Raja R Narayan1,2, Jashodeep Datta3, Debra A Goldman4, Victoria G Aveson1, Henry S Walch5, Francisco Sanchez-Vega5, Mithat Gönen4, Vinod P Balachandran1, Jeffrey A Drebin1, William R Jarnagin1, T Peter Kingham1, Alice C Wei1, Nikolaus Schultz5, Nancy E Kemeny6, Michael I D'Angelica7. 1. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2. Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. 3. Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA. 4. Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 5. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 6. Gastrointestinal Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. dangelim@mskcc.org.
Abstract
BACKGROUND: Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy. METHODS: Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis. RESULTS: Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48-65%) and 51% (95% CI 41-60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43-58%) and 45% (95% CI 36-54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25-50%] vs. 63% [95% CI 53-71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25-48%] vs. 66% [95% CI 56-74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14-40%] vs. 48% [95% CI 39-57%], p-unadj < 0.001), ER (30% [95% CI 17-45%] vs. 62% [95% CI 53-70%], p-unadj < 0.001), and LR rate (40% [95% CI 24-57%] vs. 70% [95% CI 60-77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38-3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06-3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78-4.44, p-unadj < 0.001). CONCLUSIONS: Altered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.
BACKGROUND: Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy. METHODS: Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis. RESULTS: Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48-65%) and 51% (95% CI 41-60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43-58%) and 45% (95% CI 36-54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25-50%] vs. 63% [95% CI 53-71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25-48%] vs. 66% [95% CI 56-74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14-40%] vs. 48% [95% CI 39-57%], p-unadj < 0.001), ER (30% [95% CI 17-45%] vs. 62% [95% CI 53-70%], p-unadj < 0.001), and LR rate (40% [95% CI 24-57%] vs. 70% [95% CI 60-77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38-3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06-3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78-4.44, p-unadj < 0.001). CONCLUSIONS: Altered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.
Authors: Efsevia Vakiani; Manickam Janakiraman; Ronglai Shen; Rileen Sinha; Zhaoshi Zeng; Jinru Shia; Andrea Cercek; Nancy Kemeny; Michael D'Angelica; Agnes Viale; Adriana Heguy; Philip Paty; Timothy A Chan; Leonard B Saltz; Martin Weiser; David B Solit Journal: J Clin Oncol Date: 2012-06-04 Impact factor: 44.544
Authors: Mechteld C de Jong; Carlo Pulitano; Dario Ribero; Jennifer Strub; Gilles Mentha; Richard D Schulick; Michael A Choti; Luca Aldrighetti; Lorenzo Capussotti; Timothy M Pawlik Journal: Ann Surg Date: 2009-09 Impact factor: 12.969
Authors: Georgios Antonios Margonis; Stefan Buettner; Nikolaos Andreatos; Doris Wagner; Kazunari Sasaki; Carlotta Barbon; Andrea Beer; Carsten Kamphues; Inger Marie Løes; Jin He; Timothy M Pawlik; Klaus Kaczirek; George Poultsides; Per Eystein Lønning; John L Cameron; Hans Joerg Mischinger; Federico N Aucejo; Martin E Kreis; Christopher L Wolfgang; Matthew J Weiss Journal: Ann Surg Date: 2019-06 Impact factor: 12.969
Authors: Suguru Yamashita; Yun-Shin Chun; Scott E Kopetz; Dipen Maru; Claudius Conrad; Thomas A Aloia; Jean-Nicolas Vauthey Journal: Ann Surg Date: 2020-12 Impact factor: 12.969
Authors: Paolo Goffredo; Alan F Utria; Anna C Beck; Yun Shin Chun; James R Howe; Ronald J Weigel; Jean-Nicolas Vauthey; Imran Hassan Journal: J Gastrointest Surg Date: 2018-10-01 Impact factor: 3.452
Authors: Rona Yaeger; Elizabeth Cowell; Joanne F Chou; Alexandra N Gewirtz; Laetitia Borsu; Efsevia Vakiani; David B Solit; Neal Rosen; Marinela Capanu; Marc Ladanyi; Nancy Kemeny Journal: Cancer Date: 2014-12-09 Impact factor: 6.860
Authors: James S Tomlinson; William R Jarnagin; Ronald P DeMatteo; Yuman Fong; Peter Kornprat; Mithat Gonen; Nancy Kemeny; Murray F Brennan; Leslie H Blumgart; Michael D'Angelica Journal: J Clin Oncol Date: 2007-10-10 Impact factor: 44.544
Authors: Andrew J Lee; Evelyne M Loyer; Hyunseon C Kang; Thomas A Aloia; Ching-Wei D Tzeng; Jean-Nicolas Vauthey; Yun Shin Chun Journal: Ann Surg Oncol Date: 2018-10-25 Impact factor: 5.344