational status, were generally similar between those with right and left-sided tumors. Right-sided tumors were significantly associated with a BRAF mutation (p=0.023). In addition, patient characteristics with an MSS tumor were not different from those with an MSI-H tumor. For all 153 patients, the most commonly used regimen that included cetuximab was irinotecan alone, irrespective of treatment line. There was no significant difference in treatment efficacy in either RR or disease control rate (DCR) between the MSI-H and MSS groups. There was also no difference in RR and DCR according to the location of the primary tumor (left side vs. right side). No significant difference in PFS was observed between the MSI-H and MSS groups (4.80 months vs. 5.80 months; p=0.238) or the left-side and right-side groups (6.10 months vs. 4.20 months; p=0.278). In a subgroup-analysis of 140 patients with wild-type KRAS, there was no difference in PFS following cetuximab-containing therapy based on MSI status or the location of the primary tumor. Conclusions: MSI status and the location of the primary tumor were not novel biomarkers for response to cetuximab-containing therapy in metastatic CRC. Further prospective validation of the prognostic or predictive capacity of MSI status and the sidedness of tumors is warranted.

Project description:In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups.A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by age-groups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (?65; ?70 and ?75?years).340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were >65?years, 86 >70?years and 35 >75?years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were >65?years, 46 >70 and 17 >75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were ?65?years; 29 were ?70; 9 were ?75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade ?3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients ?75?years and grade ?3 fatigue (31% vs 20%, p=0.01) in patients <75?years.Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade ?3 diarrhoea and neutropaenia in patients ?75?years and grade ?3 fatigue in patients <75?years.2009-014041-81.

Dataset Information

Tumor Sidedness and Enriched Gene Groups for Efficacy of First-line Cetuximab Treatment in Metastatic Colorectal Cancer.

Publications

Tumor Sidedness and Enriched Gene Groups for Efficacy of First-line Cetuximab Treatment in Metastatic Colorectal Cancer.

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