Genomic landscape and clinical impact of homologous recombination repair gene mutation in small bowel adenocarcinoma

Background

Small bowel adenocarcinoma (SBA) is a rare malignancy with a poor prognosis and limited treatment options. Although homologous recombination deficiency has been studied as a biomarker for other cancer types, the clinical and genomic implications of homologous recombination repair (HRR) gene mutations in SBA remain unclear.

Methods

We retrospectively analyzed the data of 628 patients with advanced or recurrent SBA from a nationwide genomic database. Patients were categorized into HRR mutation and non-HRR mutation groups and compared for their clinical and genomic characteristics including tumor mutational burden (TMB) and microsatellite instability-high (MSI-H) were compared. Treatment efficacy and overall survival (OS) were assessed based on HRR gene mutation status and primary tumor site (duodenal adenocarcinoma [DA] vs. small intestinal carcinoma [SIC]).

Results

Patients with the HRR mutations had higher frequencies of TMB and MSI-H than those without the mutation (P < 0.0001). In DA, HRR gene mutation positivity was associated with improved OS and higher overall response rates (ORR) to platinum-based chemotherapy (OS: not reached vs. 23.5 months, P = 0.040; ORR: 33 % vs. 19 %, P = 0.046), whereas no significant associations were observed with SIC.

Conclusion

HRR gene mutation may be a potential biomarker for platinum-based chemotherapy efficacy in SBA, especially in DA, highlighting the need for site-specific therapies.