{"entity":{"id":"sidedness","kind":"term","name":"Sidedness (left vs right colon)","aka":[],"tldr":"Where in the colon a tumour starts changes its biology and which drugs work. Left-sided tumours respond to EGFR antibodies; right-sided ones do not.","summary":"Right-sided (caecum to transverse) tumours are more often dMMR, BRAF-mutant, mucinous, and worse prognosis; left-sided (splenic flexure to rectum) are more often chromosomally unstable and EGFR-dependent. CALGB 80405, FIRE-3, and PARADIGM showed anti-EGFR benefit is confined to left-sided RAS wild-type disease. Embryologic origin (midgut vs hindgut) underlies the difference.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Colorectal_cancer","links":[{"label":"ClinicalTrials.gov NCT02394795: PARADIGM","url":"https://clinicaltrials.gov/study/NCT02394795"},{"label":"Arnold, Ann Oncol 2017: prognostic and predictive value of primary tumour side in RAS wild-type metastatic colorectal cancer, pooled analysis of six randomised trials (2,159 patients)","url":"https://doi.org/10.1093/annonc/mdx175"},{"label":"NICE NG151: colorectal cancer, recommendations (Lynch 1.1, local disease 1.3, biomarkers 1.4, metastatic disease 1.5, ongoing care and support including follow-up 1.6)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"},{"label":"CRUK: bowel cancer incidence statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/incidence"}],"tags":[],"related":[],"cancers":["colorectal","colon-cancer","rectal-cancer"],"sections":[],"technologies":[],"targets":["egfr","braf"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["conversion-therapy-colorectal","liver-limited-metastatic-colorectal"],"trials":["paradigm","crystal-fire3"],"people":[],"bottlenecks":[],"keyPapers":["paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017","paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017","paper-missiaglia-distal-proximal-colon-cancers-ann-oncol-2014","paper-loree-tumour-location-continuum-colorectal-ccr-2018","paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018"],"journals":[],"dependsOn":[],"notes":["Measured, not asserted: in 7,237 MSK-IMPACT samples with a named subsite, microsatellite instability was 24.3% on the right against 5.2% on the left, BRAF V600E 19.2% against 2.9%, KRAS 51.9% against 39.7%, PIK3CA 32.4% against 15.5%, APC 65.0% against 77.6% and TP53 56.7% against 79.2% (cBioPortal crc_msk_2026). The predictive effect is the reason it matters: across six randomised trials in 2,159 RAS wild-type patients, adding an EGFR antibody improved overall survival on the left (hazard ratio 0.75) and not on the right (1.12), interaction p less than 0.001 (Arnold 2017), with the same interaction inside CRYSTAL and FIRE-3 separately (Tejpar 2017). The mechanism is that right-sided microsatellite-stable tumours carry mitogenic pathway mutations while left-sided ones are ligand dependent (Yaeger 2018, Missiaglia 2014). The caution is that the bowel is a gradient, not two halves: RAS mutation falls from 70% at the caecum to 43% at the hepatic flexure and the transverse colon clusters with the left (Loree 2018).","The pooled numbers. Individual patient data from six randomised trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181) covering 2,159 people with RAS wild-type unresectable disease, 515 right-sided and 1,644 left-sided, showed a worse prognosis for right-sided tumours in both control and experimental arms (overall survival hazard ratios 2.03 and 1.38; progression-free survival 1.59 and 1.25). Adding an EGFR antibody to chemotherapy helped left-sided tumours (overall survival hazard ratio 0.75, progression-free survival 0.78) and did not help right-sided ones (1.12 for both), with a significant interaction (Arnold 2017). The analysis is retrospective and covers 37.5 percent of the patients randomised in those trials.","Side is recorded on every metastatic case alongside RAS and BRAF status before first-line treatment is chosen (NICE NG151 1.4.1). In the UK the rectum is the commonest single site of bowel cancer (Cancer Research UK, 2016 to 2018)."],"category":"Cancer biology"},"route":"/terms/sidedness/","neighbours":{"cancer":[{"id":"braf-v600e-colorectal","kind":"cancer","name":"BRAF V600E-mutant colorectal cancer","route":"/cancers/braf-v600e-colorectal/"},{"id":"colon-cancer","kind":"cancer","name":"Colon cancer (adenocarcinoma of the colon)","route":"/cancers/colon-cancer/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"early-onset-colorectal","kind":"cancer","name":"Early-onset colorectal cancer (under 50)","route":"/cancers/early-onset-colorectal/"},{"id":"her2-amplified-colorectal","kind":"cancer","name":"HER2-amplified colorectal cancer","route":"/cancers/her2-amplified-colorectal/"},{"id":"kras-g12c-colorectal","kind":"cancer","name":"KRAS G12C-mutant colorectal cancer","route":"/cancers/kras-g12c-colorectal/"},{"id":"rectal-cancer","kind":"cancer","name":"Rectal cancer","route":"/cancers/rectal-cancer/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"}],"term":[{"id":"anti-egfr-rechallenge","kind":"term","name":"Anti-EGFR rechallenge","route":"/terms/anti-egfr-rechallenge/"},{"id":"cms-subtypes","kind":"term","name":"Consensus molecular subtypes (CMS1-4)","route":"/terms/cms-subtypes/"},{"id":"conversion-therapy-colorectal","kind":"term","name":"Conversion therapy in bowel cancer","route":"/terms/conversion-therapy-colorectal/"},{"id":"cimp","kind":"term","name":"CpG island methylator phenotype (CIMP)","route":"/terms/cimp/"},{"id":"extended-ras-testing","kind":"term","name":"Extended RAS testing","route":"/terms/extended-ras-testing/"},{"id":"heracles-criteria","kind":"term","name":"HERACLES criteria (HER2 in bowel cancer)","route":"/terms/heracles-criteria/"},{"id":"liver-limited-metastatic-colorectal","kind":"term","name":"Liver-limited metastatic bowel cancer","route":"/terms/liver-limited-metastatic-colorectal/"}],"trial":[{"id":"cairo5","kind":"trial","name":"CAIRO5","route":"/trials/cairo5/"},{"id":"calgb-80405","kind":"trial","name":"CALGB/SWOG 80405","route":"/trials/calgb-80405/"},{"id":"crystal-fire3","kind":"trial","name":"CRYSTAL & FIRE-3","route":"/trials/crystal-fire3/"},{"id":"paradigm","kind":"trial","name":"PARADIGM","route":"/trials/paradigm/"},{"id":"prime","kind":"trial","name":"PRIME","route":"/trials/prime/"}],"paper":[{"id":"paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009","kind":"paper","name":"Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (CRYSTAL)","route":"/key-papers/paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009/"},{"id":"paper-loree-tumour-location-continuum-colorectal-ccr-2018","kind":"paper","name":"Classifying colorectal cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and consensus molecular subtypes","route":"/key-papers/paper-loree-tumour-location-continuum-colorectal-ccr-2018/"},{"id":"paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018","kind":"paper","name":"Clinical sequencing defines the genomic landscape of metastatic colorectal cancer","route":"/key-papers/paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018/"},{"id":"paper-missiaglia-distal-proximal-colon-cancers-ann-oncol-2014","kind":"paper","name":"Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features","route":"/key-papers/paper-missiaglia-distal-proximal-colon-cancers-ann-oncol-2014/"},{"id":"paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017","kind":"paper","name":"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)","route":"/key-papers/paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017/"},{"id":"paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","kind":"paper","name":"Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer (BEACON CRC)","route":"/key-papers/paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019/"},{"id":"paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014","kind":"paper","name":"FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3)","route":"/key-papers/paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014/"},{"id":"paper-esmo-metastatic-colorectal-cancer-guideline-ann-oncol-2023","kind":"paper","name":"Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","route":"/key-papers/paper-esmo-metastatic-colorectal-cancer-guideline-ann-oncol-2023/"},{"id":"paper-jones-non-v600-braf-colorectal-jco-2017","kind":"paper","name":"Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer","route":"/key-papers/paper-jones-non-v600-braf-colorectal-jco-2017/"},{"id":"paper-paradigm-jama-2023","kind":"paper","name":"Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial","route":"/key-papers/paper-paradigm-jama-2023/"},{"id":"paper-douillard-prime-panitumumab-ras-nejm-2013","kind":"paper","name":"Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer (PRIME)","route":"/key-papers/paper-douillard-prime-panitumumab-ras-nejm-2013/"},{"id":"paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017","kind":"paper","name":"Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials","route":"/key-papers/paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017/"},{"id":"paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017","kind":"paper","name":"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","route":"/key-papers/paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017/"},{"id":"paper-cms-guinney-nat-med-2015","kind":"paper","name":"The consensus molecular subtypes of colorectal cancer","route":"/key-papers/paper-cms-guinney-nat-med-2015/"},{"id":"paper-bettington-serrated-pathway-colorectal-histopathology-2013","kind":"paper","name":"The serrated pathway to colorectal carcinoma: current concepts and challenges","route":"/key-papers/paper-bettington-serrated-pathway-colorectal-histopathology-2013/"}],"pairing":[{"id":"anti-egfr-left-sided","kind":"pairing","name":"Anti-EGFR antibody + chemotherapy in left-sided RAS/BRAF wild-type mCRC","route":"/pairings/anti-egfr-left-sided/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"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","route":"/roadmaps/colorectal-roadmap/"}],"collection":[{"id":"colorectal-cancer-alliance","kind":"collection","name":"Colorectal Cancer Alliance","route":"/collections/colorectal-cancer-alliance/"}],"biomarker":[{"id":"ras-wild-type","kind":"biomarker","name":"RAS wild-type (extended KRAS and NRAS testing)","route":"/biomarkers/ras-wild-type/"}]}}