Y Sunakawa1, S Stintzing2, S Cao3, V Heinemann2, C Cremolini4, A Falcone4, D Yang3, W Zhang5, Y Ning5, S Stremitzer5, S Matsusaka5, S Yamauchi5, A Parekh5, S Okazaki5, M D Berger5, S Graver6, A Mendez5, S J Scherer6, F Loupakis4, H-J Lenz5. 1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA Division of Medical Oncology, Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama, Japan y.suna0825@gmail.com. 2. Department of Hematology and Oncology, Klinikum der Universität München, Munich, Germany. 3. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA. 4. U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy. 5. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA. 6. Department of Physiological Chemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
Abstract
BACKGROUND: Tumor-associated macrophages (TAMs) with the M2-like phenotype are regulated by mainly NF-kB pathway including TBK1, which can influence tumor progression by secretion of proangiogenic factors such as vascular endothelial growth factor. The CCL2/CCR2 axis, histidine-rich glycoprotein (HRG), and placenta growth factor (PIGF) play a critical role in the polarization of M1/M2 phenotypes and the recruitment of TAMs to tumor microenvironment. We therefore hypothesized that variations in genes involved in regulating TAMs may predict clinical outcomes of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We analyzed genomic DNA extracted from samples of patients receiving bevacizumab plus FOLFIRI as a first-line treatment using PCR-based direct sequencing. Twelve functional single-nucleotide polymorphisms in eight genes (CCL2, CCR2, HRG, PIGF, NFKB1, TBK1, CCL18, and IRF3) were tested for associations with clinical outcomes in a discovery cohort of 228 participants in TRIBE trial (NCT00719797), then validated in 248 KRAS exon2 (KRAS) wild-type participants in FIRE3 trial (NCT00433927). FIRE3-cetuximab cohort served as a negative control. RESULTS: TBK1 rs7486100 was significantly associated with overall survival in 95 KRAS wild-type patients of TRIBE cohort in univariate analysis and had a strong trend in multivariable analysis; furthermore, the association of the T allele was observed for progression-free survival (PFS) in both univariate and multivariable analyses in FIRE3-bevacizumab but not cetuximab cohort. CCL2 rs4586, CCL18 rs14304, and IRF3 rs2304205 had univariate and multivariable correlations with PFS in KRAS mutant patients of the TRIBE cohort, whereas they had no correlations in KRAS wild-type patients of the TRIBE cohort. No association was seen in control cohort. CONCLUSIONS: Our study demonstrates for the first time that variations in genes regulating TAMs-related functions are significantly associated with clinical outcomes in mCRC patients treated with bevacizumab-containing chemotherapy. These results also suggest that some TAM-related gene variations may predict outcomes of bevacizumab treatment in KRAS status-dependent manner.
RCT Entities:
BACKGROUND:Tumor-associated macrophages (TAMs) with the M2-like phenotype are regulated by mainly NF-kB pathway including TBK1, which can influence tumor progression by secretion of proangiogenic factors such as vascular endothelial growth factor. The CCL2/CCR2 axis, histidine-rich glycoprotein (HRG), and placenta growth factor (PIGF) play a critical role in the polarization of M1/M2 phenotypes and the recruitment of TAMs to tumor microenvironment. We therefore hypothesized that variations in genes involved in regulating TAMs may predict clinical outcomes of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We analyzed genomic DNA extracted from samples of patients receiving bevacizumab plus FOLFIRI as a first-line treatment using PCR-based direct sequencing. Twelve functional single-nucleotide polymorphisms in eight genes (CCL2, CCR2, HRG, PIGF, NFKB1, TBK1, CCL18, and IRF3) were tested for associations with clinical outcomes in a discovery cohort of 228 participants in TRIBE trial (NCT00719797), then validated in 248 KRAS exon2 (KRAS) wild-type participants in FIRE3 trial (NCT00433927). FIRE3-cetuximab cohort served as a negative control. RESULTS:TBK1rs7486100 was significantly associated with overall survival in 95 KRAS wild-type patients of TRIBE cohort in univariate analysis and had a strong trend in multivariable analysis; furthermore, the association of the T allele was observed for progression-free survival (PFS) in both univariate and multivariable analyses in FIRE3-bevacizumab but not cetuximab cohort. CCL2rs4586, CCL18rs14304, and IRF3rs2304205 had univariate and multivariable correlations with PFS in KRAS mutant patients of the TRIBE cohort, whereas they had no correlations in KRAS wild-type patients of the TRIBE cohort. No association was seen in control cohort. CONCLUSIONS: Our study demonstrates for the first time that variations in genes regulating TAMs-related functions are significantly associated with clinical outcomes in mCRC patients treated with bevacizumab-containing chemotherapy. These results also suggest that some TAM-related gene variations may predict outcomes of bevacizumab treatment in KRAS status-dependent manner.
Authors: Johan Forssell; Ake Oberg; Maria L Henriksson; Roger Stenling; Andreas Jung; Richard Palmqvist Journal: Clin Cancer Res Date: 2007-03-01 Impact factor: 12.531
Authors: Christian Korherr; Hendrik Gille; Rolf Schäfer; Kerstin Koenig-Hoffmann; Johan Dixelius; Kristi A Egland; Ira Pastan; Ulrich Brinkmann Journal: Proc Natl Acad Sci U S A Date: 2006-03-06 Impact factor: 11.205
Authors: Volker Heinemann; Ludwig Fischer von Weikersthal; Thomas Decker; Alexander Kiani; Ursula Vehling-Kaiser; Salah-Eddin Al-Batran; Tobias Heintges; Christian Lerchenmüller; Christoph Kahl; Gernot Seipelt; Frank Kullmann; Martina Stauch; Werner Scheithauer; Jörg Hielscher; Michael Scholz; Sebastian Müller; Hartmut Link; Norbert Niederle; Andreas Rost; Heinz-Gert Höffkes; Markus Moehler; Reinhard U Lindig; Dominik P Modest; Lisa Rossius; Thomas Kirchner; Andreas Jung; Sebastian Stintzing Journal: Lancet Oncol Date: 2014-07-31 Impact factor: 41.316
Authors: David A Barbie; Pablo Tamayo; Jesse S Boehm; So Young Kim; Susan E Moody; Ian F Dunn; Anna C Schinzel; Peter Sandy; Etienne Meylan; Claudia Scholl; Stefan Fröhling; Edmond M Chan; Martin L Sos; Kathrin Michel; Craig Mermel; Serena J Silver; Barbara A Weir; Jan H Reiling; Qing Sheng; Piyush B Gupta; Raymond C Wadlow; Hanh Le; Sebastian Hoersch; Ben S Wittner; Sridhar Ramaswamy; David M Livingston; David M Sabatini; Matthew Meyerson; Roman K Thomas; Eric S Lander; Jill P Mesirov; David E Root; D Gary Gilliland; Tyler Jacks; William C Hahn Journal: Nature Date: 2009-10-21 Impact factor: 49.962
Authors: E Gabriela Chiorean; Susan M Perkins; R Matthew Strother; Anne Younger; Jennifer M Funke; Safi G Shahda; Noah M Hahn; Kumar Sandrasegaran; David R Jones; Todd C Skaar; Bryan P Schneider; Christopher J Sweeney; Daniela E Matei Journal: Mol Cancer Ther Date: 2020-08-26 Impact factor: 6.261
Authors: Ana Barat; Dominiek Smeets; Bruce Moran; Wu Zhang; Shu Cao; Sudipto Das; Rut Klinger; Johannes Betge; Verena Murphy; Orna Bacon; Elaine W Kay; Nicole C T Van Grieken; Henk M W Verheul; Timo Gaiser; Nadine Schulte; Matthias P Ebert; Bozena Fender; Bryan T Hennessy; Deborah A McNamara; Darran O'Connor; William M Gallagher; Chiara Cremolini; Fotios Loupakis; Aparna Parikh; Christoph Mancao; Bauke Ylstra; Diether Lambrechts; Heinz-Josef Lenz; Annette T Byrne; Jochen H M Prehn Journal: Sci Rep Date: 2020-06-17 Impact factor: 4.379