APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Moffitt CRC Patient Samples
2.2. CMS Classification
2.3. Cetuximab Sensitivity Signature Score
2.4. Validation CRC Datasets
2.5. Statistical Analyses
3. Results
3.1. Baseline Characteristics of Moffitt CRC Tumors
3.2. Frequency of 2-Gene AP Mutation Signature across the CMS Classes
3.3. Predictive Role of 2-Gene AP Mutation Signature across the CMS Classes
3.4. Prognostic Role of 2-Gene AP Mutation Signature and CMS Classes
3.5. Predictive Role of 2-Gene AP Mutation Signature/CMS Classes in TCGA CRC Tumors
3.6. Predictive Role of 2-Gene AP Mutation Signature/CMS Classes in PDMR CRC Models
3.7. The In Vitro Cetuximab Growth Inhibition Was Preferentially Associated with the CMS2 CRC Cell Lines Harboring MUT A/P Genotypes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Allegra, C.J.; Rumble, R.B.; Hamilton, S.R.; Mangu, P.B.; Roach, N.; Hantel, A.; Schilsky, R.L. 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. J. Clin. Oncol. 2016, 34, 179–185. [Google Scholar] [CrossRef]
- Douillard, J.Y.; Siena, S.; Cassidy, J.; Tabernero, J.; Burkes, R.; Barugel, M.; Humblet, Y.; Bodoky, G.; Cunningham, D.; Jassem, J.; et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J. Clin. Oncol. 2010, 28, 4697–4705. [Google Scholar] [CrossRef]
- Maughan, T.S.; Adams, R.A.; Smith, C.G.; Meade, A.M.; Seymour, M.T.; Wilson, R.H.; Idziaszczyk, S.; Harris, R.; Fisher, D.; Kenny, S.L.; et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: Results of the randomised phase 3 MRC COIN trial. Lancet 2011, 377, 2103–2114. [Google Scholar] [CrossRef] [Green Version]
- Qin, S.; Li, J.; Wang, L.; Xu, J.; Cheng, Y.; Bai, Y.; Li, W.; Xu, N.; Lin, L.Z.; Wu, Q.; et al. Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients with RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial. J. Clin. Oncol. 2018, 36, 3031–3039. [Google Scholar] [CrossRef] [PubMed]
- Van Cutsem, E.; Kohne, C.H.; Hitre, E.; Zaluski, J.; Chang Chien, C.R.; Makhson, A.; D’Haens, G.; Pinter, T.; Lim, R.; Bodoky, G.; et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 2009, 360, 1408–1417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Boeckx, N.; Koukakis, R.; Op de Beeck, K.; Rolfo, C.; Van Camp, G.; Siena, S.; Tabernero, J.; Douillard, J.Y.; Andre, T.; Peeters, M. Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: Results from two randomized first-line panitumumab studies. Ann. Oncol. 2017, 28, 1862–1868. [Google Scholar] [CrossRef] [PubMed]
- Arnold, D.; Lueza, B.; Douillard, J.Y.; Peeters, M.; Lenz, H.J.; Venook, A.; Heinemann, V.; Van Cutsem, E.; Pignon, J.P.; Tabernero, J.; et al. 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. Ann. Oncol. 2017, 28, 1713–1729. [Google Scholar] [CrossRef] [PubMed]
- Lenz, H.J.; Ou, F.S.; Venook, A.P.; Hochster, H.S.; Niedzwiecki, D.; Goldberg, R.M.; Mayer, R.J.; Bertagnolli, M.M.; Blanke, C.D.; Zemla, T.; et al. Impact of Consensus Molecular Subtype on Survival in Patients with Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance). J. Clin. Oncol. 2019, 37, 1876–1885. [Google Scholar] [CrossRef]
- Stintzing, S.; Wirapati, P.; Lenz, H.J.; Neureiter, D.; Fischer von Weikersthal, L.; Decker, T.; Kiani, A.; Kaiser, F.; Al-Batran, S.; Heintges, T.; et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. Ann. Oncol. 2019, 30, 1796–1803. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guinney, J.; Dienstmann, R.; Wang, X.; de Reynies, A.; Schlicker, A.; Soneson, C.; Marisa, L.; Roepman, P.; Nyamundanda, G.; Angelino, P.; et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015, 21, 1350–1356. [Google Scholar] [CrossRef]
- Chang, K.; Willis, J.A.; Reumers, J.; Taggart, M.W.; San Lucas, F.A.; Thirumurthi, S.; Kanth, P.; Delker, D.A.; Hagedorn, C.H.; Lynch, P.M.; et al. Colorectal premalignancy is associated with consensus molecular subtypes 1 and 2. Ann. Oncol. 2018, 29, 2061–2067. [Google Scholar] [CrossRef] [PubMed]
- Fontana, E.; Eason, K.; Cervantes, A.; Salazar, R.; Sadanandam, A. Context matters-consensus molecular subtypes of colorectal cancer as biomarkers for clinical trials. Ann. Oncol. 2019, 30, 520–527. [Google Scholar] [CrossRef] [PubMed]
- Loree, J.M.; Pereira, A.A.L.; Lam, M.; Willauer, A.N.; Raghav, K.; Dasari, A.; Morris, V.K.; Advani, S.; Menter, D.G.; Eng, C.; et al. Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes. Clin. Cancer Res. 2018, 24, 1062–1072. [Google Scholar] [CrossRef] [Green Version]
- Mooi, J.K.; Wirapati, P.; Asher, R.; Lee, C.K.; Savas, P.; Price, T.J.; Townsend, A.; Hardingham, J.; Buchanan, D.; Williams, D.; et al. The prognostic impact of consensus molecular subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: Molecular analysis of the AGITG MAX clinical trial. Ann. Oncol. 2018, 29, 2240–2246. [Google Scholar] [CrossRef]
- Marisa, L.; Ayadi, M.; Balogoun, R.; Pilati, C.; Le Malicot, K.; Lepage, C.; Emile, J.-F.; Salazar, R.; Aust, D.E.; Duval, A.; et al. Clinical utility of colon cancer molecular subtypes: Validation of two main colorectal molecular classifications on the PETACC-8 phase III trial cohort. J. Clin. Oncol. 2017, 35 (Suppl. S15), 3509. [Google Scholar] [CrossRef]
- Okita, A.; Takahashi, S.; Ouchi, K.; Inoue, M.; Watanabe, M.; Endo, M.; Honda, H.; Yamada, Y.; Ishioka, C. Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer. Oncotarget 2018, 9, 18698–18711. [Google Scholar] [CrossRef] [PubMed]
- Pogue-Geile, K.L.; Andre, T.; Song, N.; Lipchik, C.; Wang, Y.; Kim, R.S.; Feng, H.; Gavin, P.; Van Laethem, J.-L.; Srinivasan, A.; et al. Association of colon cancer (CC) molecular signatures with prognosis and oxaliplatin prediction-benefit in the MOSAIC Trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer). J. Clin. Oncol. 2019, 37, abstr 3503. [Google Scholar] [CrossRef]
- Song, N.; Pogue-Geile, K.L.; Gavin, P.G.; Yothers, G.; Kim, S.R.; Johnson, N.L.; Lipchik, C.; Allegra, C.J.; Petrelli, N.J.; O’Connell, M.J.; et al. Clinical Outcome From Oxaliplatin Treatment in Stage II/III Colon Cancer According to Intrinsic Subtypes: Secondary Analysis of NSABP C-07/NRG Oncology Randomized Clinical Trial. JAMA Oncol. 2016, 2, 1162–1169. [Google Scholar] [CrossRef]
- Sawayama, H.; Miyamoto, Y.; Ogawa, K.; Yoshida, N.; Baba, H. Investigation of colorectal cancer in accordance with consensus molecular subtype classification. Ann. Gastroenterol. Surg. 2020, 4, 528–539. [Google Scholar] [CrossRef]
- Trinh, A.; Trumpi, K.; De Sousa, E.M.F.; Wang, X.; de Jong, J.H.; Fessler, E.; Kuppen, P.J.; Reimers, M.S.; Swets, M.; Koopman, M.; et al. Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry. Clin. Cancer Res. 2017, 23, 387–398. [Google Scholar] [CrossRef] [Green Version]
- Dienstmann, R.; Vermeulen, L.; Guinney, J.; Kopetz, S.; Tejpar, S.; Tabernero, J. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat. Rev. Cancer 2017, 17, 79–92. [Google Scholar] [CrossRef]
- Lal, N.; White, B.S.; Goussous, G.; Pickles, O.; Mason, M.J.; Beggs, A.D.; Taniere, P.; Willcox, B.E.; Guinney, J.; Middleton, G.W. KRAS Mutation and Consensus Molecular Subtypes 2 and 3 Are Independently Associated with Reduced Immune Infiltration and Reactivity in Colorectal Cancer. Clin. Cancer Res. 2018, 24, 224–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fearon, E.R.; Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 1990, 61, 759–767. [Google Scholar] [CrossRef]
- Fearon, E.R. Molecular genetics of colorectal cancer. Annu. Rev. Pathol. 2011, 6, 479–507. [Google Scholar] [CrossRef]
- Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012, 487, 330–337. [Google Scholar] [CrossRef] [Green Version]
- Giannakis, M.; Mu, X.J.; Shukla, S.A.; Qian, Z.R.; Cohen, O.; Nishihara, R.; Bahl, S.; Cao, Y.; Amin-Mansour, A.; Yamauchi, M.; et al. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep. 2016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schell, M.J.; Yang, M.; Teer, J.K.; Lo, F.Y.; Madan, A.; Coppola, D.; Monteiro, A.N.; Nebozhyn, M.V.; Yue, B.; Loboda, A.; et al. A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC. Nat. Commun. 2016, 7, 11743. [Google Scholar] [CrossRef] [Green Version]
- Yang, M.; Schell, M.J.; Loboda, A.; Nebozhyn, M.; Li, J.; Teer, J.K.; Pledger, W.J.; Yeatman, T.J. Repurposing EGFR Inhibitor Utility in Colorectal Cancer in Mutant APC and TP53 Subpopulations. Cancer Epidemiol. Biomark. Prev. 2019, 28, 1141–1152. [Google Scholar] [CrossRef] [Green Version]
- Schell, M.J.; Yang, M.; Missiaglia, E.; Delorenzi, M.; Soneson, C.; Yue, B.; Nebozhyn, M.V.; Loboda, A.; Bloom, G.; Yeatman, T.J. A Composite Gene Expression Signature Optimizes Prediction of Colorectal Cancer Metastasis and Outcome. Clin. Cancer Res. 2016, 22, 734–745. [Google Scholar] [CrossRef] [Green Version]
- Fenstermacher, D.A.; Wenham, R.M.; Rollison, D.E.; Dalton, W.S. Implementing personalized medicine in a cancer center. Cancer J. 2011, 17, 528–536. [Google Scholar] [CrossRef] [Green Version]
- Eide, P.W.; Bruun, J.; Lothe, R.A.; Sveen, A. CMScaller: An R package for consensus molecular subtyping of colorectal cancer pre-clinical models. Sci. Rep. 2017, 7, 16618. [Google Scholar] [CrossRef] [Green Version]
- Hoadley, K.A.; Yau, C.; Hinoue, T.; Wolf, D.M.; Lazar, A.J.; Drill, E.; Shen, R.; Taylor, A.M.; Cherniack, A.D.; Thorsson, V.; et al. Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. Cell 2018, 173, 291–304.e296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, B.; Dewey, C.N. RSEM: Accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform. 2011, 12, 323. [Google Scholar] [CrossRef] [Green Version]
- Medico, E.; Russo, M.; Picco, G.; Cancelliere, C.; Valtorta, E.; Corti, G.; Buscarino, M.; Isella, C.; Lamba, S.; Martinoglio, B.; et al. The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets. Nat. Commun. 2015, 6, 7002. [Google Scholar] [CrossRef] [PubMed]
- Davis, S.; Meltzer, P.S. GEOquery: A bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics 2007, 23, 1846–1847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pagès, H.; Carlson, M.; Falcon, S.; Li, N. AnnotationDbi: Manipulation of SQLite-Based Annotations in Bioconductor. R Package Version 1.54.1. 2021. Available online: https://bioconductor.org/packages/AnnotationDbi (accessed on 19 November 2020).
- Aderka, D.; Stintzing, S.; Heinemann, V. Explaining the unexplainable: Discrepancies in results from the CALGB/SWOG 80405 and FIRE-3 studies. Lancet Oncol. 2019, 20, e274–e283. [Google Scholar] [CrossRef]
- DePristo, M.A.; Banks, E.; Poplin, R.; Garimella, K.V.; Maguire, J.R.; Hartl, C.; Philippakis, A.A.; del Angel, G.; Rivas, M.A.; Hanna, M.; et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 2011, 43, 491–498. [Google Scholar] [CrossRef]
- Dunne, P.D.; Alderdice, M.; O’Reilly, P.G.; Roddy, A.C.; McCorry, A.M.B.; Richman, S.; Maughan, T.; McDade, S.S.; Johnston, P.G.; Longley, D.B.; et al. Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification. Nat. Commun. 2017, 8, 15657. [Google Scholar] [CrossRef] [Green Version]
- Mahipal, A.; Grothey, A. Role of Biologics in First-Line Treatment of Colorectal Cancer. J. Oncol. Pract. 2016, 12, 1219–1228. [Google Scholar] [CrossRef]
- von Einem, J.C.; Heinemann, V.; von Weikersthal, L.F.; Vehling-Kaiser, U.; Stauch, M.; Hass, H.G.; Decker, T.; Klein, S.; Held, S.; Jung, A.; et al. Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: An analysis of the AIO KRK-0104 trial. J. Cancer Res. Clin. Oncol. 2014, 140, 1607–1614. [Google Scholar] [CrossRef] [Green Version]
- Tejpar, S.; Stintzing, S.; Ciardiello, F.; Tabernero, J.; Van Cutsem, E.; Beier, F.; Esser, R.; Lenz, H.J.; Heinemann, V. Prognostic and Predictive Relevance of Primary Tumor Location in Patients with RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials. JAMA Oncol. 2016, 3, 194–201. [Google Scholar] [CrossRef] [PubMed]
- Holch, J.W.; Ricard, I.; Stintzing, S.; Modest, D.P.; Heinemann, V. The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials. Eur. J. Cancer 2017, 70, 87–98. [Google Scholar] [CrossRef] [PubMed]
- Moran, A.E.; Hunt, D.H.; Javid, S.H.; Redston, M.; Carothers, A.M.; Bertagnolli, M.M. Apc deficiency is associated with increased Egfr activity in the intestinal enterocytes and adenomas of C57BL/6J-Min/+ mice. J. Biol. Chem. 2004, 279, 43261–43272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pai, R.; Soreghan, B.; Szabo, I.L.; Pavelka, M.; Baatar, D.; Tarnawski, A.S. Prostaglandin E2 transactivates EGF receptor: A novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat. Med. 2002, 8, 289–293. [Google Scholar] [CrossRef] [PubMed]
- Stoddart, A.; Fernald, A.A.; Wang, J.; Davis, E.M.; Karrison, T.; Anastasi, J.; Le Beau, M.M. Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice. Blood 2014, 123, 1069–1078. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sauer, L.; Gitenay, D.; Vo, C.; Baron, V.T. Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells. Oncogene 2010, 29, 2628–2637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Garcia-Foncillas, J.; Sunakawa, Y.; Aderka, D.; Wainberg, Z.; Ronga, P.; Witzler, P.; Stintzing, S. Distinguishing Features of Cetuximab and Panitumumab in Colorectal Cancer and Other Solid Tumors. Front. Oncol. 2019, 9, 849. [Google Scholar] [CrossRef]
- Seo, Y.; Ishii, Y.; Ochiai, H.; Fukuda, K.; Akimoto, S.; Hayashida, T.; Okabayashi, K.; Tsuruta, M.; Hasegawa, H.; Kitagawa, Y. Cetuximab-mediated ADCC activity is correlated with the cell surface expression level of EGFR but not with the KRAS/BRAF mutational status in colorectal cancer. Oncol. Rep. 2014, 31, 2115–2122. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Turin, I.; Delfanti, S.; Ferulli, F.; Brugnatelli, S.; Tanzi, M.; Maestri, M.; Cobianchi, L.; Lisini, D.; Luinetti, O.; Paulli, M.; et al. In Vitro Killing of Colorectal Carcinoma Cells by Autologous Activated NK Cells is Boosted by Anti-Epidermal Growth Factor Receptor-induced ADCC Regardless of RAS Mutation Status. J. Immunother. 2018, 41, 190–200. [Google Scholar] [CrossRef]
- Bertino, E.M.; McMichael, E.L.; Mo, X.; Trikha, P.; Davis, M.; Paul, B.; Grever, M.; Carson, W.E.; Otterson, G.A. A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer. Mol. Cancer Ther. 2016, 15, 2244–2250. [Google Scholar] [CrossRef] [Green Version]
- Chen, S.; Li, X.; Chen, R.; Yin, M.; Zheng, Q. Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model. Oncol. Lett. 2016, 12, 1868–1876. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bibeau, F.; Lopez-Crapez, E.; Di Fiore, F.; Thezenas, S.; Ychou, M.; Blanchard, F.; Lamy, A.; Penault-Llorca, F.; Frebourg, T.; Michel, P.; et al. Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J. Clin. Oncol. 2009, 27, 1122–1129. [Google Scholar] [CrossRef] [PubMed]
- Lo Nigro, C.; Ricci, V.; Vivenza, D.; Monteverde, M.; Strola, G.; Lucio, F.; Tonissi, F.; Miraglio, E.; Granetto, C.; Fortunato, M.; et al. Evaluation of antibody-dependent cell-mediated cytotoxicity activity and cetuximab response in KRAS wild-type metastatic colorectal cancer patients. World J. Gastrointest. Oncol. 2016, 8, 222–230. [Google Scholar] [CrossRef]
- Kasper, S.; Breitenbuecher, F.; Reis, H.; Brandau, S.; Worm, K.; Kohler, J.; Paul, A.; Trarbach, T.; Schmid, K.W.; Schuler, M. Oncogenic RAS simultaneously protects against anti-EGFR antibody-dependent cellular cytotoxicity and EGFR signaling blockade. Oncogene 2013, 32, 2873–2881. [Google Scholar] [CrossRef]
- Rodriguez, J.; Zarate, R.; Bandres, E.; Boni, V.; Hernandez, A.; Sola, J.J.; Honorato, B.; Bitarte, N.; Garcia-Foncillas, J. Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer. Eur. J. Cancer 2012, 48, 1774–1780. [Google Scholar] [CrossRef] [PubMed]
- Nakadate, Y.; Kodera, Y.; Kitamura, Y.; Shirasawa, S.; Tachibana, T.; Tamura, T.; Koizumi, F. KRAS mutation confers resistance to antibody-dependent cellular cytotoxicity of cetuximab against human colorectal cancer cells. Int. J. Cancer 2014, 134, 2146–2155. [Google Scholar] [CrossRef]
- Trotta, A.M.; Ottaiano, A.; Romano, C.; Nasti, G.; Nappi, A.; De Divitiis, C.; Napolitano, M.; Zanotta, S.; Casaretti, R.; D’Alterio, C.; et al. Prospective Evaluation of Cetuximab-Mediated Antibody-Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy. Cancer Immunol. Res. 2016, 4, 366–374. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Veluchamy, J.P.; Spanholtz, J.; Tordoir, M.; Thijssen, V.L.; Heideman, D.A.; Verheul, H.M.; de Gruijl, T.D.; van der Vliet, H.J. Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer. PLoS ONE 2016, 11, e0157830. [Google Scholar] [CrossRef]
- Ottaiano, A.; Scala, S.; Normanno, N.; Napolitano, M.; Capozzi, M.; Rachiglio, A.M.; Roma, C.; Trotta, A.M.; D’Alterio, C.; Portella, L.; et al. Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: The CIFRA study protocol. BMC Cancer 2019, 19, 899. [Google Scholar] [CrossRef] [Green Version]
- Pozzi, C.; Cuomo, A.; Spadoni, I.; Magni, E.; Silvola, A.; Conte, A.; Sigismund, S.; Ravenda, P.S.; Bonaldi, T.; Zampino, M.G.; et al. The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat. Med. 2016, 22, 624–631. [Google Scholar] [CrossRef]
- Hecht, J.R.; Mitchell, E.; Chidiac, T.; Scroggin, C.; Hagenstad, C.; Spigel, D.; Marshall, J.; Cohn, A.; McCollum, D.; Stella, P.; et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J. Clin. Oncol. 2009, 27, 672–680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Modest, D.P.; Jung, A.; Moosmann, N.; Laubender, R.P.; Giessen, C.; Schulz, C.; Haas, M.; Neumann, J.; Boeck, S.; Kirchner, T.; et al. The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: An analysis of the AIO KRK-0104-trial. Int. J. Cancer 2012, 131, 980–986. [Google Scholar] [CrossRef] [Green Version]
- Benvenuti, S.; Sartore-Bianchi, A.; Di Nicolantonio, F.; Zanon, C.; Moroni, M.; Veronese, S.; Siena, S.; Bardelli, A. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007, 67, 2643–2648. [Google Scholar] [CrossRef] [Green Version]
- De Roock, W.; Jonker, D.J.; Di Nicolantonio, F.; Sartore-Bianchi, A.; Tu, D.; Siena, S.; Lamba, S.; Arena, S.; Frattini, M.; Piessevaux, H.; et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 2010, 304, 1812–1820. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khambata-Ford, S.; Garrett, C.R.; Meropol, N.J.; Basik, M.; Harbison, C.T.; Wu, S.; Wong, T.W.; Huang, X.; Takimoto, C.H.; Godwin, A.K.; et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol. 2007, 25, 3230–3237. [Google Scholar] [CrossRef]
- Perkins, G.; Lievre, A.; Ramacci, C.; Meatchi, T.; de Reynies, A.; Emile, J.F.; Boige, V.; Tomasic, G.; Bachet, J.B.; Bibeau, F.; et al. Additional value of EGFR downstream signaling phosphoprotein expression to KRAS status for response to anti-EGFR antibodies in colorectal cancer. Int. J. Cancer J. 2010, 127, 1321–1331. [Google Scholar] [CrossRef]
- Pentheroudakis, G.; Kotoula, V.; De Roock, W.; Kouvatseas, G.; Papakostas, P.; Makatsoris, T.; Papamichael, D.; Xanthakis, I.; Sgouros, J.; Televantou, D.; et al. Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: Interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes. BMC Cancer 2013, 13, 49. [Google Scholar] [CrossRef] [Green Version]
- Tabernero, J.; Van Cutsem, E.; Diaz-Rubio, E.; Cervantes, A.; Humblet, Y.; Andre, T.; Van Laethem, J.L.; Soulie, P.; Casado, E.; Verslype, C.; et al. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 2007, 25, 5225–5232. [Google Scholar] [CrossRef] [PubMed]
- Piskol, R.; Huw, L.; Sergin, I.; Kljin, C.; Modrusan, Z.; Kim, D.; Kljavin, N.; Tam, R.; Patel, R.; Burton, J.; et al. A Clinically Applicable Gene-Expression Classifier Reveals Intrinsic and Extrinsic Contributions to Consensus Molecular Subtypes in Primary and Metastatic Colon Cancer. Clin. Cancer Res. 2019, 25, 4431–4442. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Characteristic | Total (n = 433) | CMS1 (n = 74) | CMS2 (n = 169) | CMS3 (n = 85) | CMS4 (n = 105) | p-Value |
---|---|---|---|---|---|---|
Age (median) | Mean (SD) | 71.5 (11.6) | 62.9 (11.9) | 66.5 (13.6) | 64.5 (13.0) | <0.001 a |
Median (IQR) | 74.0 (64.0, 80.8) | 63.0 (55.0, 71.0) | 69.0 (58.0, 78.0) | 65.0 (55.8, 73.0) | - | |
Range | (44.0, 93.0) | (34.0, 93.0) | (34.0, 90.0) | (30.0, 89.0) | - | |
Stage at diagnosis | ||||||
1 | 60 (14%) | 9 (12.2%) | 29 (17.2%) | 15 (17.6%) | 7 (6.7%) | 0.016 b |
2 | 125 (29%) | 28 (37.8%) | 48 (28.4%) | 23 (27.0%) | 26 (24.8%) | - |
3 | 141 (33%) | 21 (28.4%) | 49 (29.0%) | 34 (40.0%) | 37 (35.2%) | - |
4 | 100 (23%) | 15 (20.3%) | 42 (24.8%) | 10 (11.8%) | 33 (31.4%) | - |
Unknown | 7 (1%) | 1 (1.3%) | 1 (0.6%) | 3 (3.6%) | 2 (1.9%) | |
Specimen type | ||||||
Metastatic | 90 (21%) | 9 (12.2%) | 39 (23.1%) | 3 (3.5%) | 41 (39%) | <0.001 b |
Primary | 341 (79%) | 65 (87.8%) | 130 (76.9%) | 82 (96.5%) | 64 (61%) | - |
Primary tumor | ||||||
Left | 230 (53%) | 24 (32.4%) | 132 (79.5%) | 42 (49.4%) | 63 (60.6%) | <0.001 b |
Right | 203 (47%) | 50(67.6%) | 34 (20.5%) | 43 (50.6%) | 41 (39.4%) | - |
APC mutation c | ||||||
Absent | 146 (34%) | 52 (70.3%) | 17 (10.1%) | 32 (37.6%) | 45 (42.9%) | <0.001 b |
Present | 287 (66%) | 22 (29.7%) | 152 (89.9%) | 53 (62.4%) | 60 (57.1%) | - |
TP53 mutations | ||||||
Absent | 177 (41%) | 34 (45.9%) | 38 (22.5%) | 57 (67.1%) | 48 (45.7%) | <0.001 b |
Present | 256 (59%) | 40 (54.1%) | 131 (77.5%) | 28 (32.9%) | 57 (54.3%) | - |
RAS mutation | ||||||
Absent | 248 (57%) | 56 (75.7%) | 113 (66.9%) | 33 (38.8%) | 59 (56.2%) | <0.001 b |
Present | 185 (43%) | 18 (24.3%) | 56 (33.1%) | 52 (61.2%) | 46 (43.8%) | - |
BRAF mutation d | ||||||
Absent | 381 (88%) | 33 (44.6%) | 169 (100%) | 78 (91.8%) | 101 (96.2%) | <0.001 b |
Present | 52 (12%) | 41 (55.4%) | 0 (0%) | 7 (8.2%) | 4 (3.8%) | - |
Microsatellite status | ||||||
Low | 375 (87%) | 32 (43.2%) | 168 (99.4%) | 72 (84.7%) | 103 (98.1%) | <0.001 b |
High | 58 (13%) | 42 (56.8%) | 1 (0.6%) | 13 (15.3%) | 2 (1.9%) | - |
Stage | n | CMS1 | CMS2 | CMS3 | CMS4 |
---|---|---|---|---|---|
n (%) | n (%) | n (%) | n (%) | ||
Total | 104 | 2 (2) | 77 (74) | 5 (5) | 20 (19) |
Stage 1 | 14 | 0 | 13 (93) | 1 (7) | 0 |
Stage 2 | 27 | 0 | 21 (78) | 0 | 6 (22) |
Stage 3 | 36 | 1 (3) | 25 (69) | 4 (11) | 6 (17) |
Stage 4 | 27 | 1 (4) | 18 (66) | 0 | 8 (30) |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Thota, R.; Yang, M.; Pflieger, L.; Schell, M.J.; Rajan, M.; Davis, T.B.; Wang, H.; Presson, A.; Pledger, W.J.; Yeatman, T.J. APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes. Cancers 2021, 13, 5394. https://doi.org/10.3390/cancers13215394
Thota R, Yang M, Pflieger L, Schell MJ, Rajan M, Davis TB, Wang H, Presson A, Pledger WJ, Yeatman TJ. APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes. Cancers. 2021; 13(21):5394. https://doi.org/10.3390/cancers13215394
Chicago/Turabian StyleThota, Ramya, Mingli Yang, Lance Pflieger, Michael J. Schell, Malini Rajan, Thomas B. Davis, Heiman Wang, Angela Presson, Warren Jack Pledger, and Timothy J. Yeatman. 2021. "APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes" Cancers 13, no. 21: 5394. https://doi.org/10.3390/cancers13215394