免疫序贯靶向治疗致微卫星稳定/错配修复完整型BRAF V600E突变转移性结直肠癌病理完全缓解1例

摘要/Abstract

摘要： BRAF V600E突变型转移性结直肠癌（mCRC）具有高度侵袭性,预后极差,且对常规化疗及免疫治疗反应有限。本文报道1例62岁男性、BRAF V600E突变、微卫星稳定型（MSS）直肠癌伴同时性肝多发转移（Ⅳ期）患者的诊疗经过。患者一线接受卡培他滨+奥沙利铂联合信迪利单抗治疗,最佳疗效达部分缓解,但在维持治疗期间出现肝转移灶疾病进展,一线无进展生存时间为6.5个月。二线治疗换用维莫非尼联合西妥昔单抗及伊立替康方案,治疗后肝转移灶及直肠原发灶均显著退缩。经多学科评估后,患者先后成功接受肝转移瘤切除术及直肠癌根治术,术后病理学均提示无肿瘤细胞残留,即达到病理学完全缓解（pCR）。随访截至2026年3月,患者持续保持无疾病证据状态。本病例提示,对于程序性死亡受体配体1高表达的BRAF V600E突变、MSS的mCRC患者,即使一线免疫治疗联合化疗未能阻止进展,其诱导的免疫微环境重塑仍可能为后续抗BRAF靶向治疗创造有利的转化契机,最终实现深度缓解乃至pCR,该序贯治疗策略值得进一步探索。

关键词: 直肠肿瘤, BRAF V600E突变, 免疫检查点抑制剂, BRAF抑制剂

方宇婷, 孙永琨, 齐丽娟. 免疫序贯靶向治疗致微卫星稳定/错配修复完整型BRAF V600E突变转移性结直肠癌病理完全缓解1例[J]. 肝癌电子杂志, 2026, 13(2): 33-39.

参考文献

[1] 孙可欣, 李荔, 王少明, 等. 2024年中国分地区恶性肿瘤流行情况分析[J]. 中华肿瘤杂志, 2026, 48(3):400-412.
[2] WANG H, LI X, PENG R, et al.Stereotactic ablative radiotherapy for colorectal cancer liver metastasis[J]. Semin Cancer Biol, 2020, 71: 21-32.
[3] CERVANTES A, ADAM R, ROSELLÓ S, et al.Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up[J]. Ann Oncol, 2022, 34(1): 10-32.
[4] ANGERILLI V, SABELLA G, CENTONZE G, et al.BRAF-mutated colorectal adenocarcinomas: pathological heterogeneity and clinical implications[J]. Crit Rev Oncol Hematol, 2022, 172: 103647.
[5] CREMOLINI C, LOUPAKIS F, ANTONIOTTI C, et al.FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study[J]. Lancet Oncol, 2015, 16(13): 1306-1315.
[6] CREMOLINI C, ANTONIOTTI C, ROSSINI D, et al.Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial[J]. Lancet Oncol, 2020, 21(4): 497-507.
[7] CREMOLINI C, ANTONIOTTI C, STEIN A, et al.Individual patient data Meta-analysis of FOLFOXIRI plus bevacizumab versus doublets plus bevacizumab as initial therapy of unresectable metastatic colorectal cancer[J]. J Clin Oncol, 2020: JCO2001225.
[8] KOPETZ S, GUTHRIE K A, MORRIS V K, et al.Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406)[J]. J Clin Oncol, 2020, 39(4): 285-294.
[9] TABERNERO J, GROTHEY A, VAN CUTSEM E, et al.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]. J Clin Oncol, 2021, 39(4): 273-284.
[10] BENSON A B, VENOOK A P, ADAM M, et al.Colon cancer, version 3.2024, NCCN Clinical Practice Guidelines in Oncology[J]. J Natl Compr Canc Netw, 2024, 22(2 D).
[11] ELEZ E, YOSHINO T, SHEN L, et al.Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer[J]. N Engl J Med, 2025, 392(24): 2425-2437.
[12] PATNAIK A, KANG S P, RASCO D, et al.Phase Ⅰ study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors[J]. Clin Cancer Res, 2015, 21(19): 4286-4293.
[13] TOPALIAN S L, HODI F S, BRAHMER J R, et al.Safety, activity, and immune correlates of anti-PD-1 antibody in cancer[J]. N Engl J Med, 2012, 366(26): 2443-2454.
[14] TIAN J, CHEN J H, CHAO S X, et al.Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial[J]. Nat Med, 2023, 29(2): 458-466.
[15] MORRIS V K, PARSEGHIAN C M, BAHRAMBEIGI V, et al. Phase 1/2 trial of encorafenib, cetuximab,nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer[J]. Cancer Cell, 2025, 43(11): 2106-2118.e3.
[16] CHEN D, HUANG J-F, LIU K, et al.BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and Meta-analysis[J]. PLoS One, 2014, 9(3): e90607.
[17] XU Q, XU A T, ZHU M M, et al.Predictive and prognostic roles of BRAF mutation in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a Meta-analysis[J]. J Dig Dis, 2013, 14(8): 409-416.
[18] KIKUCHI H, MATSUI A, MORITA S, et al.Increased CD8+ T-cell infiltration and efficacy for multikinase inhibitors after PD-1 blockade in hepatocellular carcinoma[J]. J Natl Cancer Inst, 2022, 114(9): 1301-1305.
[19] LE D T, URAM J N, WANG H, et al.PD-1 blockade in tumors with mismatch-repair deficiency[J]. N Engl J Med, 2015, 372(26): 2509-2520.
[20] KUANG X, XU R, LI J.Association of PD-L1 expression with survival benefit from PD-1/PD-L1 inhibitors in advanced cancer: systematic review and Meta-analysis of phaseⅢ randomized clinical trials[J]. Crit Rev Oncol Hematol, 2024, 198: 104357.
[21] MCGRANAHAN N, SWANTON C.Clonal heterogeneity and tumor evolution: past, present, and the future[J]. Cell, 2017, 168(4): 613-628.
[22] WANG Q, JU X, WANG J, et al.Immunogenic cell death in anticancer chemotherapy and its impact on clinical studies[J]. Cancer Lett, 2018, 438: 17-23.
[23] KIM R, TEHFE M, KAVAN P, et al.Pembrolizumab plus mFOLFOX7 or FOLFIRI for microsatellite stable/mismatch repair-proficient metastatic colorectal cancer: KEYNOTE-651 cohorts B and D[J]. Clin Colorectal Cancer, 2024, 23(2): 118-127.
[24] MELTZER S, NEGÅRD A, BAKKE K M, et al. Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer[J]. Br J Cancer, 2022, 127(12): 2227-2233.