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Observational Study
. 2024 Aug 15;30(16):3459-3469.
doi: 10.1158/1078-0432.CCR-24-0226.

Tissue-Free Liquid Biopsies Combining Genomic and Methylation Signals for Minimal Residual Disease Detection in Patients with Early Colorectal Cancer from the UK TRACC Part B Study

Susanna Slater  1 , Annette Bryant  1 , Maria Aresu  1 , Ruwaida Begum  1 , Hsiang-Chi Chen  1 , Clare Peckitt  1 , Retchel Lazaro-Alcausi  1 , Paul Carter  1 , Gayathri Anandappa  1 , Shelize Khakoo  1 , Lucinda Melcher  2 , Vanessa Potter  3 , Francisca M Marti  4 , Joesph Huang  5 , Graham Branagan  6 , Nicol George  7 , Muti Abulafi  8 , Sarah Duff  9 , Ashraf Raja  10 , Ashish Gupta  10 , Nicholas West  10 , Leslie Bucheit  11 , Thereasa Rich  11 , Ian Chau  1 , David Cunningham  1 , Naureen Starling  1 ; TRACC Part B trial investigators
Affiliations
Observational Study

Tissue-Free Liquid Biopsies Combining Genomic and Methylation Signals for Minimal Residual Disease Detection in Patients with Early Colorectal Cancer from the UK TRACC Part B Study

Susanna Slater et al. Clin Cancer Res. .

Abstract

Purpose: The absence of postoperative circulating tumor DNA (ctDNA) identifies patients with resected colorectal cancer (CRC) with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. Our study presents the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection.

Experimental design: TRACC (tracking mutations in cell-free tumor DNA to predict relapse in early colorectal cancer) included patients with stage I to III resectable CRC. Prospective longitudinal plasma collection for ctDNA occurred pre- and postsurgery, post-ACT, every 3 months for year 1 and every 6 months in years 2 and 3 with imaging annually. The Guardant Reveal assay evaluated genomic and methylation signals. The primary endpoint was 2-year recurrence-free survival (RFS) by postoperative ctDNA detection (NCT04050345).

Results: Between December 2016 and August 2022, 1,203 were patients enrolled. Plasma samples (n = 997) from 214 patients were analyzed. One hundred forty-three patients were evaluable for the primary endpoint; 92 (64.3%) colon, 51 (35.7%) rectal; two (1.4%) stage I, 64 (44.8%) stage II, and 77 (53.8%) stage III. Median follow-up was 30.3 months (95% CI, 29.5-31.3). Two-year RFS was 91.1% in patients with ctDNA not detected postoperatively and 50.4% in those with ctDNA detected [HR, 6.5 (2.96-14.5); P < 0.0001]. Landmark negative predictive value (NPV) was 91.2% (95% CI, 83.9-95.9). Longitudinal sensitivity and specificity were 62.1% (95% CI, 42.2-79.3) and 85.9% (95% CI, 78.9-91.3), respectively. The median lead time from ctDNA detection to radiological recurrence was 7.3 months (IQR, 3.3-12.5; n = 9).

Conclusions: Tissue-free MRD detection with longitudinal sampling predicts recurrence in patients with stage I to III CRC without the need for tissue sequencing. The UK TRACC Part C study is currently investigating the potential for ACT de-escalation in patients with undetectable postoperative ctDNA, given the high NPV indicating a low likelihood of residual disease.

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Conflict of interest statement

F.M. Marti reports personal fees from Servier and nonfinancial support from Takeda outside the submitted work. L. Bucheit is an employee of Guardant Health. T. Rich is an employee and stockholder of Guardant Health. I. Chau reports personal fees from Eli-Lilly, Bristol Myers Squibb, MSD, Roche, Merck Serono, AstraZeneca, Oncxerna, Boehringer Ingelheim, Incyte, Astella, GSK, Sotio, Eisai, Daiichi-Sankyo, Taiho, Servier, Seagen, Turning Point Therapeutics, Novartis, Takeda, and Elevation Oncology and grants from Janssen-Cilag and Eli Lilly outside the submitted work. D. Cunningham reports grants from Clovis, Eli Lilly, 4SC, Bayer, Celgene, and Roche outside the submitted work and is on the scientific advisory board for OVIBIO. N. Starling reports personal fees from Merck, Novartis, MSD Oncology, Eli Lilly, Pierre Fabre, Amgen, Eli Lilly Bangladesh, GSK, Seagen, BMS, AstraZeneca, and Servier, as well as other support from Merck, AstraZeneca, BMS, Pfizer, Guardant Health, Pfizer, Servier, AstraZeneca, MSD Oncology, Novartis, Guardant Health, Gilead, Seagen, and Janssen outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
A, Time points for blood sample collection and CT imaging. B, CONSORT diagram and analysis populations.
Figure 2.
Figure 2.
A, RFS by postoperative ctDNA status (n = 143). B, Longitudinal ctDNA results for patients with ctDNA not detected postoperatively who experienced recurrence or died due to CRC in the primary analysis population (n = 15).
Figure 3.
Figure 3.
A, RFS by landmark ctDNA status (n = 116). B, Longitudinal ctDNA results for patients with ctDNA detected at landmark time point, plus patients who experienced recurrence or died due to CRC regardless of landmark ctDNA status (n = 46). C, Longitudinal ctDNA results for patients with ctDNA detected in longitudinal time points who did not experience recurrence or die from CRC and remained in follow-up in the longitudinal analysis population (n = 18). D, Relapse sites and ctDNA status in patients with recurrence in the longitudinal analysis population (n = 29).
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