KRAS突变型微卫星稳定型晚期结直肠癌的治疗
Treatment of KRAS Mutant Microsatellite Stabilized Advanced Colorectal Cancer
DOI: 10.12677/ACM.2023.1351137, PDF,   
作者: 朱增光：青海大学临床医学院，青海 西宁；姬发祥*：青海大学附属医院，青海 西宁
关键词: 晚期结直肠癌；KRAS突变；微卫星稳定；靶向治疗；免疫治疗；Advanced Colorectal Cancer； KRAS Mutation； Microsatellite Stabilization； Targeted Therapy； Immunotherapy
摘要: 结直肠癌(CRC)是我国最常见的恶性肿瘤，大多数结直肠癌患者在发现时已处于中晚期，目前晚期CRC的治疗仍然是以化疗治疗为主。随着研究的深入及进展，靶向治疗、免疫治疗等多种治疗方式也在不断进步提升。对于微卫星高度不稳定型CRC的治疗，免疫在一线、后线辅助、新辅助治疗均取得了重大突破。但是对于大多数的微卫星稳定型(MSS)，免疫治疗的研究及治疗疗效不尽人意，特别是对于KRAS突变型微卫星稳定型CRC的治疗及生存尤为显著，目前多项研究将免疫治疗与靶向治疗、化疗等相结合作为新的突破方向。本文将对KRAS突变型MSS型晚期CRC的治疗及治疗进展进行梳理及综述。
Abstract: Colorectal cancer is the most common malignant tumor in China. Most patients with CRC are in the middle and advanced stage at the time of discovery. Chemotherapy is still the main treatment for the advanced stage CRC. With the deepening of research and progress, targeted therapy, immuno-therapy and other forms of treatment are also improving. For the treatment of highly unstable CRC with microsatellites, major breakthroughs have been made in first-line, post-line adjuvant and ne-oadjuvant therapy. However, for most microsatellite stable CRC, immunotherapy research and therapeutic efficiency are unsatisfactory, especially for the treatment and survival of KRAS mutant microsatellite stable CRC. Currently, a number of studies have taken the combination of immuno-therapy with targeted therapy and chemotherapy as a new breakthrough direction. In this paper, the treatment and treatment progress of KRAS mutant MSS advanced CRC will be reviewed and summarized.
文章引用：朱增光, 姬发祥. KRAS突变型微卫星稳定型晚期结直肠癌的治疗[J]. 临床医学进展, 2023, 13(5): 8128-8134. https://doi.org/10.12677/ACM.2023.1351137

参考文献

[1] Sung, H., Ferlay, J., Siegel, R.L., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249. [Google Scholar] [CrossRef] [PubMed]
[2] Zheng, R., Zhang, S., Zeng, H., Wang, S., Sun, K., Chen, R., et al. (2022) Cancer Incidence and Mortality in China, 2016. Journal of the National Cancer Center, 2, 1-9. [Google Scholar] [CrossRef] [PubMed]
[3] 吴春晓, 顾凯, 龚杨明, 郑荣寿, 王少明, 陈茹, 张思维, 施燕, 魏文强, 付晨, 赫捷. 2015年中国结直肠癌发病和死亡情况分析[J]. 中国癌症杂志, 2020(4): 241-245.
[4] Xu, R., Wang, W., Zhu, B., Lin, X., Ma, D., Zhu, L., et al. (2020) Disease Characteristics and Treatment Patterns of Chinese Pa-tients with Metastatic Colorectal Cancer: A Retrospective Study Using Medical Records from China. BMC Cancer, 20, Article No. 131. [Google Scholar] [CrossRef] [PubMed]
[5] Van Cutsem, E., Cervantes, A., Nordlinger, B., Arnold, D. and ESMO Guidelines Working Group (2014) Metastatic Colorectal Cancer: ESMO Clinical Practice Guide-lines for Diagnosis, Treatment and Follow-Up. Annals of Oncology, 25, iii1-9. [Google Scholar] [CrossRef] [PubMed]
[6] Lee, R.M., Cardona, K. and Russell, M.C. (2019) Historical Perspec-tive: Two Decades of Progress in Treating Metastatic Colorectal Cancer. Journal of Surgical Oncology, 119, 549-563. [Google Scholar] [CrossRef] [PubMed]
[7] Islami, F., Goding Sauer, A., Miller, K.D., et al. (2018) Proportion and Number of Cancer Cases and Deaths Attributable to Potentially Modifiable Risk Factors in the United States. CA: A Cancer Journal for Clinicians, 68, 31-54. [Google Scholar] [CrossRef] [PubMed]
[8] Diaz, L.A., Shiu, K.K., Kim, T.W., Jensen, B.V., Jensen, L.H., Punt, C., et al. (2022) Pembrolizumab versus Chemotherapy for Microsatellite Instability-High or Mismatch Repair-Deficient Meta-static Colorectal Cancer (KEYNOTE-177): Final Analysis of a Randomised, Open-Label, Phase 3 Study. The Lancet Oncology, 23, 659-670. [Google Scholar] [CrossRef] 
[9] Overman, M.J., McDermott, R., Leach, J.L., Lonardi, S., Lenz, H.J., Morse, M.A., et al. (2017) Nivolumab in Patients with Metastatic DNA Mismatch Repair-Deficient or Mi-crosatellite Instability-High Colorectal Cancer (CheckMate 142): An Open-Label, Multicentre, Phase 2 Study. The Lancet Oncology, 18, 1182-1191. [Google Scholar] [CrossRef] 
[10] Afrăsânie, V.A., Marinca, M.V., Alexa-Stratulat, T., Gafton, B., Păduraru, M., Adavidoaiei, A.M., Miron, L. and Rusu, C. (2019) KRAS, NRAS, BRAF, HER2 and Microsatellite Instability in Metastatic Colorectal Cancer-Practical Implications for the Clinician. Radiology and Oncology, 53, 265-274. [Google Scholar] [CrossRef] [PubMed]
[11] Cefalì, M., Epistolio, S., Palmarocchi, M.C., Frattini, M. and De Dosso, S. (2021) Research Progress on KRAS Mutations in Colorectal Cancer. Journal of Cancer Metastasis and Treatment, 7, Article No. 26. [Google Scholar] [CrossRef] 
[12] Testa, U., Pelosi, E. and Castelli, G. (2018) Colorectal Cancer: Genetic Abnormalities, Tumor Progression, Tumor Heterogeneity, Clonal Evolution and Tumor-Initiating Cells. Medical Sciences (Basel), 6, Article No. 31. [Google Scholar] [CrossRef] [PubMed]
[13] Modest, D.P., Pant, S. and Sartore-Bianchi, A. (2019) Treatment Se-quencing in Metastatic Colorectal Cancer. European Journal of Cancer, 109, 70-83. [Google Scholar] [CrossRef] [PubMed]
[14] Venook, A.P., Niedzwiecki, D., Lenz, H.J., Innocenti, F., Fruth, B., Meyerhardt, J.A., et al. (2017) 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, 317, 2392-2401. [Google Scholar] [CrossRef] [PubMed]
[15] Tournigand, C. andré, T., Achille, E., Lledo, G., Flesh, M., Mery-Mignard, D., et al. (2004) FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. Journal of Clinical Oncology, 22, 229-237. [Google Scholar] [CrossRef] 
[16] Grothey, A., Sargent, D., Goldberg, R.M. and Schmoll, H.J. (2004) Survival of Patients with Advanced Colorectal Cancer Improves with the Availability of Fluorouracil-Leucovorin, Iri-notecan, and Oxaliplatin in the Course of Treatment. Journal of Clinical Oncology, 22, 1209-1214. [Google Scholar] [CrossRef] 
[17] Hammond, W.A., et al. (2016) Pharmacologic Resistance in Colo-rectal Cancer: A Review. Therapeutic Advances in Medical Oncology, 8, 57-84. [Google Scholar] [CrossRef] [PubMed]
[18] Biller, L.H. and Schrag, D. (2021) Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA, 325, 669-685. [Google Scholar] [CrossRef] [PubMed]
[19] Zarour, L.R., Anand, S., Billingsley, K.G., Bisson, W.H., Cercek, A., Clarke, M.F., et al. (2017) Colorectal Cancer Liver Metas-tasis: Evolving Paradigms and Future Directions. Cellular and Molecular Gastroenterology and Hepatology, 3, 163-173. [Google Scholar] [CrossRef] [PubMed]
[20] Rosen, L.S., Jacobs, I.A. and Burkes, R.L. (2017) Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars. Targeted Oncology, 12, 599-610. [Google Scholar] [CrossRef] [PubMed]
[21] Guan, Z.Z., Xu, J.M., Luo, R.C., Feng, F.Y., Wang, L.W., Shen, L., et al. (2011) Efficacy and Safety of Bevacizumab plus Chemotherapy in Chinese Patients with Metastatic Colorectal Cancer: A Randomized Phase III ARTIST Trial. Chinese Journal of Cancer, 30, 682-689. [Google Scholar] [CrossRef] [PubMed]
[22] Parakrama, R., Fogel, E., Chandy, C., et al. (2020) Immune Characteri-zation of Metastatic Colorectal Cancer Patients Post Reovirus Administration. BMC Cancer, 20, Article No. 569. [Google Scholar] [CrossRef] [PubMed]
[23] Liu, X., Guo, A., Tu, Y., et al. (2020) Fruquintinib Inhibits VEGF/ VEGFR2 Axis of Choroidal Endothelial Cells and M1-Type Macrophages to Protect Against Mouse La-ser-Induced Choroidal Neovascularization. Cell Death & Disease, 11, Article No. 1016. [Google Scholar] [CrossRef] [PubMed]
[24] Li, J., Qin, S., Xu, R.H., Shen, L., Xu, J., Bai, Y., et al. (2018) Effect of Fruquintinib vs Placebo on Overall Survival in Patients with Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial. JAMA, 319, 2486-2496. [Google Scholar] [CrossRef] [PubMed]
[25] Burki, T.K. (2018) Fruquintinib for Previously Treated Meta-Static Colorectal Cancer. The Lancet Oncology, 19, e388. [Google Scholar] [CrossRef] 
[26] Lito, P., Solomon, M., Li, L.-S., Hansen, R. and Rosen, N. (2016) Allele-Specific Inhibitors Inactivate Mutant KRAS G12C by a Trapping Mechanism. Science, 351, 604-608. [Google Scholar] [CrossRef] [PubMed]
[27] Canon, J., Rex, K., Saiki, A.Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C.G., Koppada, N., et al. (2019) The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity. Nature, 575, 217-223. [Google Scholar] [CrossRef] [PubMed]
[28] Patel, S.A. and Weiss, J. (2020) Advances in the Treatment of Non-Small Cell Lung Cancer: Immunothera. Clinics in Chest Medicine, 41, 237-247. [Google Scholar] [CrossRef] [PubMed]
[29] Chen, L., Jiang, X., Li, Y., Zhang, Q., Li, Q., Zhang, X., et al. (2022) How to Overcome Tumor Resistance to Anti-PD-1/PD-L1 Therapy by Immunotherapy Modifying the Tumor Microenvironment in MSS CRC. Clinical Immunology, 237, Article ID: 108962. [Google Scholar] [CrossRef] [PubMed]
[30] Pu, Y. and Ji, Q. (2022) Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression. Frontiers in Immunology, 13, Article ID: 874589. [Google Scholar] [CrossRef] [PubMed]
[31] Chae, Y.K., Arya, A., Iams, W., Cruz, M.R., Chandra, S., Choi, J. and Giles, F. (2018) Current Landscape and Future of Dual Anti-CTLA4 and PD‑1/PD‑L1 Blockade Immunotherapy in Cancer: Lessons Learned from Clinical Trials with Melanoma and Non‑Small Cell Lung Cancer (NSCLC). The Journal for ImmunoTherapy of Cancer, 6, 39. [Google Scholar] [CrossRef] [PubMed]
[32] Stein, A., Moehler, M., Trojan, J., Goekkurt, E. and Vogel, A. (2018) Immuno-Oncology in GI Tumours: Clinical Evidence and Emerging Trials of PD-1/PD-L1 Antagonists. Critical Reviews in Oncology/Hematology, 130, 13-26. [Google Scholar] [CrossRef] [PubMed]
[33] Le, D.T., Kim, T.W., Van Cutsem, E., et al. (2020) Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. Journal of Clinical Oncology, 38, 11-19. [Google Scholar] [CrossRef] 
[34] Le, D.T., Uram, J.N., Wang, H., et al. (2015) PD-1 Blockade in Tu-mors with Mismatch-Repair Deficiency. The New England Journal of Medicine, 372, 2509-2520. [Google Scholar] [CrossRef] 
[35] Antoniotti, C., Rossini, D., Pietrantonio, F., et al. (2022) Upfront FOLFOXIRI plus Bevacizumab with or without Atezolizumab in the Treatment of Patients with Metastatic Colorectal Cancer (AtezoTRIBE): A Multicentre, Open-Label, Randomised, Controlled, Phase 2 Trial. The Lancet Oncology, 23, 876-887. [Google Scholar] [CrossRef] 
[36] Mettu, N.B., et al. (2019) BACCI: A Phase II Randomized, Double-Blind, Multicenter, Placebo-Controlled Study of Capecitabine (C) Bevacizumab (B) plus Atezolizumab (A) or Placebo (P) in Refractory Metastatic Colorectal Cancer (mCRC): An ACCRU Network Study. Annals of Oncology, 30, v198-v252. [Google Scholar] [CrossRef] 
[37] Lenz, H.-J., Parikh, A.R., Spigel, D.R., et al. (2022) Nivolumab (NIVO) + 5-Fluorouracil/Leucovorin/Oxaliplatin (mFOLFOX6)/Bevacizumab (BEV) versus mFOLFOX6/BEV for First-Line (1L) Treatment of Metastatic Colorectal Cancer (mCRC): Phase 2 Results from CheckMate 9X8. Journal of Clinical Oncology, 40, Article No. 8. [Google Scholar] [CrossRef] 
[38] Antoniotti, C., Rossini, D., Pietrantonio, F., Catteau, A., Salvatore, L., Lonardi, S., et al. (2022) Upfront FOLFOXIRI plus Bevacizumab with or without Atezolizumab in the Treatment of Patients with Metastatic Colorectal Cancer (AtezoTRIBE): A Multicentre, Open-Label, Randomised, Con-trolled, Phase 2 Trial. The Lancet Oncology, 23, 876-887. [Google Scholar] [CrossRef] 
[39] Damato, A., Bergamo, F., Antonuzzo, L., Nasti, G., Iachetta, F., Romagnani, A., Gervasi, E., Larocca, M. and Pinto, C. (2021) FOLFOXIRI/Bevacizumab plus Nivolumab as First-Line Treatment in Metastatic Colorectal Cancer RAS/BRAF Mutated: Safety Run-In of Phase II NIVACOR Trial. Frontiers in Oncology, 11, Article ID: 766500. [Google Scholar] [CrossRef] [PubMed]
[40] Fang, X.F., et al. (2022) A Phase 2 Trial of Sintilimab (IBI 308) in Combination with CAPEOX and Bevacizumab (BBCAPX) as First-Line Treatment in Patients with RAS-Mutant, Mi-crosatellite Stable, Unresectable Metastatic Colorectal Cancer. Journal of Clinical Oncology, 40, 3563. [Google Scholar] [CrossRef] 
[41] Ghiringhelli, F., Chibaudel, B. and Taieb, J. (2020) Dur-valumab and Tremelimumab in Combination with FOLFOX in Patients with RAS-Mutated, Microsatellite-Stable, Previ-ously Untreated Metastatic Colorectal Cancer (MCRC): Results of the First Intermediate Analysis of the Phase Ib/II MEDETREME Trial. Journal of Clinical Oncology, 38, 3006. [Google Scholar] [CrossRef] 

为你推荐