P-39 Utility of circulating tumor DNA (ctDNA) to assess tumor response in patients with locally advanced rectal cancer undergoing neoadjuvant therapy

Abstract

The current tools to assess tumor response in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant therapy (NAT) are suboptimal. As the ‘watch and wait’ (W&W) approach for patients who achieve complete clinical response (cCR) is being widely considered, accurate tumor response assessment is critical. We retrospectively explored whether circulating tumor DNA (ctDNA) can aid in tumor response assessment in patients with LARC undergoing NAT. In this multicenter, retrospective study, patients aged ≥18 years with histologically confirmed LARC undergoing NAT, either with chemoradiotherapy (CRT) or total neoadjuvant therapy (TNT), a combination of systemic chemotherapy (CT) and CRT, were included. Patients had baseline (obtained within 7 days before starting NAT), and serial blood samples were drawn during and after the completion of treatment. A tumor-informed, personalized ctDNA assay (SignateraTM, bespoke mPCR-NGS assay) was utilized to measure plasma ctDNA level expressed as mean tumor molecules (MTM)/mL. Tumor response was assessed with imaging studies, including MRI and proctoscopic examination. A correlation between complete ctDNA clearance and tumor response was explored. The study included 12 patients with LARC (clinical stage II=5, stage III=7) with a median age of 56 years (range: 44 to 68 years); 59% of patients were male. Total 34 blood samples were collected from 12 patients. In this cohort, 4 patients were excluded from the analysis, due to insufficient tissue to design the ctDNA assay (n=2) and lack of detectable ctDNA at baseline (n =2). Among 8 patients who had a baseline ctDNA level, ctDNA clearance was observed in 7 patients after a median interval of 46 days (range: 30-76 days) from the onset of NAT. The patient with persistent ctDNA level discontinued treatment within 1 month of onset of NAT due to noncompliance unrelated to treatment toxicity. Among the patients who cleared ctDNA, 3 patients have completed NAT and achieved cCR, 3 patients are currently on NAT with interim pelvic MRI showing significant shrinkage of the tumors, and 1 patient was lost to follow-up before the completion of NAT with interim MRI showing considerable tumor response. There was an agreement between the ctDNA clearance and tumor response, indicating a Cohen’s kappa of 1 for reliability. In this small cohort of patients, a high degree of correlation was observed between ctDNA clearance and response assessed by MRI and proctoscopy. However, these data are preliminary and hypothesis-generating. Larger prospective studies are warranted to further explore the potential of ctDNA-based tumor response assessment in patients with LARC undergoing NAT.