The impact of APC mutation on the efficacy of anti-EGFR therapy in metastatic colorectal cancer with RAS wild type: a retrospective analysis

초록

Background: Anti-epidermal growth factor receptor (EGFR) therapies including cetuximab are a key component of treatment for metastatic colorectal cancer (CRC) with Rat Sarcoma viral oncogene homolog (RAS) wild-type status. However, predictive biomarkers for anti-EGFR therapy beyond RAS status remain controversial. The Wnt signaling pathway, which is essential for embryonic development, becomes frequently dysregulated in the presence of APC mutations. Objectives: To evaluate the impact of APC mutation status on survival outcomes in patients with RAS wild-type CRC treated with cetuximab-containing chemotherapy Design: Single-center retrospective analysis Methods: We retrospectively analyzed patients with RAS wild-type metastatic CRC who received first-line cetuximab plus chemotherapy at Samsung Medical Center between February 2021 and June 2024. The status of the APC mutation was determined by next-generation sequencing (NGS). We evaluated the impact of APC mutation on the treatment of cetuximab-containing chemotherapy. Results: Among 104 RAS wild metastatic CRC patients with cetuximab-containing chemotherapy as first-line therapy, 75 (72%) had APC-mutant tumors and 29 (28%) had APC wild. The presence of liver metastases and primary tumor locations was significantly different between patients with APC mutation and wild type. No complete responses were observed, and partial response was achieved in 64 patients with APC-mutated tumors (85%) and 17 patients with APC wild type tumors (59%). There was a significant difference in the objective response rate (ORR) between patients with APC mutation and wild type (p-value of 0.003). The disease control rate (DCR) was 89.7% for patients with APC wild type and 97.3% for the APC-mutant group. The median OS was not reached (95% CI, 31.5-NA) in patients with the APC mutation, whereas it was 37.3 months (95% CI, 23.4-NA) in those with APC-wild type tumors (p = 0.024). Conclusion: This study showed that the status of APC mutation may be associated with clinical outcomes in patients receiving cetuximab-containing chemotherapy in RAS wild metastatic CRC. Further prospective studies are warranted to validate and incorporate APC mutation into clinical decision-making algorithms. Plain language summary How APC gene status influences response to cetuximab in RAS wild-type metastatic colorectal cancer This study looked at whether a specific gene change (called an APC mutation) affects how well a common cancer drug works in patients with advanced colorectal cancer that has spread to other parts of the body. Cetuximab is a targeted therapy used as a first-line treatment for metastatic colorectal cancer in patients whose tumors do not have RAS gene mutations. While cetuximab helps many patients, not everyone responds equally, and researchers are working to find markers that can predict who will benefit most. The researchers reviewed records of 104 patients treated at Samsung Medical Center in Seoul, Korea, between 2021 and 2024. All patients had RAS wild-type metastatic colorectal cancer and received cetuximab-based chemotherapy as their first treatment. Using genetic testing, they found that 75 patients (72%) had APC-mutated tumors and 29 (28%) had APC wild-type tumors. Key findings showed that patients with APC mutations had a significantly higher tumor response rate (85% vs. 59%) and longer overall survival compared to those without APC mutations. When looking at subgroups, the survival benefit of APC mutation was especially striking in patients without liver metastasis, where APC-mutated tumors showed significantly better progression-free and overall survival. The study suggests that APC mutation status could serve as a useful marker to help predict which patients will respond better to cetuximab-based treatment. However, since this was a single-center retrospective study with a relatively small number of patients, larger prospective studies are needed to confirm these findings.

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