Abstract 420P
Background
At diagnosis, ∼25% of colorectal cancer (CRC) patients have synchronous metastases and ∼30% develop metachronous metastases. Little is known about the heterogeneity of these tumours, which warrants better identification tools to detect recurrence. In this study, we sought to evaluate the clinical utility of circulating tumour DNA (ctDNA) in identifying minimal residual disease (MRD) and monitoring of recurrence.
Methods
The prospective, multicenter cohort study recruited patients (n=196) diagnosed with stage I-III CRC. Median follow-up time was 21.9 (1.4-41.9) months. For each patient, a personalized and tumour-informed multiplex PCR (mPCR) NGS assay was used to track ctDNA in plasma samples. The relationship between ctDNA status and clinical outcomes was evaluated. The analysis of spatial heterogeneity was performed between primary and metastatic tumours, as well as between synchronous primary tumours to track clonal and subclonal mutations.
Results
Phylogenetic comparison of paired primary and metastatic mutation profiles revealed 50% overlap in mPCR targeted variants, suggesting success in targeting clonal mutations. The mutational profiles of synchronous primary tumours were non-overlapping. This led to design of unique assays for each synchronous primary tumour to reliably detect recurrence. Postoperatively and prior to ACT, 9% (14/155) of patients showed MRD-positivity, and 78.5% (11/14) relapsed (HR: 14; 95% CI: 6.1-30; P<0.001). A shift to ctDNA-positivity during longitudinal monitoring (n=120) was associated with poor clinical outcome (HR: 58, 95% CI: 17-196; P<0.001). Multivariate analysis showed longitudinal ctDNA status to be the only significant prognostic factor associated with inferior RFS (HR: 57.7, 95% CI: 16.8-196; P<0.001). Serial ctDNA analysis detected MRD up to a median of 8.08 months (0.6 - 16.6 months) ahead of radiologic relapse (sensitivity: 87.5%, specificity: 99.1%).
Conclusions
Synchronous CRC tumours are genetically unrelated and require individual assays for ctDNA detection. Post-operative MRD status and longitudinal monitoring using ctDNA can detect patients with a high risk of recurrence and guide treatment decisions.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Dr. Andrés Cervantes and Prof. Claus L. Andersen.
Funding
Danish Council for Independent Research; Danish Council for Strategic Research; Novo Nordisk Foundation; Danish Cancer Society; Instituto de Salud Carlos III.
Disclosure
S. Sharma, H-T. Wu, S. Shchegrova, A. Tin, H. Sethi: Shareholder/Stockholder/Stock options, Full/Part-time employment: Natera Inc. B. Zimmermann: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Natera Inc. A. Aleshin: Advisory/Consultancy, Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Natera Inc. A. Cervantes: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Merck Serono; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche; Advisory/Consultancy, Research grant/Funding (self): Beigene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Servier; Advisory/Consultancy, Research grant/Funding (self): Lilly; Advisory/Consultancy, Research grant/Funding (self): Novartis; Advisory/Consultancy, Research grant/Funding (self): Takeda; Advisory/Consultancy, Research grant/Funding (self): Astelas; Research grant/Funding (self): Genentech; Research grant/Funding (self): Pierre Fabre; Research grant/Funding (self): Fibrogen; Research grant/Funding (self): Amcure; Research grant/Funding (self): Sierra Oncology; Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Medimmune; Research grant/Funding (self): BMS; Research grant/Funding (self): MSD; Speaker Bureau/Expert testimony: Angem; Speaker Bureau/Expert testimony: Foundation Medicine; Research grant/Funding (self): Serono; Officer/Board of Directors: ESMO; Leadership role, Officer/Board of Directors: INCLIVA. All other authors have declared no conflicts of interest.