What question did this study set out to answer?

This research aims to explore the relationship between GNAS activating mutations and chemotherapy outcomes in metastatic appendiceal adenocarcinoma.

February 5, 2026Open Access

Association of Activating GNAS Mutations and Outcomes with Chemotherapy in Metastatic Appendiceal Adenocarcinoma

Key Points

This research aims to explore the relationship between GNAS activating mutations and chemotherapy outcomes in metastatic appendiceal adenocarcinoma.
Identified patients treated with systemic chemotherapy for metastatic appendiceal adenocarcinoma.
Defined the primary outcome as disease event-free survival from chemotherapy initiation.
Used Kaplan-Meier estimations and Cox proportional hazards regression for outcome analysis.
30% of patients had GNAS mutations, correlating with lower disease grades and fewer high-risk features.
GNAS mutations associated with worse disease event-free survival of 10.7 months compared to 20.3 months for non-mutated patients.
Survival rates significantly differed based on surgical resection, improving event-free survival rates.

Abstract

Abstract Background Findings have linked GNAS -activating mutations, frequent in appendiceal adenocarcinoma (AA), with improved overall survival but poor response to chemotherapy. The authors hypothesized that GNAS -activating mutations are associated with differential outcomes in AA treated with chemotherapy. Methods Patients seen at the authors’ center between 2013 and 2023 who received systemic chemotherapy for metastatic/recurrent AA were identified. The primary outcome was disease event-free survival (EFS), defined as time from start of chemotherapy (5-fluorouracil/capecitabine based) to earliest disease event, including death, clinical/radiographic recurrence, or progression. Study outcomes were assessed using Kaplan-Meier estimations and Cox proportional hazards regression. Results The study included 48 patients. In 18 (37. 5 %) of the 48 patients, GNAS -activating mutations were seen. Patients with GNAS mutations were more likely to have lower grades of disease (p = 0. 003), with lower proportions of lymphovascular invasion (p = 0. 005) and perineural invasion (p = 0. 03), but a higher median peritoneal carcinomatosis index (p = 0. 03). In the multivariable analysis, GNAS mutations (10. 7 months 95 % confidence interval CI, 7. 1–19. 2 vs 20. 3 months 95 % CI, 18. 6–29. 4; adjusted HR aHR, 3. 75; 95 % CI, 1. 84–7. 63 p < 0. 001) and metachronous metastases (aHR, 5. 14; 95 % CI, 2. 08–12. 69; p < 0. 001) were associated with worse EFS. Both CC0-1 resection (aHR, 0. 12; 95 % CI, 0. 05–0. 28; p < 0. 001) and CC2-3 resection (aHR, 0. 28; 95 % CI, 0. 10–0. 81; p = 0. 02) were associated with prolonged EFS. There was no significant difference in the OS from the date of metastases diagnosis between the GNAS mt and GNAS wt patients (HR, 0. 68; 95 % CI, 0. 31–1. 47; p = 0. 33). Conclusions With systemic chemotherapy, GNAS -mutated metastatic/recurrent AAs have worse EFS despite less frequent high-risk features. Routine somatic mutation-testing of patients with AA should be considered for prognostication and possibly therapeutic decision-making.

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