# Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials

Source: https://onco.cc/key-papers/paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017/  
OnCo record `paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Pooling 2,159 patients from six trials showed that which side of the colon a tumour started on decides whether an EGFR antibody helps at all: a clear survival gain on the left, none on the right.

## Summary

Arnold, Lueza, Douillard and colleagues retrospectively investigated the influence of primary tumour location in patients with unresectable RAS wild-type metastatic colorectal cancer in six randomised trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus an EGFR antibody with chemotherapy or chemotherapy plus bevacizumab. Hazard ratios for overall and progression-free survival and odds ratios for response were pooled across studies, and the predictive value was evaluated by pooling the study-level interaction between treatment effect and tumour side.

Primary tumour location and RAS status were available for 2,159 of the 5,760 randomised patients (37.5 percent): 515 right-sided and 1,644 left-sided.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: Annals of Oncology
- Year: 2017
- DOI: 10.1093/annonc/mdx175
- Authors: Arnold D, Lueza B, Douillard JY, et al.
- Findings: Right-sided tumours had a worse prognosis in both control and experimental arms: overall survival hazard ratios 2.03 (95 percent CI 1.69 to 2.42) and 1.38 (1.17 to 1.63).; EGFR antibody benefit in left-sided tumours: overall survival hazard ratio 0.75 (0.67 to 0.84) and progression-free survival 0.78 (0.70 to 0.87).; No benefit in right-sided tumours: 1.12 (0.87 to 1.45) and 1.12 (0.87 to 1.44); p for interaction <0.001 and 0.002.; Response odds ratios 2.12 (1.77 to 2.55) on the left against 1.47 (0.94 to 2.29) on the right (p for interaction 0.07).
- What it means: The analysis that put 'left-sided, RAS and BRAF wild-type' into every guideline as the anti-EGFR population, and made an anatomical fact into a treatment-selection biomarker.
- Caveats: Retrospective pooling on 37.5 percent of the randomised patients, which the authors themselves say demands caution.; Side is a proxy for biology (BRAF, mismatch repair deficiency, consensus molecular subtype) that is now measurable directly.; None of the six trials tested a whole treatment sequence, so the analysis speaks only to the first-line choice.

## Sources

- Ann Oncol 2017: https://doi.org/10.1093/annonc/mdx175
- PubMed: https://pubmed.ncbi.nlm.nih.gov/28407110/
- Europe PMC full text (PMC6246616): https://europepmc.org/article/MED/28407110

## Connected records

- key papers: [Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in KRAS wild-type advanced or metastatic colorectal cancer (CALGB/SWOG 80405)](https://onco.cc/key-papers/paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017/), [FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3)](https://onco.cc/key-papers/paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014/), [Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up](https://onco.cc/key-papers/paper-esmo-metastatic-colorectal-cancer-guideline-ann-oncol-2023/), [Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer (PRIME)](https://onco.cc/key-papers/paper-douillard-prime-panitumumab-ras-nejm-2013/)
- biomarkers: [RAS wild-type (extended KRAS and NRAS testing)](https://onco.cc/biomarkers/ras-wild-type/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/), [NRAS](https://onco.cc/targets/nras/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Panitumumab](https://onco.cc/drugs/panitumumab/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Consensus molecular subtypes (CMS1-4)](https://onco.cc/terms/cms-subtypes/), [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/), [Wild-type (WT)](https://onco.cc/terms/wild-type/)
- trials: [CRYSTAL & FIRE-3](https://onco.cc/trials/crystal-fire3/), [PARADIGM](https://onco.cc/trials/paradigm/)
- people: [Alan P. Venook](https://onco.cc/people/alan-venook/), [Andrés Cervantes](https://onco.cc/people/andres-cervantes/), [Eric Van Cutsem](https://onco.cc/people/eric-van-cutsem/), [Heinz-Josef Lenz](https://onco.cc/people/heinz-josef-lenz/), [Josep Tabernero](https://onco.cc/people/josep-tabernero/), [Volker Heinemann](https://onco.cc/people/volker-heinemann/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/)
- journals: [Annals of Oncology](https://onco.cc/journals/annals-of-oncology/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/)

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