Ultra-sensitive detection of circulating tumor DNA by WGS of blood samples from locally advanced rectal cancer patients receiving neoadjuvant therapy and enrolled in watch-and-wait strategies for organ preservation

Introduction

Colorectal cancer is the third most common cancer in the United States and rectal cancer accounts for 1/3 of all new cases (>44,000 per year). Most rectal cancer patients are diagnosed with non-metastatic, locally advanced rectal cancer (LARC). Patients with a pathological complete response (pCR) – which can only be identified after radical resection – have significantly better outcomes. Accurate diagnosis of clinical complete response (cCR) is critical and may allow patients to avoid surgery and undergo non-operative management with frequent surveillance to ensure durability.

We analyzed data from 31 LARC patients treated with neoadjuvant therapy (NAT). Patients were randomized to receive either systemic chemotherapy (FOLFOX) followed by chemoradiation (INCT-CRT) or chemoradiation followed by systemic chemotherapy (CRT-CNCT). Patients with a cCR were enrolled in watch-and-wait, while the rest underwent surgical resection.

Study Aim

To investigate the clinical utility of circulating tumor DNA (ctDNA) for accurate assessment of complete response and as a prognostic biomarker using C2inform, a whole genome minimal residual disease (MRD) test.

Conclusion

• The C2inform platform exhibited very high sensitivity for detection at baseline.
• Tumor fraction across multiple time points separated responders from non-responders, suggesting potential value as a prognostic marker.
• Detection of ctDNA at follow-up for all patients who recurred is indicative of potential clinical utility for treatment de-escalation in the context of organ preservation strategies.
• WGS analysis also provides valuable insights about tumor etiology and tumor progression during and after treatment.