Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress
Abstract
:1. Introduction
2. From Morphological to Molecular Classifications
3. Targeting HER2 beyond Trastuzumab: Novel Steps towards Precision Medicine
4. Targeting MET, EGFR, PI3K/AKT/mTOR Pathways and NTRK Fusions
5. The Role of Stemness and Metalloprotease in GEA
6. Angiogenesis-Targeting Drugs
7. The Search for Biomarkers for Precision Immunotherapy
8. Novel Potentially Druggable Pathways: Tight Junction Proteins, Fibroblast Growth Factor Pathway and DNA Damage Repair Response
8.1. Claudin 18.2
8.2. FGFR Pathway
8.3. DNA Damage Response Pathway in GEA
9. Conclusions
Author Contributions
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, 394–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nagaraja, A.K.; Kikuchi, O.; Bass, A.J. Genomics and Targeted Therapies in Gastroesophageal Adenocarcinoma. Cancer Discov. 2019. [Google Scholar] [CrossRef] [PubMed]
- Anderson, W.F.; Rabkin, C.S.; Turner, N.; Fraumeni, J.F.J.; Rosenberg, P.S.; Camargo, M.C. The Changing Face of Noncardia Gastric Cancer Incidence among US Non-Hispanic Whites. J. Natl. Cancer Inst. 2018, 110110, 608–615. [Google Scholar] [CrossRef] [PubMed]
- Lin, S.J.; Gagnon-bartsch, J.A.; Tan, I.B.; Earle, S.; Ruff, L.; Pettinger, K.; Ylstra, B.; van Grieken, N.; Rha, S.Y.; Chung, Y.C.; et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut 2015, 64, 1721–1731. [Google Scholar] [CrossRef]
- Cervantes, A.; Roda, D.; Tarazona, N.; Roselló, S. Current questions for the treatment of advanced gastric cancer. Cancer Treat. Rev. 2013, 3939, 60–67. [Google Scholar] [CrossRef]
- Lordick, F.; Allum, W.; Carneiro, F.; Mitryd, E.; Tabernero, J.; Tan, P.; Van Cutsem, E.; van de Veldeh, C.; Cervantes, A. Unmet needs and challenges in gastric cancer: The way forward. Cancer Treat. Rev. 2014, 4040, 692–700. [Google Scholar] [CrossRef] [Green Version]
- Lauren, P. The two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called Intestinal-Type Carcinoma. An Attempt at a Histo-Clinical Classification. Acta Pathol. Microbiol. Scand. 1965, 64, 31–49. [Google Scholar] [CrossRef]
- Cunningham, D.; Allum, W.H.; Stenning, S.P.; Thompson, J.N.; Van de Velde, C.; Nicolson, M.; Scarffe, J.H.; Lofts, F.J.; Falk, S.J.; Iveson, T.J.; et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N. Engl. J. Med. 2006, 355355, 11–20. [Google Scholar] [CrossRef]
- Al-Batran, S.-E.; Homann, N.; Pauligk, C.; Goetze, T.G.; Meiler, J.; Kasper, S.; Kopp, H.-G.; Mayer, F.; Haag, G.H.; Luley, K. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): A randomised, phase 2/3 trial. Lancet 2019, 393393, 1948–1957. [Google Scholar] [CrossRef]
- Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014, 513, 202–209. [Google Scholar] [CrossRef] [Green Version]
- Cristescu, R.; Lee, J.; Nebozhyn, M.; Aggwarl, A. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat. Med. 2015, 21, 449–456. [Google Scholar] [CrossRef] [PubMed]
- Sohn, B.H.; Hwang, J.-E.; Jang, H.-J.; Lee, H.S.; Oh, S.C.; Shim, J.J.; Lee, K.W.; Kim, E.H.; Yim, S.Y.; Lee, S.H.; et al. Clinical Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer Genome Atlas Project. Clin. Cancer Res. J. Am. Assoc. Cancer Res. 2017. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pectasides, E.; Stachler, M.D.; Derks, S.; Liu, Y.; Maron, S.; Islam, M.; Alpert, L.; Kwak, H.; Kindler, H.; Polite, B.; et al. Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. Cancer Discov. 2018, 8, 37–48. [Google Scholar] [CrossRef] [Green Version]
- Arteaga, C.L.; Engelman, J.A. ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014, 25, 282–303. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yarden, Y.; Sliwkowski, M.X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2001, 2, 127–137. [Google Scholar] [CrossRef]
- Gambardella, V.; Fleitas, T.; Tarazona, N.; Cejalvo, J.M.; Gimeno-Valiente, F.; Martinez-Ciarpaglini, C.; Huerta, M.; Roselló, S.; Castillo, J.; Roda, D.; et al. Towards precision oncology for HER2 blockade in gastroesophageal adenocarcinoma. Ann. Oncol. 2019, 30, 1254–1264. [Google Scholar] [CrossRef] [Green Version]
- Wang, H.-B.; Liao, X.-F.; Zhang, J. Clinicopathological factors associated with HER2-positive gastric cancer: A meta-analysis. Medicine (Baltimore) 2017, 96, e8437. [Google Scholar] [CrossRef]
- Bang, Y.-J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatmentof HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010, 376, 687–697. [Google Scholar] [CrossRef]
- Tarazona, N.; Gambardella, V.; Huerta, M.; Roselló, S.; Cervantes, A. Personalised Treatment in Gastric Cancer: Myth or Reality? Curr. Oncol. Rep. 2016, 18, 41. [Google Scholar] [CrossRef]
- Sicklick, J.K.; Kato, S.; Okamura, R.; Schwaederle, M.; Hahn, M.E.; Williams, C.B.; De, P.; Krie, A.; Piccioni, D.E.; Miller, V.A.; et al. Molecular profiling of cancer patients enables personalized combination therapy: The I-PREDICT study. Nat. Med. 2019. [Google Scholar] [CrossRef]
- Gomez-Martin, C.; Plaza, J.C.; Pazo-Cid, R.; Pons, F.; Fonseca, P.; Leon, A.; Alsina, M.; Visa, L.; Rivera, F.; Galan, M.C.; et al. Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2013, 31, 4445–4452. [Google Scholar] [CrossRef] [PubMed]
- Hecht, J.R.; Bang, Y.-J.; Qin, S.K.; Chung, H.C.; Xu, J.M.; Park, J.O.; Jeziorski, K.; Shparyk, Y.; Hoff, P.M.; Sobrero, A.; et al. Lapatinib in Combination with Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC—A Randomized Phase III Trial. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2016, 34, 443–451. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Satoh, T.; Xu, R.-H.; Chung, H.C.; Sun, G.P.; Doi, T.; Xu, J.M.; Tsuji, A.; Omuro, Y.; Li, J.; Wang, J.W.; et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN—A randomized, phase III study. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2014, 32, 2039–2049. [Google Scholar] [CrossRef] [PubMed]
- Tabernero, J.; Hoff, P.M.; Shen, L.; Ohtsu, A.; Shah, M.A.; Cheng, K.; Song, C.; Wu, H.; Eng-Wong, J.; Kim, K.; et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018, 19, 1372–1384. [Google Scholar] [CrossRef]
- Thuss-Patience, P.C.; Shah, M.A.; Ohtsu, A.; Van Cutsem, E.; Ajani, J.A.; Castro, H.; Mansoor, W.; Chung, H.C.; Bodoky, G.; Shitara, K.; et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): An international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017, 18, 640–653. [Google Scholar] [CrossRef]
- Makiyama, A.; Sukawa, Y.; Kashiwada, T.; Kawada, J. Original reports abstract Randomized Phase II Study of Trastuzumab Beyond Progression in Patients with HER2-Positive Advanced Gastric or Gastroesophageal Junction Cancer: WJOG7112G (T-ACT Study). J. Clin. Onciol. 2020, 38, 1919–1928. [Google Scholar] [CrossRef]
- Pietrantonio, F.; Caporale, M.; Morano, F.; Sugimoto, N.; Ryu, M.H.; Sakai, D.; Chung, H.C.; Kawakami, H.; Yabusaki, H.; Lee, J.; et al. HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research. Int. J. Cancer 2016, 139, 2859–2864. [Google Scholar] [CrossRef] [Green Version]
- Gambardella, V.; Gimeno-Valiente, F.; Tarazona, N.; Martinez-Ciarpaglini, C.; Roda, D.; Fleitas, T.; Tolosa, P.; Cejalvo, J.M.; Huerta, M.; Roselló, S.; et al. Nrf2 through RPs6 activation is related to anti-HER2 drug resistance in HER2-amplified gastric cancer. Clin. Cancer Res. 2019, 25, 1639–1649. [Google Scholar] [CrossRef]
- Janjigian, Y.Y.; Sanchez-Vega, F.; Jonsson, P.; Chatila, W.C.; Hechtman, J.F.; Ku, G.Y.; Riches, J.C.; Tuvy, Y.; Kundra, R.; Bouvie, N.; et al. Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer. Cancer Discov. 2018, 8, 49–58. [Google Scholar] [CrossRef] [Green Version]
- Kim, S.T.; Banks, K.C.; Pectasides, E.; Kim, S.Y.; Kim, K.; Lanman, R.B.; Talasaz, A.; An, J.; Choi, M.G.; Lee, J.H.; et al. Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients. Ann. Oncol. J. Eur. Soc. Med. Oncol. 2018, 29, 1037–1048. [Google Scholar] [CrossRef]
- Bang, Y.J.; Giaccone, G.; Im, S.A.; Oh, Y.D.; Bauer, T.M.; Nordstrom, J.L.; Li, H.; Chichili, G.R.; Moore, P.A.; Hong, S.; et al. First-in-human phase 1 study of margetuximab antibody, in patients with HER2-positive advanced solid tumors. Ann. Oncol. 2017, 28, 855–861. [Google Scholar] [CrossRef] [PubMed]
- Catenacci, D.V.; Kang, Y.K.; Park, H.; Uronis, H.E.; Lee, K.W.; Ng, M.C.; Enzinger, P.C.; Park, S.H.; Gold, P.J.; Lacy, J.; et al. Articles Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal phase 1b-2 trial. Lancet Oncol. 2020, 2045, 1–11. [Google Scholar] [CrossRef]
- Loi, S.; Giobbie-Hurder, A.; Gombos, A.; Bachelot, T.; Hui, R.; Curigliano, G.; Campone, M.; Bingazoli, L.; Bonnefoi, H.; Jerusalem, G.; et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): A single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 2019, 20, 371–382. [Google Scholar] [CrossRef]
- Varadan, V.; Gilmore, H.; Miskimen, K.L.S.; Tuck, D.; Parsai, S.; Awadallah, A.; Krop, I.E.; Winer, E.P.; Bossuyt, C.; Somlo, G.; et al. Immune Signatures Following Single Dose Trastuzumab Predict Pathologic Response to PreoperativeTrastuzumab and Chemotherapy in HER2-Positive Early Breast Cancer. Clin. Cancer Res. J. Am. Assoc. Cancer Res. 2016, 22, 3249–3259. [Google Scholar] [CrossRef] [Green Version]
- Taylor, C.; Hershman, D.; Shah, N.; Suciu-Foca, N.; Petrylak, D.P.; Taub, R.; Vahdat, L.; Cheng, B.; Pegram, M.; Knutson, L.K.; et al. Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin. Cancer Res. J. Am. Assoc. Cancer Res. 2007, 13, 5133–5143. [Google Scholar] [CrossRef] [Green Version]
- Park, S.; Jiang, Z.; Mortenson, E.D.; Deng, L.; Radkevich-Brown, O.; Yang, X.; Sattar, H.; Wang, Y.; Brown, N.K.; Greene, M.; et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 2010, 18, 160–170. [Google Scholar] [CrossRef] [Green Version]
- Fuchs, C.S.; Doi, T.; Jang, R.W.; Muro, K.; Satoh, T.; Machado, M.; Sun, W.; Jalal, S.I.; Shah, M.A.; Metges, J.P.; et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018, 4, e180013. [Google Scholar] [CrossRef]
- Janjigian, Y.Y.; Maron, S.B.; Chatila, W.K.; Millang, B.; Chavan, S.; Alterman, C.; Chou, J.F.; Segal, M.F.; Simmons, M.Z.; Momtaz, P.; et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: An open-label, single-arm, phase 2 trial. Lancet Oncol. 2020, 21, 821–831. [Google Scholar] [CrossRef]
- Ogitani, Y.; Aida, T.; Hagihara, K.; Yamaguchi, J.; Ishii, C.; Harada, N.; Soma, M.; Okamoto, H.; Oitate, M.; Arakawa, S.; et al. DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clin. Cancer Res. J. Am. Assoc. Cancer Res. 2016, 22, 5097–5108. [Google Scholar] [CrossRef] [Green Version]
- Nagai, Y.; Oitate, M.; Shiozawa, H.; Ando, O. Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys. Xenobiotica 2019, 49, 1086–1096. [Google Scholar] [CrossRef]
- Mohamed, M.M.; Sloane, B.F. Cysteine cathepsins: Multifunctional enzymes in cancer. Nat. Rev. Cancer 2006, 6, 764–775. [Google Scholar] [CrossRef] [PubMed]
- Ogitani, Y.; Hagihara, K.; Oitate, M.; Naito, H.; Agatsuma, T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016, 107, 1039–1046. [Google Scholar] [CrossRef] [PubMed]
- Grabsch, H.; Sivakumar, S.; Gray, S.; Gabbert, H.E.; Müller, W. HER2 expression in gastric cancer: Rare, heterogeneous and of no prognostic value—Conclusions from 924 cases of two independent series. Cell Oncol. J. Int. Soc. Cell Oncol. 2010, 32, 57–65. [Google Scholar] [CrossRef]
- Doi, T.; Shitara, K.; Naito, Y.; Shimomura, A.; Fujiwara, Y.; Yanemori, K.; Shimizu, C.; Shimoi, T.; Kuboki, Y.; Matsubara, N.; et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody–drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: A phase 1 dose-escalation study. Lancet Oncol. 2017, 18, 1512–1522. [Google Scholar] [CrossRef]
- Shitara, K.; Bang, Y.-J.; Iwasa, S.; Sugimoto, N.; Ryu, M.H.; Sakai, D.; Chung, H.C.; Kawakami, H.; Yabusaki, H.; Lee, J.; et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N. Engl. J. Med. 2020, 382, 2419–2430. [Google Scholar] [CrossRef]
- Takegawa, N.; Tsurutani, J.; Kawakami, H.; Yonesaka, K.; Kato, R.; Haratani, K.; Hayashi, H.; Takeda, M.; Nonagase, Y.; Maenishi, O.; et al. [fam-] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification. Int. J. Cancer 2019, 145, 3414–3424. [Google Scholar] [CrossRef]
- Marcoux, J.; Champion, T.; Colas, O.; Wagner-Rousset, E.; Corvaia, N.; Dorsselaer, A.V.; Beck, A.; Cianférani, S. Native mass spectrometry and ion mobility characterization of trastuzumab emtansine, a lysine-linked antibody drug conjugate. Protein Sci. 2015, 24, 1210–1223. [Google Scholar] [CrossRef] [Green Version]
- Deng, N.; Goh, L.K.; Wang, H.; Das, K.; Tao, J.; Tan, I.B.; Zhang, S.; Lee, M.; Wu, J.; Lim, K.H.; et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 2012, 61, 673–684. [Google Scholar] [CrossRef]
- Maron, S.B.; Alpert, L.; Kwak, H.A.; Lomnicki, S.; Chase, L.; Xu, D.; O’Day, E.; Nagy, R.J.; Lanman, R.B.; Cecchi, F.; et al. Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma. Cancer Discov. 2018, 8, 696–713. [Google Scholar] [CrossRef] [Green Version]
- Lordick, F.; Kang, Y.-K.; Chung, H.-C.; Salman, P.; Oh, S.C.; Bodoky, G.; Kurteva, G.; Volovat, C.; Moiseyenko, V.M.; Gorbunova, V.; et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. Lancet Oncol. 2013, 14, 490–499. [Google Scholar] [CrossRef]
- Waddell, T.; Chau, I.; Cunningham, D.; Gonzalez, D.; Okines, A.F.C.; Okines, C.; Wotherspoon, A.; Saffery, C.; Middleton, G.; Wadsley, J.; et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol. 2013, 14, 481–489. [Google Scholar] [CrossRef] [Green Version]
- Dutton, S.J.; Ferry, D.R.; Blazeby, J.M.; Abbas, H.; Dahle-Smith, A.; Mansoor, W.; Thompson, J.; Harrison, M.; Chatterjee, A.; Falk, S.; et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): A phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 2014, 15, 894–904. [Google Scholar] [CrossRef]
- Shah, M.A.; Bang, Y.-J.; Lordick, F.; Alsina, M.; Chen, M.; Hack, S.P.; Bruey, J.M.; Smith, D.; McCaffery, I.; Shames, D.S.; et al. Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial. JAMA Oncol. 2017, 3, 620–627. [Google Scholar] [CrossRef] [PubMed]
- Catenacci, D.V.T.; Tebbutt, N.C.; Davidenko, I.; Murad, A.M.; Al-Batran, S.-E.; Ilson, D.H.; Tjulandin, S.; Gotovkin, E.; Karaszewska, B.; Bondarenki, I.; et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017, 18, 1467–1482. [Google Scholar] [CrossRef]
- Van Cutsem, E.; Karaszewska, B.; Kang, Y.-K.; Chung, H.C.; Shankaran, V.; Siena, S.; Go, N.F.; Yang, H.; Schupp, M.; Cunningham, D.; et al. A Multicenter Phase II Study of AMG 337 in Patients with MET-Amplified Gastric/Gastroesophageal Junction/Esophageal Adenocarcinoma and Other MET-Amplified Solid Tumors. Clin. Cancer Res. J. Am. Assoc. Cancer Res. 2019, 25, 2414–2423. [Google Scholar] [CrossRef] [Green Version]
- Ohtsu, A.; Ajani, J.A.; Bai, Y.-X.; Bang, Y.J.; Chung, H.C.; Sahmund, H.-M.; Shen, L.; Yeh, K.-H.; Chin, K.; Muro, K.; et al. Everolimus for previously treated advanced gastric cancer: Results of the randomized, double-blind, phase III GRANITE-1 study. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2013, 31, 3935–3943. [Google Scholar] [CrossRef]
- Lee, J.; Kim, S.T.; Kim, K.; Lee, H.; Kozarewa, I.; Mortimer, P.G.S.; Odegaard, J.I.; Harrington, E.A.; Lee, J.; Lee, T.; et al. Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial. Cancer Discov. 2019, 9, 1388–1405. [Google Scholar] [CrossRef] [Green Version]
- 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]
- Shah, M.A.; Starodub, A.; Sharma, S.; Berlin, J.; Patel, M.; Wainberg, Z.A.; Chaves, J.; Gordon, M.; Windsor, K.; Brachmann, C.B.; et al. Andecaliximab/GS-5745 Alone and Combined with mFOLFOX6 in Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Results from a Phase I Study. Clin. Cancer Res. 2018, 24, 3829–3837. [Google Scholar] [CrossRef] [Green Version]
- Ohtsu, A.; Shah, M.A.; Van Cutsem, E.; Rha, S.Y.; Sawaki, A.; Park, S.R.; Lim, H.Y.; Yamada, Y.; Wu, J.; Langer, B.; et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2011, 29, 3968–3976. [Google Scholar] [CrossRef]
- Fuchs, C.S.; Shitara, K.; Di Bartolomeo, M.; Lonardi, S.; Al-Batran, S.-E.; Van Cutsem, E.; Ilson, D.H.; Alsina, M.; Chau, I.; Lacy, J.; et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019, 20, 420–435. [Google Scholar] [CrossRef]
- Fuchs, C.S.; Tomasek, J.; Yong, C.J.; Dumitru, F.; Passalacqua, R.; Goswami, C.; Safran, H.; Vieira dos Santos, L.; Aprile, G.; Ferry, D.R.; et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014, 383, 31–39. [Google Scholar] [CrossRef]
- Wilke, H.; Muro, K.; Van Cutsem, E.; Oh, S.-C.; Bodoky, G.; Shimada, Y.; Hironaka, S.; Sugimoto, N.; Lipatov, O.; Kim, T.-Y.; et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol. 2014, 15, 1224–1235. [Google Scholar] [CrossRef]
- Li, J.; Qin, S.; Xu, J.; Xiong, J.; Wu, C.; Bai, Y.; Liu, W.; Tong, J.; Liu, Y.; Xu, R.; et al. Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Apatinib in Patients with Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2016, 34, 1448–1454. [Google Scholar] [CrossRef]
- Kang, Y.-K.; Boku, N.; Satoh, T.; Ryu, M.-H.; Chao, Y.; Kato, K.; Chung, H.C.; Chen, J.S.; Muro, K.; Kang, W.K.; et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017, 390, 2461–2471. [Google Scholar] [CrossRef]
- Janjigian, Y.Y.; Bendell, J.; Calvo, E.; Kim, J.W.; Ascierto, P.A.; Sharma, P.; Ott, P.A.; Peltola, K.; Jaeger, D.; Evans, J.; et al. CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2018, 36, 2836–2844. [Google Scholar] [CrossRef]
- Kim, S.T.; Cristescu, R.; Bass, A.J.; Kim, K.M.; Odegaard, J.I.; Kim, K.; Liu, X.Q.; Sher, X.; Jung, H.; Lee, M.; et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat. Med. 2018, 24, 1449–1458. [Google Scholar] [CrossRef]
- Le, D.T.; Uram, J.N.; Wang, H.; Bartlett, B.R.; Kemberling, H.; Eyring, A.; Skora, A.; 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]
- Sundar, R.; Qamra, A.; Tan, A.L.K.; Zhang, S.; Ng, C.C.; Teh, B.T.; Lee, J.; Kim, K.M.; Tan, P. Transcriptional analysis of immune genes in Epstein-Barr virus-associated gastric cancer and association with clinical outcomes. Gastric Cancer 2018, 21, 1064–1070. [Google Scholar] [CrossRef] [Green Version]
- Sundar, R.; Huang, K.K.; Qamra, A.; Kim, K.M.; Kim, S.T.; Kang, W.K.; Tan, A.L.K.; Lee, J.; Tan, P. Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer. Ann. Oncol. J. Eur. Soc. Med. Oncol. 2019, 30, 424–430. [Google Scholar] [CrossRef]
- Gambardella, V.; Fleitas, T.; Cervantes, A. Understanding mechanisms of primary resistance to checkpoint inhibitors will lead to precision immunotherapy of advanced gastric cancer. Ann. Oncol. J. Eur. Soc. Med. Oncol. 2019, 30, 351–352. [Google Scholar] [CrossRef] [PubMed]
- Kawazoe, A.; Fukuoka, S.; Nakamura, Y.; Kuboki, Y.; Wakabayashi, M.; Nomura, S.; Mikamoto, Y.; Shima, H.; Fujishiro, N.; Higuchi, T.; et al. Articles Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting. Lancet Oncol. 2020, 21, 1057–1065. [Google Scholar] [CrossRef]
- Cascinu, S. Comment Lenvatinib and pembrolizumab in advanced gastric cancer. Lancet Oncol. 2020, 2045, 1–2. [Google Scholar] [CrossRef]
- Fukuoka, S.; Hara, H.; Takahashi, N.; Kojima, T.; Kawazoe, A.; Asayama, M.; Yoshii, T.; Kotani, D.; Tamura, H.; Mikamoto, Y.; et al. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2020, 38, 2053–2061. [Google Scholar] [CrossRef]
- Sahin, U.; Koslowski, M.; Dhaene, K.; Usener, D.; Brandenburg, G.; Seitz, G.; Huber, C.; Türeci, O. Human Cancer Biology Claudin-18 Splice Variant 2 Is a Pan-Cancer T arget Suitable for Therapeutic Antibody Development. Clin. Cancer Res. 2008, 14, 7624–7634. [Google Scholar] [CrossRef] [Green Version]
- Sahin, U.; Schuler, M.; Richly, H.; Bauer, S.; Krilova, S.; Dechow, T.; Jerling, M.; Utsch, M.; Rohde, C.; Dhaene, K.; et al. ScienceDirect A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer *. Eur. J. Cancer 2018, 100, 17–26. [Google Scholar] [CrossRef] [Green Version]
- Tu, O. Original article a multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: The MONO study. Ann. Oncol. 2019, 30, 1487–1495. [Google Scholar] [CrossRef] [Green Version]
- Dienstmann, R.; Rodon, J.; Prat, A.; Perez-Garcia, J.; Adamo, B.; Felip, E.; Cortes, J.; Iafrate, A.J.; Nuciforo, P.; Tabernero, J. Genomic aberrations in the FGFR pathway: Opportunities for targeted therapies in solid tumors. Ann. Oncol. J. Eur. Soc. Med. Oncol. 2014, 25, 552–563. [Google Scholar] [CrossRef]
- Babina, I.S.; Turner, N.C. Advances and challenges in targeting FGFR signalling in cancer. Nat. Rev. Cancer. 2017, 17, 318–332. [Google Scholar] [CrossRef]
- Gambardella, V.; Tarazona, N.; Cejalvo, J.M.; Lombardi, P.; Huerta, M.; Roselló, S.; Fleitas, T.; Roda, D.; Cervantes, A. Personalized Medicine: Recent Progress in Cancer Therapy. Cancers 2020, 12. [Google Scholar] [CrossRef] [Green Version]
- Abou-Alfa, G.K.; Sahai, V.; Hollebecque, A.; Vaccaro, G.; Melisi, D.; Al-Rajabi, R.; Paulson, A.S.; Borad, M.J.; Gallinson, D.; Murphy, G.A.; et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study. Lancet Oncol. 2020, 21, 671–684. [Google Scholar] [CrossRef]
- Schuler, M.; Cho, B.C.; Sayehli, C.M.; Navarro, A.; Soo, R.A.; Richly, H.; Cassier, P.A.; Tai, D.; Penel, N.; Nogova, L.; et al. Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: A phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019, 20, 1454–1466. [Google Scholar] [CrossRef]
- Bahleda, R.; Meric-Bernstam, F.; Goyal, L.; Tran, B.; He, Y.; Yamamiya, I.; Benhadji, K.A.; Matos, I.; Arkenau, H.T. Phase 1, First-in-Human Study of Futibatinib, a Highly Selective, Irreversible FGFR1-4 Inhibitor in Patients with Advanced Solid Tumors. Ann. Oncol. J. Eur. Soc. Med. Oncol. 2020. [Google Scholar] [CrossRef] [PubMed]
- Bahleda, R.; Italiano, A.; Hierro, C.; Mita, A.; Cervantes, A.; Chan, N.; Awad, M.; Calvo, E.; Moreno, V.; Ramaswamy, G.; et al. Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors. Clin. Cancer Res. J. Am. Assoc. Cancer Res. 2019, 25, 4888–4897. [Google Scholar] [CrossRef] [PubMed]
- Ahn, S.; Lee, J.; Hong, M.; Kim, S.; Park, S.H.; Choi, M.G.; Lee, J.-H.; Sohn, T.S.; Bae, J.M.; Kim, S.; et al. FGFR2 in gastric cancer: Protein overexpression predicts gene amplification and high H-index predicts poor survival. Mod. Pathol. 2016, 29, 1095–1103. [Google Scholar] [CrossRef]
- Zhang, J.; Tang, P.M.K.; Zhou, Y.; Cheng, A.S.-L.; Yu, J.; Kang, W.; To, K.F. Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis. Cells 2019, 8. [Google Scholar] [CrossRef] [Green Version]
- Paik, P.K.; Shen, R.; Berger, M.F.; Ferry, D.; Soria, J.-C.; Mathewson, A.; Rooney, C.; Smith, N.R.; Cullberg, M.; Kilgour, E.; et al. A phase Ib open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers. Clin. Cancer Res. 2017, 23, 5366–5373. [Google Scholar] [CrossRef] [Green Version]
- Van Cutsem, E.; Bang, Y.-J.; Mansoor, W.; Petty, R.D.; Chao, Y.; Cunningham, D.; Ferry, D.R.; Smith, N.R.; Frewer, P.; Ratnayake, J.; et al. A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification. Ann. Oncol. J. Eur. Soc. Med. Oncol. 2017, 28, 1316–1324. [Google Scholar] [CrossRef]
- Catenacci, D.V.; Tesfaye, A.; Tejani, M.; Cheung, E.; Eisenberg, P.; Scott, A.J.; Eng, C.; Hnatyszyn, J.; Marina, N.; Powers, J.; et al. Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT Phase III study design. Future Oncol. 2019, 15, 2073–2082. [Google Scholar] [CrossRef] [Green Version]
- Bang, Y.; Im, S.-A.; Lee, K.W.; Cho, J.Y.; Song, E.-K.; Kim, K.H.; Park, J.O.; Chun, H.J.; Zang, D.Y.; Fielding, A.; et al. Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer. J. Clin. Oncol. 2015, 33, 3858–3865. [Google Scholar] [CrossRef]
- Bang, Y.; Xu, R.-H.; Chin, K.; Lee, K.-W.; Hoon Park, S.H.; Rha, S.Y.; Shen, L.; Qin, S.; Xu, N.; Im, S.A.; et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017, 18, 1637–1651. [Google Scholar] [CrossRef]
GS | EBV | MSI | CIN |
---|---|---|---|
CDH1 and RHOA mutations | DNA hypermethylation | Hypermutation | RTK-RAS activation |
CLDN18-ARHGAP 26 fusion | PIK3CA and ARID1A mutations | MLH1 silencing | TP53 mutation |
Cell adhesion | JAK2 amplification | RAS activation | Cell cycle activation |
CDKN2 silencing | |||
Immune activation | Mitotic pathway |
TRIAL. | Phase | Experimental Drug | Chemotherapy Backbone | Line of Therapy | Number of Included Patients | HR for OS | p Value | Response Rate | Increase in Median Survival |
---|---|---|---|---|---|---|---|---|---|
ToGA [19] | III | Trastuzumab | Cisplatin+5-FU/capecitabine | First | 584 | 0.74 | 0.04 | 51% vs. 37% p = 0.0017 | +2.8 months |
LOGiC [23] | III | Lapatinib | Oxaliplatin/capecitabine +/−Lapatinib | First | 545 | 0.91 | 0.35 | 53% vs. 39% p = 0.031 | +1.7 months |
TyTAN [24] | III | Lapatinib | Paclitaxel+/−Lapatinib | Second | 261 | 0.84 | 0.20 | 27% vs. 9% p = 0.001 | +2.1 months |
GATSBY [26] | II/III | TDM-1 | TDM-1 vs. Taxane | Second | 345 | 1.15 | 0.85 | NP | −0.7 months |
JACOB [25] | III | Pertuzumab | Cisplatin+5-FU/ capecitabine /Trastuzumab +/− Pertuzumab | First | 780 | 0.84 | 0.056 | 56% vs. 48% p = 0.026 | 3.3 months |
DESTINY-Gastric01 [46] | II | Trastuzumab Deruxtecan | Trastuzumab Deruxtecan vs. Paclitaxel or Irinotecan | Third | 187 | 0.59 | 0.01 | 51% vs. 14% | 4.1 months |
Trial | Chemotherapy | Experimental Drug | HR | Trial | Chemotherapy |
---|---|---|---|---|---|
AVAGAST [62] | Cisplatin+ capecitabine | Bevacizumab | 0.87 | 0.10 | +2.0 months |
RAINFALL [63] | Cisplatin+5-FU/capecitabine | Ramucirumab | 0.96 | 0.68 | 0.5 month |
EXPAND [51] | Cisplatin+ capecitabine | Cetuximab | 1.00 | 0.95 | −1.3 months |
REAL-3 [52] | Oxaliplatin+ epi- + capecitabine | Panitumumab | 1.37 | 0.013 | −2.5 months |
RILOMET-1 [55] | Cisplatin+ epi+capecitabine | Rilotumumab | -- | -- | Stopped in futility analysis |
METGASTRIC [54] | FOLFOX6 | Onartuzumab | 1.06 | 0.83 | −0.6 months |
Compound | Type | Mechanisms of Action | Predictive Biomarkers | Clinical Phase of Development |
---|---|---|---|---|
Bemarituzumab | mAb | Inhibitor of FGF7, FGF10, and FGF22 ligand of the splice-variant FGFR2b | II, III | |
AZD4547 | TKi | Potent and selective inhibitor of FGFR 1, 2, and 3 | II | |
Infigratinib | TKi | Selective, ATP-competitive inhibitor of FGFR1, 2, and 3 | I | |
E-7090 | TKi | Oral and selective inhibitor of FGFR1, 2, and 3 | I | |
LY2874455 | TKi | Potent Pan FGFR inhibitor | I | |
Pemigatinib [81] | TKi | Potent inhibitor of FGFR1, 2, and 3 | FGFR2 fusions | II |
Rogaratinib [82] | TKi | Potent Pan FGFR inhibitor | FGFR1-3 mRNA expression | I |
Futibatinib [83] | TKi | Potent and highly specific against wildtype FGFR1–4 as well as against some FGFR2 kinase domain mutations | FGFR2 fusions, FGFR1 mutations | I |
Fisogatinib | TKi | Potent and selective inhibitor of FGFR4 | I | |
H3B-6527 | TKi | Selective and covalent inhibitor of FGFR4 | I | |
Roblitinib | TKi | Potent and selective, reversible-covalent small-molecule inhibitor of FGFR4 | I | |
Erdafitinib | TKi | Potent Pan FGFR inhibitor | FGFR3 mutations, FGFR2/3 fusions | II |
© 2020 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 (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Gambardella, V.; Fleitas, T.; Tarazona, N.; Papaccio, F.; Huerta, M.; Roselló, S.; Gimeno-Valiente, F.; Roda, D.; Cervantes, A. Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress. J. Clin. Med. 2020, 9, 3049. https://doi.org/10.3390/jcm9093049
Gambardella V, Fleitas T, Tarazona N, Papaccio F, Huerta M, Roselló S, Gimeno-Valiente F, Roda D, Cervantes A. Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress. Journal of Clinical Medicine. 2020; 9(9):3049. https://doi.org/10.3390/jcm9093049
Chicago/Turabian StyleGambardella, Valentina, Tania Fleitas, Noelia Tarazona, Federica Papaccio, Marisol Huerta, Susana Roselló, Francisco Gimeno-Valiente, Desamparados Roda, and Andrés Cervantes. 2020. "Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress" Journal of Clinical Medicine 9, no. 9: 3049. https://doi.org/10.3390/jcm9093049