556P - Predicting the efficacy of neoadjuvant chemoradiotherapy in rectal cancer patients based on dynamic tumor-informed ctDNA-MRD

Background

Standard treatment for locally advanced rectal cancer (LARC) patients involves neoadjuvant chemoradiotherapy (NACRT) followed by surgery and adjuvant chemotherapy. Patients who achieve clinical complete response (cCR) can choose a watch-and-wait strategy. Accurate prediction of pathologic complete response and tumore regression grade using circulating tumor DNA will further help guide personlized treatment by dynamically informing tumor response. Thus the efficacy assessment using ctDNA should be analyzed and validated.

Methods

In this prospective observational study, 100 LARC patients will be enrolled and treated with NACRT. Tumor tissues were collected prior to treatment, and whole exome sequencing (WES) at a depth of 1000x were performed. A tumor-informed personized ctDNA panel called mClear was designed by HaploX based on WES results incorporating 40 SNVs or Indels to test minimal residual disease (MRD) in plasma at multiple time points during treatment course, together with a core panel including 21 tumor driver genes. ctDNA-MRD were monitored by 100,000x ultra-deep sequencing. The dynamic changes and clearance rate of ctDNA-MRD will be analyzed correlating with treatment outcomes.

Results

From June 1st 2023 to date, 49 patients have been enrolled. The most common somatic gene mutations are TP53 (74%), APC (64%), and KRAS (46%). The ctDNA baseline positivity rate is 93.5%, compared with 58% and 26% for CEA and CA19-9, respectively. Dynamic results showed ctDNA-MRD positivity rate dropped from 93.5% to 40% during NACRT, while ctDNA concentration levels also show a general downward trend indicating tumor regression. Two patients have completed surgery and both patients' pathological results showed ypT3N0 and the ctDNA-MRD results at the time point of completion of NACRT also showed positive, which were consistent. The trial is still going and recuiting patients.

Conclusions

The tumor-informed ctDNA-MRD mClear is very sensitive in baseline ctDNA detection for LARC, which is far superior to CEA and CA19-9. And mClear can also dynamically monitor tumor regression during NACRT. It’s efficacy assessment accurary will be reported when data are mature.

Clinical trial identification

NCT05969938.

Editorial acknowledgement

Legal entity responsible for the study

Sun Yat-sen University Cancer Center.

Funding

Has not received any funding.

Disclosure

J. GUO: Financial Interests, Personal, Full or part-time Employment: Haplox Biotechnology. J. Teng: Financial Interests, Personal, Full or part-time Employment: Haplox Biotechnology. J. Zheng: Financial Interests, Personal, Full or part-time Employment: Haplox Biotechnology. S. Chen: Financial Interests, Personal, Stocks or ownership: Haplox Biotechnology. All other authors have declared no conflicts of interest.