Background/Objectives: Locally advanced rectal cancer is treated with neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). As this approach achieves complete pathologic remissions (pCR) in approximately 30% of patients, it raises the question of whether surgery is always necessary. Non-surgical strategies, such as “watch and wait” (W&W), have shown similarly promising outcomes. However, there is an unmet need for reliable biomarkers predicting pCR. Analysis of circulating tumor DNA (ctDNA) has shown potential for monitoring treatment response and detecting minimal residual disease. We hypothesized that monitoring ctDNA changes during nCRT might facilitate the identification of individuals who achieve pCR. Methods: In the prospective single-center NEORECT trial, the plasma of forty rectal cancer patients was collected before, during, and after nCRT and before TME. Informative somatic mutations were identified in tissue biopsies by NGS and subsequently used for ctDNA quantification by dPCR. Results: The results identified three distinct ctDNA patterns: increase, decrease, and absence. Remarkably, undetectable DNA was observed in good responders, while a tenfold ctDNA increase was associated with the emergence of new metastases. Despite these insights, ctDNA alone demonstrated low specificity, with no significant correlation to pCR or long-term prognosis. A multimodal approach incorporating routinely available clinical parameters remains inadequate for accurately predicting pCR prior to TME. Conclusions: In conclusion, the NEORECT trial establishes the feasibility of ctDNA-based personalized monitoring for rectal cancer patients undergoing nCRT. However, the utility of ctDNA in enhancing pCR prediction for a W&W strategy warrants further investigation. Larger studies integrating multi-gene analyses and expanded clinical datasets are essential in the future.
背景/目的：局部进展期直肠癌的治疗通常采用新辅助放化疗（nCRT）后进行全直肠系膜切除术（TME）。由于该方案可使约30%的患者达到病理完全缓解（pCR），这引发了手术是否始终必要的思考。非手术策略如"观察等待"（W&W）已显示出同样良好的疗效前景。然而，目前仍缺乏能够可靠预测pCR的生物标志物。循环肿瘤DNA（ctDNA）分析在监测治疗反应和检测微小残留病灶方面展现出潜力。我们假设监测nCRT期间ctDNA的动态变化可能有助于识别达到pCR的患者。方法：在前瞻性单中心NEORECT试验中，收集了40例直肠癌患者在nCRT前、中、后及TME前的血浆样本。通过二代测序技术（NGS）在组织活检中鉴定出具有信息性的体细胞突变，随后采用数字PCR（dPCR）进行ctDNA定量分析。结果：研究识别出三种不同的ctDNA动态模式：升高型、降低型和持续阴性型。值得注意的是，治疗反应良好者ctDNA持续不可检出，而ctDNA十倍升高与新发转移灶的出现相关。尽管获得这些发现，但单独使用ctDNA检测显示特异性较低，与pCR或长期预后无显著相关性。结合常规临床参数的多模态方法仍不足以在TME前准确预测pCR。结论：NEORECT试验证实了基于ctDNA的个体化监测在接受nCRT的直肠癌患者中具有可行性。然而，ctDNA在提升W&W策略中pCR预测效能方面的应用价值仍需进一步研究。未来需要开展更大规模的研究，整合多基因分析和扩展临床数据集。
肿瘤(癌症)患者之家