Advertisement

The CIRCULATE Trial: Circulating Tumor DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation (AIO-KRK-0217)

Published:September 14, 2021DOI:https://doi.org/10.1016/j.clcc.2021.09.005

      Abstract

      Background

      Guidance regarding adjuvant treatment decisions in stage II colorectal cancer (CRC) remains uncertain due to lack of predictive clinical or molecular markers. Recently, postoperative circulating tumour (ct)DNA has been demonstrated to be a strong prognostic marker in early colon cancer.

      Patients and Methods

      CIRCULATE enrols patients with stage II microsatellite stable CRC in Germany (AIO) and Austria (ABCSG). Within the AIO, screening is supported by ColoPredict Plus 2.0, a molecular registry, and screening platform for interventional trials.
      Patient-specific mutations are centrally analysed by next generation sequencing in the resected primary tumour. A postoperative plasma sample is subsequently screened for the specific mutation(s).
      ctDNA positive (ctDNApos) patients are randomised (2:1) chemotherapy (capecitabine, oxaliplatin added an investigator's choice) or to follow-up (control group).
      ctDNA negative (ctDNAneg) patients are randomised (1:4) to be followed-up within CIRCULATE (control group) or outside the trial. Patients in the control group remain blinded to the ctDNA results.
      The primary objective is to compare disease free survival (DFS) of ctDNApos patients with chemotherapy or control. To demonstrate a treatment effect with a hazard ratio of 0.617 (3-year DFS rates 42.5% vs. 25%), 231 ctDNApos and estimated 2079 ctDNAneg patients are randomised.
      Secondary aims include to compare overall survival and DFS in the ctDNApos and ctDNAneg patient cohorts and ctDNA kinetics.

      Conclusion

      The CIRCULATE trial may establish ctDNA for adjuvant treatment decision in stage II colon cancer – and with the secondary objectives – support a ctDNA guided follow up in colon cancer stage II and beyond.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Colorectal Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ferlay J
        • Steliarova-Foucher E
        • Lortet-Tieulent J
        • et al.
        Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.
        Eur J Cancer. 2013; 49: 1374-1403https://doi.org/10.1016/j.ejca.2012.12.027
        • O'Connell JB
        • Maggard M a
        • Ko CY.
        Colon cancer survival rates with the new American joint committee on cancer sixth edition staging.
        J Natl Cancer Inst. 2004; 96: 1420-1425https://doi.org/10.1093/jnci/djh275
        • Figueredo A
        • Charette ML
        • Maroun J
        • Brouwers MC
        • Zuraw L
        Adjuvant therapy for stage II colon cancer: a systematic review from the cancer care Ontario program in evidence-based care's gastrointestinal cancer disease site group.
        J Clin Oncol. 2004; 22: 3395-3407https://doi.org/10.1200/JCO.2004.03.087
        • Gray R
        • McConkey CC
        • et al.
        • Quasar-Collaborative-Group
        • Quasar-Collaborative-Group
        Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study.
        Lancet. 2007; 370: 2020-2029https://doi.org/10.1016/S0140-6736(07)61866-2
        • Argilés G
        • Tabernero J
        • Labianca R
        • et al.
        Localised colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up†.
        Ann Oncol. 2020; 31: 1291-1305https://doi.org/10.1016/j.annonc.2020.06.022
        • O'Connor ES
        • Greenblatt DY
        • LoConte NK
        • et al.
        Adjuvant chemotherapy for stage II colon cancer with poor prognostic features.
        J Clin Oncol. 2011; 29: 3381-3388https://doi.org/10.1200/JCO.2010.34.3426
        • Saglio G
        • Kim D-W
        • Issaragrisil S
        • et al.
        Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia.
        N Engl J Med. 2010; 362: 2251-2259https://doi.org/10.1056/NEJMoa0912614
        • Tie J
        • Wang Y
        • Tomasetti C
        • et al.
        Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer.
        Sci Transl Med. 2016; 8 (346ra92–346ra92)https://doi.org/10.1126/scitranslmed.aaf6219
        • Tie J
        • Cohen JD
        • Wang Y
        • et al.
        Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study.
        Gut. 2018; https://doi.org/10.1136/gutjnl-2017-315852
        • Reinert T
        • Henriksen T V
        • Rasmussen MH
        • et al.
        Abstract 1590: Personalized circulating tumor DNA analysis to monitor colorectal cancer.
        Cancer Res. 2018; 78: 1590https://doi.org/10.1158/1538-7445.AM2018-1590
        • Garcia-Murillas I
        • Schiavon G
        • Weigelt B
        • et al.
        Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer.
        Sci Transl Med. 2015; 7: 302ra133https://doi.org/10.1126/scitranslmed.aab0021
        • Stasik S
        • Schuster C
        • Ortlepp C
        • et al.
        An optimized targeted Next-Generation Sequencing approach for sensitive detection of single nucleotide variants.
        Biomol Detect Quantif. 2018; 15: 6-12https://doi.org/10.1016/j.bdq.2017.12.001
        • Wörmann B
        • Bokemeyer C
        • Burmeister T
        • et al.
        Dihydropyrimidine dehydrogenase testing prior to treatment with 5-fluorouracil, capecitabine, and tegafur: a consensus paper.
        Oncol Res Treat. 2020; 43: 628-636https://doi.org/10.1159/000510258
        • IMPACT-investigators
        Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International multicentre pooled analysis of colon cancer trials (IMPACT) investigators.
        Lancet. 1995; 345: 939-944https://doi.org/10.1016/S0140-6736(95)90696-7
        • Andre T
        • de Gramont A
        • Vernerey D
        • et al.
        Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study.
        J Clin Oncol. 2015; 33: 4176-4187https://doi.org/10.1200/JCO.2015.63.4238
        • Grothey A
        • Sobrero A
        • Shields A
        • et al.
        Duration of adjuvant chemotherapy for stage III colon cancer.
        N Engl J Med. 2018; 378: 1177-1188https://doi.org/10.1056/NEJMoa1713709
        • Sargent DJ
        • Marsoni S
        • Monges G
        • et al.
        Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.
        J Clin Oncol. 2010; 28: 3219-3226https://doi.org/10.1200/JCO.2009.27.1825
        • André T
        • Shiu K-K
        • Kim TW
        • et al.
        Pembrolizumab in microsatellite-instability–high advanced colorectal cancer.
        N Engl J Med. 2020; 383: 2207-2218https://doi.org/10.1056/nejmoa2017699