Biomarkers in Metastatic Colorectal Cancer: Status Quo and Future Perspective
Abstract
:Simple Summary
Abstract
1. Introduction
2. Established Biomarkers in mCRC
2.1. Sidedness
2.2. DNA Mismatch Repair Deficiency (dMMR) and/or Microsatellite Instability (MSI)
2.3. RAS Mutations
KRASG12C Mutation
2.4. BRAFV600E Mutation
2.5. HER2 Amplification
3. Beyond Classical Biomarkers in CRC
3.1. NTRK Fusions
3.1.1. FGFR
3.1.2. DNA Damage Repair Genes
3.1.3. POLE
3.1.4. RET
3.1.5. RSPO Fusions and RNF43 Mutations
3.1.6. Other Promising Biomarkers
3.2. A Selection of Emerging Biomarkers in the TME
3.3. Circulating Tumor DNA (ctDNA)
4. Preclinical Models for Target Discovery
4.1. Patient Derived Organoids
4.2. Patient-Derived Xenograft Models (PDX)
4.3. Patient-Derived Tumor Fragment Platform (PDTF)
5. Challenges in Biomarker Research and Future Perspective
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
- Xi, Y.; Xu, P. Global colorectal cancer burden in 2020 and projections to 2040. Transl. Oncol. 2021, 14, 101174. [Google Scholar] [CrossRef] [PubMed]
- Lavin, P.; Mittelman, A.; Douglass, H.; Engstrom, P.; Klaassen, D. Survival and response to chemotherapy for advanced colorectal adenocarcinoma. An eastern cooperative oncology group report. Cancer 1980, 46, 1536–1543. [Google Scholar] [CrossRef]
- Venook, A.P.; Niedzwiecki, D.; Lenz, H.J.; Innocenti, F.; Fruth, B.; Meyerhardt, J.A.; Schrag, D.; Greene, C.; O’Neil, B.H.; Atkins, J.N.; et al. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA 2017, 317, 2392–2401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Berger, M.D.; Lenz, H.-J. The safety of monoclonal antibodies for treatment of colorectal cancer. Expert Opin. Drug Saf. 2016, 15, 799–808. [Google Scholar] [CrossRef]
- Grothey, A.; Van Cutsem, E.; Sobrero, A.; Siena, S.; Falcone, A.; Ychou, M.; Humblet, Y.; Bouché, O.; Mineur, L.; Barone, C.; et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013, 381, 303–312. [Google Scholar] [CrossRef]
- Mayer, R.J.; Van Cutsem, E.; Falcone, A.; Yoshino, T.; Garcia-Carbonero, R.; Mizunuma, N.; Yamazaki, K.; Shimada, Y.; Tabernero, J.; Komatsu, Y.; et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N. Engl. J. Med. 2015, 372, 1909–1919. [Google Scholar] [CrossRef] [Green Version]
- Holch, J.W.; Ricard, I.; Stintzing, S.; Modest, D.P.; Heinemann, V. The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials. Eur. J. Cancer 2017, 70, 87–98. [Google Scholar] [CrossRef]
- Yoshino, T.; Arnold, D.; Taniguchi, H.; Pentheroudakis, G.; Yamazaki, K.; Xu, R.-H.; Kim, T.; Ismail, F.; Tan, I.; Yeh, K.-H.; et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: A JSMO–ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann. Oncol. 2017, 29, 44–70. [Google Scholar] [CrossRef]
- Andre, T.; Shiu, K.K.; Kim, T.W.; Jensen, B.V.; Jensen, L.H.; Punt, C.; Smith, D.; Garcia-Carbonero, R.; Benavides, M.; Gibbs, P.; et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N. Engl. J. Med. 2020, 383, 2207–2218. [Google Scholar] [CrossRef]
- 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] [PubMed] [Green Version]
- Kopetz, S.; Grothey, A.; Yaeger, R.; Ciardiello, F.; Desai, J.; Kim, T.W.; Maughan, T.; Cutsem, E.V.; Wasan, H.S.; Yoshino, T.; et al. BREAKWATER: Randomized phase 3 study of encorafenib (enco) + cetuximab (cet) ± chemotherapy for first-line treatment (tx) of BRAF V600E-mutant (BRAFV600) metastatic colorectal cancer (mCRC). J. Clin. Oncol. 2022, 40, TPS211. [Google Scholar] [CrossRef]
- Weiss, J.; Yaeger, R.D.; Johnson, M.L.; Spira, A.; Klempner, S.J.; Barve, M.A.; Christensen, J.G.; Chi, A.; Der-Torossian, H.; Velastegui, K.; et al. KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (cetux) in patients (pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann. Oncol. 2021, 32, 1283–1346. [Google Scholar] [CrossRef]
- Hong, D.S.; DuBois, S.G.; Kummar, S.; Farago, A.F.; Albert, C.M.; Rohrberg, K.S.; van Tilburg, C.M.; Nagasubramanian, R.; Berlin, J.D.; Federman, N.; et al. Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020, 21, 531–540. [Google Scholar] [CrossRef]
- Doebele, R.C.; Drilon, A.; Paz-Ares, L.; Siena, S.; Shaw, A.T.; Farago, A.F.; Blakely, C.M.; Seto, T.; Cho, B.C.; Tosi, D.; et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1–2 trials. Lancet Oncol. 2020, 21, 271–282. [Google Scholar] [CrossRef]
- Subbiah, V.; Konda, B.; Bauer, T.; McCoach, C.; Falchook, G.; Takeda, M.; Patel, J.; Weiss, J.; Peled, N.; Bazhenova, L.; et al. Abstract CT011: Efficacy and safety of selpercatinib in RET fusion-positive cancers other than lung or thyroid cancers. Cancer Res. 2021, 81, CT011. [Google Scholar] [CrossRef]
- Hemmatazad, H.; Berger, M.D. CCR5 is a potential therapeutic target for cancer. Expert Opin. Ther. Targets 2021, 25, 311–327. [Google Scholar] [CrossRef] [PubMed]
- Rhyner Agocs, G.; Assarzadegan, N.; Kirsch, R.; Dawson, H.; Galván, J.A.; Lugli, A.; Zlobec, I.; Berger, M.D. LAG-3 Expression Predicts Outcome in Stage II Colon Cancer. J. Pers. Med. 2021, 11, 749. [Google Scholar] [CrossRef]
- Califf, R.M. Biomarker definitions and their applications. Exp. Biol. Med. 2018, 243, 213–221. [Google Scholar] [CrossRef]
- Strimbu, K.; Tavel, J.A. What are biomarkers? Curr. Opin. HIV AIDS 2010, 5, 463–466. [Google Scholar] [CrossRef]
- Mayeux, R. Biomarkers: Potential uses and limitations. NeuroRx 2004, 1, 182–188. [Google Scholar] [CrossRef] [PubMed]
- Raskin, W.; Cheema, P.; Perdrizet, K.; Iafolla, M.; Dudani, S.; Sheffield, B. Rapid point of care NGS in colorectal cancer. J. Clin. Oncol. 2022, 40, 172. [Google Scholar] [CrossRef]
- Raza, A.; Khan, A.Q.; Inchakalody, V.P.; Mestiri, S.; Yoosuf, Z.S.K.M.; Bedhiafi, T.; El-Ella, D.M.A.; Taib, N.; Hydrose, S.; Akbar, S.; et al. Dynamic liquid biopsy components as predictive and prognostic biomarkers in colorectal cancer. J. Exp. Clin. Cancer Res. 2022, 41, 99. [Google Scholar] [CrossRef] [PubMed]
- Ballman, K.V. Biomarker: Predictive or Prognostic? J. Clin. Oncol. 2015, 33, 3968–3971. [Google Scholar] [CrossRef]
- Salem, M.E.; Puccini, A.; Tie, J. Redefining Colorectal Cancer by Tumor Biology. Am. Soc. Clin. Oncol. Educ. Book 2020, 40, 147–159. [Google Scholar] [CrossRef]
- Martelli, V.; Pastorino, A.; Sobrero, A.F. Prognostic and predictive molecular biomarkers in advanced colorectal cancer. Pharmacol. Ther. 2022, 236, 108239. [Google Scholar] [CrossRef]
- Kim, S.Y.; Kim, T.W. Current challenges in the implementation of precision oncology for the management of metastatic colorectal cancer. ESMO Open 2020, 5, e000634. [Google Scholar] [CrossRef] [Green Version]
- Boni, V.; Drilon, A.; Deeken, J.; Garralda, E.; Chung, H.; Kinoshita, I.; Oh, D.; Patel, J.; Xu, R.; Norenberg, R.; et al. SO-29 Efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase fusion-positive gastrointestinal cancer: An expanded dataset. Ann. Oncol. 2021, 32, S214–S215. [Google Scholar] [CrossRef]
- 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]
- Di Nicolantonio, F.; Vitiello, P.P.; Marsoni, S.; Siena, S.; Tabernero, J.; Trusolino, L.; Bernards, R.; Bardelli, A. Precision oncology in metastatic colorectal cancer—From biology to medicine. Nat. Rev. Clin. Oncol. 2021, 18, 506–525. [Google Scholar] [CrossRef]
- 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. 2017, 3, 194–201. [Google Scholar] [CrossRef] [PubMed]
- Aljehani, M.A.; Morgan, J.W.; Guthrie, L.A.; Jabo, B.; Ramadan, M.; Bahjri, K.; Lum, S.S.; Selleck, M.; Reeves, M.E.; Garberoglio, C.; et al. Association of Primary Tumor Site With Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer. JAMA Surg. 2018, 153, 60–67. [Google Scholar] [CrossRef] [PubMed]
- Arnold, D.; Lueza, B.; Douillard, J.Y.; Peeters, M.; Lenz, H.J.; Venook, A.; Heinemann, V.; Van Cutsem, E.; Pignon, J.P.; Tabernero, J.; et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann. Oncol. 2017, 28, 1713–1729. [Google Scholar] [CrossRef] [PubMed]
- Puccini, A.; Lenz, H.J. Colorectal cancer in 2017: Practice-changing updates in the adjuvant and metastatic setting. Nat. Rev. Clin. Oncol. 2018, 15, 77–78. [Google Scholar] [CrossRef]
- Nawa, T.; Kato, J.; Kawamoto, H.; Okada, H.; Yamamoto, H.; Kohno, H.; Endo, H.; Shiratori, Y. Differences between right- and left-sided colon cancer in patient characteristics, cancer morphology and histology. J. Gastroenterol. Hepatol. 2008, 23, 418–423. [Google Scholar] [CrossRef]
- Salem, M.E.; Weinberg, B.A.; Xiu, J.; El-Deiry, W.S.; Hwang, J.J.; Gatalica, Z.; Philip, P.A.; Shields, A.F.; Lenz, H.J.; Marshall, J.L. Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Oncotarget 2017, 8, 86356–86368. [Google Scholar] [CrossRef] [Green Version]
- Hu, W.; Yang, Y.; Li, X.; Huang, M.; Xu, F.; Ge, W.; Zhang, S.; Zheng, S. Multi-omics Approach Reveals Distinct Differences in Left- and Right-Sided Colon Cancer. Mol. Cancer Res. 2018, 16, 476–485. [Google Scholar] [CrossRef] [Green Version]
- Lee, M.S.; Menter, D.G.; Kopetz, S. Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes. J. Natl. Compr. Canc. Netw. 2017, 15, 411–419. [Google Scholar] [CrossRef] [Green Version]
- Schrag, D.; Weng, S.; Brooks, G.; Meyerhardt, J.A.; Venook, A.P. The relationship between primary tumor sidedness and prognosis in colorectal cancer. J. Clin. Oncol. 2016, 34, 3505. [Google Scholar] [CrossRef]
- Lee, M.S.; Advani, S.M.; Morris, J.; Jiang, Z.-Q.; Manyam, G.C.; Menter, D.; Broom, B.M.; Eng, C.; Overman, M.J.; Maru, D.M. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. J. Clin. Oncol. 2016, 34, 3506. [Google Scholar] [CrossRef]
- Stintzing, S.; Tejpar, S.; Gibbs, P.; Thiebach, L.; Lenz, H.J. Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes. Eur. J. Cancer 2017, 84, 69–80. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Boeckx, N.; Koukakis, R.; Op de Beeck, K.; Rolfo, C.; Van Camp, G.; Siena, S.; Tabernero, J.; Douillard, J.Y.; Andre, T.; Peeters, M. Effect of Primary Tumor Location on Second- or Later-line Treatment Outcomes in Patients With RAS Wild-type Metastatic Colorectal Cancer and All Treatment Lines in Patients With RAS Mutations in Four Randomized Panitumumab Studies. Clin. Colorectal. Cancer 2018, 17, 170–178.e173. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Salem, M.E.; Battaglin, F.; Goldberg, R.M.; Puccini, A.; Shields, A.F.; Arguello, D.; Korn, W.M.; Marshall, J.L.; Grothey, A.; Lenz, H.J. Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer. Oncologist 2020, 25, 404–413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yoshino, T.; Uetake, H.; Tsuchihara, K.; Shitara, K.; Yamazaki, K.; Watanabe, J.; Oki, E.; Sato, T.; Naitoh, T.; Komatsu, Y.; et al. PARADIGM study: A multicenter, randomized, phase III study of mFOLFOX6 plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer. J. Clin. Oncol. 2021, 39, 85. [Google Scholar] [CrossRef]
- Yoshino, T.; Watanabe, J.; Shitara, K.; Yasui, H.; Ohori, H.; Shiozawa, M.; Yamazaki, K.; Oki, E.; Sato, T.; Naitoh, T.; et al. Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC): Results from the phase 3 PARADIGM trial. J. Clin. Oncol. 2022, 40, LBA1. [Google Scholar] [CrossRef]
- Cremolini, C.; Antoniotti, C.; Moretto, R.; Masi, G.; Falcone, A. First-line therapy for mCRC—The influence of primary tumour location on the therapeutic algorithm. Nat. Rev. Clin. Oncol. 2017, 14, 113. [Google Scholar] [CrossRef] [Green Version]
- Kawakami, H.; Zaanan, A.; Sinicrope, F.A. Microsatellite instability testing and its role in the management of colorectal cancer. Curr. Treat. Options. Oncol. 2015, 16, 30. [Google Scholar] [CrossRef]
- Puccini, A.; Berger, M.D.; Zhang, W.; Lenz, H.J. What We Know About Stage II and III Colon Cancer: It’s Still Not Enough. Target Oncol. 2017, 12, 265–275. [Google Scholar] [CrossRef]
- Boland, C.R.; Goel, A. Microsatellite instability in colorectal cancer. Gastroenterology 2010, 138, 2073–2087.e2073. [Google Scholar] [CrossRef]
- Koopman, M.; Kortman, G.A.M.; Mekenkamp, L.; Ligtenberg, M.J.L.; Hoogerbrugge, N.; Antonini, N.F.; Punt, C.J.A.; van Krieken, J.H.J.M. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br. J. Cancer 2009, 100, 266–273. [Google Scholar] [CrossRef]
- Guyot D’Asnières De Salins, A.; Tachon, G.; Cohen, R.; Karayan-Tapon, L.; Junca, A.; Frouin, E.; Godet, J.; Evrard, C.; Randrian, V.; Duval, A.; et al. Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer. ESMO Open 2021, 6, 100120. [Google Scholar] [CrossRef] [PubMed]
- Luchini, C.; Bibeau, F.; Ligtenberg, M.J.L.; Singh, N.; Nottegar, A.; Bosse, T.; Miller, R.; Riaz, N.; Douillard, J.Y.; Andre, F.; et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: A systematic review-based approach. Ann. Oncol. 2019, 30, 1232–1243. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sinicrope, F.A. Lynch Syndrome-Associated Colorectal Cancer. N. Engl. J. Med. 2018, 379, 764–773. [Google Scholar] [CrossRef] [PubMed]
- NICE|The National Institute for Health and Care Excellence. Molecular Testing Strategies for Lynch Syndrome in People with Colorectal Cancer. Diagnostics Guidance. Available online: www.nice.org.uk/guidance/dg27 (accessed on 22 February 2017).
- Taieb, J.; Karoui, M.; Basile, D. How I treat stage II colon cancer patients. ESMO Open 2021, 6, 100184. [Google Scholar] [CrossRef]
- Koenig, J.L.; Toesca, D.A.S.; Harris, J.P.; Tsai, C.J.; Haraldsdottir, S.; Lin, A.Y.; Pollom, E.L.; Chang, D.T. Microsatellite Instability and Adjuvant Chemotherapy in Stage II Colon Cancer. Am. J. Clin. Oncol. 2019, 42, 573–580. [Google Scholar] [CrossRef] [PubMed]
- 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]
- 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] [Green Version]
- 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]
- Le, D.T.; Diaz, L.; Kim, T.W.; Van Cutsem, E.; Geva, R.; Jäger, D.; Hara, H.; Burge, M.; O’Neil, B.; Kavan, P.; et al. 432P Pembrolizumab (pembro) for previously treated, microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC): Final analysis of KEYNOTE-164. Ann. Oncol. 2021, 32, S550. [Google Scholar] [CrossRef]
- Battaglin, F.; Naseem, M.; Lenz, H.J.; Salem, M.E. Microsatellite instability in colorectal cancer: Overview of its clinical significance and novel perspectives. Clin. Adv. Hematol. Oncol. 2018, 16, 735–745. [Google Scholar]
- Overman, M.J.; Lonardi, S.; Wong, K.Y.M.; Lenz, H.J.; Gelsomino, F.; Aglietta, M.; Morse, M.A.; 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] [PubMed]
- Overman, M.J.; Lenz, H.J.; Andre, T.; Aglietta, M.; Wong, M.K.; Luppi, G.; Van Cutsem, E.; McDermott, R.S.; Hendlisz, A.; Cardin, D.B.; et al. Nivolumab (NIVO) +/- ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Five-year follow-up from CheckMate 142. J. Clin. Oncol. 2022, 40. no. 16_suppl:3510-3510. [Google Scholar] [CrossRef]
- Andre, T.; Lonardi, S.; Wong, K.Y.M.; Lenz, H.J.; Gelsomino, F.; Aglietta, M.; Morse, M.A.; Van Cutsem, E.; McDermott, R.; Hill, A.; et al. Nivolumab + low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142. Ann. Oncol. 2022. [Google Scholar] [CrossRef]
- Lenz, H.-J.; Cutsem, E.V.; Limon, M.L.; Wong, K.Y.M.; Hendlisz, A.; Aglietta, M.; García-Alfonso, P.; Neyns, B.; Luppi, G.; Cardin, D.B.; et al. First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. J. Clin. Oncol. 2022, 40, 161–170. [Google Scholar] [CrossRef]
- Diaz, L.A.; Shiu, K.-K.; Kim, T.-W.; Jensen, B.V.; Jensen, L.H.; Punt, C.; Smith, D.; Garcia-Carbonero, R.; Benavides, M.; Gibbs, P.; et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): Final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022, 23, 659–670. [Google Scholar] [CrossRef]
- André, T.; Cohen, R.; Salem, M.E. Immune Checkpoint Blockade Therapy in Patients With Colorectal Cancer Harboring Microsatellite Instability/Mismatch Repair Deficiency in 2022. Am. Soc. Clin. Oncol. Educ. Book 2022, 42, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Cohen, R.; Hain, E.; Buhard, O.; Guilloux, A.; Bardier, A.; Kaci, R.; Bertheau, P.; Renaud, F.; Bibeau, F.; Flejou, J.F.; 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. 2019, 5, 551–555. [Google Scholar] [CrossRef] [Green Version]
- Puccini, A.; Battaglin, F.; Iaia, M.L.; Lenz, H.J.; Salem, M.E. Overcoming resistance to anti-PD1 and anti-PD-L1 treatment in gastrointestinal malignancies. J. Immunother. Cancer 2020, 8, e000404. [Google Scholar] [CrossRef]
- Fuca, G.; Cohen, R.; Lonardi, S.; Shitara, K.; Elez, M.E.; Fakih, M.; Chao, J.; Klempner, S.J.; Emmett, M.; Jayachandran, P.; et al. Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers. J. Immunother. Cancer 2022, 10, e004001. [Google Scholar] [CrossRef]
- Cercek, A.; Lumish, M.; Sinopoli, J.; Weiss, J.; Shia, J.; Lamendola-Essel, M.; El Dika, I.H.; Segal, N.; Shcherba, M.; Sugarman, R.; et al. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N. Engl. J. Med. 2022, 386, 2363–2376. [Google Scholar] [CrossRef]
- Cercek, A.; Lumish, M.A.; Sinopoli, J.C.; Weiss, J.A.; Shia, J.; Stadler, Z.K.; Yaeger, R.; Smith, J.J.; Saltz, L.B.; El Dika, I.H.; et al. Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer. J. Clin. Oncol. 2022, 40, LBA5. [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, 26, 566–576. [Google Scholar] [CrossRef] [PubMed]
- Chalabi, M.; Verschoor, Y.; Berg, J.V.D.; Sikorska, K.; Beets, G.; Lent, A.; Grootscholten, M.; Aalbers, A.; Buller, N.; Marsman, H.; et al. LBA7 Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. Ann. Oncol. 2022, 33, S1389. [Google Scholar] [CrossRef]
- Prior, I.A.; Lewis, P.D.; Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012, 72, 2457–2467. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Malumbres, M.; Barbacid, M. RAS oncogenes: The first 30 years. Nat. Rev. Cancer 2003, 3, 459–465. [Google Scholar] [CrossRef]
- Simanshu, D.K.; Nissley, D.V.; McCormick, F. RAS Proteins and Their Regulators in Human Disease. Cell 2017, 170, 17–33. [Google Scholar] [CrossRef] [Green Version]
- Patelli, G.; Tosi, F.; Amatu, A.; Mauri, G.; Curaba, A.; Patane, D.A.; Pani, A.; Scaglione, F.; Siena, S.; Sartore-Bianchi, A. Strategies to tackle RAS-mutated metastatic colorectal cancer. ESMO Open 2021, 6, 100156. [Google Scholar] [CrossRef]
- Benvenuti, S.; Sartore-Bianchi, A.; Di Nicolantonio, F.; Zanon, C.; Moroni, M.; Veronese, S.; Siena, S.; Bardelli, A. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007, 67, 2643–2648. [Google Scholar] [CrossRef] [Green Version]
- Waring, P.; Tie, J.; Maru, D.; Karapetis, C.S. RAS Mutations as Predictive Biomarkers in Clinical Management of Metastatic Colorectal Cancer. Clin. Color. Cancer 2016, 15, 95–103. [Google Scholar] [CrossRef]
- 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]
- Cox, A.D.; Fesik, S.W.; Kimmelman, A.C.; Luo, J.; Der, C.J. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug. Discov. 2014, 13, 828–851. [Google Scholar] [CrossRef] [PubMed]
- Salem, M.E.; El-Refai, S.M.; Sha, W.; Puccini, A.; Grothey, A.; George, T.J.; Hwang, J.J.; O’Neil, B.; Barrett, A.S.; Kadakia, K.C.; et al. Landscape of KRAS(G12C), Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers. JCO Precis. Oncol. 2022, 6, e2100245. [Google Scholar] [CrossRef] [PubMed]
- Negri, F.; Bottarelli, L.; de’Angelis, G.L.; Gnetti, L. KRAS: A Druggable Target in Colon Cancer Patients. Int. J. Mol. Sci. 2022, 23, 4120. [Google Scholar] [CrossRef] [PubMed]
- Van Cutsem, E.; Lenz, H.J.; Köhne, C.H.; Heinemann, V.; Tejpar, S.; Beier, I.M.; Stroh, C.; Rougier, P.; van Krieken, J.H.; Ciardiello, F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J. Clin. Oncol. 2015, 33, 692–700. [Google Scholar] [CrossRef] [Green Version]
- Heinemann, V.; von Weikersthal, L.F.; Decker, T.; Kiani, A.; Vehling-Kaiser, U.; Al-Batran, S.E.; Heintges, T.; Lerchenmuller, C.; Kahl, C.; Seipelt, G.; 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, 1065–1075. [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]
- 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]
- Morano, F.; Corallo, S.; Lonardi, S.; Raimondi, A.; Cremolini, C.; Rimassa, L.; Murialdo, R.; Zaniboni, A.; Sartore-Bianchi, A.; Tomasello, G.; et al. Negative Hyperselection of Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer Who Received Panitumumab-Based Maintenance Therapy. J. Clin. Oncol. 2019, 37, 3099–3110. [Google Scholar] [CrossRef]
- Neumann, J.; Zeindl-Eberhart, E.; Kirchner, T.; Jung, A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol. Res. Pract. 2009, 205, 858–862. [Google Scholar] [CrossRef]
- Araujo, L.H.; Souza, B.M.; Leite, L.R.; Parma, S.A.F.; Lopes, N.P.; Malta, F.S.V.; Freire, M.C.M. Molecular profile of KRAS G12C-mutant colorectal and non-small-cell lung cancer. BMC Cancer 2021, 21, 193. [Google Scholar] [CrossRef]
- Henry, J.T.; Coker, O.; Chowdhury, S.; Shen, J.P.; van Morris, K.; Dasari, A.; Raghav, K.; Nusrat, M.; Kee, B.; Parseghian, C.; et al. Comprehensive Clinical and Molecular Characterization of KRASG12C-Mutant Colorectal Cancer. JCO Precis. Oncol. 2021, 5, PO.20.00256. [Google Scholar]
- Canon, J.; Rex, K.; Saiki, A.Y.; Mohr, C.; Cooke, K.; Bagal, D.; Gaida, K.; Holt, T.; Knutson, C.G.; Koppada, N.; et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019, 575, 217–223. [Google Scholar] [CrossRef] [PubMed]
- Hallin, J.; Engstrom, L.D.; Hargis, L.; Calinisan, A.; Aranda, R.; Briere, D.M.; Sudhakar, N.; Bowcut, V.; Baer, B.R.; Ballard, J.A.; et al. The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2020, 10, 54–71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hong, D.S.; Fakih, M.G.; Strickler, J.H.; Desai, J.; Durm, G.A.; Shapiro, G.I.; Falchook, G.S.; Price, T.J.; Sacher, A.; Denlinger, C.S.; et al. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N. Engl. J. Med. 2020, 383, 1207–1217. [Google Scholar] [CrossRef] [PubMed]
- Fakih, M.G.; Kopetz, S.; Kuboki, Y.; Kim, T.W.; Munster, P.N.; Krauss, J.C.; Falchook, G.S.; Han, S.; Heinemann, V.; Muro, K.; et al. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): A prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022, 23, 115–124. [Google Scholar] [PubMed]
- Ji, J.; Wang, C.; Fakih, M. Targeting KRASG12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments. Onco Targets Ther. 2022, 15, 747–756. [Google Scholar] [CrossRef]
- Taieb, J.; Lapeyre-Prost, A.; Laurent Puig, P.; Zaanan, A. Exploring the best treatment options for BRAF-mutant metastatic colon cancer. Br. J. Cancer 2019, 121, 434–442. [Google Scholar] [CrossRef]
- Fanelli, G.N.; Dal Pozzo, C.A.; Depetris, I.; Schirripa, M.; Brignola, S.; Biason, P.; Balistreri, M.; Dal Santo, L.; Lonardi, S.; Munari, G.; et al. The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer. Cancer Cell Int. 2020, 20, 30. [Google Scholar] [CrossRef]
- Sanz-Garcia, E.; Argiles, G.; Elez, E.; Tabernero, J. BRAF mutant colorectal cancer: Prognosis, treatment, and new perspectives. Ann. Oncol. 2017, 28, 2648–2657. [Google Scholar] [CrossRef]
- Eng, C. BRAF Mutation in Colorectal Cancer: An Enigmatic Target. J. Clin. Oncol. 2021, 39, 259–261. [Google Scholar] [CrossRef]
- Goel, A.; Boland, C.R. Epigenetics of colorectal cancer. Gastroenterology 2012, 143, 1442–1460 e1441. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Clarke, C.N.; Kopetz, E.S. BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: Clinical characteristics, clinical behavior, and response to targeted therapies. J. Gastrointest. Oncol. 2015, 6, 660–667. [Google Scholar] [CrossRef] [PubMed]
- Leclerc, J.; Vermaut, C.; Buisine, M.-P. Diagnosis of lynch syndrome and strategies to distinguish lynch-related tumors from sporadic MSI/dMMR tumors. Cancers 2021, 13, 467. [Google Scholar] [CrossRef] [PubMed]
- Zhu, L.; Dong, C.; Cao, Y.; Fang, X.; Zhong, C.; Li, D.; Yuan, Y. Prognostic Role of BRAF Mutation in Stage II/III Colorectal Cancer Receiving Curative Resection and Adjuvant Chemotherapy: A Meta-Analysis Based on Randomized Clinical Trials. PLoS ONE 2016, 11, e0154795. [Google Scholar] [CrossRef] [Green Version]
- Farina-Sarasqueta, A.; van Lijnschoten, G.; Moerland, E.; Creemers, G.J.; Lemmens, V.; Rutten, H.J.T.; van den Brule, A.J.C. The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann. Oncol. 2010, 21, 2396–2402. [Google Scholar] [CrossRef]
- Kopetz, S.; Desai, J.; Chan, E.; Hecht, J.R.; O’Dwyer, P.J.; Maru, D.; Morris, V.; Janku, F.; Dasari, A.; Chung, W.; et al. Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer. J. Clin. Oncol. 2015, 33, 4032–4038. [Google Scholar] [CrossRef]
- 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]
- Kopetz, S.; Guthrie, K.A.; Morris, V.K.; Lenz, H.J.; Magliocco, A.M.; Maru, D.; Yan, Y.; Lanman, R.; Manyam, G.; Hong, D.S.; et al. Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406). J. Clin. Oncol. 2021, 39, 285–294. [Google Scholar] [CrossRef]
- Tabernero, J.; Grothey, A.; Van Cutsem, E.; Yaeger, R.; Wasan, H.; Yoshino, T.; Desai, J.; Ciardiello, F.; Loupakis, F.; Hong, Y.S. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: Updated survival results and subgroup analyses from the BEACON study. J. Clin. Oncol. 2021, 39, 273–284. [Google Scholar] [CrossRef]
- Grothey, A.; Yaeger, R.; Paez, D.; Tabernero, J.; Taïeb, J.; Yoshino, T.; Groc, M.; Vedovato, J.; Chetaille, E.; Van Cutsem, E. ANCHOR CRC: A phase 2, open-label, single arm, multicenter study of encorafenib (ENCO), binimetinib (BINI), plus cetuximab (CETUX) in patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer (mCRC). Ann. Oncol. 2019, 30, iv109. [Google Scholar] [CrossRef]
- Morris, V.K.; Parseghian, C.M.; Escano, M.; Johnson, B.; Raghav, K.P.S.; Dasari, A.; Huey, R.; Overman, M.J.; Willis, J.; Lee, M.S.; et al. Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAFV600E metastatic colorectal cancer. J. Clin. Oncol. 2022, 40, 12. [Google Scholar] [CrossRef]
- Djaballah, S.A.; Daniel, F.; Milani, A.; Ricagno, G.; Lonardi, S. HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target. Am. Soc. Clin. Oncol. Educ. Book 2022, 42, 1–14. [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] [PubMed]
- 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] [Green Version]
- Baraibar, I.; Ros, J.; Mulet, N.; Salvà, F.; Argilés, G.; Martini, G.; Cuadra, J.L.; Sardo, E.; Ciardiello, D.; Tabernero, J.; et al. Incorporating traditional and emerging biomarkers in the clinical management of metastatic colorectal cancer: An update. Expert Rev. Mol. Diagn. 2020, 20, 653–664. [Google Scholar] [CrossRef] [PubMed]
- 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]
- Sartore-Bianchi, A.; Lonardi, S.; Martino, C.; Fenocchio, E.; Tosi, F.; Ghezzi, S.; Leone, F.; Bergamo, F.; Zagonel, V.; Ciardiello, F.; et al. Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: The phase II HERACLES-B trial. ESMO Open 2020, 5, e000911. [Google Scholar] [CrossRef]
- 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]
- Okamoto, W.; Nakamura, Y.; Kato, T.; Esaki, T.; Komoda, M.; Kato, K.; Komatsu, Y.; Masuishi, T.; Nishina, T.; Sawada, K.; et al. Pertuzumab plus trastuzumab and real-world standard of care (SOC) for patients (pts) with treatment refractory metastatic colorectal cancer (mCRC) with HER2 (ERBB2) amplification (amp) confirmed by tumor tissue or ctDNA analysis (TRIUMPH, EPOC1602). J. Clin. Oncol. 2021, 39, 3555. [Google Scholar] [CrossRef]
- Strickler, J.; Zemla, T.; Ou, F.-S.; Cercek, A.; Wu, C.; Sanchez, F.; Hubbard, J.; Jaszewski, B.; Bandel, L.; Schweitzer, B. 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]
- Modi, S.; Saura, C.; Yamashita, T.; Park, Y.H.; Kim, S.B.; Tamura, K.; Andre, F.; Iwata, H.; Ito, Y.; Tsurutani, J.; et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N. Engl. J. Med. 2020, 382, 610–621. [Google Scholar] [CrossRef] [PubMed]
- Siena, S.; Di Bartolomeo, M.; Raghav, K.; Masuishi, T.; Loupakis, F.; Kawakami, H.; Yamaguchi, K.; Nishina, T.; Fakih, M.; Elez, E.; et al. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): A multicentre, open-label, phase 2 trial. Lancet Oncol. 2021, 22, 779–789. [Google Scholar] [CrossRef]
- Yoshino, T.; Bartolomeo, M.D.; Raghav, K.P.S.; Masuishi, T.; Kawakami, H.; Yamaguchi, K.; Nishina, T.; Wainberg, Z.A.; Elez, E.; Rodriguez, J.; et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J. Clin. Oncol. 2022, 40, 119. [Google Scholar] [CrossRef]
- Raghav, K.P.S.; Yoshino, T.; Guimbaud, R.; Chau, I.; Eynde, M.V.D.; Maurel, J.; Tie, J.; Kim, T.W.; Yeh, K.-H.; Barrios, D.; et al. Trastuzumab deruxtecan in patients with HER2-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC): A randomized, multicenter, phase 2 study (DESTINY-CRC02). J. Clin. Oncol. 2022, 40, TPS224. [Google Scholar] [CrossRef]
- Nakagawara, A. Trk receptor tyrosine kinases: A bridge between cancer and neural development. Cancer Lett. 2001, 169, 107–114. [Google Scholar] [CrossRef]
- Chao, M.V. Neurotrophins and their receptors: A convergence point for many signalling pathways. Nat. Rev. Neurosci. 2003, 4, 299–309. [Google Scholar] [CrossRef]
- Tognon, C.; Knezevich, S.R.; Huntsman, D.; Roskelley, C.D.; Melnyk, N.; Mathers, J.A.; Becker, L.; Carneiro, F.; MacPherson, N.; Horsman, D.; et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2002, 2, 367–376. [Google Scholar] [CrossRef] [Green Version]
- Vaishnavi, A.; Capelletti, M.; Le, A.T.; Kako, S.; Butaney, M.; Ercan, D.; Mahale, S.; Davies, K.D.; Aisner, D.L.; Pilling, A.B.; et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat. Med. 2013, 19, 1469–1472. [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]
- Scott, L.J. Larotrectinib: First Global Approval. Drugs 2019, 79, 201–206. [Google Scholar] [CrossRef]
- Drilon, A.; Ou, S.I.; Cho, B.C.; Kim, D.; Lee, J.; Lin, J.J.; Zhu, V.W.; Ahn, M.; Camidge, D.R.; Nguyen, J.; et al. Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer Discov. 2018, 8, 1227–1236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Papadopoulos, K.P.; Borazanci, E.; Shaw, A.T.; Katayama, R.; Shimizu, Y.; Zhu, V.W.; Sun, T.Y.; Wakelee, H.A.; Madison, R.; Schrock, A.B.; et al. U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors. Clin. Cancer Res. 2020, 26, 4785–4794. [Google Scholar] [CrossRef]
- Wang, H.; Li, Z.W.; Ou, Q.; Wu, X.; Nagasaka, M.; Shao, Y.; Ou, S.I.; Yang, Y. NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability. Cancer Med. 2022, 11, 2541–2549. [Google Scholar] [CrossRef]
- Guo, Y.; Guo, X.-L.; Wang, S.; Chen, X.; Shi, J.; Wang, J.; Wang, K.; Klempner, S.J.; Wang, W.; Xiao, M. Genomic Alterations of NTRK, POLE, ERBB2, and Microsatellite Instability Status in Chinese Patients with Colorectal Cancer. Oncologist 2020, 25, e1671–e1680. [Google Scholar] [CrossRef]
- Lengyel, C.G.; Hussain, S.; Seeber, A.; Nidhamalddin, S.J.; Trapani, D.; Habeeb, B.S.; Elfaham, E.; Mazher, S.A.; Seid, F.; Khan, S.Z.; et al. FGFR Pathway Inhibition in Gastric Cancer: The Golden Era of an Old Target? Life 2022, 12, 81. [Google Scholar] [CrossRef] [PubMed]
- Lonic, A.; Barry, E.F.; Quach, C.; Kobe, B.; Saunders, N.; Guthridge, M.A. Fibroblast Growth Factor Receptor 2 Phosphorylation on Serine 779 Couples to 14-3-3 and Regulates Cell Survival and Proliferation. Mol. Cell. Biol. 2008, 28, 3372–3385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mandal, S.; Bandyopadhyay, S.; Tyagi, K.; Roy, A. Recent advances in understanding the molecular role of phosphoinositide-specific phospholipase C gamma 1 as an emerging onco-driver and novel therapeutic target in human carcinogenesis. Biochim. Biophys. Acta Rev. Cancer 2021, 1876, 188619. [Google Scholar] [CrossRef]
- Lee, M.-S.; Cho, H.J.; Hong, J.Y.; Lee, J.; Park, S.H.; Park, J.O.; Park, Y.S.; Lim, H.Y.; Kang, W.K.; Cho, Y.B.; et al. Clinical and molecular distinctions in patients with refractory colon cancer who benefit from regorafenib treatment. Ther. Adv. Med. Oncol. 2020, 12, 1758835920965842. [Google Scholar] [CrossRef]
- Javle, M.; Roychowdhury, S.; Kelley, R.K.; Sadeghi, S.; Macarulla, T.; Weiss, K.H.; Waldschmidt, D.-T.; Goyal, L.; Borbath, I.; El-Khoueiry, A.; et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: Mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol. Hepatol. 2021, 6, 803–815. [Google Scholar] [CrossRef]
- Siefker-Radtke, A.O.; Necchi, A.; Park, S.H.; García-Donas, J.; A Huddart, R.; Burgess, E.F.; Fleming, M.T.; Kalebasty, A.R.; Mellado, B.; Varlamov, S.; et al. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: Long-term follow-up of a phase 2 study. Lancet Oncol. 2022, 23, 248–258. [Google Scholar] [CrossRef]
- Meric-Bernstam, F.; Bahleda, R.; Hierro, C.; Sanson, M.; Bridgewater, J.; Arkenau, H.; Tran, B.; Kelley, R.K.; Park, J.O.; Javle, M.; et al. Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study. Cancer Discov. 2022, 12, 402–415. [Google Scholar] [CrossRef] [PubMed]
- Lord, C.J.; Ashworth, A. The DNA damage response and cancer therapy. Nature 2012, 481, 287–294. [Google Scholar] [CrossRef] [PubMed]
- Zimmer, K.; Kocher, F.; Puccini, A.; Seeber, A. Targeting BRCA and DNA Damage Repair Genes in GI Cancers: Pathophysiology and Clinical Perspectives. Front. Oncol. 2021, 11, 662055. [Google Scholar] [CrossRef] [PubMed]
- Naccarati, A.; Rosa, F.; Vymetalkova, V.; Barone, E.; Jiraskova, K.; Di Gaetano, C.; Novotny, J.; Levy, M.; Vodickova, L.; Gemignani, F.; et al. Double-strand break repair and colorectal cancer: Gene variants within 3′ UTRs and microRNAs binding as modulators of cancer risk and clinical outcome. Oncotarget 2015, 7, 23156–23169. [Google Scholar] [CrossRef] [Green Version]
- Venkitaraman, A.R. Cancer Susceptibility and the Functions of BRCA1 and BRCA2. Cell 2002, 108, 171–182. [Google Scholar] [CrossRef] [Green Version]
- Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005, 434, 913–917. [Google Scholar] [CrossRef]
- Golan, T.; Hammel, P.; Reni, M.; Van Cutsem, E.; Macarulla, T.; Hall, M.J.; Park, J.O.; Hochhauser, D.; Arnold, D.; Oh, D.Y.; et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N. Engl. J. Med. 2019, 38, 317–327. [Google Scholar] [CrossRef] [PubMed]
- Knijnenburg, T.A.; Wang, L.; Zimmermann, M.T.; van Cutsem, E.; Macarulla, T.; Hall, M.J.; Park, J.; Hochhauser, D.; Arnold, D.; Oh, D.; et al. Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep. 2018, 23, 239–254.e6. [Google Scholar] [CrossRef] [Green Version]
- Leichman, L.; Groshen, S.; O’Neil, B.H.; Messersmith, W.; Berlin, J.; Chan, E.; Leichman, C.G.; Cohen, S.J.; Cohen, D.; Lenz, H.; et al. Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer. Oncologist 2016, 21, 172–177. [Google Scholar] [CrossRef] [Green Version]
- Gorbunova, V.; Beck, J.T.; Hofheinz, R.D.; Garcia-Alfonso, P.; Nechaeva, M.; Gracian, A.C.; Mangel, L.; Fernandez, E.E.; Deming, D.A.; Ramanathan, R.K.; et al. A phase 2 randomised study of veliparib plus FOLFIRI±bevacizumab versus placebo plus FOLFIRI±bevacizumab in metastatic colorectal cancer. Br. J. Cancer 2019, 120, 183–189. [Google Scholar] [CrossRef] [Green Version]
- Pishvaian, M.J.; Slack, R.S.; Jiang, W.; He, A.R.; Hwang, J.J.; Hankin, A.; Dorsch-Vogel, K.; Kukadiya, D.; Weiner, L.M.; Marshall, J.L.; et al. A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer. Cancer 2018, 124, 2337–2346. [Google Scholar] [CrossRef]
- Reilly, N.M.; Novara, L.; Di Nicolantonio, F.; Bardelli, A. Exploiting DNA repair defects in colorectal cancer. Mol. Oncol. 2019, 13, 681–700. [Google Scholar] [CrossRef]
- Pursell, Z.F.; Isoz, I.; Lundström, E.; Johansson, E.; Kunkel, T.A. Yeast DNA polymerase epsilon participates in leading-strand DNA replication. Science 2007, 317, 127–133. [Google Scholar] [CrossRef] [Green Version]
- Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012, 487, 330–337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hino, H.; Shiomi, A.; Kusuhara, M.; Kagawa, H.; Yamakawa, Y.; Hatakeyama, K.; Kawabata, T.; Oishi, T.; Urakami, K.; Nagashima, T.; et al. Clinicopathological and mutational analyses of colorectal cancer with mutations in the POLE gene. Cancer Med. 2019, 8, 4587–4597. [Google Scholar] [CrossRef] [Green Version]
- Mo, S.; Ma, X.; Li, Y.; Zhang, L.; Hou, T.; Han-Zhang, H.; Qian, J.; Cai, S.; Huang, D.; Peng, J. Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer. J. Immunother. Cancer 2020, 8, e000881. [Google Scholar] [CrossRef] [PubMed]
- Domingo, E.; Freeman-Mills, L.; Rayner, E.; Glaire, M.; Briggs, S.; Vermeulen, L.; Fessler, E.; Medema, J.P.; Boot, A.; Morreau, H.; et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: A retrospective, pooled biomarker study. Lancet Gastroenterol. Hepatol. 2016, 1, 207–216. [Google Scholar] [CrossRef] [Green Version]
- Rousseau, B.-C.; Bieche, I.; Pasmant, E.; Simmet, V.; Hamzaoui, N.; Masliah-Planchon, J.; Pouessel, D.; Bruyas, A.; Augereau, P.; Grob, J.-J.; et al. 526O High activity of nivolumab in patients with pathogenic exonucleasic domain POLE (edPOLE) mutated Mismatch Repair proficient (MMRp) advanced tumours. Ann. Oncol. 2020, 31, S463. [Google Scholar] [CrossRef]
- Oh, C.R.; Kim, J.E.; Hong, Y.S.; Kim, S.Y.; Ahn, J.B.; Baek, J.Y.; Lee, M.; Kang, M.J.; Cho, S.H.; Beom, S.; et al. Phase II study of durvalumab monotherapy in patients with previously treated microsatellite instability-high/mismatch repair-deficient or POLE -mutated metastatic or unresectable colorectal cancer. Int. J. Cancer 2022, 150, 2038–2045. [Google Scholar] [CrossRef]
- Huyghe, N.; Benidovskaya, E.; Stevens, P.; Van den Eynde, M. Biomarkers of Response and Resistance to Immunotherapy in Microsatellite Stable Colorectal Cancer: Toward a New Personalized Medicine. Cancers 2022, 14, 2241. [Google Scholar] [CrossRef]
- Romei, C.; Ciampi, R.; Elisei, R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat. Rev. Endocrinol. 2016, 12, 192–202. [Google Scholar] [CrossRef] [PubMed]
- Kohno, T.; Ichikawa, H.; Totoki, Y.; Yasuda, K.; Hiramoto, M.; Nammo, T.; Sakamoto, H.; Tsuta, K.; Furuta, K.; Shimada, Y.; et al. KIF5B-RET fusions in lung adenocarcinoma. Nat. Med. 2012, 18, 375–377. [Google Scholar] [CrossRef] [PubMed]
- Le Rolle, A.F.; Klempner, S.J.; Garrett, C.R.; Seery, T.; Sanford, E.M.; Balasubramanian, S.; Ross, J.S.; Stephens, P.J.; Miller, V.A.; Ali, S.M.; et al. Identification and characterization of RET fusions in advanced colorectal cancer. Oncotarget 2015, 6, 28929–28937. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, S.Y.; Oh, S.O.; Kim, K.; Lee, J.; Kang, S.; Kim, K.; Lee, W.; Kim, S.T.; Nam, D.N. NCOA4-RET fusion in colorectal cancer: Therapeutic challenge using patient-derived tumor cell lines. J. Cancer 2018, 9, 3032–3037. [Google Scholar] [CrossRef] [Green Version]
- Pietrantonio, F.; Di Nicolantonio, F.; Schrock, A.; Lee, J.; Morano, F.; Fucà, G.; Nikolinakos, P.; Drilon, A.; Hechtman, J.; Christiansen, J.; et al. RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. Ann. Oncol. 2018, 29, 1394–1401. [Google Scholar] [CrossRef]
- Randon, G.; Maddalena, G.; Germani, M.M.; Pircher, C.C.; Manca, P.; Bergamo, F.; Giordano, M.; Sposetti, C.; Montagna, A.; Vetere, G.; et al. Negative Ultraselection of Patients With RAS/BRAF Wild-Type, Microsatellite-Stable Metastatic Colorectal Cancer Receiving Anti-EGFR-Based Therapy. JCO Precis. Oncol. 2022, 6, e2200037. [Google Scholar] [CrossRef]
- Michael, M.; Gibbs, P.; Smith, R.; Godwood, A.; Oliver, S.; Tebbutt, N. Open-label phase I trial of vandetanib in combination with mFOLFOX6 in patients with advanced colorectal cancer. Investig. New Drugs 2008, 27, 253–261. [Google Scholar] [CrossRef]
- Iwasa, S.; Okita, N.; Kuchiba, A.; Ogawa, G.; Kawasaki, M.; Nakamura, K.; Shoji, H.; Honma, Y.; Takashima, A.; Kato, K.; et al. Phase II study of lenvatinib for metastatic colorectal cancer refractory to standard chemotherapy: The LEMON study (NCCH1503). ESMO Open 2020, 5, e000776. [Google Scholar] [CrossRef] [PubMed]
- Gozgit, J.M.; Chen, T.-H.; Song, Y.; Wardwell, S.; Wang, F.; Cai, J.; Li, H.; Edgren, H.; Rivera, V.M.; Pritchard, J. RET fusions observed in lung and colorectal cancers are sensitive to ponatinib. Oncotarget 2018, 9, 29654–29664. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- NCT03157128: A Study of Selpercatinib (LOXO-292) in Participants with Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001). Available online: https://clinicaltrials.gov/ct2/show/NCT03157128 (accessed on 14 July 2022).
- NCT03037385: Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Participants With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors (ARROW). Available online: https://clinicaltrials.gov/ct2/show/NCT03037385 (accessed on 14 July 2022).
- Sansom, O.J.; Reed, K.R.; Hayes, A.J.; Ireland, H.; Brinkmann, H.; Newton, I.P.; Batlle, E.; Simon-Assmann, P.; Clevers, H.; Nathke, I.S.; et al. Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev. 2004, 18, 1385–1390. [Google Scholar] [CrossRef] [Green Version]
- Berger, M.D.; Ning, Y.; Stintzing, S.; Heinemann, V.; Cao, S.; Zhang, W.; Yang, D.; Miyamoto, Y.; Suenaga, M.; Schirripa, M.; et al. A polymorphism within the R-spondin 2 gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab: Data from FIRE-3 and TRIBE trials. Eur. J. Cancer 2020, 131, 89–97. [Google Scholar] [CrossRef]
- Cheng, X.; Xu, X.; Chen, D.; Zhao, F.; Wang, W. Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer. Biomed. Pharmacother. 2018, 110, 473–481. [Google Scholar] [CrossRef] [PubMed]
- Giannakis, M.; Hodis, E.; Mu, X.J.; Yamauchi, M.; Rosenbluh, J.; Cibulskis, K.; Saksena, G.; Lawrence, M.S.; Qian, Z.R.; Nishihara, R.; et al. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat. Genet. 2014, 46, 1264–1266. [Google Scholar] [CrossRef] [PubMed]
- Seshagiri, S.; Stawiski, E.W.; Durinck, S.; Modrusan, Z.; Storm, E.E.; Conboy, C.B.; Chaudhuri, S.; Guan, Y.; Janakiraman, V.; Jaiswal, B.S.; et al. Recurrent R-spondin fusions in colon cancer. Nature 2012, 488, 660–664. [Google Scholar] [CrossRef] [Green Version]
- Seeber, A.; Battaglin, F.; Zimmer, K.; Kocher, F.; Baca, Y.; Xiu, J.; Spizzo, G.; Novotny-Diermayr, V.; Rieder, D.; Puccini, A.; et al. Comprehensive analysis of R-spondin fusions and RNF43 mutations implicate novel therapeutic options in colorectal cancer. Clin. Cancer Res. 2022, 28, 1863–1870. [Google Scholar] [CrossRef]
- NCT03604445: This Study Aims to Find and Test a Safe Dose of BI 905677 in Patients with Different Types of Cancer (Solid Tumors). Available online: https://clinicaltrials.gov/ct2/show/NCT03604445 (accessed on 14 July 2022).
- Berger, M.D.; Stintzing, S.; Heinemann, V.; Yang, D.; Cao, S.; Sunakawa, Y.; Ning, Y.; Matsusaka, S.; Okazaki, S.; Miyamoto, Y.; et al. Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 and TRIBE trials. Ann. Oncol. 2017, 28, 2780–2785. [Google Scholar] [CrossRef]
- Berger, M.D.; Stintzing, S.; Heinemann, V.; Cao, S.; Yang, D.; Sunakawa, Y.; Matsusaka, S.; Ning, Y.; Okazaki, S.; Miyamoto, Y.; et al. A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab. Clin. Cancer Res. 2018, 24, 784–793. [Google Scholar] [CrossRef] [Green Version]
- Anderson, N.M.; Simon, M.C. The tumor microenvironment. Curr. Biol. 2020, 30, R921–R925. [Google Scholar] [CrossRef] [PubMed]
- Kumar, V.; Patel, S.; Tcyganov, E.; Gabrilovich, D.I. The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol. 2016, 37, 208–220. [Google Scholar] [CrossRef] [Green Version]
- Zhou, J.; Tang, Z.; Gao, S.; Li, C.; Feng, Y.; Zhou, X. Tumor-Associated Macrophages: Recent Insights and Therapies. Front. Oncol. 2020, 10, 188. [Google Scholar] [CrossRef]
- Pagès, F.; Mlecnik, B.; Marliot, F.; Bindea, G.; Ou, F.; Bifulco, C.; Lugli, A.; Zlobec, I.; Rau, T.T.; Berger, M.D.; et al. International validation of the consensus Immunoscore for the classification of colon cancer: A prognostic and accuracy study. Lancet 2018, 391, 2128–2139. [Google Scholar] [CrossRef]
- Galon, J.; Mlecnik, B.; Hermitte, F.; Bifulco, C.; Lugli, A.; Nagtegaal, I.D.; Hartmann, A.; van den Eynde, M.; Roehrl, M.; Ohashi, P.; et al. MSI status plus immunoscore to select metastatic colorectal cancer patients for immunotherapies. Ann. Oncol. 2018, 29 (Suppl. 10), X4. [Google Scholar] [CrossRef]
- Baldin, P.; Eynde, M.V.D.; Mlecnik, B.; Galon, J. Immunity to live: An immunopathoscore using the consensus Immunoscore to best define the risk of recurrence and death in stage IV metastatic patients. OncoImmunology 2020, 9, 1826133. [Google Scholar] [CrossRef]
- Guinney, J.; Dienstmann, R.; Wang, X.; De Reyniès, A.; Schlicker, A.; Soneson, C.; Marisa, L.; Roepman, P.; Nyamundanda, G.; Angelino, P.; et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015, 21, 1350–1356. [Google Scholar] [CrossRef]
- Becht, E.; de Reyniès, A.; Giraldo, N.A.; Pilati, C.; Buttard, B.; Lacroix, L.; Selves, J.; Sautès-Fridman, C.; Laurent-Puig, P.; Fridman, W.H.; et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision Immunotherapy. Clin. Cancer Res. 2016, 22, 4057. [Google Scholar] [CrossRef] [Green Version]
- Lenz, H.-J.; Ou, F.-S.; Venook, A.P.; Hochster, H.S.; Niedzwiecki, D.; Goldberg, R.M.; Mayer, R.J.; Bertagnolli, M.M.; Blanke, C.D.; Zemla, T.; et al. Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance). J. Clin. Oncol. 2019, 37, 1876–1885. [Google Scholar] [CrossRef] [PubMed]
- Stintzing, S.; Wirapati, P.; Lenz, H.J.; Neureiter, D.; von Weikersthal, L.F.; Decker, T.; Kiani, A.; Kaiser, F.; Al-Batran, S.; Heintges, T.; et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE-3 (AIO KRK-0306) trial. Ann. Oncol. 2019, 30, 1796–1803. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tie, J.; Kinde, I.; Wang, Y.; Wong, H.L.; Roebert, J.; Christie, M.; Tacey, M.; Wong, R.; Singh, M.; Karapetis, C.S.; et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann. Oncol. 2015, 26, 1715–1722. [Google Scholar] [CrossRef]
- Bettegowda, C.; Sausen, M.; Leary, R.J.; Kinde, I.; Wang, Y.; Agrawal, N.; Bartlett, B.R.; Wang, H.; Luber, B.; Alani, R.M.; et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 2014, 6, 224ra224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Arisi, M.F.; Dotan, E.; Fernandez, S.V. Circulating Tumor DNA in Precision Oncology and Its Applications in Colorectal Cancer. Int. J. Mol. Sci. 2022, 23, 4441. [Google Scholar] [CrossRef]
- Tarazona, N.; Gimeno-Valiente, F.; Gambardella, V.; Zuniga, S.; Rentero-Garrido, P.; Huerta, M.; Rosello, S.; Martinez-Ciarpaglini, C.; Carbonell-Asins, J.A.; Carrasco, F.; et al. Targeted next-generation sequencing of circulating-tumor DNA for tracking minimal residual disease in localized colon cancer. Ann. Oncol. 2019, 30, 1804–1812. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tie, J.; Cohen, J.D.; Lahouel, K.; Lo, S.N.; Wang, Y.; Kosmider, S.; Wong, R.; Shapiro, J.; Lee, M.; Harris, S.; et al. Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer. N. Engl. J. Med. 2022, 386, 2261–2272. [Google Scholar] [CrossRef] [PubMed]
- Chin, R.I.; Chen, K.; Usmani, A.; Chua, C.; Harris, P.K.; Binkley, M.S.; Azad, T.D.; Dudley, J.C.; Chaudhuri, A.A. Detection of Solid Tumor Molecular Residual Disease (MRD) Using Circulating Tumor DNA (ctDNA). Mol. Diagn. Ther. 2019, 23, 311–331. [Google Scholar] [CrossRef] [PubMed]
- 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]
- Ooft, S.; Weeber, F.; Schipper, L.; Dijkstra, K.; McLean, C.; Kaing, S.; van de Haar, J.; Prevoo, W.; van Werkhoven, E.; Snaebjornsson, P.; et al. Prospective experimental treatment of colorectal cancer patients based on organoid drug responses. ESMO Open 2021, 6, 100103. [Google Scholar] [CrossRef]
- Vlachogiannis, G.; Hedayat, S.; Vatsiou, A.; Jamin, Y.; Fernández-Mateos, J.; Khan, K.; Lampis, A.; Eason, K.; Huntingford, I.; Burke, R.; et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 2018, 359, 920–926. [Google Scholar] [CrossRef] [Green Version]
- Narasimhan, V.; Wright, J.A.; Churchill, M.; Wang, T.; Rosati, R.; Lannagan, T.R.M.; Vrbanac, L.; Richardson, A.B.; Kobayashi, H.; Price, T.; et al. Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy. Clin. Cancer Res. 2020, 26, 3662–3670. [Google Scholar] [CrossRef]
- Wensink, G.E.; Elias, S.G.; Mullenders, J.; Koopman, M.; Boj, S.F.; Kranenburg, O.W.; Roodhart, J.M.L. Patient-derived organoids as a predictive biomarker for treatment response in cancer patients. NPJ Precis. Oncol. 2021, 5, 30. [Google Scholar] [CrossRef]
- Rizzo, G.; Bertotti, A.; Leto, S.M.; Vetrano, S. Patient-derived tumor models: A more suitable tool for pre-clinical studies in colorectal cancer. J. Exp. Clin. Cancer Res. 2021, 40, 178. [Google Scholar] [CrossRef]
- Voabil, P.; de Bruijn, M.; Roelofsen, L.M.; Hendriks, S.H.; Brokamp, S.; van den Braber, M.; Broeks, A.; Sanders, J.; Herzig, P.; Zippelius, A.; et al. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer. Nat. Med. 2021, 27, 1250–1261. [Google Scholar] [CrossRef]
- Stintzing, S.; Modest, D.P.; Rossius, L.; Lerch, M.M.; von Weikersthal, L.F.; Decker, T.; Kiani, A.; Vehling-Kaiser, U.; Al-Batran, S.; Heintges, T.; et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): A post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016, 17, 1426–1434. [Google Scholar] [CrossRef]
- Spizzo, G.; Siebert, U.; Gastl, G.; Voss, A.; Schuster, K.; Leonard, R.; Seeber, A. Cost-comparison analysis of a multiplatform tumour profiling service to guide advanced cancer treatment. Cost Eff. Resour. Alloc. 2019, 17, 23. [Google Scholar] [CrossRef] [PubMed]
- Wolff, H.B.; Steeghs, E.M.; Mfumbilwa, Z.A.; Groen, H.J.; Adang, E.M.; Willems, S.M.; Grünberg, K.; Schuuring, E.; Ligtenberg, M.J.; Tops, B.B.; et al. Cost-Effectiveness of Parallel Versus Sequential Testing of Genetic Aberrations for Stage IV Non–Small-Cell Lung Cancer in the Netherlands. JCO Precis. Oncol. 2022, 6, e2200201. [Google Scholar] [CrossRef]
- Banerjee, S.; Kumar, A.; Lopez, N.; Zhao, B.; Tang, C.; Yebra, M.; Yoon, H.; Murphy, J.D.; Sicklick, J.K. Cost-effectiveness Analysis of Genetic Testing and Tailored First-Line Therapy for Patients With Metastatic Gastrointestinal Stromal Tumors. JAMA Netw Open 2020, 3, e2013565. [Google Scholar] [CrossRef]
- Doble, B.; John, T.; Thomas, D.; Fellowes, A.; Fox, S.; Lorgelly, P. Cost-effectiveness of precision medicine in the fourth-line treatment of metastatic lung adenocarcinoma: An early decision analytic model of multiplex targeted sequencing. Lung Cancer 2017, 107, 22–35. [Google Scholar] [CrossRef]
- Schwarze, K.; Buchanan, J.; Taylor, J.C.; Wordsworth, S. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Genet. Med. 2018, 20, 1122–1130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Park, J.J.H.; Hsu, G.; Siden, E.G.; Thorlund, K.; Mills, E.J. An overview of precision oncology basket and umbrella trials for clinicians. CA Cancer J. Clin. 2020, 70, 125–137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- NCT03256344. Study of Talimogene Laherparepvec with Atezolizumab for Triple Negative Breast Cancer and Colorectal Cancer with Liver Metastases. Available online: https://clinicaltrials.gov/ct2/show/NCT03256344 (accessed on 6 August 2022).
- NCT05120596. First in Human Study of T3P-Y058-739 (T3P). Available online: https://clinicaltrials.gov/ct2/show/NCT05120596 (accessed on 6 August 2022).
- Budinska, E.; Popovici, V.; Tejpar, S.; D’Ario, G.; Lapique, N.; Sikora, K.O.; Di Narzo, A.F.; Yan, P.; Hodgson, J.G.; Weinrich, S.; et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J. Pathol. 2013, 231, 63–76. [Google Scholar] [CrossRef]
- Sadanandam, A.; Lyssiotis, C.A.; Homicsko, K.; Collisson, E.A.; Gibb, W.J.; Wullschleger, S.; Ostos, L.C.G.; Lannon, W.A.; Grötzinger, C.; Del Rio, M.; et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat. Med. 2013, 19, 619–625. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Overacre-Delgoffe, A.E.; Bumgarner, H.J.; Cillo, A.R.; Burr, A.H.; Tometich, J.T.; Bhattacharjee, A.; Bruno, T.C.; Vignali, D.A.; Hand, T.W. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. Immunity 2021, 54, 2812–2824.e4. [Google Scholar] [CrossRef]
- Kadosh, E.; Snir-Alkalay, I.; Venkatachalam, A.; May, S.; Lasry, A.; Elyada, E.; Zinger, A.; Shaham, M.; Vaalani, G.; Mernberger, M.; et al. The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic. Nature 2020, 586, 133–138. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.; Shah, K. The Potential of the Gut Microbiome to Reshape the Cancer Therapy Paradigm: A Review. JAMA Oncol. 2022, 8, 1059–1067. [Google Scholar] [CrossRef] [PubMed]
- Sivan, A.; Corrales, L.; Hubert, N.; Williams, J.B.; Aquino-Michaels, K.; Earley, Z.M.; Benyamin, F.W.; Lei, Y.M.; Jabri, B.; Alegre, M.L.; et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015, 350, 1084–1089. [Google Scholar] [CrossRef] [Green Version]
- Wong, S.H.; Yu, J. Gut microbiota in colorectal cancer: Mechanisms of action and clinical applications. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 690–704. [Google Scholar] [CrossRef] [PubMed]
Prediction with high accuracy [19,20] |
Cost effective [19,21] |
Easy to assess [20,21] |
Reproducible/Reliable [19,21] |
Consistent and rapid turnaround time [22] |
Prognostic/predictive impact confirmed in validation sets [19,20,21] |
Proven useful in a given clinical context [19,20] |
Longitudinal and non-invasive measurements [23] |
Biomarker | Trial | Phase | N | Setting | Treatment | Outcomes |
---|---|---|---|---|---|---|
Sidedness (retrospective analyses, except PARADIGM) | CALGB/SWOG 80405 | III | 476 | First-line mCRC | FOLFOX/FOLFIRI + cetuximab vs. FOLFOX/FOLFIRI + bevacizumab | mOS right 16.4 vs. 24.5 months mOS left 37.5 vs. 32.1 months |
FIRE-3 | III | 394 | First-line mCRC | FOLFIRI + cetuximab vs. FOLFIRI + bevacizumab | mOS right 18.3 vs. 23.0 months mOS left 38.3 vs. 28.0 months | |
PEAK | II | 143 | First-line mCRC | FOLFOX + panitumumab vs. FOLFOX + bevacizumab | mOS right 17.5 vs. 21.0 months mOS left 43.4 vs. 32.0 months | |
PARADIGM | III | 802 | First-line mCRC | FOLFOX + panitumumab vs. FOLFOX + bevacizumab | mOS right 20.2 vs. 23.2 months mOS left 37.9 vs. 34.3 months | |
CRYSTAL | III | 364 | First-line mCRC | FOLFIRI + cetuximab vs. FOLFIRI | mOS right 18.5 vs. 15.0 months mOS left 28.7 vs. 21.7 months | |
PRIME | III | 408 | First-line mCRC | FOLFOX + panitumumab vs. FOLFOX | mOS right 11.1 vs. 15.4 months mOS left 30.3 vs. 23.6 months | |
dMMR/MSI-H | KEYNOTE-164 | II | 124 | MSI-H/dMMR mCRC treated with ≥2 prior lines of standard therapy | Pembrolizumab | PFS 31% at 24 months OS 55% at 24 months |
CheckMate-142 | II | 74 | MSI-H/dMMR mCRC who had ≥ 1 prior treatment | Nivolumab | PFS 36% at 48 months OS 49% at 48 months | |
CheckMate-142 | II | 119 | MSI-H/dMMR mCRC who had ≥1 prior treatment | Nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3w × 4 followed by nivolumab 3 mg/kg q2w | PFS 53% at 48 months OS 71% at 48 months | |
KEYNOTE-177 | III | 307 | First-line MSI-H/dMMRmCRC | Pembrolizumab | mPFS 16.5 months mOS not reached | |
RAS | CRYSTAL | III | retrospective analysis of 827 pts evaluable for RAS mutational status | First-line mCRC | FOLFIRI vs. FOLFIRI + cetuximab | RAS wild-type mOS 20.2 vs. 28.4 months, HR 0.69 RAS mutant mOS 17.7 vs. 16.4 months, HR 1.05 |
PRIME | III | 656 | First-line mCRC KRAS wild-type | FOLFOX vs. FOLFOX + panitumumab | mOS 19.4 vs. 23.8 months, HR 0.83 | |
PARADIGM | III | 604 | First-line mCRC RAS wild-type left-sided | FOLFOX + bevacizumab vs. FOLFOX + panitumumab | mOS 34.3 vs. 37.9 months, HR 0.82 | |
KRASG12C | CodeBreak 100 | II | 62 | Refractory mCRC | Sotorasib | ORR 9.7%, DCR 82.3% |
KRYSTAL-1 | I/II | 46 | Refractory mCRC | Adagrasib | ORR 22%, DCR 87% | |
BRAFV600E | BEACON | III | 665 | Refractory mCRC | Encorafenib + binimetinib + cetuximab vs. encorafenib + cetuximab vs. FOLFIRI or cetuximab + irinotecan | mPFS 4.5 vs. 4.3 vs. 1.5 months mOS 9.3 vs. 9.3 vs. 5.9 months |
HER2 | HERACLES | II | 27 | Refractory mCRC | Lapatinib + trastuzumab | ORR 30% |
HERACLES-B | II | 31 | Refractory mCRC | Pertuzumab + trastuzumab-emtansine | ORR 9.7% | |
MyPathway | II | 43 | Refractory mCRC KRAS wild-type | Pertuzumab + trastuzumab | mPFS 5.3 months mOS 14.0 months ORR 40% | |
TRIUMPH | II | 27 | Refractory mCRC | Pertuzumab + trastuzumab | mPFS 4.0 months mOS 10.1 months ORR 30% | |
MOUNTAINEER | II | 26 | Refractory mCRC | Tucatinib + trastuzumab | mPFS 6.2 months mOS 17.3 months ORR 55% | |
DESTINY-CRC01 | II | 53 | Refractory mCRC | Trastuzumab-deruxtecan | mPFS 6.9 months mOS 15.5 months ORR 45.3% | |
NTRK | NAVIGATE | II | 10 | Refractory mCRC NTRK fusion-positive | Larotrectinib | mPFS 5.5 months mOS 29.4 months ORR 50% |
ALKA-372-001, STARTRK-1, and STARTRK-2 | I/II | 4 | mCRC NTRK fusion-positive | Entrectinib | ORR 25% |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Puccini, A.; Seeber, A.; Berger, M.D. Biomarkers in Metastatic Colorectal Cancer: Status Quo and Future Perspective. Cancers 2022, 14, 4828. https://doi.org/10.3390/cancers14194828
Puccini A, Seeber A, Berger MD. Biomarkers in Metastatic Colorectal Cancer: Status Quo and Future Perspective. Cancers. 2022; 14(19):4828. https://doi.org/10.3390/cancers14194828
Chicago/Turabian StylePuccini, Alberto, Andreas Seeber, and Martin D. Berger. 2022. "Biomarkers in Metastatic Colorectal Cancer: Status Quo and Future Perspective" Cancers 14, no. 19: 4828. https://doi.org/10.3390/cancers14194828