{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:25:41Z","timestamp":1787009141375,"version":"build-2736575974"},"reference-count":15,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"ARCAD Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation\/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared with right-sided metastatic colorectal cancer patients (n\u2009=\u20092421, 26.1%), left-sided metastatic colorectal cancer patients (n\u2009=\u20096856, 73.9%) had better OS (median = 21.6 vs 15.9\u2009months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67 to 0.76; P &amp;lt; .001) and PFS (median = 8.6 vs 7.5\u2009months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P &amp;lt; .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction &amp;lt; .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P\u2009=\u2009.01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P &amp;lt; .001) but not for right-sidedness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jnci\/djab112","type":"journal-article","created":{"date-parts":[[2021,5,30]],"date-time":"2021-05-30T23:06:58Z","timestamp":1622416018000},"page":"1705-1713","source":"Crossref","is-referenced-by-count":25,"title":["Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer"],"prefix":"10.1093","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3242-9664","authenticated-orcid":false,"given":"Jun","family":"Yin","sequence":"first","affiliation":[{"name":"Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-5162","authenticated-orcid":false,"given":"Romain","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Saint-Antoine Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7844-5833","authenticated-orcid":false,"given":"Zhaohui","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heshan","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5902-8882","authenticated-orcid":false,"given":"Levi","family":"Pederson","sequence":"additional","affiliation":[{"name":"Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3915-7243","authenticated-orcid":false,"given":"Richard","family":"Adams","sequence":"additional","affiliation":[{"name":"Cardiff University and Velindre Cancer Centre, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Grothey","sequence":"additional","affiliation":[{"name":"West Cancer Center and Research Institute, OneOncology, Germantown, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0580-5065","authenticated-orcid":false,"given":"Timothy S","family":"Maughan","sequence":"additional","affiliation":[{"name":"CRUK\/MRC Oxford Institute for Radiation Oncology, Oxford, UK"},{"name":"St James\u2019s Hospital, University of Leeds, Leeds, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Venook","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Van Cutsem","sequence":"additional","affiliation":[{"name":"Digestive Oncology, University Hospitals Gasthuisberg Leuven, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelis","family":"Punt","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1550-1978","authenticated-orcid":false,"given":"Miriam","family":"Koopman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5840-2529","authenticated-orcid":false,"given":"Alfredo","family":"Falcone","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niall C","family":"Tebbutt","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Austin Health, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2441-9629","authenticated-orcid":false,"given":"Matthew T","family":"Seymour","sequence":"additional","affiliation":[{"name":"NIHR Clinical Research Network, St James\u2019s Hospital, University of Leeds, Leeds, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6071-7810","authenticated-orcid":false,"given":"Carsten","family":"Bokemeyer","sequence":"additional","affiliation":[{"name":"Department of Oncology, Haematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Diaz","family":"Rubio","sequence":"additional","affiliation":[{"name":"Universidad Complutense Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0189-8348","authenticated-orcid":false,"given":"Richard","family":"Kaplan","sequence":"additional","affiliation":[{"name":"MRC Clinical Trials Unit at UCL, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1349-3321","authenticated-orcid":false,"given":"Volker","family":"Heinemann","sequence":"additional","affiliation":[{"name":"University Hospital Grosshadern, Ludwig Maximilian University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoist","family":"Chibaudel","sequence":"additional","affiliation":[{"name":"Institut Franco-Britannique, Levallois-Perret, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Yoshino","sequence":"additional","affiliation":[{"name":"National Cancer Center Hospital East, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6624-0782","authenticated-orcid":false,"given":"John","family":"Zalcberg","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5103-7095","authenticated-orcid":false,"given":"Thierry","family":"Andre","sequence":"additional","affiliation":[{"name":"H\u00f4pital Saint-Antoine, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7940-9877","authenticated-orcid":false,"given":"Aimery","family":"De Gramont","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4640-8832","authenticated-orcid":false,"given":"Qian","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2178-9568","authenticated-orcid":false,"given":"Heinz-Josef","family":"Lenz","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Oncology, Keck School of Medicine at USC, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"issue":"3","key":"2021120111054766500_djab112-B1","doi-asserted-by":"crossref","DOI":"10.1093\/jnci\/dju427","article-title":"Primary tumor location as a prognostic factor in metastatic colorectal cancer","volume":"107","author":"Loupakis","year":"2015","journal-title":"J Natl Cancer Inst"},{"issue":"8","key":"2021120111054766500_djab112-B2","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1093\/annonc\/mdx175","article-title":"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","volume":"28","author":"Arnold","year":"2017","journal-title":"Ann Oncol"},{"issue":"5","key":"2021120111054766500_djab112-B3","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1001\/jamaoncol.2015.5226","article-title":"Microsatellite instability and BRAF and KRAS mutations in stage III colon cancer: requirements for accurate prognosis assessment","volume":"2","author":"Klingbiel","year":"2016","journal-title":"JAMA Oncol"},{"issue":"3","key":"2021120111054766500_djab112-B4","doi-asserted-by":"crossref","first-page":"e171","DOI":"10.1016\/j.clcc.2016.09.010","article-title":"Prognostic impact of primary tumor location on clinical outcomes of metastatic colorectal cancer treated with cetuximab plus oxaliplatin-based chemotherapy: a subgroup analysis of the JACCRO CC-05\/06 trials","volume":"16","author":"Sunakawa","year":"2017","journal-title":"Clin Colorectal Cancer"},{"issue":"3","key":"2021120111054766500_djab112-B5","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.clcc.2020.02.012","article-title":"Understanding the prognostic value of primary tumor location and KRAS in metastatic colorectal cancer: a post hoc analysis of the OPTIMOX3 DREAM phase III study","volume":"19","author":"Chibaudel","year":"2020","journal-title":"Clin Colorectal Cancer"},{"issue":"7","key":"2021120111054766500_djab112-B6","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1093\/annonc\/mdy140","article-title":"Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO","volume":"29","author":"Cremolini","year":"2018","journal-title":"Ann Oncol"},{"issue":"2","key":"2021120111054766500_djab112-B7","doi-asserted-by":"crossref","first-page":"e77","DOI":"10.1634\/theoncologist.2018-0180","article-title":"Another chapter of the right versus left story: Is primary tumor location a prognostic feature in RAS mutant metastatic colorectal cancer?","volume":"24","author":"Loupakis","year":"2019","journal-title":"Oncologist"},{"key":"2021120111054766500_djab112-B8","doi-asserted-by":"crossref","first-page":"3504","DOI":"10.1200\/JCO.2016.34.15_suppl.3504","article-title":"Impact of primary (1\u00ba) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB\/SWOG 80405 (Alliance)","volume":"34(15_suppl","author":"Venook","year":"2016","journal-title":"J Clin Oncol"},{"issue":"6","key":"2021120111054766500_djab112-B9","first-page":"e000599","article-title":"Tumour location and efficacy of first-line EGFR inhibitors in KRAS\/RAS wild-type metastatic colorectal cancer: retrospective analyses of two phase II randomised Spanish TTD trials","volume":"4","author":"Benavides","year":"2019","journal-title":"ESMO Open"},{"issue":"3","key":"2021120111054766500_djab112-B10","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41416-018-0165-z","article-title":"Relationships between tumour response and primary tumour location, and predictors of long-term survival, in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab therapy: retrospective analyses of the PRIME and PEAK clinical trials","volume":"119","author":"Peeters","year":"2018","journal-title":"Br J Cancer"},{"issue":"8","key":"2021120111054766500_djab112-B11","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1093\/annonc\/mdx119","article-title":"Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies","volume":"28","author":"Boeckx","year":"2017","journal-title":"Ann Oncol"},{"issue":"1","key":"2021120111054766500_djab112-B12","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/annonc\/mdy461","article-title":"Biomarker analysis beyond angiogenesis: RAS\/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study","volume":"30","author":"Yoshino","year":"2019","journal-title":"Ann Oncol"},{"issue":"12","key":"2021120111054766500_djab112-B13","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1038\/s41416-018-0304-6","article-title":"Impact of primary tumour location on efficacy of bevacizumab plus chemotherapy in metastatic colorectal cancer","volume":"119","author":"Loupakis","year":"2018","journal-title":"Br J Cancer"},{"issue":"1","key":"2021120111054766500_djab112-B14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/biomet\/70.1.41","article-title":"The central role of the propensity score in observational studies for causal effects","volume":"70","author":"Rosenbaum","year":"1983","journal-title":"Biometrika"},{"issue":"2","key":"2021120111054766500_djab112-B15","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1200\/JCO.2015.63.9674","article-title":"Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion update 2015","volume":"34","author":"Allegra","year":"2016","journal-title":"J Clin Oncol"}],"container-title":["JNCI: Journal of the National Cancer Institute"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jnci\/advance-article-pdf\/doi\/10.1093\/jnci\/djab112\/39708054\/djab112.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jnci\/article-pdf\/113\/12\/1705\/41382039\/djab112.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jnci\/article-pdf\/113\/12\/1705\/41382039\/djab112.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T10:38:34Z","timestamp":1638355114000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jnci\/article\/113\/12\/1705\/6290718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,1]]},"references-count":15,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,6,1]]},"published-print":{"date-parts":[[2021,11,29]]}},"URL":"https:\/\/doi.org\/10.1093\/jnci\/djab112","relation":{},"ISSN":["0027-8874","1460-2105"],"issn-type":[{"value":"0027-8874","type":"print"},{"value":"1460-2105","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,1]]},"published":{"date-parts":[[2021,6,1]]}}}