Jonathan B Yuval1, Jasme Lee2, Fan Wu3, Hannah M Thompson1, Floris S Verheij1, Hersh V Gupta4, Takeshi Irie5, Joseph R Scarpa6, Patrick J McCormick5, J Joshua Smith1, Jinru Shia7, Martin R Weiser1, Francisco Sánchez-Vega3, Kay See Tan2, Gregory W Fischer5, Julio Garcia-Aguilar1, Joshua S Mincer8. 1. Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2. Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 4. Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. 5. Department of Anesthesiology & Critical Care Medicine, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA. 6. Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA. 7. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 8. Department of Anesthesiology & Critical Care Medicine, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA. Electronic address: mincerj@mskcc.org.
Abstract
BACKGROUND: Opioid-induced immunomodulation may be important in colon adenocarcinoma, where tumour DNA mismatch repair (MMR) can determine the level of immune activation with consequences for therapeutic response and prognosis. We evaluated the relationship between intraoperative opioid exposure, MMR subtype, and oncological outcomes after surgery for colon adenocarcinoma. METHODS: Intraoperative opioid use (standardised by calculating morphine milligram equivalents) during stage I-III colon adenocarcinoma resection was reviewed retrospectively. Tumours were classified as DNA mismatch repair deficient (dMMR) or proficient (pMMR) by immunohistochemistry. The primary outcome was local tumour recurrence, distant tumour recurrence, or both (multivariable analysis). The exposures of interest were intraoperative analgesia and tumour subtype. Opioid-related gene expression was analysed using The Cancer Genome Atlas Colon Adenocarcinoma transcriptomic data. RESULTS: Clinical and pathological data were analysed from 1157 subjects (median age, 60 [51-70] yr; 49% female) who underwent curative resection for stage I-III colon adenocarcinoma. Higher intraoperative opioid doses were associated with reduced risk of tumour recurrence (hazard ratio=0.92 per 10 morphine milligram equivalents; 95% confidence interval [95% CI], 0.87-0.98; P=0.007), but not with overall survival. In tumours deficient in DNA MMR, tumour recurrence was less likely (HR=0.38; 95% CI, 0.21-0.68; P=0.001), with higher opioid dose associated with eightfold lower recurrence rates. Gene expression related to opioid signalling was different between dMMR and pMMR tumours. CONCLUSIONS: Higher intraoperative opioid dose was associated with a lower risk of tumour recurrence after surgery for stage I-III colon adenocarcinoma, but particularly so in tumours in which DNA MMR was deficient.
BACKGROUND: Opioid-induced immunomodulation may be important in colon adenocarcinoma, where tumour DNA mismatch repair (MMR) can determine the level of immune activation with consequences for therapeutic response and prognosis. We evaluated the relationship between intraoperative opioid exposure, MMR subtype, and oncological outcomes after surgery for colon adenocarcinoma. METHODS: Intraoperative opioid use (standardised by calculating morphine milligram equivalents) during stage I-III colon adenocarcinoma resection was reviewed retrospectively. Tumours were classified as DNA mismatch repair deficient (dMMR) or proficient (pMMR) by immunohistochemistry. The primary outcome was local tumour recurrence, distant tumour recurrence, or both (multivariable analysis). The exposures of interest were intraoperative analgesia and tumour subtype. Opioid-related gene expression was analysed using The Cancer Genome Atlas Colon Adenocarcinoma transcriptomic data. RESULTS: Clinical and pathological data were analysed from 1157 subjects (median age, 60 [51-70] yr; 49% female) who underwent curative resection for stage I-III colon adenocarcinoma. Higher intraoperative opioid doses were associated with reduced risk of tumour recurrence (hazard ratio=0.92 per 10 morphine milligram equivalents; 95% confidence interval [95% CI], 0.87-0.98; P=0.007), but not with overall survival. In tumours deficient in DNA MMR, tumour recurrence was less likely (HR=0.38; 95% CI, 0.21-0.68; P=0.001), with higher opioid dose associated with eightfold lower recurrence rates. Gene expression related to opioid signalling was different between dMMR and pMMR tumours. CONCLUSIONS: Higher intraoperative opioid dose was associated with a lower risk of tumour recurrence after surgery for stage I-III colon adenocarcinoma, but particularly so in tumours in which DNA MMR was deficient.
Authors: Dung T Le; Jennifer N Uram; Hao Wang; Bjarne R Bartlett; Holly Kemberling; Aleksandra D Eyring; Andrew D Skora; Brandon S Luber; Nilofer S Azad; Dan Laheru; Barbara Biedrzycki; Ross C Donehower; Atif Zaheer; George A Fisher; Todd S Crocenzi; James J Lee; Steven M Duffy; Richard M Goldberg; Albert de la Chapelle; Minori Koshiji; Feriyl Bhaijee; Thomas Huebner; Ralph H Hruban; Laura D Wood; Nathan Cuka; Drew M Pardoll; Nickolas Papadopoulos; Kenneth W Kinzler; Shibin Zhou; Toby C Cornish; Janis M Taube; Robert A Anders; James R Eshleman; Bert Vogelstein; Luis A Diaz Journal: N Engl J Med Date: 2015-05-30 Impact factor: 91.245
Authors: Nicolas J Llosa; Michael Cruise; Ada Tam; Elizabeth C Wicks; Elizabeth M Hechenbleikner; Janis M Taube; Richard L Blosser; Hongni Fan; Hao Wang; Brandon S Luber; Ming Zhang; Nickolas Papadopoulos; Kenneth W Kinzler; Bert Vogelstein; Cynthia L Sears; Robert A Anders; Drew M Pardoll; Franck Housseau Journal: Cancer Discov Date: 2014-10-30 Impact factor: 39.397
Authors: Christine M Ribic; Daniel J Sargent; Malcolm J Moore; Stephen N Thibodeau; Amy J French; Richard M Goldberg; Stanley R Hamilton; Pierre Laurent-Puig; Robert Gryfe; Lois E Shepherd; Dongsheng Tu; Mark Redston; Steven Gallinger Journal: N Engl J Med Date: 2003-07-17 Impact factor: 91.245
Authors: Joseph R Scarpa; Renzo G DiNatale; Roy Mano; Andrew W Silagy; Fengshen Kuo; Takeshi Irie; Patrick J McCormick; Gregory W Fischer; A Ari Hakimi; Joshua S Mincer Journal: Cancer Res Date: 2020-12-14 Impact factor: 13.312
Authors: Giacomo Montagna; Hersh V Gupta; Margaret Hannum; Kay See Tan; Jasme Lee; Joseph R Scarpa; George Plitas; Takeshi Irie; Patrick J McCormick; Gregory W Fischer; Monica Morrow; Joshua S Mincer Journal: Br J Anaesth Date: 2020-11-19 Impact factor: 9.166