ctDNA From Patients with Colon Cancer Is Indicative of Outcome Following 3 Versus 6 Months of Oxaliplatin-Based Adjuvant Treatment

Patients with advanced colon cancer and plasma samples containing circulating tumour DNA (ctDNA) were less likely to achieve 2-year disease-free survival (DFS) with oxaliplatin-based adjuvant treatment than patients with ctDNA-negative samples, according to findings presented at the ESMO Congress 2019 in Barcelona, Spain. Both patient cohorts responded more favourably to six months of adjuvant treatment.

Julien Taieb, Hopital European George Pompidou in Paris, France remarked that the predictive value of ctDNA was unknown for adjuvant treatment, which prompted this analysis of ctDNA from patients participating in the IDEA-FRANCE trial (NCT00958737).¹ The IDEA-FRANCE study investigated 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for patients with stage III colon cancer. The aim of this analysis was to determine the prognostic and predictive value of ctDNA for adjuvant treatment duration lasting 3 versus 6 months.

The investigators tested ctDNA using 2 methylated markers, WIF1 and NPY, by digital droplet PCR accordingly to a method developed and validated for colorectal cancer.^2-4

Comparisons regarding tumour characteristics and disease-free survival (DFS) were done between patients with ctDNA positive and negative samples in the 6- and 3-month treatment arms and reported at ESMO 2019 Congress. Comparison between the ctDNA tested patients and the full study population and DFS are ongoing, as are preplanned subgroup analyses for high- and low-risk patients.

A total of1345 out of 2010 patients consenting to the IDEA translational research programme had available blood sample for ctDNA testing. Of these, 805 patients were sampled prior to initiation of chemotherapy and fully analysed. This patient population had more performance status 0 (77% versus 71%) and more stage T4 tumours and/or N2 status (28% versus 23%) than the remaining 1205 consenting patients.

The samples from these 805 patients were ctDNA-negative in 696 patients and 109 patients (13.5%) had ctDNA-positive samples. Analysis of these samples and a comparison of patients with ctDNA-positive and ctDNA-negative samples indicated that patients with ctDNA-positive samples had more advanced tumours that included characteristics such as stage T4, poor differentiation, and tumour perforation.

The 2-year DFS rates in these patients was significantly less at 64% compared to 82% in patients with ctDNA-negative samples, respectively (hazard ratio [HR] 1.75; (95% confidence interval [CI], 1.25-2.45; p = 0.001).

Multivariate analysis including variables of age, gender, microsatellite instability (MSI), tumour perforation, T stage, N stage, and treatment arm confirmed the presence of ctDNA as an independent prognostic marker (adj.HR 1.85; 95% CI, 1.31-2.61; p < 0.001).

In both cohorts of patients, adjuvant treatment carried out for 6 months was superior to 3 months; in patients having ctDNA-negative samples (HR 0.69; 95%CI, 0.52-0.93; p = 0.015) and patients with ctDNA-positive samples (HR, 0.50; 95%CI, 0.27-0.95; p = 0.033).

Discussant points

Clara Montagut of the University Hospital del Mar, Barcelona, Spain discussed the study findings around next questions: Is ctDNA analysis after surgery (1) prognostic marker and (2) predictive marker for treatment duration? She concluded that clinical practice changing requires prospective interventional large clinical trials that show benefit from ctDNA-guided adjuvant therapy.

Conclusions

Professor Taieb commented that this is first ctDNA assessment done on a large series of patients in a phase III clinical trial of adjuvant therapy to find 13.5% of patients with ctDNA post-surgery.

The ensuing analysis confirmed ctDNA as an independent prognostic marker. In this series, 6 months of treatment was better in patients with ctDNA-positive and ctDNA-negative samples.

Interestingly ctDNA-positive patients treated for 6 months had a similar prognosis to ctDNA-negative patients treated for just 3 months.

Citations

1. André T, Vernerey D, Mineur L, et al. Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial. J Clin Oncol 2018; 36(15):1469-1477.
2. Garrigou S, Perkins G, Garlan F, et al. A Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer Biomarker. Clin Chem 2016; 62:1129-1139.
3. Garlan F, Laurent-Puig P, Sefrioui D, et al. Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study). Clin Cancer Res 2017; 23:5416-5425.
4. Bachet JB, Bouché O, Taieb J, et al. RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study. Ann Oncol 2018; 29(5):1211-1219.                                         

Disclosure

INCa funded the clinical trial with GERCOR and ARC (Association de Recherche Contre le Cancer), Paris, France funded the translational project.

Reference

LBA30_PR – Taieb J, Taly V, Vernerey D, et al. Analysis of circulating tumor DNA (ctDNA) from patients enrolled in the IDEA-FRANCE phase III trial: prognostic and predictive value for adjuvant treatment duration.