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. 2024 Jul 15;30(14):2964-2973.
doi: 10.1158/1078-0432.CCR-23-3660.

Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment

Aparna R Parikh  1 , Bryant H Chee  2 , Jill Tsai  3 , Thereasa A Rich  3 , Kristin S Price  3 , Sonia A Patel  3 , Li Zhang  2   4   5 , Faaiz Ibrahim  2 , Mikaela Esquivel  2 , Emily E Van Seventer  6 , Joy X Jarnagin  1 , Victoria M Raymond  1 , Carlos U Corvera  2   7 , Kenzo Hirose  2   7 , Eric K Nakakura  2   7 , Ryan B Corcoran  1 , Katherine Van Loon  2   6 , Chloe E Atreya  2   6
Affiliations

Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment

Aparna R Parikh et al. Clin Cancer Res. .

Abstract

Purpose: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell-free DNA detection status with radiographic disease recurrence.

Experimental design: Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS).

Results: From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31-12.0; P < 0.0001) and OS (HR, 12.83; 95% CI, 3.6-45.9; P < 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4-15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, >90% 3 years postprocedure.

Conclusions: In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes.

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Conflict of interest statement

A.R. Parikh reports grants from Guardant during the conduct of the study, as well as equity in C2i Genomics, XGenomes, Cadex, Vionix, and Parithera. A.R. Parikh also reports being an advisor/consultant for Eli Lilly, Mirati, Pfizer, Inivata, Biofidelity, Checkmate Pharmaceuticals, FMI, Guardant, AbbVie, Bayer, Delcath, Taiho, CVS, Value Analytics Lab, Seagen, Saga, AstraZeneca, Scare Inc., Illumina, Taiho, Hookipa, Kahar Medical, Xilio Therapeutics, Sirtex, Takeda, and Science For America; fees from UpToDate; travel fees from Karkinos Healthcare; being on the DSMC for a Roche study and on the Steering Committee for Exilixis; and research funding to institution from PureTech, PMV Pharmaceuticals, Plexxicon, Takeda, BMS, Mirati, Novartis, Erasca, Genentech, Daiichi Sankyo, Syndax, Revolution Medicine, and Parthenon. J. Tsai reports other support from Guardant Health outside the submitted work, and is a shareholder with Guardant Health. T.A. Rich reports employment and stock holdings of Guardant Health. K.S. Price reports other support from Guardant Health during the conduct of the study, as well as other support from Guardant Health outside the submitted work. L. Zhang reports personal fees from Samay Inc. and Smith-Kettlewell Eye Research Institute outside the submitted work. E.E. Van Seventer reports other support from Blueprint Medicines outside the submitted work. V.M. Raymond reports other support from Guardant Health during the conduct of the study, as well as other support from Guardant Health outside the submitted work. R.B. Corcoran reports personal fees from Guardant and Natera, as well as personal fees and other support from nRichDx, Alterome Therapeutics, and Sidewinder Therapeutics outside the submitted work. K. Van Loon reports other support from Natera outside the submitted work. C.E. Atreya reports other support from Guardant Health during the conduct of the study, as well as other support from Inivata, Roche/GNE, Pfizer, Novartis, Merck, Bristol-Myers Squibb, Erasca, and Gossamer Bio outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
CONSORT flow diagram. Diagram depicts patient enrollment, exclusions, the number of patients included in the primary and longitudinal analyses, and the number of ctDNA-positive vs. ctDNA-negative results. NPV, negative predictive value; PPV, positive predictive value.
Figure 2.
Figure 2.
Swimmer plot describing the treatment course and ctDNA results by patient ID (N = 52). Time at 0 year denotes the time of curative intent procedure. Neoadjuvant course only shown for patients with treatment within 3 months of curative intent procedure. Dotted lines around neoadjuvant data points represent −1.5 and −3 months before procedure. Record IDs with an asterisk (*) indicate patients who received radiation as their curative intent procure. All other patients received curative intent surgery.
Figure 3.
Figure 3.
Primary postprocedure ctDNA status predicts RFS and OS. A, Recurrence rate stratified by ctDNA status. Ninety-five percent CI as follows: sensitivity (40.8%–73.6%), specificity (62.3%–99.5%), PPV (75.4%–99.7%), and NPV (25.6%–63.2%). Kaplan–Meier curves at the primary time point stratified by ctDNA status (n = 42) for (B) RFS and (C) OS. CI, confidence interval.
Figure 4.
Figure 4.
Multivariable analysis of risk factors associated with RFS. ctDNA positivity is defined as ctDNA positive at the primary time point. In this study, “preoperative therapy” refers to chemotherapy within 3 months of procedure. Primary tumor types were binned into ascending (ascending or transverse tumor) or descending (descending, sigmoid, or rectal tumor).
Figure 5.
Figure 5.
Longitudinal ctDNA analysis improves sensitivity to detect relapse. A, Patient-level ctDNA status 95% CI as follows: sensitivity (64.2%–93.3%), specificity (57.8%–97.3%), PPV (72.2%–98.4%), and NPV (48.1%–89.1%). B, Lead time comparison of ctDNA vs. CEA as measured by disease recurrence measured by time to relapse (months; n = 20; P < 0.0001).
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