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

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.

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.

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).

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.