Cyclin-Dependent Kinase 4/6 Inhibition as a Novel Therapy for Peritoneal Mucinous Carcinomatosis With GNAS Mutations.

Autor:	Weitz J; Department of Surgery, University of California, San Diego, La Jolla, CA., Nishizaki D; Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, CA., Liau J; Department of Radiology, University of California San Diego, La Jolla, CA., Patel J; Department of Surgery, University of California, San Diego, La Jolla, CA., Ng I; Department of Surgery, University of California, San Diego, La Jolla, CA., Sun S; Department of Surgery, University of California, San Diego, La Jolla, CA., Ramms D; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA., Zou J; Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA.; Moores Cancer Center, UCSD, La Jolla, CA., Wishart B; Department of Surgery, University of Wisconsin, Madison, WI., Rull J; Department of Surgery, University of Wisconsin, Madison, WI., Baumgartner J; Department of Surgery, University of California, San Diego, La Jolla, CA., Kelly K; Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA.; Moores Cancer Center, UCSD, La Jolla, CA., White R; Department of Surgery, University of California, San Diego, La Jolla, CA., Veerapong J; Department of Surgery, University of California, San Diego, La Jolla, CA., Hosseini M; Department of Pathology, University of California San Diego, La Jolla, CA., Patel H; Department of Surgery, University of California, San Diego, La Jolla, CA., Botta G; Department of Surgery, University of California, San Diego, La Jolla, CA., Gutkind JS; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA., Tiriac H; Department of Surgery, University of California, San Diego, La Jolla, CA., Kato S; Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, CA., Lowy AM; Department of Surgery, University of California, San Diego, La Jolla, CA.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2024 Oct 16, pp. JCO2400511. Date of Electronic Publication: 2024 Oct 16.
DOI:	10.1200/JCO.24.00511
Abstrakt:	Purpose: Mucinous neoplasms of the gastrointestinal tract are characterized by a propensity for metastasis to the peritoneum, resulting in peritoneal mucinous carcinomatosis (PMC). A subset of these tumors, most often originating in the appendix, harbor mutations in the GNAS oncogene. While the natural history of GNAS -mutant PMC varies, patient outcomes are generally poor, as is response to cytotoxic chemotherapy. The purpose of this study was to evaluate the clinical efficacy of single-agent palbociclib, a cyclin-dependent kinase (CDK)4/6 inhibitor, in patients with GNAS -mutant PMC. Patients and Methods: We enrolled 16 patients with PMC in a single-arm personalized cancer therapy trial. For all patients, tumor tissue and/or circulating tumor DNA genomic profiling using next-generation sequencing and, when possible, PD-L1 expression, tumor mutational burden, and microsatellite instability status was assessed. Twelve of 16 patients had previous disease progression on at least one previous line of chemotherapy. The primary tumor was appendix in 13 patients, unknown in two patients, and pancreas in one patient. Eleven cases were classified as low grade, and five as high grade. Results: In 13 of 16 patients, we observed a decrease in carcinoembryonic antigen (CEA), and in six patients, the CEA declined by >50%. As measured by clinical and modified peritoneal RECIST criteria, 50% of evaluable patients had stable disease after 12 months of palbociclib. At a median follow-up of 17.6 months, median survival has not been reached. Clinical response to CDK4/6 inhibition was mirrored in tumors with GNAS mutation and mucinous histology using an ex vivo preclinical platform. Conclusion: CDK4/6 inhibition with palbociclib had clinical activity in PMC characterized by mutations in GNAS that was superior to that previously reported with cytotoxic chemotherapy. CDK4/6 inhibition is a novel therapeutic strategy worthy of further evaluation in this subgroup of gastrointestinal neoplasms.
Databáze:	MEDLINE
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