Georgios A Margonis1, Neda Amini1, Nikolaos Andreatos1, Kazunari Sasaki2, Jack McVey2, Muhammad B Mirza1, Samuel Warner1, Stefan Buettner1, Carlotta Barbon1, Jane Wang1, Alessandra Pulvirenti3, Anastasios Angelou4, Carsten Kamphues5, Efstathios Antoniou4, Emmanouil Pikoulis4, Timothy M Pawlik6, Klaus Kaczirek7, George Poultsides8, Doris Wagner9, Itaru Endo10, Katsunori Imai11, Federico Aucejo2, Martin E Kreis5, Christopher L Wolfgang1, Matthew J Weiss12. 1. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA. 2. Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA. 3. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 4. First Surgery Department, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece. 5. Department of General, Visceral and Vascular Surgery, Charite Campus Benjamin Franklin, Berlin, Germany. 6. Department of Surgery, Wexner Medical Center at the Ohio State University, Columbus, OH, United States. 7. Department of General Surgery, Medical University of Vienna, Vienna, Austria. 8. Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. 9. Department of General Surgery, Medical University of Graz, Graz, Austria. 10. Department of Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan. 11. Department of Gastroenterological Surgery, Graduate School of Life Sciences Kumamoto University, Kumamoto, Japan. 12. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA. Electronic address: mweiss5@jhmi.edu.
Abstract
BACKGROUND: A major response to pre-hepatectomy chemotherapy has been associated with improved survival in patients who undergo resection of colorectal liver metastases (CRLM). However, the role of tumor biology, as exemplified by overall and codon-specific KRAS mutational status, in predicting response to chemotherapy is not well defined. METHODS: Pathologic response was characterized as minor or major depending on the percentage of remnant viable cells (>50% vs <50%, respectively). Multivariable logistic regression was used to identify factors associated with major response. RESULTS: 319 patients met inclusion criteria. 229 patients had a KRAS wild-type (wtKRAS) tumor and 90 harbored KRAS mutations (mutKRAS). A major pathologic response was more commonly noted in patients with wtKRAS compared to mutKRAS (48.5% vs 33.3%, P = 0.01) and wtKRAS status remained independently associated with a major response (P = 0.04). On a codon-specific level, major pathologic response occurred less frequently in those with codon 13 mutations (17.7%) compared to those with codon 12 (35.4%), and other KRAS mutations (33.3%). Importantly, codon 13 mutations were independently associated with minor pathologic response (P = 0.023). CONCLUSIONS: Patients with wtKRAS tumors appear to have the highest likelihood of experiencing a major response after preoperative chemotherapy. Future studies in "all-comer" cohorts are needed to confirm these findings and further investigate the response of codon 13 mutations.
BACKGROUND: A major response to pre-hepatectomy chemotherapy has been associated with improved survival in patients who undergo resection of colorectal liver metastases (CRLM). However, the role of tumor biology, as exemplified by overall and codon-specific KRAS mutational status, in predicting response to chemotherapy is not well defined. METHODS: Pathologic response was characterized as minor or major depending on the percentage of remnant viable cells (>50% vs <50%, respectively). Multivariable logistic regression was used to identify factors associated with major response. RESULTS: 319 patients met inclusion criteria. 229 patients had a KRAS wild-type (wtKRAS) tumor and 90 harbored KRAS mutations (mutKRAS). A major pathologic response was more commonly noted in patients with wtKRAS compared to mutKRAS (48.5% vs 33.3%, P = 0.01) and wtKRAS status remained independently associated with a major response (P = 0.04). On a codon-specific level, major pathologic response occurred less frequently in those with codon 13 mutations (17.7%) compared to those with codon 12 (35.4%), and other KRAS mutations (33.3%). Importantly, codon 13 mutations were independently associated with minor pathologic response (P = 0.023). CONCLUSIONS:Patients with wtKRAS tumors appear to have the highest likelihood of experiencing a major response after preoperative chemotherapy. Future studies in "all-comer" cohorts are needed to confirm these findings and further investigate the response of codon 13 mutations.