Circulating tumor DNA analysis predicts recurrence and avoids unnecessary adjuvant chemotherapy in I-IV colorectal cancer

Wenhua Fan; Zhiyuan Xia; Rongrong Chen; Dagui Lin; Fang Li; Yang Zheng; Jiongyong Luo; Yuanyuan Xiong; Pengli Yu; Wei Gao; Yuhua Gong; Feiran Zhang; Sen Zhang; Liren Li

doi:10.1177/17588359231220607

Circulating tumor DNA analysis predicts recurrence and avoids unnecessary adjuvant chemotherapy in I-IV colorectal cancer

Ther Adv Med Oncol. 2024 Jan 27:16:17588359231220607. doi: 10.1177/17588359231220607. eCollection 2024.

Authors

Wenhua Fan^{1

2}, Zhiyuan Xia³, Rongrong Chen⁴, Dagui Lin^{1

2}, Fang Li⁴, Yang Zheng⁵, Jiongyong Luo⁵, Yuanyuan Xiong⁴, Pengli Yu⁴, Wei Gao⁴, Yuhua Gong⁴, Feiran Zhang⁶, Sen Zhang⁷, Liren Li^{1

8}

Affiliations

¹ Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.
² Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
³ Department of Colorectal & Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
⁴ Geneplus-Beijing, Beijing, China.
⁵ Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
⁶ Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, No. 57 Changping Road, Jinping District, Shantou, Guangdong 515041, China.
⁷ Department of Colorectal & Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, China.
⁸ Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China.

Abstract

Background: Circulating tumor DNA (ctDNA) has emerged as a biomarker that can define the risk of recurrence after curative-intent surgery for patients with colorectal cancer (CRC). However, beyond the predictive power of postoperative ctDNA detection, the efficacy and potential limitations of ctDNA detection urgently need to be fully elucidated in a large cohort of CRC.

Objectives: To define potentially cured CRC patients through ctDNA monitoring following surgery.

Design: A prospective, multicenter, observational study.

Methods: We enrolled 309 patients with stages I-IV CRC who underwent definitive surgery. Tumor tissues were sequenced by a custom-designed next-generation sequencing panel to identify somatic mutations. Plasma was analyzed using a ctDNA-based molecular residual disease (MRD) assay which integrated tumor-genotype-informed and tumor-genotype-naïve ctDNA analysis. The turnaround time of the assay was 10-14 days.

Results: Postoperative ctDNA was detected in 5.4%, 13.8%, 15%, and 30% of patients with stage I, II, III, and IV disease, respectively, and in 17.5% of all longitudinal samples. Patients with positive postsurgery MRD had a higher recurrence rate than those with negative postsurgery MRD [hazard ratio (HR), 13.17; p < 0.0001], producing a sensitivity of 64.6%, a specificity of 94.8%, a positive predictive value (PPV) of 75.6%, and a negative predictive value (NPV) of 91.5%. Furthermore, patients with positive longitudinal MRD also had a significantly higher recurrence rate (HR, 14.44; p < 0.0001), with increased sensitivity (75.0%), specificity (94.9%), PPV (79.6%), and NPV (93.4%). Subgroup analyses revealed that adjuvant therapy did not confer superior survival for patients with undetectable or detectable MRD. In addition, MRD detection was less effective in identifying lung-only and peritoneal metastases.

Conclusion: Postoperative ctDNA status is a strong predictor of recurrence independent of stage and microsatellite instability status. Longitudinal undetectable MRD could be used to define the potentially cured population in CRC patients undergoing curative-intent surgery.

Keywords: adjuvant therapy; circulating tumor DNA; colorectal cancer; cure; molecular residual disease.