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Background <p>Findings have linked <i>GNAS</i>-activating mutations, frequent in appendiceal adenocarcinoma (AA), with improved overall survival but poor response to chemotherapy. The authors hypothesized that <i>GNAS</i>-activating mutations are associated with differential outcomes in AA treated with chemotherapy.</p> Methods <p>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.</p> Results <p>The study included 48 patients. In 18 (37.5 %) of the 48 patients, <i>GNAS</i>-activating mutations were seen. Patients with <i>GNAS</i> mutations were more likely to have lower grades of disease (<i>p</i> = 0.003), with lower proportions of lymphovascular invasion (<i>p</i> = 0.005) and perineural invasion (<i>p</i> = 0.03), but a higher median peritoneal carcinomatosis index (<i>p</i> = 0.03). In the multivariable analysis, <i>GNAS</i> 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] <i>p</i> &lt; 0.001) and metachronous metastases (aHR, 5.14; 95 % CI, 2.08–12.69; <i>p</i> &lt; 0.001) were associated with worse EFS. Both CC0-1 resection (aHR, 0.12; 95 % CI, 0.05–0.28; <i>p</i> &lt; 0.001) and CC2-3 resection (aHR, 0.28; 95 % CI, 0.10–0.81; <i>p</i> = 0.02) were associated with prolonged EFS. There was no significant difference in the OS from the date of metastases diagnosis between the <i>GNAS</i><sup>mt</sup> and <i>GNAS</i><sup>wt</sup> patients (HR, 0.68; 95 % CI, 0.31–1.47; <i>p</i> = 0.33).</p> Conclusions <p>With systemic chemotherapy, <i>GNAS</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月3日

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  • Rushabh Gujarathi,
  • Christopher Rodman,
  • Varun Vivek Bansal,
  • Erika Belmont,
  • Namrata Setia,
  • Lindsay Alpert,
  • John Hart,
  • Mecker G. Möller,
  • Oliver S. Eng,
  • Grace Lee,
  • Blase N. Polite,
  • Kiran K. Turaga,
  • Ardaman Shergill

摘要

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 GNASmt and GNASwt 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.