Rethinking treatment for non-metastatic deficient mismatch repair colorectal and small bowel cancers

Abstract

BACKGROUND

Deficient mismatch repair (dMMR), present in approximately 15% of colorectal cancers (CRC), defines a tumor subset with sensitivity to immune checkpoint inhibitors (ICIs). Landmark clinical trials have established ICI therapy as a transformative treatment for non-metastatic dMMR CRC; however, evidence from routine clinical practice remains limited.

AIM

To describe real-world clinical, radiological, and pathological responses (pCR) to ICI therapy in patients with non-metastatic dMMR colorectal and small bowel adenocarcinoma (ADC), outside clinical trial settings.

METHODS

This retrospective, single-center observational study included eight consecutive patients with non-metastatic dMMR colorectal or small bowel ADC treated with ICI therapy between January 2023 and June 2026. Mismatch repair (MMR) status was determined by immunohistochemistry for MLH1, MSH2, MSH6, and PMS2. Treatment response was assessed using computed tomography, magnetic resonance imaging and/or positron emission tomography/computed tomography, endoscopy, and digital rectal examination, as appropriate according to tumor. Complete clinical response (cCR) was defined as the simultaneous absence of radiological, endoscopic, and clinical evidence of disease. Complete pCR was defined as ypT0N0 after surgery. All treatment decisions were made by a multidisciplinary tumor board.

RESULTS

Eight patients (four females, four males; median age 59.5 years) were included: Four colon cancers, three locally advanced rectal cancers (LARC), and one small bowel ADC. Two patients had known lynch syndrome. ICI regimens included pembrolizumab, dostarlimab, nivolumab, and ipilimumab. Among patients with LARC, two achieved a sustained cCR and remained on watch-and-wait for more than 20 months; the third underwent surgery for stenosis and achieved pCR. The three patients with locally advanced colon cancer underwent minimally invasive surgery and achieved pCR. One frail patient with colon cancer achieved cCR and is managed non-operatively. The patient with small bowel ADC remained radiologically disease-free at 12 months. No grade ≥ 3 immune-related adverse events necessitating treatment discontinuation were recorded.

CONCLUSION

ICI therapy achieves high rates of complete response in non-metastatic dMMR colorectal and small bowel ADC treated in routine clinical practice, facilitating organ-preservation and minimally invasive surgery. Systematic upfront MMR testing at diagnosis is essential to avoid treatment delays and ensure timely identification of candidates for these treatments.

Keywords: Colorectal cancer; Mismatch repair deficiency; Immune checkpoint inhibitors; Rectal cancer; Small bowel neoplasm; Pembrolizumab; Dostarlimab; Nivolumab; Lynch syndrome

Core Tip: This real-world retrospective study describes eight patients with non-metastatic mismatch repair (MMR)-deficient colorectal and small bowel adenocarcinoma treated with immunotherapy in different clinical settings. Favorable responses were observed across all tumor subsites. Complete clinical responses enabled a watch-and-wait strategy in some patients with locally advanced rectal cancer. In colon cancer immunotherapy facilitated minimally invasive surgery with pathological complete responses in all operated patients. Delayed MMR testing postponed treatment initiation in some cases, highlighting the need for systematic upfront immunohistochemical assessment at diagnosis. These findings support the feasibility of implementing immunotherapy-based strategies in routine surgical oncology practice beyond clinical trial settings.