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ctDNA Analysis is Feasible for Detection of Minimal Residual Disease After Treatment Across a Variety of MMRd Tumour Types

Circulating tumour DNA analysis is a feasible tumour agnostic approach for evaluation of the efficacy of checkpoint blockade in patients at high risk of recurrence
02 Jul 2021
Personalised medicine

Minimal residual disease (MRD) after curative resection or chemotherapy was detected using a circulating tumour DNA (ctDNA) screen in patients with diverse tumours harbouring mismatch repair deficiency (MMRd), according to findings from a phase II study presented at the ESMO World Congress on Gastrointestinal Cancer 2021, which was held from 30 June to 3 July.

Melissa Lumish, a clinical fellow at Memorial Sloan Kettering Cancer Center in New York, NY, US reported the results on behalf of colleagues from a study (NCT03832569) evaluating the utility of ctDNA in screening patients at high risk for recurrence following surgery or adjuvant chemotherapy to identify those who would most benefit from immune checkpoint blockade treatment.

Dr. Lumish explained that, while MMRd tumours are highly sensitive to checkpoint blockade in patients with metastatic disease regardless of tumour type, the efficacy in the adjuvant setting is unknown.

In order to assess the frequency of ctDNA in patients with resected MMRd tumours the investigators  prospectively screened patients with MMRd tumours who completed standard perioperative chemotherapy and surgery.

DNA from resected tumours and matched postoperative plasma were sequenced for the detection of somatic mutations. Patients were considered to have MRD when the mutations identified in the tumour were identical to those in matched plasma DNA. Somatic tissue mutations were assessed using MSK-IMPACT and ctDNA was assessed using FoundationOne, Guardant360 or MSK-ACCESS.

Low recurrence rates observed in minimal residual disease-negative patients

Screening was performed for the presence of MRD in 94 patients. The patients had diverse tumour types; the most commonly occurring tumour types were colorectal in 53% of patients, endometrial in 20%, and oesophagogastric in 17% of patients. Small bowel cancer was present in 4%, pancreatic in 1% and other tumours in 4%. The majority of patients had stage III.

MRD was detected in 18% of cases, which represented 14 of 78 patients with viable results; some samples failed ctDNA analysis due to technical reasons.

Just one patient among the patients with MRD-negative results developed disease recurrence. The authors commented that tumour matched ctDNA alterations predicted relapse. ctDNA predicted disease-free survival (DFS) in MSI-high tumours after surgery. In 64 patients with negative ctDNA, median DFS was not reached, while in 5 patients with positive ctDNA, median DFS was 9.7 months (p < 0.0001 by log-rank test).

Conclusions

The authors commented that commercially available ctDNA predicts outcome in resected MSI-high patients. It is critical to ensure ctDNA originates from the tumour of interest, to filter clonal haematopoietic and germline abnormalities.

MRD could be identified in 18% of resected MMRd tumours using ctDNA analysis, which suggested to the investigators that ctDNA analysis is a feasible tumour agnostic approach for evaluation of the efficacy of checkpoint blockade in patients at high risk of recurrence.

They plan future studies to assess the impact of checkpoint blockade in MRD-positive patients with MMRd tumours.

No external funding was disclosed.

Reference

O-5. Janjigian Y, Lumish M, Jayakumaran G, et al. Frequency of minimal residual disease as measured by ctDNA in mismatch repair deficient tumors following curative resection. ESMO World Congress on Gastrointestinal Cancer 2021 (30 June – 3 July).

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