Impact of homologous recombination deficiency on survival and chemotherapy response in small bowel adenocarcinoma.
Authors: Kono Yoshiyasu , Ozato Toshiki , Horiguchi Shigeru , Tsutsumi Koichiro , Yamamoto Hideki , Hirasawa Akira , Ennishi Daisuke , Tomida Shuta , Toyooka Shinichi , Otsuka Motoyuki 
Published: January 2025

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Background:
Small bowel adenocarcinoma (SBA) is a rare malignancy, and its genomic profile is distinct from that of gastric and colorectal cancers. However, the role of homologous recombination repair (HRR) gene mutations in SBA remains unexplored. This study aims to investigate the clinical significance of HRR gene mutations in SBA.
Methods:
We retrospectively analyzed data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) utilization portal, in accordance with its policy. Between June 2019 and February 2024, patients with SBA who underwent comprehensive genomic profiling (Foundation One CDx, Foundation One Liquid, OncoGuide NCC Oncopanel, Guardant 360 CDx, and GenMineTOP) were included. The frequency of HRR variants (
ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C, RAD51D, RAD51, ATRX, ARID1A, BAP1, CDK12, MRE11, NBN, PTEN, FANCA, FANCC
) was analyzed. Homologous recombination deficiency (HRD) was defined as the presence of one or more alterations in HRR variants. Clinicopathological features, treatment outcomes, and survival were compared between HRD-positive and HRD-negative groups.
Results:
A total of 628 cases were analyzed, with a median age of 65 years, including 238 males and 390 females. The primary tumor sites were the duodenum in 332 cases and the jejunum in 296 cases. HRD was observed in 165 cases (26.5%) overall. The incidence of microsatellite instability-high (MSI-H) was significantly higher in the HRD-positive group compared to the HRD-negative group (15% vs. 1.1%, P < 0.001). Similarly, the median tumor mutational burden (TMB) values were significantly higher in the HRD-positive group compared to the HRD-negative group (5 Mut/Mb vs. 3.8 Mut/Mb, P < 0.001). The median overall survival (OS) was similar between HRD-positive and HRD-negative groups (1,243 days vs. 1,055 days, P = 0.22). However, in duodenal primary cases, the median OS was significantly longer in the HRD-positive group compared to the HRD-negative group (1,243 days vs. 702 days, P = 0.025). No significant difference in median OS was observed between HRD-positive and HRD-negative groups in jejunal primary cases (1,145 days vs. not reached, P = 0.51). The overall response rate (ORR) to platinum-based chemotherapy in first-line treatment was significantly higher in the HRD-positive group compared to the HRD-negative group in duodenal primary cases (34% vs. 18%, P < 0.05). Conversely, there was no significant difference in ORR between HRD-positive and HRD-negative groups in jejunal primary cases (23% vs. 20%, P = 0.70).
Conclusions:
Duodenal primary SBA with HRD showed better response rates to platinum-based chemotherapy and had a more favorable prognosis compared to non-HRD cases. In duodenal cancer, which typically has a worse prognosis than jejunal cancer, HRD may represent a novel prognostic and predictive marker for treatment efficacy.