Liquid Biopsy has Prognostic Role in Colorectal Cancer and Potential for Guiding Therapy

BARCELONA, Spain – Liquid biopsy is likely to play an increasing role in identifying patients with colorectal cancer (CRC) who are likely to relapse after surgery, and has potential for optimising treatment for individual patients, according to new research presented at the ESMO Congress 2019. (1,2).

Of 805 patients in the phase III IDEA-FRANCE trial who had liquid biopsy prior to adjuvant chemotherapy for stage III CRC, 109 (13.5%) had circulating tumour DNA (ctDNA) in their blood. (1) In this group, two-year disease-free survival (DFS) was 64%, compared to 82% in those who were ctDNA negative.

“In this large prospective trial, we confirmed that ctDNA is an independent prognostic factor in colorectal cancer and that approximately six out of 10 patients who are ctDNA positive will remain disease-free two years after standard adjuvant chemotherapy, compared to eight out of 10 of those who are ctDNA negative,” said study author Prof Julien Taieb, Hôpital European Georges Pompidou, Paris, France.

IDEA-FRANCE also showed that six months of adjuvant treatment was superior to three months in both ctDNA positive and negative patients, and that ctDNA positive patients treated for six months had a similar prognosis to ctDNA negative patients treated for three months (Figure 1). Adjuvant therapy was FOLFOX (folinic acid, fluorouracil and oxaliplatin) in 90% of cases.

“ctDNA testing did not predict which patients should have three or six months of adjuvant chemotherapy and there is continuing debate over the optimal type and duration of treatment for patients who are ctDNA positive, but we do now know that ctDNA is a major prognostic factor which will be very useful in stratifying patients and driving future trials of colorectal cancer,” said Taieb. “In all subgroups, ctDNA positive patients who only had three months of adjuvant therapy had the worst prognosis,” he added.

Thirty to 50% of patients with localised CRC relapse despite primary optimal therapy, and a second study reported at the ESMO Congress 2019 investigated whether ctDNA can be used to detect minimal residual disease and identify those at risk of recurrence. (2) The results showed that post-surgical plasma ctDNA predicted metastatic relapse a median of 10 months before recurrence was visible on radiological scans (hazard ratio 11.33; p=0.0001). The researchers concluded that plasma ctDNA testing opens up an opportunity for precision treatment of patients with localised CRC.

Commenting on the results of the CRC presentations, Prof Alberto Bardelli, University of Turin, Italy, said: “When patients have surgery for early stage colorectal cancer, doubts remain as to whether the disease has been completely eradicated and, as a result, patients often receive adjuvant chemotherapy. However, the IDEA-FRANCE results have shown we can now use a blood test to say whether the patient is clear or not.”

“The study is also one of the first to show that, in the future, it may be possible to use liquid biopsy to direct therapy and identify which patients can avoid chemotherapy after their surgery and which should have it. If further studies confirm the results of IDEA-FRANCE, I think they will change clinical practice, so the new data are very exciting,” added Bardelli.

Figure 1. Disease-free survival according to the ctDNA status

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References

1. LBA30_PR ‘Analysis of Circulating tumour DNA (ctDNA) from patients enrolled in the IDEA-FRANCE Phase III trial: prognostic and predictive value for adjuvant treatment duration’ will be presented by Julien Taieb during the Proffered paper session on Saturday, 28 September 2019, 14:45-16:15 CEST in Barcelona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019
2. Abstract 522O ‘Mutation tracking in circulating tumor DNA (ctDNA) detects minimal residual disease (MRD) in patients with localized colorectal cancer (CRC) and identifies those at high risk of recurrence regardless of stage, lack of CDX2 expression and CMS subtype’ will be presented by Noelia Tarazona Llavero during the Proffered paper session on Saturday, 28 September 2019, 14:45-16:15 CEST in Barcelona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019 

LBA30_PR - Analysis of circulating tumor DNA (ctDNA) from patients enrolled in the IDEA-FRANCE phase III trial: prognostic and predictive value for adjuvant treatment duration

J. Taieb¹, V. Taly², D. Vernerey³, C. bourreau², J. Bennouna⁴, R. Faroux⁵, J. Desrame⁶, O. Bouche⁷, C. Borg⁸, J. Egreteau⁹, L. Mineur¹⁰, C. Lepere¹¹, G. Deplanque¹², C. mulot², C. Louvet¹³, M. Mabro¹⁴, M. Ychou¹⁵, A. de Gramont¹⁶, T. Andre¹⁷, P. Laurent-Puig^2
1Department Of Gastroenterology And Digestive Oncology, Hopital European George Pompidou, Paris, France, ²Sorbonne Université, Uspc, Université Paris Descartes, Université Paris Diderot, Centre de Recherche des Cordeliers, INSERM, CNRS, Paris, France, ³Methodological And Quality Of Life In Oncology Unit, CHRU Besancon - Hopital Jean Minjoz, BESANCON, France, ⁴Digestive And Lung Oncology Department, Nantes University Hospital, Nantes, France, ⁵Gastroenterology And Hepatology, CHD Vendee - Hopital Les Oudairies, La Roche sur Yon, France, ⁶Medical Oncology, Hôpital privé Jean Mermoz, Lyon, France, ⁷Gastroenterology, CHU de Reims - Hôpital Robert Debré, Reims, France, ⁸Department Of Medical Oncology, CHU Besançon, Hôpital Jean Minjoz, Besançon, France, ⁹Oncology, CH Sud Bretagne, Lorient, France, ¹⁰Radiotherapy And Oncology Gi And Liver, Institut Sainte Catherine, Avignon, France, ¹¹Gi Oncology, European George Pompidou Hospital, Paris, France, ¹²Oncologie Médicale, Hôpital Riviera-Chablais, Vevey, Switzerland, ¹³Oncologie Médicale, Institut Mutualiste Montsouris, Paris, France, ¹⁴Oncology, Hopital Foch, Suresnes, France, ¹⁵Ircm (institute Of Cancer Research Of Montpellier), ICM Regional Cancer Institute of Montpellier, Montpellier, France, ¹⁶Oncology, Institut hospitalier Franco-Britannique, Levallois-Perret, France, ¹⁷Medical Oncology, Hopital Saint-Antoine, Paris, France

Background: ctDNA has been recently suggested as a major prognostic factor in resected stage II and III colon cancer patients (pts)^1,2. Its predictive value for adjuvant treatment intensity or duration is currently unknown. We have analyzed here ctDNA from pts enrolled in the IDEA-FRANCE trial³, its prognostic value and its predictive value for treatment duration (3 or 6 months).
Methods: ctDNA was tested by using the detection of 2 methylated markers (WIF1 and NPY) by digital droplet PCR accordingly to a method developed and validated for colorectal cancer ^4-6. Comparisons for pts and tumor characteristics and DFS will be done between the ctDNA tested pts and the full study population and between ctDNA positive and negative pts. DFS has been analyzed in the 6 and 3M treatment arms according to ctDNA results. Subgroup analyses for high- and low-risk pts were pre-planned.
Results: Of the 1345/2010 pts that consented to the IDEA translational research program, with available blood sample for ctDNA testing, 805 have been sampled before chemotherapy start and fully analyzed. More PS 0 (77% vs 71%) and more T4 and/or N2 (28% vs 23%) were observed in the 805 pts studied here than in the 1205 pts left. 696 pts were found ctDNA- and 109 ctDNA+ (13.5%). ctDNA+ pts were more often T4, poorly differentiated and with tumor perforation. 2-year DFS was 64% vs 82% in ctDNA+ and – pts, respectively (HR :1.75 (95%CI 1.25-2.45) p=0.001). In multivariate analysis including Age, Gender, MSI, perforation, T stage, N stage and treatment arm, ctDNA was confirmed as an independent prognostic marker (adj.HR: 1.85 (95%CI 1.31 to 2.61) p<0.001). Adjuvant treatment for 6 months was superior to 3 months in both ctDNA– (HR :0.69 (95%CI 0.52 to 0.93) p=0.015) and ctDNA+ pts (HR: 0.50 (95%CI 0.27 to 0.95) p=0.033). Interestingly ctDNA+ pts treated 6 months had a similar prognosis to ctDNA- pts treated 3 months.
Conclusions: In this first ctDNA assessment on a large series coming from a phase III clinical trial we found 13.5% of pts with ctDNA post-surgery. ctDNA was confirmed as an independent prognostic marker. In this series, 6 months of treatment seems better in both ctDNA+ and- pts.

Clinical trial identification: NCT00958737
Editorial acknowledgement: [1]Tie J, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer.Sci Transl Med. 2016 Jul 6;8(346):346ra92. [2]Schøler LV, et al. Clinical Implications of Monitoring Circulating Tumor DNA in Patients with Colorectal Cancer. Clin Cancer Res. 2017 Sep 15;23(18):5437-5445. [3] André T, 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 May 20;36(15):1469-1477. [4] Garrigou S, et al. A Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer Biomarker. Clin Chem. 2016;62:1129-1139. [5] Garlan F, 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. [6] Bachet JB, et al. RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study. Ann Oncol. 2018May 1;29(5):1211-1219.
Legal entity responsible for the study: GERCOR-PRODIGE
Funding: INCa funded the clinical trial with GERCOR and ARC (association de recherche contre le cancer) Paris, France funded the translational project
Disclosure: J. Taieb: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: servier; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: pierre fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi.
D. Vernerey: Honoraria (self), Advisory / Consultancy: HalioDX; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Janssen.
J. Bennouna: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy: Astra-Zeneca; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim.