编者按：波士顿马萨诸塞州总医院的胃肠道肿瘤学家Priyadarshini Pathak在2024年美国临床肿瘤学会（ASCO）年会的教育专场“结直肠癌的管理艺术：治疗发展与革新”中汇报了ctDNA在结直肠癌中的实践应用和未来发展。Dr.Pathak在《肿瘤瞭望-消化时讯》的访谈中为我们详细分享了如何应用ctDNA指导高危结直肠癌的辅助治疗决策。

《肿瘤瞭望-消化时讯》：我们知道，结直肠癌的复发问题是影响患者生存和预后的重要因素，您认为临床上结直肠癌治疗后复发的高危因素有哪些？

Dr.Pathak：目前仅通过手术，Ⅰ期结肠癌的治愈率接近95%。对于 Ⅱ 期和 Ⅲ期结肠癌，影响复发率的因素有哪些呢？对于Ⅱ期结肠癌，我们认为一些传统的高危临床病理因素包括：<12个淋巴结取样;低分化肿瘤;伴肠梗阻或穿孔的肿瘤以及淋巴血管浸润的肿瘤。当存在这些危险因素时，我们会考虑行辅助化疗。对于Ⅲ期结肠癌，则全部接受辅助化疗，因为Ⅲ期肠癌涉及淋巴结浸润。到目前为止，传统危险因素一直是决定患者是否接受辅助化疗的因素。该领域取得了一系列发展，现在我们可以通过一种非常强大的预后生物标志物——循环肿瘤DNA（ctDNA）预测患者的复发风险。

Dr Pathak: Thank you. That is a great question. Currently, the stage I colon cancer cure rate is nearly 95% with surgery alone. The question becomes in stage II and III colon cancer, what affects recurrence rates? For stage II colon cancer, some of the high risk traditional clinical pathologic factors that we take into consideration as high risk for recurrence are: <12 lymph nodes sampled; poorly differentiated tumor; tumors that are obstructed or perforated; and of course, tumors that have lymph-vascular invasion. When these risk factors are present, we consider adjuvant chemotherapy. For stage III colon cancer, everybody gets adjuvant chemotherapy since lymph nodes are involved in stage III. So far, traditional risk factors have been the deciding factors in who receives adjuvant chemotherapy. But the field is advancing, and now we have circulating tumor DNA (ctDNA), which is a very strong prognostic biomarker that tells us about risk for recurrence.

Dr Pathak: Of course. Circulating tumor DNA is extracellular DNA that is derived from tumor cells. This derived from tumor cells either via apoptosis, necrosis or secretion of the tumor DNA. This can be detected in the blood, as well as other body fluids. There are a few things we know about ctDNA. We know it is the most powerful biomarker to predict micrometastatic persistent disease after definitive treatment. This can be after surgery or after adjuvant chemotherapy. One thing we know is that it is a very strong prognostic biomarker. Presence of minimal residual disease (MRD) after surgery is associated with a very high risk of recurrence. In fact, nearly all patients who have ctDNA detected after surgery will recur, usually within two years without any additional systemic therapy. The question about if it is a predictive biomarker? I think it is potentially a predictive biomarker. Numerous studies, such as the BESPOKE trial and the GALAXY study (which is the observational arm of the ongoing CIRCULATE-Japan trial), have shown us it can be predictive of outcomes, at least in the short term. Adjuvant chemotherapy in patients who are MRD-positive, gives better disease-free survival outcomes. In the short term, we are seeing evidence of it being potentially predictive, but we are still awaiting long term outcomes or long term cure rates.

Dr.Pathak：我认为这就是该领域的发展方向——如何利用ctDNA来指导辅助化疗决策。到目前为止，指南不建议常规使用ctDNA来指导决策。我在大会的演讲中讨论了一些关于敏感性和特异性的事情。单个时间点对ctDNA检测的灵敏度较低，约40%~50%，这意味着目前的检测仍然会遗漏一些ctDNA阴性的高危患者。因此，对于 ctDNA 检测阴性的患者，我还不建议常规降级治疗。但我认为我们有足够的关于ctDNA的预后和潜在预测价值的信息。如果Ⅱ期结肠癌患者的ctDNA检测呈阳性，那么可以考虑给予升级治疗。同样，我们仍然需要知道ctDNA引导的治疗干预如何影响患者的长期生存或治愈率，目前我们只有短期数据：对于微小残留病灶阳性的患者，辅助化疗的两年和三年生存结果更好。