Nishioka Yujiro, Chun Yun Shin, Overman Michael J, Cao Hop S Tran, Tzeng Ching-Wei D, Mason Meredith C, Kopetz Scott W, Bauer Todd W, Vauthey Jean-Nicolas, Newhook Timothy E
From the Departments of Surgical Oncology (Nishioka, Chun, Cao, Tzeng, Mason, Vauthey, Newhook), The University of Texas MD Anderson Cancer Center, Houston, TX.
Gastrointestinal Medical Oncology (Overman, Kopetz), The University of Texas MD Anderson Cancer Center, Houston, TX.
J Am Coll Surg. 2022 Apr 1;234(4):474-483. doi: 10.1097/XCS.0000000000000093.
Circulating tumor DNA (ctDNA) is a promising biomarker for patients undergoing hepatectomy for colorectal liver metastases (CLM). We hypothesized that post-hepatectomy ctDNA detection would identify patients at highest risk for early recurrence of CLM.
Patients with CLM who underwent curative-intent hepatectomy with ctDNA analysis within 180 days postoperatively (1/2013 and 6/2020) were included. Tissue somatic mutations and ctDNA analyses were performed by next-generation sequencing panels. Survival analyses determined factors associated with clinical recurrence 1 year or earlier after hepatectomy. Patients with primary tumors in situ and without 1-year follow-up were excluded. Median follow-up was 28.3 months.
Of 105 patients, 32 (30%) were ctDNA positive (ctDNA+) after curative-intent hepatectomy. Compared with ctDNA-negative patients, ctDNA+ patients had multiple CLM (84% vs 55%, p = 0.002) and co-mutated RAS/TP53 (47% vs 23%, p = 0.018). Multiple CLM (odds ration (OR), 5.43; p = 0.005) and co-mutated RAS/TP53 (OR, 3.30; p = 0.019) were independently associated with post-hepatectomy ctDNA. Although perioperative carcinoembryonic antigen levels were not prognostic, postoperative ctDNA+ (hazard ratio (HR), 2.04; p = 0.011) and extrahepatic disease (HR, 2.45, p = 0.004) were independently associated with worse recurrence-free survival. After adjusting for extrahepatic disease, preoperative chemotherapy, multiple CLM, tumor viability of 50% or greater, and co-mutated RAS/TP53, ctDNA+ within 180 days was the only independent risk factor for recurrence 1 year or earlier after hepatectomy (94% vs 49%; HR, 11.8; p = 0.003).
Postoperative ctDNA detection is associated with early recurrence 1 year or earlier after curative-intent hepatectomy for CLM, and RAS/TP53 co-mutations result in a more than 3-fold increased risk for postoperative ctDNA positivity. This highlights the complementary effect of tumor tissue and circulating mutational profiling for patients with CLM.
循环肿瘤DNA（ctDNA）是接受结直肠癌肝转移（CLM）肝切除术患者的一种有前景的生物标志物。我们假设肝切除术后ctDNA检测可识别出CLM早期复发风险最高的患者。
纳入在术后180天内（2013年1月至2020年6月）接受根治性肝切除术并进行ctDNA分析的CLM患者。通过二代测序平台进行组织体细胞突变和ctDNA分析。生存分析确定与肝切除术后1年或更早临床复发相关的因素。排除原位原发性肿瘤且无1年随访的患者。中位随访时间为28.3个月。
105例患者中，32例（30%）在根治性肝切除术后ctDNA呈阳性（ctDNA+）。与ctDNA阴性患者相比，ctDNA+患者有多发CLM（84%对55%，p = 0.002）和RAS/TP53共突变（47%对23%，p = 0.018）。多发CLM（比值比（OR），5.43；p = 0.005）和RAS/TP53共突变（OR，3.30；p = 0.019）与肝切除术后ctDNA独立相关。虽然围手术期癌胚抗原水平无预后价值，但术后ctDNA+（风险比（HR），2.04；p = 0.011）和肝外疾病（HR，2.45，p = 0.004）与无复发生存期较差独立相关。在调整肝外疾病、术前化疗、多发CLM、肿瘤活性≥50%和RAS/TP53共突变后，180天内ctDNA+是肝切除术后1年或更早复发的唯一独立危险因素（94%对49%；HR，11.8；p = 0.003）。
术后ctDNA检测与CLM根治性肝切除术后1年或更早的早期复发相关，RAS/TP53共突变使术后ctDNA阳性风险增加3倍以上。这突出了肿瘤组织和循环突变谱分析对CLM患者的互补作用。
