circulating DNA bases treatment in colon cancer

CT dna based ca colon treatment

1. ctDNA Guided Rx

2. High-Risk Feature 5-Year OS (%) Reference No high-risk features (standard stage II) 75–87% NCCN Guidelines; O’Connor et al., JCO 2011​ Poorly differentiated histology 50–70% Quah et al., Dis Colon Rectum, 2008​ Positive surgical margins (R1 resection) 30–60% Compton et al., Arch Pathol Lab Med, 2000; NCCN Guidelines​ Localized tumor perforation 40–60% McArdle et al., Br J Surg, 2004​ High tumor budding 45-65% Lugli et al., Mod Pathol , 2012; Zlobec et al., J Clin Oncol , 2011 Elevated preoperative CEA (>5 ng/mL) 55–70% Lin et al., Ann Surg Oncol, 2014; NCCN Guidelines​ Combination of ≥3 high-risk features <50% Zhang et al., Medicine, 2016 (Prognostic Model Study)​ LN 1-7 8-12 >13 5 year OS 49.8% 56.2% 63.4% NEED FOR ADJUVANT CHEMOTHERAPY LN dissection Swanson et al Stage 5 year OS INFERENCE IIb and IIc (T4) 72.2% Deeper penetration into the bowel can be a poor prognostic factor than limited node involvement 1,2 IIIA(T3) 83.4% T3/T4 Connel et al (1) Amin et al (2) In a prospective analysis conducted on 448 patients with stage II CC, lymphatic, vascular and perineural invasion demonstrated high risk of recurrence (HR 2.1; 95% CI 1-4.4; P=0.04) LVI/PNI Gonen et al

3. Nancy et al,JCO 40:890-910,2021

4. BENEFIT OF ADJUVANT CHEMOTHERAPY STAGE II : 1 IN 25 Benefit from adjuvant 5-FU based chemotherapy STAGE III : 1 (20%) IN 5 Benefit from adjuvant Oxaliplatin based chemotherapy

5. STAGE II : OUT OF 100 PATIENTS 4% CURED BY CHEMO (4 PATIENTS) 80% CURED BY SURGERY ALONE (80 PATIENTS) 16% RECUR IRRESPECTIVE OF TREATMENT (16 PATIENTS) Moertel et al.,NEJM 1990,Gray et al.,Lancet 2007

6. Pachman et al,JCO 33:3416-3422,2015

7. ADJUVANT THERAPY IN COLORECTAL CANCER Current estimates of benefit based on historical data. Better pre-op staging / Surgery Lower recurrence risk Lower gain from adjuvant treatment Bertelsen et al , JCO 2019 : 20 : 1556-65

8. The present guidelines for adjuvant chemotherapy in stage II colon cancer with and without risk factors and in stage III disease are based on recurrence risks from the past. They are much lower today, although we do not know precisely how much lower.

9. Even if the relative gains from administering adjuvant chemotherapy with or without oxaliplatin are the same as those shown in the trials (with the higher absolute risk figures), the absolute gains are less than they were, and they may be too low to recommend therapy. It is not realistic to conduct a new surgery-alone trial in the groups of greatest interest ( ie , those with anticipated recurrence risks of 10% to 20%, or most patients with stage II and many with stage III disease). Conclusion : The number needed to treat is high, and thus, many patients will unnecessarily be harmed. Today, we must re-evaluate the need for administering routine adjuvant chemotherapy to many patients with colon cancer when they are receiving high-quality multidisciplinary care.

10. ROLE OF ctDNA

11. ctDNA predicts recurrence: Sp >95%,PPV>95% PEGASUS TRIAL Stage II HR-III GALAXY TRIAL Stage II-IV UKTRACC TRIAL NO147 Stage III

12. Higher ctDNA – Worse RFS and OS DYNAMIC II (POST - OP) DYNAMIC III(POST - OP)

13. GALAXY - NAKAMURA et al.,Nature 2025

14. DYNAMIC II – Tie et al,.Nature 2025

15. Better outcomes with sustained clearance GALAXY DYNAMIC III

16. SUMMARY OF CTDNA TRIALS IN COLON CANCER Trial Stage Strategy Key Point DYNAMIC II De-escalation Less chemo, non-inferior RFS DYNAMIC-III III De - escalation / Escalation Extending DYNAMIC to Stage III GALAXY Registry Surveillance Tracks ctDNA dynamics VEGA III De-escalation Surgery alone in ctDNA-negative ALTAIR III Escalation TAS-102 in ctDNA-positive IMPROVE-IT III De-escalation ctDNA-guided vs SOC PEGASUS Obs Surveillance Early detection vs imaging BESPOKE Obs Real-world impact Treatment decision aid NCT05174169 III De-escalation Validate observation in ctDNA-neg

17. CTDNA TESTING FAVORABLE IMPROVEMENTS OVER PAST DECADE Feature Improvement Reference Sensitivity From ~1% (TAM-Seq, 2012) to ~0.004% ( iDES -CAPP-Seq, 2023) Newman AM et al. Nat Biotechnol . 2023;41:534–544 Specificity >99% with tumor-informed assays and CHIP filtering Abbosh C et al. Nature . 2024;605(7909):489–495 Cost ~$3000 to ~$1000–1500 per test Chen LM et al. JAMA Health Forum . 2024;5(3):e240290. Turnaround Time 2–4 weeks to ~1 week; real-time trial integration Tie J et al. Clin Cancer Res . 2023;29(9):1650–1659 Assay Standardization FDA/IVD-cleared (Guardant360, FoundationOne) Nature Rev Clin Oncol. 2024;21(2):85–97. Clinical Utility Non-inferior in DYNAMIC trial; safe de-escalation Tie J et al. NEJM . 2022;386:2261–2272. False Positives Mitigated CHIP filtering using leukocyte sequencing Razavi P et al. Science Adv . 2022;8(20):eabo7546. False Negatives Mitigated Serial testing of ctDNA Reinert T et al. Clin Cancer Res .2022;28(7):1361–70.

18. TAKE HOME POINTS Paradigm shift in colorectal cancer management—from empirical treatment to precision-guided therapy. ctDNA is the game-changer : Personalizes care without compromising response. Spares unnecessary chemotherapy. Routine adjuvant chemo based on outdated recurrence risks must be re-evaluated—ctDNA leads the way.

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