MRD / ctDNA / DTP — 从检测到治疗决策
dMMR/MSI-H结直肠癌对PD-1抑制剂的突出敏感性早已确立：pembrolizumab与nivolumab先后在转移性疾病中获得加速批准[1][5]，CheckMate-142还显示纳武利尤单抗联合伊匹木单抗可将客观缓解率提高至55%[2]，这种敏感性被认为与MSI-H肿瘤更充沛的免疫浸润和更高的免疫原性相关[4]。随后探索自然前移至早期阶段：一项单中心II期试验在局限性MSI-H/dMMR实体瘤（含27例肠癌）中新辅助应用pembrolizumab，最佳总缓解率达82%，接受手术者中65%取得病理完全缓解（pCR）[3]，新辅助免疫治疗由此成为局部晚期MSI-H肠癌的热点方向[6]。但卡点也很清楚：缓解深度因人而异，术前缺少可靠的分子工具对患者分层。
这则来自AACR26的社交媒体消息（发布方声明与AACR并无关联）恰好对准这一卡点。多中心II期NEOPRISM-CRC试验在高危II–III期dMMR/MSI-H肠癌中按肿瘤突变负荷分层评估新辅助pembrolizumab[7]，此前疗效报告为32例患者经3周期治疗后主要病理缓解率78%、pCR率59%、6个月无病生存率100%[8]。本次由UCL Cancer的Jiang博士汇报的，则是用NeXT Personal®检测所做的分子应答分析：超级分子应答者（super molecular responders）100%达到pCR，应答不佳者100%未达pCR，术后预测复发的阴性预测值与特异度均为100%，并识别出三个不同的应答组。同一消息还公布了万人级真实世界数据（中位检测下限1.92 PPM）、用于耐药监测的新功能Real-Time Variant Tracker™，以及DARWIN 2研究中该检测对接受免疫治疗的NSCLC患者的风险分层结果。
相对已有认识，这一步的推进在于把术前分子应答与病理终点、术后复发风险直接挂钩：既往新辅助研究回答的是“整组缓解率有多高”[3]，而稳定的分子分层一旦成立，就为“哪些患者可以降级甚至豁免后续治疗”提供了可操作的依据；DARWIN 2则提示同一检测框架或可延伸至肺癌免疫治疗人群。
当然，局限同样明显：消息未给出本次分析的样本量、随访时长与复发事件数，100%这类极端比例的可信区间无从评估（据报道随访期内未见复发[9]）；分子应答分层能否前瞻性地改变手术或辅助治疗决策，仍需专门试验回答。
- 1.Immunotherapy in colorectal cancer: rationale, challenges and potential · Nat Rev Gastroenterol Hepatol 2019
- 2.Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer · J Clin Oncol 2018
- 3.Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors · J Clin Oncol 2023
- 4.Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer · Front Immunol 2020
- 5.Immunotherapy in colorectal cancer: current achievements and future perspective · Int J Biol Sci 2021
- 6.Neoadjuvant Immunotherapy for MSI-H/dMMR Locally Advanced Colorectal Cancer: New Strategies and Unveiled Opportunities · Front Immunol 2022
- 7.NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to ... · ascopubs.org 2026
- 8.Challenges of neoadjuvant immunotherapy in mismatch repair ... · pmc.ncbi.nlm.nih.gov 2026
- 9.Neoadjuvant Pembrolizumab Produces High pCR Rate ... · onclive.com 2026
We’re here at #AACR26!
Stop by and say hello to our team at booth # 2325.
Join us tomorrow for a podium talk highlighting NEOPRISM-CRC: highlighting ultrasensitive ctDNA monitoring by NeXT Personal® during neoadjuvant pembrolizumab treatment in stage II-III dMMR/MSI colorectal
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Timothy A. Yap, Andrae Vandross, Jenny Amaya-Amaya, Chris N. Barnes, Shuguang Ma, Martin Decaris, Keithryn Nicolas, Alexander Spira, Jacqueline Brown, Patricia LoRusso, Manish R. Sharma
Read the abstract →Karen L. Reckamp, Mary W. Redman, Konstantin H. Dragnev, Maya Khalil, Brian S. Henick, James Moon, Pasarlai Ahmadzai, Michael LeBlanc, Daniel R. Carrizosa, Paul J. Hesketh, Ellen V. Sigal, Jeff Allen, Andreas N. Saltos, Bryan A. Faller, Roy S. Herbst, Charles D. Blanke, Jhanelle E. Gray
Read the abstract →Salah-Eddine Bentebibel, Daniel J McGrail, Veena Kochat, Emre Arslan, Reham Abdel-Wahab, Sung-Nam Cho, Xiaodong Yang, Daniel H Johnson, Rodabe N Amaria, Isabella C Glitza, Patrick Hwu, Hussein A Tawbi, Jared K Burks, Michael A Davies, Kunal Rai, Suhendan Ekmekcioglu, Adi Diab
Read the abstract →Barbara Burtness, Ravindra Uppaluri, Michael J. Dennis, Annette M. Lim, Richard A. Scolyer, Erin Alesi, Ayako Wakatsuki Pedersen, Amy Wesa, Ravi K. Adapala, Ulla Kring Hansen, Marcos Iglesias, Bushi Wang, Cecilie Abildgaard, Qasim Ahmad, Francois Ringeisen, Georgina V. Long, Robert I. Haddad
Read the abstract →Source: Personalis, Inc. · x.com