Molecular Targets for the Treatment of Metastatic Colorectal Cancer
Abstract
:1. Introduction
2. RAS/RAF Wild-Type Tumors and Anti-EGFR Agents
2.1. Predictive Factors for The Efficacy of Anti-EGFR Agents
2.2. Current Management of Anti-EGFR Therapy
2.3. Primary Tumor Sidedness
2.4. Rechallenge and Liquid Biopsies
3. BRAFV600E Mutation and Targeted Therapies
3.1. Antiangiogenic Agents for the BRAFV600E Mutants
3.2. Anti-EGFR Agents for BRAFV600E Mutants
3.3. BRAF Inhibitors
4. RAS Mutants and Targeted Therapies
5. Microsatellite Instability and Immune Checkpoint Inhibitors
5.1. Colorectal Cancers, Mismatch Repair Deficiency, and Microsatellite Instability
5.2. Targeting the Immune System
5.3. Predictive Biomarkers among MSI/dMMR CRC Patients Treated with Immunotherapy
6. HER2 and Anti-HER2 Agents
7. NTRK Gene Fusions and TRK Inhibitors
8. Conclusions
Funding
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chibaudel, B.; Tournigand, C.; Bonnetain, F.; Richa, H.; Benetkiewicz, M.; André, T.; de Gramont, A. Therapeutic strategy in unresectable metastatic colorectal cancer: An updated review. Ther. Adv. Med. Oncol. 2015, 7, 153–169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lièvre, A.; Bachet, J.-B.; Le Corre, D.; Boige, V.; Landi, B.; Emile, J.-F.; Côté, J.-F.; Tomasic, G.; Penna, C.; Ducreux, M.; et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006, 66, 3992–3995. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cercek, A.; Braghiroli, M.I.; Chou, J.F.; Hechtman, J.F.; Kemeny, N.; Saltz, L.; Capanu, M.; Yaeger, R. Clinical features and outcomes of patients with colorectal cancers harboring NRAS mutations. Clin. Cancer Res. 2017, 23, 4753–4760. [Google Scholar] [CrossRef] [Green Version]
- 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]
- Van Cutsem, E.; Cervantes, A.; Adam, R.; Sobrero, A.; Van Krieken, J.H.; Aderka, D.; Aranda Aguilar, E.; Bardelli, A.; Benson, A.; Bodoky, G.; et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 2016, 27, 1386–1422. [Google Scholar] [CrossRef]
- Parseghian, C.M.; Napolitano, S.; Loree, J.M.; Kopetz, S. Mechanisms of innate and acquired resistance to anti-EGFR therapy: A review of current knowledge with a focus on rechallenge therapies. Clin. Cancer Res. 2019, 25, 6899–6908. [Google Scholar] [CrossRef]
- Pietrantonio, F.; Vernieri, C.; Siravegna, G.; Mennitto, A.; Berenato, R.; Perrone, F.; Gloghini, A.; Tamborini, E.; Lonardi, S.; Morano, F.; et al. Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. Clin. Cancer Res. 2017, 23, 2414–2422. [Google Scholar] [CrossRef] [Green Version]
- Karapetis, C.S.; Jonker, D.; Daneshmand, M.; Hanson, J.E.; O’Callaghan, C.J.; Marginean, C.; Zalcberg, J.R.; Simes, J.; Moore, M.J.; Tebbutt, N.C.; et al. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer—Results from NCIC CTG/AGITG CO.17. Clin. Cancer Res. 2014, 20, 744–753. [Google Scholar] [CrossRef] [Green Version]
- Jhawer, M.; Goel, S.; Wilson, A.J.; Montagna, C.; Ling, Y.-H.; Byun, D.-S.; Nasser, S.; Arango, D.; Shin, J.; Klampfer, L.; et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 2008, 68, 1953–1961. [Google Scholar] [CrossRef] [Green Version]
- Cremolini, C.; Morano, F.; Moretto, R.; Berenato, R.; Tamborini, E.; Perrone, F.; Rossini, D.; Gloghini, A.; Busico, A.; Zucchelli, G.; et al. Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: The PRESSING case–control study. Ann. Oncol. 2017, 28, 3009–3014. [Google Scholar] [CrossRef] [PubMed]
- Laurent-Puig, P.; Grisoni, M.-L.; Heinemann, V.; Liebaert, F.; Neureiter, D.; Jung, A.; Montestruc, F.; Gaston-Mathe, Y.; Thiébaut, R.; Stintzing, S. Validation of miR-31-3p expression to predict cetuximab efficacy when used as first-line treatment in RAS wild-type metastatic colorectal cancer. Clin. Cancer Res. 2019, 25, 134–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Anandappa, G.; Lampis, A.; Cunningham, D.; Khan, K.H.; Kouvelakis, K.; Vlachogiannis, G.; Hedayat, S.; Tunariu, N.; Rao, S.; Watkins, D.; et al. miR-31-3p expression and benefit from anti-EGFR inhibitors in metastatic colorectal cancer patients enrolled in the prospective phase II PROSPECT-C trial. Clin. Cancer Res. 2019, 25, 3830–3838. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pugh, S.; Thiébaut, R.; Bridgewater, J.; Grisoni, M.-L.; Moutasim, K.; Rousseau, F.; Thomas, G.J.; Griffiths, G.; Liebaert, F.; Primrose, J.; et al. Association between miR-31-3p expression and cetuximab efficacy in patients with KRAS wild-type metastatic colorectal cancer: A post-hoc analysis of the new EPOC trial. Oncotarget 2017, 8, 93856–93866. [Google Scholar] [CrossRef] [Green Version]
- Taieb, J.; Tabernero, J.; Mini, E.; Subtil, F.; Folprecht, G.; Van Laethem, J.-L.; Thaler, J.; Bridgewater, J.; Petersen, L.N.; Blons, H.; et al. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): An open-label, randomised phase 3 trial. Lancet Oncol. 2014, 15, 862–873. [Google Scholar] [CrossRef]
- Bridgewater, J.A.; Pugh, S.A.; Maishman, T.; Eminton, Z.; Mellor, J.; Whitehead, A.; Stanton, L.; Radford, M.; Corkhill, A.; Griffiths, G.O.; et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): Long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020, 21, 398–411. [Google Scholar] [CrossRef]
- Gholami, S.; Grothey, A. EGFR antibodies in resectable metastatic colorectal liver metastasis: More harm than benefit? Lancet Oncol. 2020, 21, 324–326. [Google Scholar] [CrossRef]
- Modest, D.P.; Martens, U.M.; Riera-Knorrenschild, J.; Greeve, J.; Florschütz, A.; Wessendorf, S.; Ettrich, T.; Kanzler, S.; Nörenberg, D.; Ricke, J.; et al. FOLFOXIRI plus panitumumab as first-line treatment of RAS wild-type metastatic colorectal cancer: The randomized, open-label, phase II VOLFI study (AIO KRK0109). J. Clin. Oncol. 2019, 37, 3401–3411. [Google Scholar] [CrossRef]
- Douillard, J.-Y.; Oliner, K.S.; Siena, S.; Tabernero, J.; Burkes, R.; Barugel, M.; Humblet, Y.; Bodoky, G.; Cunningham, D.; Jassem, J.; et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 2013, 369, 1023–1034. [Google Scholar] [CrossRef] [Green Version]
- Van Cutsem, E.; Köhne, C.-H.; Hitre, E.; Zaluski, J.; Chang Chien, C.-R.; Makhson, A.; D’Haens, G.; Pintér, 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] [Green Version]
- Bokemeyer, C.; Bondarenko, I.; Makhson, A.; Hartmann, J.T.; Aparicio, J.; de Braud, F.; Donea, S.; Ludwig, H.; Schuch, G.; Stroh, C.; et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the First-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 2008, 27, 663–671. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moosmann, N.; von Weikersthal, L.F.; Vehling-Kaiser, U.; Stauch, M.; Hass, H.G.; Dietzfelbinger, H.; Oruzio, D.; Klein, S.; Zellmann, K.; Decker, T.; et al. Cetuximab plus Capecitabine and irinotecan compared with cetuximab plus capecitabine and oxaliplatin as first-line treatment for patients with metastatic colorectal cancer: AIO KRK-0104—A Randomized trial of the german AIO CRC study group. J. Clin. Oncol. 2011, 29, 1050–1058. [Google Scholar] [CrossRef] [PubMed]
- Bokemeyer, C.; Cutsem, E.V.; Rougier, P.; Ciardiello, F.; Heeger, S.; Schlichting, M.; Celik, I.; Köhne, C.-H. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur. J. Cancer 2012, 48, 1466–1475. [Google Scholar] [CrossRef] [PubMed]
- André, T.; Blons, H.; Mabro, M.; Chibaudel, B.; Bachet, J.-B.; Tournigand, C.; Bennamoun, M.; Artru, P.; Nguyen, S.; Ebenezer, C.; et al. Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: A GERCOR efficacy, tolerance, and translational molecular study. Ann. Oncol. 2013, 24, 412–419. [Google Scholar] [CrossRef]
- Seymour, M.T.; Brown, S.R.; Middleton, G.; Maughan, T.; Richman, S.; Gwyther, S.; Lowe, C.; Seligmann, J.F.; Wadsley, J.; Maisey, N.; et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): A prospectively stratified randomised trial. Lancet Oncol. 2013, 14, 749–759. [Google Scholar] [CrossRef] [Green Version]
- Cunningham, D.; Humblet, Y.; Siena, S.; Khayat, D.; Bleiberg, H.; Santoro, A.; Bets, D.; Mueser, M.; Harstrick, A.; Verslype, C.; et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 2004, 351, 337–345. [Google Scholar] [CrossRef] [Green Version]
- Carrato, A.; Abad, A.; Massuti, B.; Grávalos, C.; Escudero, P.; Longo-Muñoz, F.; Manzano, J.-L.; Gómez, A.; Safont, M.J.; Gallego, J.; et al. First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: A randomised, phase II trial (PLANET-TTD). Eur. J. Cancer 2017, 81, 191–202. [Google Scholar] [CrossRef]
- Jonker, D.J.; O’Callaghan, C.J.; Karapetis, C.S.; Zalcberg, J.R.; Tu, D.; Au, H.-J.; Berry, S.R.; Krahn, M.; Price, T.; Simes, R.J.; et al. Cetuximab for the treatment of colorectal cancer. N. Engl. J. Med. 2007, 357, 2040–2048. [Google Scholar] [CrossRef] [Green Version]
- Sobrero, A.F.; Maurel, J.; Fehrenbacher, L.; Scheithauer, W.; Abubakr, Y.A.; Lutz, M.P.; Vega-Villegas, M.E.; Eng, C.; Steinhauer, E.U.; Prausova, J.; et al. EPIC: Phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J. Clin. Oncol. 2008, 26, 2311–2319. [Google Scholar] [CrossRef] [Green Version]
- Tveit, K.M.; Guren, T.; Glimelius, B.; Pfeiffer, P.; Sorbye, H.; Pyrhonen, S.; Sigurdsson, F.; Kure, E.; Ikdahl, T.; Skovlund, E.; et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: The NORDIC-VII study. J. Clin. Oncol. 2012, 30, 1755–1762. [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]
- Price, T.J.; Peeters, M.; Kim, T.W.; Li, J.; Cascinu, S.; Ruff, P.; Suresh, A.S.; Thomas, A.; Tjulandin, S.; Zhang, K.; 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, 569–579. [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. [Google Scholar] [CrossRef]
- 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]
- Yin, J.; Cohen, R.; Jin, Z.; Liu, H.; Pederson, L.; Adams, R.; Maughan, T.; Venook, A.P.; Van Cutsem, E.; Cremolini, C.; et al. Prognostic and predictive impact of primary tumor sidedness in first-line trials for advanced colorectal cancer: An analysis of 7,828 patients in the ARCAD database. J. Clin. Oncol. 2020, 38, 188. [Google Scholar] [CrossRef]
- Benson, A.B.; Venook, A.P.; Al-Hawary, M.M.; Cederquist, L.; Chen, Y.-J.; Ciombor, K.K.; Cohen, S.; Cooper, H.S.; Deming, D.; Engstrom, P.F.; et al. NCCN guidelines insights: Colon cancer, version 2.2018. J. Natl. Compr. Cancer Netw. 2018, 16, 359–369. [Google Scholar] [CrossRef] [Green Version]
- Mauri, G.; Pizzutilo, E.G.; Amatu, A.; Bencardino, K.; Palmeri, L.; Bonazzina, E.F.; Tosi, F.; Carlo Stella, G.; Burrafato, G.; Scaglione, F.; et al. Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: Systematic review of different strategies. Cancer Treat. Rev. 2019, 73, 41–53. [Google Scholar] [CrossRef]
- Tonini, G.; Imperatori, M.; Vincenzi, B.; Frezza, A.M.; Santini, D. Rechallenge therapy and treatment holiday: Different strategies in management of metastatic colorectal cancer. J. Exp. Clin. Cancer Res. 2013, 32, 92. [Google Scholar] [CrossRef] [Green Version]
- Siravegna, G.; Mussolin, B.; Buscarino, M.; Corti, G.; Cassingena, A.; Crisafulli, G.; Ponzetti, A.; Cremolini, C.; Amatu, A.; Lauricella, C.; et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat. Med. 2015, 21, 827. [Google Scholar] [CrossRef]
- Martinelli, E.; Ciardiello, D.; Martini, G.; Troiani, T.; Cardone, C.; Vitiello, P.P.; Normanno, N.; Rachiglio, A.M.; Maiello, E.; Latiano, T.; et al. Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: Challenges and future perspectives. Ann. Oncol. 2020, 31, 30–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cremolini, C.; Rossini, D.; Dell’Aquila, E.; Lonardi, S.; Conca, E.; Del Re, M.; Busico, A.; Pietrantonio, F.; Danesi, R.; Aprile, G.; et al. Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: A phase 2 single-arm clinical trial. JAMA Oncol. 2019, 5, 343–350. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Venderbosch, S.; Nagtegaal, I.D.; Maughan, T.S.; Smith, C.G.; Cheadle, J.P.; Fisher, D.; Kaplan, R.; Quirke, P.; Seymour, M.T.; Richman, S.D.; et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin. Cancer Res. 2014, 20, 5322–5330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jones, J.C.; Renfro, L.A.; Al-Shamsi, H.O.; Schrock, A.B.; Rankin, A.; Zhang, B.Y.; Kasi, P.M.; Voss, J.S.; Leal, A.D.; Sun, J.; et al. Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J. Clin. Oncol. 2017, 35, 2624. [Google Scholar] [CrossRef]
- Yaeger, R.; Kotani, D.; Mondaca, S.; Parikh, A.R.; Bando, H.; Van Seventer, E.E.; Taniguchi, H.; Zhao, H.; Thant, C.N.; de Stanchina, E.; et al. Response to anti-EGFR therapy in patients with BRAF non-V600-mutant metastatic colorectal cancer. Clin. Cancer Res. 2019, 25, 7089–7097. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Johnson, B.; Loree, J.M.; Morris, V.K.; Dasari, A.; Pant, S.; Raghav, K.P.S.; Kopetz, S. Activity of EGFR inhibition in atypical (non-V600E) BRAF-mutated metastatic colorectal cancer. J. Clin. Oncol. 2019, 37, 596. [Google Scholar] [CrossRef]
- Pagani, F.; Randon, G.; Guarini, V.; Raimondi, A.; Prisciandaro, M.; Lobefaro, R.; Di Bartolomeo, M.; Sozzi, G.; de Braud, F.; Gasparini, P.; et al. The landscape of actionable gene fusions in colorectal cancer. Int. J. Mol. Sci. 2019, 20, 5319. [Google Scholar] [CrossRef] [Green Version]
- Cocco, E.; Benhamida, J.; Middha, S.; Zehir, A.; Mullaney, K.; Shia, J.; Yaeger, R.; Zhang, L.; Wong, D.; Villafania, L.; et al. Colorectal carcinomas containing hypermethylated MLH1 promoter and wild-type BRAF/KRAS are enriched for targetable kinase fusions. Cancer Res. 2019, 79, 1047–1053. [Google Scholar] [CrossRef] [Green Version]
- Tran, B.; Kopetz, S.; Tie, J.; Gibbs, P.; Jiang, Z.-Q.; Lieu, C.H.; Agarwal, A.; Maru, D.M.; Sieber, O.; Desai, J. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 2011, 117, 4623–4632. [Google Scholar] [CrossRef] [Green Version]
- Overman, M.; Lonardi, S.; Wong, K.; Lenz, H.; Gelsomino, F.; Aglietta, M.; Morse, M.; Van Cutsem, E.; McDermott, R.; Hill, A.; et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal. Cancer J. Clin. Oncol. 2018, 36, 773–779. [Google Scholar] [CrossRef]
- Morris, V.; Overman, M.J.; Jiang, Z.-Q.; Garrett, C.; Agarwal, S.; Eng, C.; Kee, B.; Fogelman, D.; Dasari, A.; Wolff, R.; et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin. Color. Cancer 2014, 13, 164–171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Seligmann, J.F.; Fisher, D.; Smith, C.G.; Richman, S.D.; Elliott, F.; Brown, S.; Adams, R.; Maughan, T.; Quirke, P.; Cheadle, J.; et al. Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: Analysis from 2530 patients in randomised clinical trials. Ann. Oncol. 2017, 28, 562–568. [Google Scholar] [CrossRef] [PubMed]
- de la Fouchardière, C.; Cohen, R.; Malka, D.; Guimbaud, R.; Bourien, H.; Lièvre, A.; Cacheux, W.; Artru, P.; François, E.; Gilabert, M.; et al. Characteristics of BRAFV600E mutant, deficient mismatch repair/proficient mismatch repair, metastatic colorectal cancer: A multicenter series of 287 patients. Oncologist 2019, 24, e1331–e1340. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Loupakis, F.; Cremolini, C.; Antoniotti, C.; Lonardi, S.; Ronzoni, M.; Zaniboni, A.; Tonini, G.; Salvatore, L.; Chiara, S.; Carlomagno, C.; et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as initial treatment for metastatic colorectal cancer (TRIBE study): Updated survival results and final molecular subgroups analyses. J. Clin. Oncol. 2015, 33, 3510. [Google Scholar] [CrossRef]
- Cremolini, C.; Antoniotti, C.; Lonardi, S.; Rossini, D.; Morano, F.; Cordio, S.; Bergamo, F.; Marmorino, F.; Maiello, E.; Passardi, A.; et al. Updated results of TRIBE2, a phase III, randomized strategy study by GONO in the 1st- and 2nd-line treatment of unresectable mCRC. Ann. Oncol. 2019, 37, 3058. [Google Scholar] [CrossRef]
- Hurwitz, H.; Fehrenbacher, L.; Novotny, W.; Cartwright, T.; Hainsworth, J.; Heim, W.; Berlin, J.; Baron, A.; Griffing, S.; Holmgren, E.; et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 2004, 350, 2335–2342. [Google Scholar] [CrossRef] [Green Version]
- Price, T.J.; Hardingham, J.E.; Lee, C.K.; Weickhardt, A.; Townsend, A.R.; Wrin, J.W.; Chua, A.; Shivasami, A.; Cummins, M.M.; Murone, C.; et al. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J. Clin. Oncol. 2011, 29, 2675–2682. [Google Scholar] [CrossRef]
- Wirapati, P.; Pomella, V.; VandenBosch, B.; Kerr, P.; Maiello, E.; Grahame, M.J.; Curca, R.-O.D.; Karthaus, M.; Bridgewater, J.A.; Mihailov, A.C.; et al. LBA-005VELOUR trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity. Ann. Oncol. 2017, 28, iii151–iii152. [Google Scholar] [CrossRef]
- Yoshino, T.; Portnoy, D.C.; Obermannová, R.; Bodoky, G.; Prausová, J.; Garcia-Carbonero, R.; Ciuleanu, T.; García-Alfonso, P.; Cohn, A.L.; Van Cutsem, E.; et al. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. Ann. Oncol. 2019, 30, 124–131. [Google Scholar] [CrossRef] [Green Version]
- Gelsomino, F.; Casadei-Gardini, A.; Rossini, D.; Boccaccino, A.; Masi, G.; Cremolini, C.; Spallanzani, A.; Viola, M.G.; Garajovà, I.; Salati, M.; et al. The role of anti-angiogenics in pre-treated metastatic BRAF-mutant colorectal cancer: A pooled analysis. Cancers 2020, 12, 1022. [Google Scholar] [CrossRef] [Green Version]
- Pietrantonio, F.; Petrelli, F.; Coinu, A.; Di Bartolomeo, M.; Borgonovo, K.; Maggi, C.; Cabiddu, M.; Iacovelli, R.; Bossi, I.; Lonati, V.; et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis. Eur. J. Cancer 2015, 51, 587–594. [Google Scholar] [CrossRef] [PubMed]
- Rowland, A.; Dias, M.M.; Wiese, M.D.; Kichenadasse, G.; McKinnon, R.A.; Karapetis, C.S.; Sorich, M.J. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br. J. Cancer 2015, 112, 1888–1894. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stintzing, S.; Miller-Phillips, L.; Modest, D.P.; Fischer von Weikersthal, L.; Decker, T.; Kiani, A.; Vehling-Kaiser, U.; Al-Batran, S.-E.; Heintges, T.; Kahl, C.; et al. Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: Analysis of the FIRE-3 (AIO KRK-0306) study. Eur. J. Cancer 2017, 79, 50–60. [Google Scholar] [CrossRef] [PubMed]
- Kopetz, S.; Grothey, A.; Yaeger, R.; Van Cutsem, E.; Desai, J.; Yoshino, T.; Wasan, H.; Ciardiello, F.; Loupakis, F.; Hong, Y.S.; et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer. N. Engl. J. Med. 2019, 381, 1632–1643. [Google Scholar] [CrossRef] [Green Version]
- Corcoran, R.B.; Ebi, H.; Turke, A.B.; Coffee, E.M.; Nishino, M.; Cogdill, A.P.; Brown, R.D.; Della Pelle, P.; Dias-Santagata, D.; Hung, K.E.; 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, 227–235. [Google Scholar] [CrossRef] [Green Version]
- Yaeger, R.; Cercek, A.; O’Reilly, E.M.; Reidy, D.L.; Kemeny, N.; Wolinsky, T.; Capanu, M.; Gollub, M.J.; Rosen, N.; Berger, M.F.; et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin. Cancer Res. 2015, 21, 1313–1320. [Google Scholar] [CrossRef] [Green Version]
- Hong, D.S.; Morris, V.K.; El Osta, B.; Sorokin, A.V.; Janku, F.; Fu, S.; Overman, M.J.; Piha-Paul, S.; Subbiah, V.; Kee, B.; et al. Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAF V600E mutation. Cancer Discov. 2016, 6, 1352–1365. [Google Scholar] [CrossRef] [Green Version]
- Van Geel, R.M.J.M.; Tabernero, J.; Elez, E.; Bendell, J.C.; Spreafico, A.; Schuler, M.; Yoshino, T.; Delord, J.-P.; Yamada, Y.; Lolkema, M.P.; et al. A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer. Cancer Discov. 2017, 7, 610–619. [Google Scholar] [CrossRef] [Green Version]
- Kopetz, S.; McDonough, S.L.; Morris, V.K.; Lenz, H.-J.; Magliocco, A.M.; Atreya, C.E.; Diaz, L.A.; Allegra, C.J.; Wang, S.E.; Lieu, C.H.; et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J. Clin. Oncol. 2017, 35, 520. [Google Scholar] [CrossRef] [Green Version]
- Corcoran, R.B.; André, T.; Atreya, C.E.; Schellens, J.H.M.; Yoshino, T.; Bendell, J.C.; Hollebecque, A.; McRee, A.J.; Siena, S.; Middleton, G.; et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer. Cancer Discov. 2018, 8, 428–443. [Google Scholar] [CrossRef] [Green Version]
- Kopetz, S.; Grothey, A.; Van Cutsem, E.; Yaeger, R.; Wasan, H.S.; Yoshino, T.; Desai, J.; Ciardiello, F.; Loupakis, F.; Hong, Y.S.; et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: Updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J. Clin. Oncol. 2020, 38, 4001. [Google Scholar] [CrossRef]
- Kopetz, S.; Grothey, A.; Van Cutsem, E.; Yaeger, R.; Wasan, H.S.; Yoshino, T.; Desai, J.; Ciardiello, F.; Loupakis, F.; Hong, Y.S.; et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J. Clin. Oncol. 2020, 38, 8. [Google Scholar] [CrossRef]
- Battaglin, F.; Puccini, A.; Intini, R.; Schirripa, M.; Ferro, A.; Bergamo, F.; Lonardi, S.; Zagonel, V.; Lenz, H.-J.; Loupakis, F. The role of tumor angiogenesis as a therapeutic target in colorectal cancer. Expert Rev. Anticancer Ther. 2018, 18, 251–266. [Google Scholar] [CrossRef] [PubMed]
- Wirapati, P.; Pomella, V.; Kerr, P.; Maiello, E.; Jeffery, G.; Curca, R.-O.; Karthaus, M.; Bridgewater, J.; Mihailov, A. Velour trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity. J. Clin. Oncol. 2017, 35, 3538. [Google Scholar] [CrossRef]
- Nagasaka, M.; Li, Y.; Sukari, A.; Ou, S.-H.I.; Al-Hallak, M.N.; Azmi, A.S. KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat. Rev. 2020, 84, 101974. [Google Scholar] [CrossRef]
- Fakih, M.; Desai, J.; Kuboki, Y.; Strickler, J.H.; Price, T.J.; Durm, G.A.; Falchook, G.S.; Denlinger, C.S.; Krauss, J.C.; Shapiro, G.; et al. CodeBreak 100: Activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer. J. Clin. Oncol. 2020, 38, 4018. [Google Scholar] [CrossRef]
- Colle, R.; Cohen, R.; Cochereau, D.; Duval, A.; Lascols, O.; Lopez-Trabada, D.; Afchain, P.; Trouilloud, I.; Parc, Y.; Lefevre, J.; et al. Immunotherapy and patients treated for cancer with microsatellite instability. Bull. Cancer 2017, 104, 42–51. [Google Scholar] [CrossRef] [Green Version]
- André, T.; de Gramont, A.; Vernerey, D.; Chibaudel, B.; Bonnetain, F.; Tijeras-Raballand, A.; Scriva, A.; Hickish, T.; Tabernero, J.; Van Laethem, J.; et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: Updated 10-year survival and outcomes According to BRAF mutation and mismatch repair status of the mosaic study. J. Clin. Oncol. 2015, 33, 4176–4187. [Google Scholar] [CrossRef]
- Sargent, D.J.; Marsoni, S.; Monges, G.; Thibodeau, S.N.; Labianca, R.; Hamilton, S.R.; French, A.J.; Kabat, B.; Foster, N.R.; Torri, V.; et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J. Clin. Oncol. 2010, 28, 3219–3226. [Google Scholar] [CrossRef] [Green Version]
- Zaanan, A.; Shi, Q.; Taieb, J.; Alberts, S.R.; Meyers, J.P.; Smyrk, T.C.; Julie, C.; Zawadi, A.; Tabernero, J.; Mini, E.; et al. Role of deficient DNA mismatch repair status in patients with stage III colon cancer treated with FOLFOX adjuvant chemotherapy: A pooled analysis from 2 randomized clinical trials. JAMA Oncol. 2018, 4, 379–383. [Google Scholar] [CrossRef]
- Innocenti, F.; Ou, F.-S.; Qu, X.; Zemla, T.J.; Niedzwiecki, D.; Tam, R.; Mahajan, S.; Goldberg, R.M.; Bertagnolli, M.M.; Blanke, C.D.; et al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J. Clin. Oncol. 2019, 37, 1217. [Google Scholar] [CrossRef] [PubMed]
- Tougeron, D.; Sueur, B.; Zaanan, A.; Fouchardiére, C.; Sefrioui, D.; Lecomte, T.; Aparicio, T.; Des Guetz, G.; Artru, P.; Hautefeuille, V.; et al. Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study. Int. J. Cancer 2020, 147, 285–296. [Google Scholar] [CrossRef] [PubMed]
- Taieb, J.; Shi, Q.; Pederson, L.; Alberts, S.; Wolmark, N.; Van Cutsem, E.; de Gramont, A.; Kerr, R.; Grothey, A.; Lonardi, S.; et al. Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: Results of an ACCENT pooled analysis of seven studies. Ann. Oncol. 2019, 30, 1466–1471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stadler, Z.K.; Battaglin, F.; Middha, S.; Hechtman, J.F.; Tran, C.; Cercek, A.; Yaeger, R.; Segal, N.H.; Varghese, A.M.; Reidy-Lagunes, D.L.; et al. Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels. J. Clin. Oncol. 2016, 34, 2141–2147. [Google Scholar] [CrossRef] [PubMed]
- Muzny, D.M.; Bainbridge, M.N.; Chang, K.; Dinh, H.H.; Drummond, J.A.; Fowler, G.; Kovar, C.L.; Lewis, L.R.; Morgan, M.B.; Newsham, I.F.; et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012, 487, 330–337. [Google Scholar] [CrossRef] [Green Version]
- Maby, P.; Tougeron, D.; Hamieh, M.; Mlecnik, B.; Kora, H.; Bindea, G.; Angell, H.K.; Fredriksen, T.; Elie, N.; Fauquembergue, E.; et al. Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: A rationale for personalized immunotherapy. Cancer Res. 2015, 75, 3446–3455. [Google Scholar] [CrossRef] [Green Version]
- Marisa, L.; Svrcek, M.; Collura, A.; Becht, E.; Cervera, P.; Wanherdrick, K.; Buhard, O.; Goloudina, A.; Jonchère, V.; Selves, J.; et al. The balance between cytotoxic T-cell lymphocytes and immune checkpoint expression in the prognosis of colon tumors. J. Natl. Cancer Inst. 2018, 110. [Google Scholar] [CrossRef]
- Llosa, N.J.; Cruise, M.; Tam, A.; Wicks, E.C.; Hechenbleikner, E.M.; Taube, J.M.; Blosser, R.L.; Fan, H.; Wang, H.; Luber, B.S.; et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015, 5, 43–51. [Google Scholar] [CrossRef]
- Le, D.T.; Kim, T.W.; Van Cutsem, E.; Geva, R.; Jäger, D.; Hara, H.; Burge, M.; O’Neil, B.; Kavan, P.; Yoshino, T.; et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability–high/mismatch repair–deficient metastatic colorectal cancer: KEYNOTE-164. J. Clin. Oncol. 2019, 38, 11–19. [Google Scholar] [CrossRef]
- Le, D.T.; Durham, J.N.; Smith, K.N.; Wang, H.; Bartlett, B.R.; Aulakh, L.K.; Lu, S.; Kemberling, H.; Wilt, C.; Luber, B.S.; et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017, 357, 409–413. [Google Scholar] [CrossRef] [Green Version]
- André, T.; Berton, D.; de Braud, F.; Curigliano, G.; Guo, W.; Danaee, H.; Lu, S.; Im, E.; Starling, N. Safety and efficacy of anti-PD-1 antibody dostarlimab in patients (pts) with mismatch repair deficient (dMMR) GI cancers. J. Clin. Oncol. 2020, 38, 218. [Google Scholar] [CrossRef]
- Kim, J.H.; Kim, S.Y.; Baek, J.Y.; Cha, Y.J.; Ahn, J.B.; Kim, H.S.; Lee, K.-W.; Kim, J.-W.; Kim, T.-Y.; Chang, W.J.; et al. A Phase II study of avelumab monotherapy in patients with mismatch repair-deficient/microsatellite instability-high or POLE-mutated metastatic or unresectable colorectal cancer. Cancer Res. Treat. 2020. [Google Scholar] [CrossRef] [PubMed]
- Segal, N.H.; Wainberg, Z.A.; Overman, M.J.; Ascierto, P.A.; Arkenau, H.-T.; Butler, M.O.; Eder, J.P.; Kim, D.-W.; Cunningham, D.; Khleif, S.N.; et al. Safety and clinical activity of durvalumab monotherapy in patients with microsatellite instability–high (MSI-H) tumors. J. Clin. Oncol. 2019, 37, 670. [Google Scholar] [CrossRef]
- Le, D.T.; Uram, J.N.; Wang, H.; Bartlett, B.R.; Kemberling, H.; Eyring, A.D.; Skora, A.D.; Luber, B.S.; Azad, N.S.; Laheru, D.; et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015, 372, 2509–2520. [Google Scholar] [CrossRef]
- Lenz, H.-J.J.; Van Cutsem, E.; Limon, M.L.; Wong, K.Y.; Hendlisz, A.; Aglietta, M.; Garcia-Alfonso, P.; Neyns, B.; Luppi, G.; Cardin, D.; et al. LBA18_PRDurable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Ann. Oncol. 2018, 29. [Google Scholar] [CrossRef]
- Andre, T.; Shiu, K.-K.; Kim, T.W.; Jensen, B.V.; Jensen, L.H.; Punt, C.J.A.; Smith, D.M.; Garcia-Carbonero, R.; Benavides, M.; Gibbs, P.; et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 Study. J. Clin. Oncol. 2020, 38, LBA4. [Google Scholar] [CrossRef]
- Chalabi, M.; Fanchi, L.F.; Dijkstra, K.K.; Van den Berg, J.G.; Aalbers, A.G.; Sikorska, K.; Lopez-Yurda, M.; Grootscholten, C.; Beets, G.L.; Snaebjornsson, P.; et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 2020. [Google Scholar] [CrossRef]
- Loupakis, F.; Depetris, I.; Biason, P.; Intini, R.; Prete, A.A.; Leone, F.; Lombardi, P.; Filippi, R.; Spallanzani, A.; Cascinu, S.; et al. Prediction of benefit from checkpoint inhibitors in mismatch repair deficient metastatic colorectal cancer: Role of tumor infiltrating lymphocytes. Oncologist 2020. [Google Scholar] [CrossRef] [Green Version]
- Cohen, R.; Hain, E.; Buhard, O.; Guilloux, A.; Bardier, A.; Kaci, R.; Bertheau, P.; Renaud, F.; Bibeau, F.; Fléjou, J.; et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol. 2018. [Google Scholar] [CrossRef]
- Middha, S.; Yaeger, R.; Shia, J.; Stadler, Z.K.; King, S.; Guercio, S.; Paroder, V.; Bates, D.D.B.; Rana, S.; Diaz, L.A.; et al. Majority of B2M-mutant and -deficient colorectal carcinomas achieve clinical benefit from immune checkpoint inhibitor therapy and are microsatellite instability-high. J. Clin. Oncol. 2019, 3. [Google Scholar] [CrossRef]
- Shin, D.S.; Zaretsky, J.M.; Escuin-Ordinas, H.; Garcia-Diaz, A.; Hu-Lieskovan, S.; Kalbasi, A.; Grasso, C.S.; Hugo, W.; Sandoval, S.; Torrejon, D.Y.; et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017, 7, 188–201. [Google Scholar] [CrossRef] [Green Version]
- Schrock, A.B.; Ouyang, C.; Sandhu, J.; Sokol, E.; Jin, D.; Ross, J.S.; Miller, V.A.; Lim, D.; Amanam, I.; Chao, J.; et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann. Oncol. 2019, 30, 1096–1103. [Google Scholar] [CrossRef]
- Mandal, R.; Samstein, R.M.; Lee, K.-W.; Havel, J.J.; Wang, H.; Krishna, C.; Sabio, E.Y.; Makarov, V.; Kuo, F.; Blecua, P.; et al. Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotherapy response. Science 2019, 364, 485–491. [Google Scholar] [CrossRef]
- Richman, S.D.; Southward, K.; Chambers, P.; Cross, D.; Barrett, J.; Hemmings, G.; Taylor, M.; Wood, H.; Hutchins, G.; Foster, J.M.; 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. 2016, 238, 562–570. [Google Scholar] [CrossRef]
- Shimada, Y.; Yagi, R.; Kameyama, H.; Nagahashi, M.; Ichikawa, H.; Tajima, Y.; Okamura, T.; Nakano, M.; Nakano, M.; Sato, Y.; et al. Utility of comprehensive genomic sequencing for detecting HER2-positive colorectal cancer. Hum. Pathol. 2017, 66, 1–9. [Google Scholar] [CrossRef]
- Nam, S.K.; Yun, S.; Koh, J.; Kwak, Y.; Seo, A.N.; Park, K.U.; Kim, D.-W.; Kang, S.-B.; Kim, W.H.; Lee, H.S. BRAF, PIK3CA, and HER2 oncogenic alterations according to KRAS mutation status in advanced colorectal cancers with distant metastasis. PLoS ONE 2016, 11, e0151865. [Google Scholar] [CrossRef] [Green Version]
- Ross, J.S.; Fakih, M.; Ali, S.M.; Elvin, J.A.; Schrock, A.B.; Suh, J.; Vergilio, J.-A.; Ramkissoon, S.; Severson, E.; Daniel, S.; et al. Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3. Cancer 2018, 124, 1358–1373. [Google Scholar] [CrossRef] [Green Version]
- Missiaglia, E.; Jacobs, B.; D’Ario, G.; Di Narzo, A.F.; Soneson, C.; Budinska, E.; Popovici, V.; Vecchione, L.; Gerster, S.; Yan, P.; et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann. Oncol. 2014, 25, 1995–2001. [Google Scholar] [CrossRef]
- Sartore-Bianchi, A.; Trusolino, L.; Martino, C.; Bencardino, K.; Lonardi, S.; Bergamo, F.; Zagonel, V.; Leone, F.; Depetris, I.; Martinelli, E.; et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): A proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016, 17, 738–746. [Google Scholar] [CrossRef]
- Siena, S.; Sartore-Bianchi, A.; Marsoni, S.; Hurwitz, H.I.; McCall, S.J.; Penault-Llorca, F.; Srock, S.; Bardelli, A.; Trusolino, L. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann. Oncol. 2018, 29, 1108–1119. [Google Scholar] [CrossRef]
- Wang, G.; He, Y.; Sun, Y.; Wang, W.; Qian, X.; Yu, X.; Pan, Y. Prevalence, prognosis and predictive status of HER2 amplification in anti-EGFR-resistant metastatic colorectal cancer. Clin. Transl. Oncol. 2020, 22, 813–822. [Google Scholar] [CrossRef]
- Valtorta, E.; Martino, C.; Sartore-Bianchi, A.; Penaullt-Llorca, F.; Viale, G.; Risio, M.; Rugge, M.; Grigioni, W.; Bencardino, K.; Lonardi, S.; et al. Assessment of a HER2 scoring system for colorectal cancer: Results from a validation study. Mod. Pathol. 2015, 28, 1481–1491. [Google Scholar] [CrossRef] [Green Version]
- Meric-Bernstam, F.; Hurwitz, H.; Raghav, K.P.S.; McWilliams, R.R.; Fakih, M.; VanderWalde, A.; Swanton, C.; Kurzrock, R.; Burris, H.; Sweeney, C.; et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): An updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019, 20, 518–530. [Google Scholar] [CrossRef]
- Strickler, J.H.; Zemla, T.; Ou, F.-S.; Cercek, A.; Wu, C.; Sanchez, F.A.; Hubbard, J.; Jaszewski, B.; Bandel, L.; Schweitzer, B.; et al. Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): Initial results from the MOUNTAINEER trial. Ann. Oncol. 2019, 30, v200. [Google Scholar] [CrossRef]
- Sartore-Bianchi, A.; Martino, C.; Lonardi, S.; Fenocchio, E.; Amatu, A.; Ghezzi, S.; Zagonel, V.; Ciardiello, F.; Ardizzoni, A.; Tosi, F.; et al. Phase II study of pertuzumab and trastuzumab-emtansine (T-DM1) in patients with HER2-positive metastatic colorectal cancer: The HERACLES-B (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification, cohort B) trial. Ann. Oncol. 2019, 30, v869–v870. [Google Scholar] [CrossRef]
- Drilon, A.; Laetsch, T.W.; Kummar, S.; DuBois, S.G.; Lassen, U.N.; Demetri, G.D.; Nathenson, M.; Doebele, R.C.; Farago, A.F.; Pappo, A.S.; et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 2018, 378, 731–739. [Google Scholar] [CrossRef]
- Drilon, A.; Siena, S.; Ou, S.-H.I.; Patel, M.; Ahn, M.J.; Lee, J.; Bauer, T.M.; Farago, A.F.; Wheler, J.J.; Liu, S.V.; et al. Safety and antitumor activity of the multitargeted Pan-TRK, ROS1, and ALK inhibitor entrectinib: Combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017, 7, 400–409. [Google Scholar] [CrossRef] [Green Version]
- Solomon, J.P.; Benayed, R.; Hechtman, J.F.; Ladanyi, M. Identifying patients with NTRK fusion cancer. Ann. Oncol. 2019, 30 (Suppl. 8), viii16–viii22. [Google Scholar] [CrossRef] [Green Version]
- Yoshino, T.; Pentheroudakis, G.; Mishima, S.; Overman, M.J.; Yeh, K.-H.; Baba, E.; Naito, Y.; Calvo, F.; Saxena, A.; Chen, L.-T.; et al. JSCO/ESMO/ASCO/JSMO/TOS: International expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions. Ann. Oncol. 2020. [Google Scholar] [CrossRef]
- Lasota, J.; Chłopek, M.; Lamoureux, J.; Christiansen, J.; Kowalik, A.; Wasąg, B.; Felisiak-Gołąbek, A.; Agaimy, A.; Biernat, W.; Canzonieri, V.; et al. Colonic adenocarcinomas harboring NTRK fusion genes: A clinicopathologic and molecular genetic study of 16 cases and review of the literature. Am. J. Surg. Pathol. 2020, 44, 162–173. [Google Scholar] [CrossRef]
- Pietrantonio, F.; Di Nicolantonio, F.; Schrock, A.B.; Lee, J.; Tejpar, S.; Sartore-Bianchi, A.; Hechtman, J.F.; Christiansen, J.; Novara, L.; Tebbutt, N.; et al. ALK, ROS1, and NTRK rearrangements in metastatic colorectal Cancer. J. Natl. Cancer Inst. 2017, 109. [Google Scholar] [CrossRef] [Green Version]
- Okamura, R.; Boichard, A.; Kato, S.; Sicklick, J.K.; Bazhenova, L.; Kurzrock, R. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: Implications for NTRK-targeted therapeutics. J. Clin. Oncol. 2018. [Google Scholar] [CrossRef]
- Cocco, E.; Scaltriti, M.; Drilon, A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat. Rev. Clin. Oncol. 2018, 1. [Google Scholar] [CrossRef]
- Chou, A.; Fraser, T.; Ahadi, M.; Fuchs, T.; Sioson, L.; Clarkson, A.; Sheen, A.; Singh, N.; Corless, C.L.; Gill, A.J. NTRK gene rearrangements are highly enriched in MLH1/PMS2 deficient, BRAF wild-type colorectal carcinomas—A study of 4569 cases. Mod. Pathol. 2019, 33, 1–9. [Google Scholar] [CrossRef]
Therapy | Phase | Condition | Primary Endpoint | NCT Identifier |
---|---|---|---|---|
Encorafenib 1 + cetuximab 2 + nivolumab 4 | 1/2 | 2 or 3rd line | ORR, DLT | NCT04017650 |
Encorafenib 1 + binimetinib 3 + nivolumab 4 | 1/2 | >1st line | ORR, DLT | NCT04044430 |
Dabrafenib 1 + trametinib 3 + PDR 001 4 | 2 | Any line | ORR, DLT | NCT03668431 |
FOLFOXIRI + cetuximab 2 or bevacizumab 5 | 2 | 1st line | ORR | NCT04034459 |
FOLFIRI + cetuximab 2 + vemurafenib 1 | 2 | - | ORR | NCT03727763 |
Irinotecan + AZD 1775 6 | 1 | >1st line | DLT | NCT02906059 |
Panitumumab 2 + trametinib 3 | 2 | >2nd line | ORR | NCT03087071 |
Molecular Subtypes | Targeted Therapies |
---|---|
MSI, whatever the RAS/RAF mutational status | Immune checkpoint inhibitor(s) |
RAS/RAF wild-type | Anti-EGRF mAbs |
BRAFV600E mutated | Encorafenib + cetuximab +/− binimetinib |
RAS mutated | No current targeted therapy, ongoing trials with new-generation KRAS inhibitors |
HER2 amplified/mutated | Anti-HER2 mAbs/inhibitors (trastuzumab, pertuzumab, lapatinib), anti-HER2 antibody-drug conjugate (trastuzuab deruxtecan) |
NTRK fusion-positive | TRK inhibitor (Larotrectinib, entrectinib) |
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Cohen, R.; Pudlarz, T.; Delattre, J.-F.; Colle, R.; André, T. Molecular Targets for the Treatment of Metastatic Colorectal Cancer. Cancers 2020, 12, 2350. https://doi.org/10.3390/cancers12092350
Cohen R, Pudlarz T, Delattre J-F, Colle R, André T. Molecular Targets for the Treatment of Metastatic Colorectal Cancer. Cancers. 2020; 12(9):2350. https://doi.org/10.3390/cancers12092350
Chicago/Turabian StyleCohen, Romain, Thomas Pudlarz, Jean-François Delattre, Raphaël Colle, and Thierry André. 2020. "Molecular Targets for the Treatment of Metastatic Colorectal Cancer" Cancers 12, no. 9: 2350. https://doi.org/10.3390/cancers12092350