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 tumour 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 tumour 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. [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.

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

Clinical trial: INCa, GERCOR; Translational project: ARC (Association de Recherche contre le Cancer, Paris, France).

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: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background

Although staging provides prognostic information and guides therapeutic decisions, 30-50% of patients with localized CRC will relapse despite optimal primary treatment. CEA and imaging studies are insufficient to detect micrometastases at an early stage. The identification of prognostic markers beyond TNM is crucial to define high risk of relapse and to establish potential therapeutic strategies to optimize adjuvant treatment.

Methods

150 patients diagnosed with localized CRC were prospectively recruited from October 2015 to October 2017 at our institution. Clinicopathological features (stage, grade, vascular/perineural invasion, sidedness, MMR status and CDX2 expression) were collected. DNA and RNA extracted from FFPE samples were assessed with a custom 29-gene panel recurrently mutated in CRC (NGS) and a validated NanoCRCA assay (NanoString). ctDNA from plasma was tracked in serial samples to detect MRD (ddPCR). Plasma Interleukin-6 levels were measured (ELISA). Log-rank test, univariate and multivariate Cox regression analysis and ROC curves were used for statistics.

Results

Known somatic mutations in tumour were found in 120 (80%) patients for mutation tracking ctDNA analysis. After a median follow-up of 24.7 months, 18 patients recurred. Postoperative CEA was not predictive of disease-free survival (P = 0.229). ctDNA in serial plasma after surgery predicted metastatic relapse with a median lead time of 10 months over radiologic recurrences [HR 11.33; P = 0.0001]. CMS subtypes were significantly associated with CDX2 expression (loss in CMS1, P = 0.03), IL-6 levels (high in CMS1 and CMS4, P = 0.002) and perineural invasion (present in CMS1 and CMS4, P = 0.001). CMS1 and CMS4 subtypes were significantly associated with relapse (P = 0.016). A multivariable analysis confirmed T stage, loss of CDX2 expression and mutation tracking ctDNA were significantly associated with recurrence (P = 0.041, P = 0.004, P < 0.001, respectively).

Conclusions

In localized CRC, plasma ctDNA detects MRD in relapsing patients earlier than clinical methods and opens an opportunity for precision treatment.

Legal entity responsible for the study

The authors.

Funding

Instituto de Salud Carlos III (PI15/02180 and PI18/01909 to AC; PI18/01508 to TF). NT was supported by Rio Hortega contract CM15/00246 from the Instituto de Salud Carlos III. DR was supported by Joan Rotes contract 16/00040 from the Instituto de Salud Carlos III. TF was supported by Joan Rodes contract 17/00026 from the Instituto de Salud Carlos III. VG was supported by ESMO 2014 fellowship programme, and by Rio Hortega contract CM18/00241 from the Instituto de salud Carlos III.

Disclosure

A. Cervantes: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Servier; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy: Pierre Fabre; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Foundation Medicine; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Sierra Oncology. All other authors have declared no conflicts of interest.

Background

NAC has an established role in many solid tumours but its utility has not previously been formally evaluated in colon cancer.

Methods

Pts with CT-staged T3-4 N0-2 M0 colon cancer were randomised in a 2:1 ratio to pre-and-postoperative (NAC/AC) or postoperative (control) FOLFOX chemotherapy. Total planned chemotherapy was the same in both arms, but NAC/AC pts received the first 6 weeks before surgery. Pts with RAS-wt tumours could be subrandomised 1:1 to receive 6 wks panitumumab or not with NAC; if not randomised, CapOx was permitted. The primary endpoint was freedom from recurrent/residual disease at 2 years. Secondary outcomes included histological response/downstaging, safety and mortality. Analyses were by intent-to-treat.

Results

1053 pts entered at 98 hospitals in the UK, Denmark and Sweden. Of 699 allocated NAC/AC, 674 (97%) started and 612 (88%) completed 6 wks NAC. 684/699 (97.8%) NAC/AC and 349/354 (98.6%) control pts had tumour surgery. Signs of obstruction developed before surgery in 20 (3%) NAC/AC and 3 (1%) control pts. 3/699 NAC/AC and 1/354 control pt died before surgery. Serious perioperative morbidity was lower after NAC: anastomotic leaks [3.6% (26/684) vs 8.0% (28/349)]; complications prolonging hospital stay and re-operations [4.3% (29/684) vs 6.7% (23/349)]. 30-day postop mortality was 0.4% (3/677) vs 0.6% (2/343). Stoma rate was 12% vs 9%, (p = 0.18). There was marked histological downstaging after NAC, with lower pT and pN-stage (both p < 0.0001). 25/699 (3.8%) NAC/AC pts had pCR and 32 (4.6%) had near-complete tumour regression (Dworak TRG2/ Modified RyanTRS1). Incomplete (R1/R2) resections were reduced: 4.8% (33/684) vs 9.1% (32/348), p = 0.01. Dukes’ stage C2/D was seen in 4% (29/677) vs 9% (32/348), p = 0.002. There was also a trend towards less recurrent/residual disease within 2 years: 98/699 vs 62/354, HR = 0.77 (95%CI 0.56-1.06), P = 0.11.

Conclusions

Six weeks NAC for operable primary colon cancer can be delivered safely, with improved perioperative morbidity and marked pathological downstaging including some pCRs. There is a trend toward better disease control at 2 years. Subgroup analyses including impact by MMR status and effect of panitumumab will be presented at the meeting.

Clinical trial identification

ISRCTN 87163246.

Legal entity responsible for the study

University of Birmingham.

Funding

Primary funder Cancer Research UK; Additional support: Amgen Pharma.

Disclosure

The author has declared no conflicts of interest.

Background

To assess the effects of bevacizumab plus chemotherapy as first-line treatment for RAS mutant unresectable colorectal liver metastases (CLMs).

Methods

From June 2013 to December 2017, patients with RAS mutant unresectable liver-limited metastases from colorectal cancer were randomly assigned to receive chemotherapy (mFOLFOX6 [modified fluorouracil, leucovorin,and oxaliplatin]) plus bevacizumab (arm A) or chemotherapy alone (arm B). The resectability of liver metastases was determined by a local multidisciplinary team. The primary end point was the rate of patients converted to resection for liver metastases. Secondary end points included tumor response, survival and toxicity. Block randomization method was used.

Results

The intent-to-treat population comprised 241 patients. 121 patients were randomly assigned to arm A and 120 to arm B. For all patients, 35.7% (86/241) had right-sided colon cancer; 47.3% (114/241) had primary tumour resection before randomization; 86.3% (208/241) had liver metastases more than three; 33.2 (80/241) with the diameter of liver metastases more than 5 cm; 78.4% (189/241) were bilobar metastases. The median follow-up time was 37.0 months for all patients. The R0 resection rates for liver metastases were 22.3% (27 of 121 patients) in arm A and 5.8% (7 of 120 patients) in arm B, with significant difference (P < 0.01). Patients in arm A had significantly better objective response rates (54.5% v 36.7%; P < 0.01), median PFS (9.5 v 5.6 months; P < 0.01) and median OS (25.7 v 20.5 months; P = 0.03) compared with those in arm B. Addition of bevacizumab was associated with more frequent proteinuria(9.9% v 3.3%; P = 0.04) and hypertension ( 8.3% v 2.5%; P < 0.05).

Conclusions

For patients with initially unresectable RAS mutant CLMs, bevacizumab combined with chemotherapy improved the resectability of liver metastases and improved response rates and survival compared with chemotherapy alone.

Clinical trial identification

NCT01972490.

Legal entity responsible for the study

Zhongshan Hospital.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.