Trametinib and Hydroxychloroquine (HCQ) Combination Treatment in KRAS-Mutated Advanced Pancreatic Adenocarcinoma: Detail
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MGMT. OF COMPLEX CASES IN GI ONCOLOGY
Trametinib and Hydroxychloroquine (HCQ) Combination Treatment in KRAS-Mutated Advanced Pancreatic Adenocarcinoma: Detailed Description of Two Cases Camila B. Xavier 1
&
Katia R. Marchetti 2 & Tiago B. Castria 1 & Denis L. F. Jardim 1 & Gustavo S. Fernandes 2
Accepted: 15 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Over the last decades, cytotoxic chemotherapy has been the cornerstone of metastatic pancreatic adenocarcinoma treatment. In late-stage disease, a range of treatment regimens still offers minor benefits. Molecular profiling studies have shown that pancreatic adenocarcinoma (PDAC) is a mutation-driven tumor type, with KRAS mutations found in approximately 90% of cases, which could partially explain the resistance to chemotherapy. Preclinical data on selective targeting of a downstream point of the RAF–MEK–ERK pathway with a MEK inhibitor along with the concurrent use of an autophagy inhibitor such as hydroxychloroquine appears to be one alternative approach to overcome resistance and inhibit cell proliferation. Methods We herein aim to investigate the rationale of autophagy inhibitors use and describe the outcomes of patients who received this experimental treatment. Results Two patients have received this experimental regimen from January 2020 to the present date, achieving disease stabilization that is clinically meaningful, considering the chemoresistance scenario of the included patients. Conclusions Our real-life data regarding KRAS-mutated PDAC patients who received treatment with the MEK inhibitor trametinib combined with hydroxychloroquine after experiencing disease progression are consistent with the preclinical data, pointing to the clinical benefits of this regimen. Keywords Autophagy . Hydroxychloroquine . KRAS protein . Pancreatic cancer
Introduction Pancreatic adenocarcinoma (PADC) is a lethal disease with an approximately [12-]month median overall survival (mOS) duration in the advanced setting. Even when diagnosed at an early and potentially resectable stage, most patients who undergo resection will experience disease recurrence. Over the last decades, cytotoxic chemotherapy with [5-]fluorouracil or gemcitabine has been the cornerstone of metastatic PADC treatment [1]. No regimen made a substantial breakthrough when compared to single-agent gemcitabine until the last decade. In 2011, FOLFIRINOX (bolus and infusional
* Camila B. Xavier [email protected] 1
Oncology Department, Hospital Sírio-Libanês, São Paulo, Brazil
2
Oncology Department, Hospital Sírio-Libanês, Brasília, Brazil
[5-]fluorouracil, irinotecan, and oxaliplatin) emerged as a treatment advance for patients with metastatic pancreatic cancer and a good ECOG performance score, increasing the mOS from 6.8 to 11.1 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P < 0.001) [2]. Another regimen that is more effective than gemcitabine alone is its combination with n
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