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Review

Novel therapeutics in metastatic colorectal cancer: molecular insights and pharmacogenomic implications

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Pages 1091-1108 | Received 15 Feb 2016, Accepted 29 Mar 2016, Published online: 14 Apr 2016

References

  • Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. doi:10.3322/caac.21262. PubMed PMID: 25651787.
  • Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–1919. doi:10.1056/NEJMoa1414325. PubMed PMID: 25970050.
  • Capdevila J, Carrato A, Tabernero J, et al. What could nintedanib (BIBF 1120), a triple inhibitor of VEGFR, PDGFR, and FGFR, add to the current treatment options for patients with metastatic colorectal cancer? Crit Rev Oncol Hematol. 2014. doi:10.1016/j.critrevonc.2014.05.004. PubMed PMID: 24924525.
  • Saridaki Z, Androulakis N, Vardakis N, et al. A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial. Br J Cancer. 2012;107(12):1932–1937. doi:10.1038/bjc.2012.509. PubMed PMID: 23169296; PubMed Central PMCID: PMC3516691.
  • Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–337. doi:10.1038/nature11252. PubMed PMID: 22810696; PubMed Central PMCID: PMC3401966.
  • Duschinsky RPE, Heidelberger C. The synthesis of 5-fluoropyrimidines. J Am Chem Soc. 1957;79(16):4559–4560.
  • Heidelberger C, Chaudhuri NK, Danneberg P, et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature. 1957;179(4561):663–666. PubMed PMID: 13418758.
  • Wilson PM, Danenberg PV, Johnston PG, et al. Standing the test of time: targeting thymidylate biosynthesis in cancer therapy. Nat Rev Clin Oncol. 2014;11(5):282–298. doi:10.1038/nrclinonc.2014.51. PubMed PMID: 24732946.
  • Saito K, Nagashima H, Noguchi K, et al. First-in-human, phase I dose-escalation study of single and multiple doses of a first-in-class enhancer of fluoropyrimidines, a dUTPase inhibitor (TAS-114) in healthy male volunteers. Cancer Chemother Pharmacol. 2014;73(3):577–583. doi:10.1007/s00280-014-2383-2. PubMed PMID: 24452393.
  • Nukatsuka M, Nakagawa F, Takechi T. Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with oxaliplatin on human colorectal and gastric cancer xenografts. Anticancer Res. 2015;35(9):4605–4615. PubMed PMID: 26254349.
  • Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 2005;23(16):3706–3712. Epub 2005/05/04. doi:10.1200/JCO.2005.00.232. PubMed PMID: 15867200.
  • Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–2342. Epub 2004/06/04. doi:10.1056/NEJMoa032691350/23/2335[pii]. PubMed PMID: 15175435.
  • Arnold DAT, Bennouna J, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). J Clin Oncol. 2012;30(suppl):abstr CRA3503.
  • Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clinl Oncol. 2012;30(28):3499–3506. doi:10.1200/JCO.2012.42.8201. PubMed PMID: 22949147.
  • Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99(17):11393–11398. Epub 2002/08/15. doi:10.1073/pnas.172398299. PubMed PMID: 12177445; PubMed Central PMCID: PMC123267.
  • Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508. doi:10.1016/S1470-2045(15)70127-0. PubMed PMID: 25877855.
  • Baeriswyl V, Christofori G. The angiogenic switch in carcinogenesis. Semin Cancer Biol. 2009;19(5):329–337. doi:10.1016/j.semcancer.2009.05.003. PubMed PMID: 19482086.
  • Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68(12):4774–4782. doi:10.1158/0008-5472.CAN-07-6307. PubMed PMID: 18559524.
  • Kutluk Cenik B, Ostapoff KT, Gerber DE, et al. BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol Cancer Ther. 2013;12(6):992–1001. doi:10.1158/1535-7163.MCT-12-0995. PubMed PMID: 23729403; PubMed Central PMCID: PMC3681897.
  • Du Bois A, Huober J, Stopfer P, et al. A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies. Ann Oncol. 2010;21(2):370–375. doi:10.1093/annonc/mdp506. PubMed PMID: 19889612.
  • Ellis PM, Kaiser R, Zhao Y, et al. Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients. Clin Cancer Res. 2010;16(10):2881–2889. doi:10.1158/1078-0432.CCR-09-2944. PubMed PMID: 20460487.
  • Mross K, Stefanic M, Gmehling D, et al. Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res. 2010;16(1):311–319. doi:10.1158/1078-0432.CCR-09-0694. PubMed PMID: 20028771.
  • Okamoto I, Kaneda H, Satoh T, et al. Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther. 2010;9(10):2825–2833. doi:10.1158/1535-7163.MCT-10-0379. PubMed PMID: 20688946.
  • Lenz HJTJ, Yoshino T, Oum’Hamed Z, et al. LUME-Colon 1: a double-blind, randomized phase III study of nintedanib plus best supportive care (BSC) versus placebo plus BSC in patients with colorectal cancer (CRC) refractory to standard therapies. J Clin Oncol. 2015;33(suppl):abstr TPS3625.
  • Bouche O, Maindrault-Goebel F, Ducreux M, et al. Phase II trial of weekly alternating sequential BIBF 1120 and afatinib for advanced colorectal cancer. Anticancer Res. 2011;31(6):2271–2281. PubMed PMID: 21737652.
  • Van Cutsem EA. Phase l/lI, open-label, randomised study of BIBF 1120 plus mFOLFOX6 compared to bevacizumab plus mFOLFOX6 in patients with metastatic colorectal cancer. Eur J Cancer. 2011;47(Supplement 2):8–9.
  • Garcia-Carbonero R, Rivera F, Maurel J, et al. An open-label phase II study evaluating the safety and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy for metastatic colorectal cancer. Oncologist. 2014;19(4):350–351. doi:10.1634/theoncologist.2014-0028. PubMed PMID: 24674871; PubMed Central PMCID: PMC3983832.
  • Yoshino T, Yamazaki K, Gotoh M, et al. Safety and pharmacokinetics of second-line ramucirumab plus FOLFIRI in Japanese patients with metastatic colorectal carcinoma. Anticancer Res. 2015;35(7):4003–4007. PubMed PMID: 26124348.
  • Zhou A, Zhang W, Chang C, et al. Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib. Cancer Chemother Pharmacol. 2013;72(5):1043–1053. doi:10.1007/s00280-013-2282-y. PubMed PMID: 24043137.
  • Xu RSL, Wang K, Wu G, et al. A randomized, double-blind, parallel-group, placebo-controlled, multicenter, phase II clinical study of famitinib in the treatment of advanced metastatic colorectal cancer. J Clin Oncol. 2015;33(suppl 3):abstr 513.
  • Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–2048. doi:10.1056/NEJMoa071834. PubMed PMID: 18003960.
  • Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014;15(6):569–579. doi:10.1016/S1470-2045(14)70118-4. PubMed PMID: 24739896.
  • Bokemeyer C, Bondarenko I, Makhson A, et al. Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study. J Clin Oncol. 2007;25(suppl; abstr 4035):172s.
  • Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011;22(7):1535–1546. doi:10.1093/annonc/mdq632. PubMed PMID: 21228335.
  • Heinemann V, Von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065–1075. doi:10.1016/S1470-2045(14)70330-4. PubMed PMID: 25088940.
  • Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clinl Oncol. 2011;29(15):2011–2019. doi:10.1200/JCO.2010.33.5091. PubMed PMID: 21502544.
  • Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clinl Oncol. 2010;28(31):4706–4713. doi:10.1200/JCO.2009.27.6055. PubMed PMID: 20921462.
  • Siena S, Sartore-Bianchi A, Di Nicolantonio F, et al. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009;101(19):1308–1324. doi:10.1093/jnci/djp280. PubMed PMID: 19738166; PubMed Central PMCID: PMC2758310.
  • Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clinl Oncol. 2008;26(35):5705–5712. doi:10.1200/JCO.2008.18.0786. PubMed PMID: 19001320.
  • Arena S, Bellosillo B, Siravegna G, et al. Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer. Clin Cancer Res. 2015;21(9):2157–2166. doi:10.1158/1078-0432.CCR-14-2821. PubMed PMID: 25623215.
  • Sanchez-Martin FJ, Bellosillo B, Gelabert M, et al. The first-in-class anti-EGFR antibody mixture Sym004 overcomes cetuximab-resistance mediated by EGFR extracellular domain mutations in colorectal cancer. Clin Cancer Res. 2016. doi:10.1158/1078-0432.CCR-15-2400. PubMed PMID: 26888827.
  • Skartved NJ, Jacobsen HJ, Pedersen MW, et al. Preclinical pharmacokinetics and safety of Sym004: a synergistic antibody mixture directed against epidermal growth factor receptor. Clin Cancer Res. 2011;17(18):5962–5972. doi:10.1158/1078-0432.CCR-11-1209. PubMed PMID: 21825041.
  • Pedersen MW, Jacobsen HJ, Koefoed K, et al. Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. Cancer Res. 2010;70(2):588–597. doi:10.1158/0008-5472.CAN-09-1417. PubMed PMID: 20068188.
  • Dienstmann R, Patnaik A, Garcia-Carbonero R, et al. Safety and activity of the first-in-class Sym004 anti-EGFR antibody mixture in patients with refractory colorectal cancer. Cancer Discov. 2015;5(6):598–609. doi:10.1158/2159-8290.CD-14-1432. PubMed PMID: 25962717.
  • Stintzing S, Heinemann V. Sym004: truly a new level of anti-EGFR treatment? Cancer Discov. 2015;5(6):578–580. doi:10.1158/2159-8290.CD-15-0441. PubMed PMID: 26037914.
  • Kearns JD, Bukhalid R, Sevecka M, et al. Enhanced targeting of the EGFR network with MM-151, an oligoclonal anti-EGFR antibody therapeutic. Mol Cancer Ther. 2015;14(7):1625–1636. doi:10.1158/1535-7163.MCT-14-0772. PubMed PMID: 25911688.
  • Arena S, Siravegna G, Mussolin B, et al. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations. Sci Transl Med. 2016;8(324):324ra14. doi:10.1126/scitranslmed.aad5640. PubMed PMID: 26843189.
  • Lieu CHBM, Harb WA, Kearns JD, et al. Safety, pharmacology, and preliminary clinical activity of MM-151: an oligocolnal anti-EGFR theraputic in patients with cetuximab-resistant CRC and other refractory solid tumors. J Clin Oncol. 2015;33(suppl 3):abstr 647.
  • Schirripa M, Lenz HJ. Colorectal cancer: overcoming resistance to anti-EGFR therapy - where do we stand? Nat Rev Gastroenterol Hepatol. 2016. doi:10.1038/nrgastro.2016.52. PubMed PMID: 27006256.
  • Kopetz S, Desai J, Chan E, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clinl Oncol. 2015;33(34):4032–4038. doi:10.1200/JCO.2015.63.2497. PubMed PMID: 26460303; PubMed Central PMCID: PMC4669589.
  • Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100–103. doi:10.1038/nature10868. PubMed PMID: 22281684.
  • Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2(3):227–235. doi:10.1158/2159-8290.CD-11-0341. PubMed PMID: 22448344; PubMed Central PMCID: PMC3308191.
  • Morris MKWJ, Adam L, Tian F, et al. Role of MEK inhibition in improving anti-tumor responses in xenograft models of BRAF-mutated metastatic colorectal cancer. J Clin Oncol. 2016;34(suppl 4S):abstr 265.
  • Yaeger R, Cercek A, O’Reilly EM, et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res. 2015;21(6):1313–1320. doi:10.1158/1078-0432.CCR-14-2779. PubMed PMID: 25589621.
  • Hong DSMV, Osta BE, Fu S, et al. Phase Ib study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated metastatic colorectal cancer and advanced cancers. J Clin Oncol. 2015;33(suppl):abstr 3511.
  • Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clinl Oncol. 2015;33(34):4023–4031. doi:10.1200/JCO.2015.63.2471. PubMed PMID: 26392102; PubMed Central PMCID: PMC4669588.
  • Van Cutsem CA, André T, Bendell J, et al. Updated results of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC). Ann Onc. 2015;26(suppl4):iv119LBA–07.
  • Deming DA, Cavalcante LL, Lubner SJ, et al. A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer: for submission to investigational new drugs. Invest New Drugs. 2015. doi:10.1007/s10637-015-0314-7. PubMed PMID: 26666244.
  • Do K, Speranza G, Bishop R, et al. Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Invest New Drugs. 2015;33(3):720–728. doi:10.1007/s10637-015-0212-z. PubMed PMID: 25637165.
  • Hochster HS, Uboha N, Messersmith W, et al. Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer. Cancer Chemother Pharmacol. 2015;75(1):17–23. doi:10.1007/s00280-014-2609-3. PubMed PMID: 25322874.
  • Flanigan SA, Pitts TM, Newton TP, et al. Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models. Clin Cancer Res. 2013;19(22):6219–6229. doi:10.1158/1078-0432.CCR-13-0145. PubMed PMID: 24045180; PubMed Central PMCID: PMC3843359.
  • Puzanov I, Lindsay CR, Goff L, et al. A phase I study of continuous oral dosing of OSI-906, a dual inhibitor of insulin-like growth factor-1 and insulin receptors, in patients with advanced solid tumors. Clin Cancer Res. 2015;21(4):701–711. doi:10.1158/1078-0432.CCR-14-0303. PubMed PMID: 25212606.
  • Wilky BA, Rudek MA, Ahmed S, et al. A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours. Br J Cancer. 2015;112(1):24–31. doi:10.1038/bjc.2014.515. PubMed PMID: 25268371; PubMed Central PMCID: PMC4453594.
  • Hong S, Kim S, Kim HY, et al. Targeting the PI3K signaling pathway in KRAS mutant colon cancer. Cancer Med. 2015. doi:10.1002/cam4.591. PubMed PMID: 26715098.
  • Rodon J, Brana I, Siu LL, et al. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2014;32(4):670–681. doi:10.1007/s10637-014-0082-9. PubMed PMID: 24652201.
  • McRee AJ, Sanoff HK, Carlson C, et al. A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors. Invest New Drugs. 2015. doi:10.1007/s10637-015-0298-3. PubMed PMID: 26490655.
  • Geel RVEE, Bendell JC, Faris JE, et al. Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer. J Clin Oncol. 2014;32(suppl; abstr 3514):5s.
  • Elez E, Van Geel R, Bendell J, et al. Results of a phase 1b study of the selective BRAF V600 inhibitor encorafenib in combination with cetuximab alone or cetuximab + alpelisib for treatment of patients with advanced BRAF-mutant metastatic colorectal cancer. Ann Onc. 2015;26(suppl 4):iv120.
  • Kloth M, Ruesseler V, Engel C, et al. Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer. Gut. 2015. doi:10.1136/gutjnl-2014-309026. PubMed PMID: 26001389.
  • Valtorta E, Martino C, Sartore-Bianchi A, et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Modern Pathol. 2015;28(11):1481–1491. doi:10.1038/modpathol.2015.98. PubMed PMID: 26449765.
  • Richman SD, Southward K, Chambers P, et al. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials. J Pathol. 2015. doi:10.1002/path.4679. PubMed PMID: 26690310.
  • Ingold Heppner B, Behrens HM, Balschun K, et al. HER2/neu testing in primary colorectal carcinoma. Br J Cancer. 2014;111(10):1977–1984. doi:10.1038/bjc.2014.483. PubMed PMID: 25211663; PubMed Central PMCID: PMC4229629.
  • Ramanathan RK, Hwang JJ, Zamboni WC, et al. Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (herceptin) and irinotecan as therapy. A phase II trial. Cancer Invest. 2004;22(6):858–865. PubMed PMID: 15641483.
  • Bertotti A, Migliardi G, Galimi F, et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011;1(6):508–523. doi:10.1158/2159-8290.CD-11-0109. PubMed PMID: 22586653.
  • Leto SM, Sassi F, Catalano I, et al. Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas. Clin Cancer Res. 2015;21(24):5519–5531. doi:10.1158/1078-0432.CCR-14-3066. PubMed PMID: 26296355.
  • Van Cutsem E, Eng C, Nowara E, et al. Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer. Clin Cancer Res. 2014;20(16):4240–4250. doi:10.1158/1078-0432.CCR-13-2752. PubMed PMID: 24919569; PubMed Central PMCID: PMC4371780.
  • Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010;11(12):834–848. doi:10.1038/nrm3012. PubMed PMID: 21102609.
  • Kammula US, Kuntz EJ, Francone TD, et al. Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett. 2007;248(2):219–228. doi:10.1016/j.canlet.2006.07.007. PubMed PMID: 16945480.
  • Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci. 2003;4(4):299–309. doi:10.1038/nrn1078. PubMed PMID: 12671646.
  • Pulciani S, Santos E, Lauver AV, et al. Oncogenes in solid human tumours. Nature. 1982;300(5892):539–542. PubMed PMID: 7144906.
  • Ardini E, Bosotti R, Borgia AL, et al. The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Mol Oncol. 2014;8(8):1495–1507. doi:10.1016/j.molonc.2014.06.001. PubMed PMID: 24962792.
  • Sartore-Bianchi A, Ardini E, Bosotti R, et al. Sensitivity to entrectinib associated with a novel LMNA-NTRK1 gene fusion in metastatic colorectal cancer. J Natl Cancer Inst. 2016;108(1). doi:10.1093/jnci/djv306. PubMed PMID: 26563355; PubMed Central PMCID: PMC4712682.
  • Amatu A, Somaschini A, Cerea G, et al. Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer. Br J Cancer. 2015;113(12):1730–1734. doi:10.1038/bjc.2015.401. PubMed PMID: 26633560; PubMed Central PMCID: PMC4701996.
  • Lee J, Kim HC, Hong JY, et al. Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening. Oncotarget. 2015;6(27):24320–24332. doi:10.18632/oncotarget.4462. PubMed PMID: 26172300; PubMed Central PMCID: PMC4695188.
  • Russo M, Misale S, Wei G, et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov. 2016;6(1):36–44. doi:10.1158/2159-8290.CD-15-0940. PubMed PMID: 26546295.
  • Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353(25):2654–2666. doi:10.1056/NEJMoa051424. PubMed PMID: 16371631.
  • Guidoboni M, Gafa R, Viel A, et al. Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am J Pathol. 2001;159(1):297–304. doi:10.1016/S0002-9440(10)61695-1. PubMed PMID: 11438476; PubMed Central PMCID: PMC1850401.
  • Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520. doi:10.1056/NEJMoa1500596. PubMed PMID: 26028255; PubMed Central PMCID: PMC4481136.
  • Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111(7):3635–3643. doi:10.1182/blood-2007-11-123141. PubMed PMID: 18223165; PubMed Central PMCID: PMC2275025.
  • Chung KY, Gore I, Fong L, et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clinl Oncol. 2010;28(21):3485–3490. doi:10.1200/JCO.2010.28.3994. PubMed PMID: 20498386.
  • Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465. doi:10.1056/NEJMoa1200694. PubMed PMID: 22658128; PubMed Central PMCID: PMC3563263.
  • Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–2454. doi:10.1056/NEJMoa1200690. PubMed PMID: 22658127; PubMed Central PMCID: PMC3544539.
  • Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–567. doi:10.1038/nature14011. PubMed PMID: 25428504.
  • Kohrt HE, Colevas AD, Houot R, et al. Targeting CD137 enhances the efficacy of cetuximab. J Clin Invest. 2014;124(6):2668–2682. doi:10.1172/JCI73014. PubMed PMID: 24837434; PubMed Central PMCID: PMC4089447.
  • Beg MSMM, Tan BR, Kim RD, et al. A phase II multicenter study of the chimeric monoclonal antibody NEO102 (N) in adults with refractory colorectal cancer (CC). J Clin Oncol. 2015;33(suppl):abstr e14013.
  • Moore PAAR, Shah K, Yang Y, et al. Development of MGD007, a gpA33 x CD3 bi-specific DART for T-cell immunotherapy of metastatic colorectal cancer. Cancer Res. 2014;74(19Suppl):Abstractnr 669.
  • Hong F, Hansen RD, Yan J, et al. Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells. Cancer Res. 2003;63(24):9023–9031. PubMed PMID: 14695221.
  • Qi C, Cai Y, Gunn L, et al. Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived beta-glucans. Blood. 2011;117(25):6825–6836. doi:10.1182/blood-2011-02-339812. PubMed PMID: 21531981; PubMed Central PMCID: PMC3128477.
  • Salvador C, Li B, Hansen R, et al. Yeast-derived beta-glucan augments the therapeutic efficacy mediated by anti-vascular endothelial growth factor monoclonal antibody in human carcinoma xenograft models. Clin Cancer Res. 2008;14(4):1239–1247. doi:10.1158/1078-0432.CCR-07-1669. PubMed PMID: 18281559; PubMed Central PMCID: PMC2394864.
  • Yang H, Bueso-Ramos C, DiNardo C, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28(6):1280–1288. doi:10.1038/leu.2013.355. PubMed PMID: 24270737; PubMed Central PMCID: PMC4032802.
  • Tel J, Hato SV, Torensma R, et al. The chemotherapeutic drug oxaliplatin differentially affects blood DC function dependent on environmental cues. Cancer Immunol Immunother. 2012;61(7):1101–1111. doi:10.1007/s00262-011-1189-x. PubMed PMID: 22193989; PubMed Central PMCID: PMC3378839.
  • Shalapour S, Font-Burgada J, Di Caro G, et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature. 2015;521(7550):94–98. doi:10.1038/nature14395. PubMed PMID: 25924065; PubMed Central PMCID: PMC4501632.
  • Fu S, Hu W, Iyer R, et al. Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. Cancer. 2011;117(8):1661–1669. doi:10.1002/cncr.25701. PubMed PMID: 21472713; PubMed Central PMCID: PMC3062960.
  • Li Y, Hu W, Shen D-Y, et al. Azacitidine enhances sensitivity of platinum-resistant ovarian cancer cells to carboplatin through induction of apoptosis. Am J Obstet Gynecol. 2009;200(2):177.e1-9. doi:10.1016/j.ajog.2008.08.030. PubMed PMID: 19110234.
  • Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. doi:10.1056/NEJMoa1504030. PubMed PMID: 26027431.
  • Sanmamed MF, Rodriguez I, Schalper KA, et al. Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2R null immunodeficient mice. Cancer Res. 2015;75(17):3466–3478. doi:10.1158/0008-5472.CAN-14-3510. PubMed PMID: 26113085.
  • Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843–851. doi:10.1038/mt.2010.24. PubMed PMID: 20179677; PubMed Central PMCID: PMC2862534.
  • Parkhurst MR, Yang JC, Langan RC, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19(3):620–626. doi:10.1038/mt.2010.272. PubMed PMID: 21157437; PubMed Central PMCID: PMC3048186.
  • Wolmark N, Fisher B, Rockette H, et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst. 1988;80(1):30–36. PubMed PMID: 3276901.
  • Gutterman JU, Mavligit GM, Blumenshein G, et al. Immunotherapy of human solid tumors with bacillus Calmette-Guerin: prolongation of disease-free interval and survival in malignant melanoma, breast, and colorectal cancer. Ann N Y Acad Sci. 1976;277(00):135–159. PubMed PMID: 1069546.
  • Mavligit GM, Gutterman JU, Malahy MA, et al. Adjuvant immunotherapy and chemoimmunotherapy in colorectal cancer (Dukes’ class C): prolongation of disease-free interval and survival. Cancer. 1977;40(5Suppl):2726–2730. PubMed PMID: 922710.
  • Dinarello CA. Interleukin-1alpha neutralisation in patients with cancer. Lancet Oncol. 2014;15(6):552–553. doi:10.1016/S1470-2045(14)70164-0. PubMed PMID: 24746840.
  • Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633–652. doi:10.1038/nrd3800. PubMed PMID: 22850787; PubMed Central PMCID: PMC3644509.
  • Tomimatsu S, Ichikura T, Mochizuki H. Significant correlation between expression of interleukin-1alpha and liver metastasis in gastric carcinoma. Cancer. 2001;91(7):1272–1276. PubMed PMID: 11283926.
  • Rock KL, Latz E, Ontiveros F, et al. The sterile inflammatory response. Annu Rev Immunol. 2010;28:321–342. doi:10.1146/annurev-immunol-030409-101311. PubMed PMID: 20307211; PubMed Central PMCID: PMC4315152.
  • Hong DS, Janku F, Naing A, et al. Xilonix, a novel true human antibody targeting the inflammatory cytokine interleukin-1 alpha, in non-small cell lung cancer. Invest New Drugs. 2015;33(3):621–631. doi:10.1007/s10637-015-0226-6. PubMed PMID: 25822109; PubMed Central PMCID: PMC4482235.
  • Moon SU, Kang MH, Sung JH, et al. Effect of Smad3/4 on chemotherapeutic drug sensitivity in colorectal cancer cells. Oncol Rep. 2015;33(1):185–192. doi:10.3892/or.2014.3582. PubMed PMID: 25370208.
  • Meyer SC, Levine RL. Molecular pathways: molecular basis for sensitivity and resistance to JAK kinase inhibitors. Clin Cancer Res. 2014;20(8):2051–2059. doi:10.1158/1078-0432.CCR-13-0279. PubMed PMID: 24583800; PubMed Central PMCID: PMC3990645.
  • Malilas W, Koh SS, Kim S, et al. Cancer upregulated gene 2, a novel oncogene, enhances migration and drug resistance of colon cancer cells via STAT1 activation. Int J Oncol. 2013;43(4):1111–1116. doi:10.3892/ijo.2013.2049. PubMed PMID: 23917355.
  • Overman MJ, Kopetz S, Varadhachary G, et al. Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008;26(8):794–799. doi:10.1080/07357900802087242. PubMed PMID: 18798063.
  • Stuart E, Buchert M, Putoczki T, et al. Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice. Mol Cancer Ther. 2014;13(2):468–474. doi:10.1158/1535-7163.MCT-13-0583-T. PubMed PMID: 24398427.
  • Van Schaeybroeck S, Kalimutho M, Dunne PD, et al. ADAM17-dependent c-MET-STAT3 signaling mediates resistance to MEK inhibitors in KRAS mutant colorectal cancer. Cell Rep. 2014;7(6):1940–1955. doi:10.1016/j.celrep.2014.05.032. PubMed PMID: 24931611.
  • An HJ, Choi EK, Kim JS, et al. INCB018424 induces apoptotic cell death through the suppression of pJAK1 in human colon cancer cells. Neoplasma. 2014;61(1):56–62. PubMed PMID: 24195509.
  • Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839–1844. doi:10.1073/pnas.1424171112. PubMed PMID: 25605917; PubMed Central PMCID: PMC4330785.
  • Hubbard JMONB, Jonker DJ, Halfdanarson TR, et al. Phase Ib study of cancer stem cell (CSC) pathway inhibitor BBI-608 administered in combination with FOLFIRI with and without bevacizumab (Bev) in patients (pts) with advanced colorectal cancer (CRC). J Clin Oncol. 2016;34(suppl 4S):abstr 569.
  • Ciombor KKEW, Hubbard JM, O’Dwyer PJ, et al. A phase Ib/II study of cancer stem cell inhibitor BBI608 administered with panitumumab in KRAS wild-type (wt) patients (pts) with metastatic colorectal cancer (mCRC) following progression on anti-EGFR therapy. J Clin Oncol. 2015;33(suppl):abstr 3617.
  • Miyoshi Y, Nagase H, Ando H, et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992;1(4):229–233. PubMed PMID: 1338904.
  • Powell SM, Zilz N, Beazer-Barclay Y, et al. APC mutations occur early during colorectal tumorigenesis. Nature. 1992;359(6392):235–237. doi:10.1038/359235a0. PubMed PMID: 1528264.
  • Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127(3):469–480. doi:10.1016/j.cell.2006.10.018. PubMed PMID: 17081971.
  • de Sousa EM, Vermeulen L, Richel D, et al. Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res. 2011;17(4):647–653. doi:10.1158/1078-0432.CCR-10-1204. PubMed PMID: 21159886.
  • Ma H, Nguyen C, Lee KS, et al. Differential roles for the coactivators CBP and p300 on TCF/beta-catenin-mediated survivin gene expression. Oncogene. 2005;24(22):3619–3631. Epub 2005/03/23. doi:10.1038/sj.onc.1208433. PubMed PMID: 15782138.
  • Varnat F, Siegl-Cachedenier I, Malerba M, et al. Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas. EMBO Mol Med. 2010;2(11):440–457. doi:10.1002/emmm.201000098. PubMed PMID: 20941789; PubMed Central PMCID: PMC3394505.
  • Janssen KP, Alberici P, Fsihi H, et al. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology. 2006;131(4):1096–1109. doi:10.1053/j.gastro.2006.08.011. PubMed PMID: 17030180.
  • Eguchi M, Nguyen C, Lee SC, et al. ICG-001, a novel small molecule regulator of TCF/beta-catenin transcription. Med Chem. 2005;1(5):467–472. Epub 2006/06/22. PubMed PMID: 16787331.
  • Emami KH, Nguyen C, Ma H, et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci U S A. 2004;101(34):12682–12687. Epub 2004/08/18. doi:10.1073/pnas.0404875101. PubMed PMID: 15314234; PubMed Central PMCID: PMCPmc515116.
  • Sack U, Walther W, Scudiero D, et al. S100A4-induced cell motility and metastasis is restricted by the Wnt/beta-catenin pathway inhibitor calcimycin in colon cancer cells. Mol Biol Cell. 2011;22(18):3344–3354. doi:10.1091/mbc.E10-09-0739. PubMed PMID: 21795396; PubMed Central PMCID: PMC3172260.
  • Stein U, Arlt F, Smith J, et al. Intervening in beta-catenin signaling by sulindac inhibits S100A4-dependent colon cancer metastasis. Neoplasia. 2011;13(2):131–144. PubMed PMID: 21403839; PubMed Central PMCID: PMC3033592.
  • Stein U, Arlt F, Walther W, et al. The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer. Gastroenterology. 2006;131(5):1486–1500. doi:10.1053/j.gastro.2006.08.041. PubMed PMID: 17101323.
  • El-Khoueiry AB, Ning Y, Yang D, et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors [abstract]. J Clin Oncol. 2013;31(suppl):abstr 2501.
  • Proffitt KD, Virshup DM. Precise regulation of porcupine activity is required for physiological Wnt signaling. J Biol Chem. 2012;287(41):34167–34178. doi:10.1074/jbc.M112.381970. PubMed PMID: 22888000; PubMed Central PMCID: PMC3464525.
  • Madan B, Ke Z, Harmston N, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2015. doi:10.1038/onc.2015.280. PubMed PMID: 26257057; PubMed Central PMCID: PMC4650263.
  • Wang YPM, Jaeger S, Bagdasarian L, et al. Dual Wnt and EGFR-MAPK dependency of BRAFV600E-mutant colorectal cancer. Cancer Res. 2015;75(15Suppl):Abstractnr 2140. doi:10.1158/1538-7445AM2015-2140.
  • Fu LL, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget. 2015;6(8):5501–5516. doi:10.18632/oncotarget.3551. PubMed PMID: 25849938; PubMed Central PMCID: PMC4467383.
  • McCleland ML, Mesh K, Lorenzana E, et al. CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016;126(2):639–652. doi:10.1172/JCI83265. PubMed PMID: 26752646.
  • Forouhar F, Anderson JL, Mowat CG, et al. Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2007;104(2):473–478. doi:10.1073/pnas.0610007104. PubMed PMID: 17197414; PubMed Central PMCID: PMC1766409.
  • Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. doi:10.1038/nrc3239. PubMed PMID: 22437870.
  • Thaker AI, Rao MS, Bishnupuri KS, et al. IDO1 metabolites activate beta-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice. Gastroenterology. 2013;145(2):416-25e1-4. doi:10.1053/j.gastro.2013.05.002. PubMed PMID: 23669411; PubMed Central PMCID: PMC3722304.
  • Takamatsu M, Hirata A, Ohtaki H, et al. Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice. Cancer Sci. 2015;106(8):1008–1015. doi:10.1111/cas.12705. PubMed PMID: 26033215; PubMed Central PMCID: PMC4556390.
  • Cremolini C, Loupakis F, Antoniotti C, et al. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol. 2015;26(6):1188–1194. doi:10.1093/annonc/mdv112. PubMed PMID: 25712456.
  • Piessevaux H, Buyse M, Schlichting M, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clinl Oncol. 2013;31(30):3764–3775. doi:10.1200/JCO.2012.42.8532. PubMed PMID: 24043732.
  • Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371(17):1609–1618. doi:10.1056/NEJMoa1403108. PubMed PMID: 25337750.
  • Fornaro L, Lonardi S, Masi G, et al. FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO). Ann Oncol. 2013;24(8):2062–2067. doi:10.1093/annonc/mdt165. PubMed PMID: 23666916.
  • Kerbel RS, Grothey A. Gastrointestinal cancer: rationale for metronomic chemotherapy in phase III trials. Nat Rev Clin Oncol. 2015;12(6):313–314. doi:10.1038/nrclinonc.2015.89. PubMed PMID: 25963090.
  • Simkens LH, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015;385(9980):1843–1852. doi:10.1016/S0140-6736(14)62004-3. PubMed PMID: 25862517.
  • Triff K, Konganti K, Gaddis S, et al. Genome-wide analysis of the rat colon reveals proximal-distal differences in histone modifications and proto-oncogene expression. Physiol Genomics. 2013;45(24):1229–1243. doi:10.1152/physiolgenomics.00136.2013. PubMed PMID: 24151245; PubMed Central PMCID: PMC3882682.
  • Benedix F, Kube R, Meyer F, et al., Colon/Rectum Carcinomas Study G. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53(1):57–64. doi:10.1007/DCR.0b013e3181c703a4. PubMed PMID: 20010352.
  • Sinicrope FA, Mahoney MR, Smyrk TC, et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clinl Oncol. 2013;31(29):3664–3672. doi:10.1200/JCO.2013.48.9591. PubMed PMID: 24019539; PubMed Central PMCID: PMC3789216.
  • Loupakis F, Yang D, Yau L, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst. 2015;107(3). doi:10.1093/jnci/dju427. PubMed PMID: 25713148; PubMed Central PMCID: PMC4565528.
  • Lynch PM, Lynch HT, Harris RE. Hereditary proximal colonic cancer. Dis Colon Rectum. 1977;20(8):661–668. PubMed PMID: 923394.
  • Sadler TW, Langman J. Langman’s medical embryology. 11th ed. Philadelphia: Wolters Kluwer Lippincott Williams & Wilkins; 2010.
  • Glebov OK, Rodriguez LM, Nakahara K, et al. Distinguishing right from left colon by the pattern of gene expression. Cancer Epidemiol Biomark Prev. 2003;12(8):755–762. PubMed PMID: 12917207.
  • Oikonomou E, Koustas E, Goulielmaki M, et al. BRAF vs RAS oncogenes: are mutations of the same pathway equal? Differential signalling and therapeutic implications. Oncotarget. 2014;5(23):11752–11777. PubMed PMID: 25361007; PubMed Central PMCID: PMC4322985.
  • Brule SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51(11):1405–1414. doi:10.1016/j.ejca.2015.03.015. PubMed PMID: 25979833.
  • Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–1417. doi:10.1056/NEJMoa0805019. PubMed PMID: 19339720.
  • Tejpar S, Shen L, Wang X, et al. Integrating biomarkers in colorectal cancer trials in the West and China. Nat Rev Clin Oncol. 2015;12(9):553–560. doi:10.1038/nrclinonc.2015.88. PubMed PMID: 25963094.
  • Wang Y, Poulin EJ, Coffey RJ. LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor. Br J Cancer. 2013;108(9):1765–1770. doi:10.1038/bjc.2013.138. PubMed PMID: 23558895; PubMed Central PMCID: PMC3658528.
  • Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–1356. doi:10.1038/nm.3967. PubMed PMID: 26457759; PubMed Central PMCID: PMC4636487.
  • Gillis NK, Patel JN, Innocenti F. Clinical implementation of germ line cancer pharmacogenetic variants during the next-generation sequencing era. Clin Pharmacol Ther. 2014;95(3):269–280. doi:10.1038/clpt.2013.214. PubMed PMID: 24136381; PubMed Central PMCID: PMC4128332.
  • Deenen MJ, Meulendijks D, Cats A, et al. Upfront genotyping of DPYD*2A to individualize fluoropyrimidine therapy: a safety and cost analysis. J Clinl Oncol. 2016;34(3):227–234. doi:10.1200/JCO.2015.63.1325. PubMed PMID: 26573078.
  • Zhang W, Press OA, Haiman CA, et al. Association of methylenetetrahydrofolate reductase gene polymorphisms and sex-specific survival in patients with metastatic colon cancer. J Clinl Oncol. 2007;25(24):3726–3731. doi:10.1200/JCO.2007.11.4710. PubMed PMID: 17704422.
  • Pullarkat ST, Stoehlmacher J, Ghaderi V, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1(1):65–70. PubMed PMID: 11913730.
  • Caronia D, Martin M, Sastre J, et al. A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome. Clin Cancer Res. 2011;17(7):2006–2013. doi:10.1158/1078-0432.CCR-10-1741. PubMed PMID: 21325291.
  • Zhang W, Gordon M, Schultheis AM, et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clinl Oncol. 2007;25(24):3712–3718. doi:10.1200/JCO.2006.08.8021. PubMed PMID: 17704420.
  • Volz NB, Stintzing S, Zhang W, et al. Genes involved in pericyte-driven tumor maturation predict treatment benefit of first-line FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer. Pharmacogenomics J. 2015;15(1):69–76. doi:10.1038/tpj.2014.40. PubMed PMID: 25069475.
  • Sebio A, Gerger A, Matsusaka S, et al. Genetic variants within obesity-related genes are associated with tumor recurrence in patients with stages II/III colon cancer. Pharmacogenet Genomics. 2015;25(1):30–37. doi:10.1097/FPC.0000000000000101. PubMed PMID: 25379721; PubMed Central PMCID: PMC4260998.
  • Sebio A, Matsusaka S, Zhang W, et al. Germline polymorphisms in genes involved in the Hippo pathway as recurrence biomarkers in stages II/III colon cancer. Pharmacogenomics J. 2015. doi:10.1038/tpj.2015.64. PubMed PMID: 26370619.
  • Ning Y, Gerger A, Zhang W, et al. Plastin polymorphisms predict gender- and stage-specific colon cancer recurrence after adjuvant chemotherapy. Mol Cancer Ther. 2014;13(2):528–539. doi:10.1158/1535-7163.MCT-13-0646. PubMed PMID: 24170770; PubMed Central PMCID: PMC3945969.
  • Gerger A, El-Khoueiry A, Zhang W, et al. Pharmacogenetic angiogenesis profiling for first-line bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Clin Cancer Res. 2011;17(17):5783–5792. doi:10.1158/1078-0432.CCR-11-1115. PubMed PMID: 21791631; PubMed Central PMCID: PMC3174848.
  • Pohl A, El-Khoueiry A, Yang D, et al. Pharmacogenetic profiling of CD133 is associated with response rate (RR) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), treated with bevacizumab-based chemotherapy. Pharmacogenomics J. 2013;13(2):173–180. doi:10.1038/tpj.2011.61. PubMed PMID: 22231565; PubMed Central PMCID: PMC3326190.
  • Lambrechts D, Lenz HJ, De Haas S, et al. Markers of response for the antiangiogenic agent bevacizumab. J Clinl Oncol. 2013;31(9):1219–1230. doi:10.1200/JCO.2012.46.2762. PubMed PMID: 23401453.
  • Loupakis F, Antoniotti C, Cremolini C, et al. Prospective study of EGFR intron 1 (CA)n repeats variants as predictors of benefit from cetuximab and irinotecan in chemo-refractory metastatic colorectal cancer (mCRC) patients. Pharmacogenomics J. 2014;14(4):322–327. doi:10.1038/tpj.2014.1. PubMed PMID: 24513691.
  • Wang WS, Chen PM, Chiou TJ, et al. Epidermal growth factor receptor R497K polymorphism is a favorable prognostic factor for patients with colorectal carcinoma. Clin Cancer Res. 2007;13(12):3597–3604. doi:10.1158/1078-0432.CCR-06-2601. PubMed PMID: 17575224.

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