RESUMO
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RESUMO
Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de IgG/genética , Receptores KIR/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Genes MCC , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estudos Prospectivos , Resultado do TratamentoRESUMO
Biliopancreatic cancer is one of the most aggressive solid neoplasms, and incidence is rising worldwide. It is known that ATF6α is one of the transmembrane proteins that acts crucially in endoplasmic reticulum stress response, and knockdown induces apoptosis of pancreatic cells. Apart from this, p-p38 has been previously correlated with better outcome in pancreatic cancer. Interestingly, ATF6α knockdown pancreatic cells showed increased p-p38. The aim of this study was to evaluate the expression of these 2 proteins, p-p38 and ATF6α, and their correlation with the outcome of biliopancreatic adenocarcinoma patients. Samples from patients with biliopancreatic adenocarcinoma that underwent pancreaticoduodenectomy from 2007 to 2013 were used to construct a tissue microarray to evaluate p-p38 and ATF6α proteins by immunohistochemistry. We observed that both markers showed a tendency to impact in the time to recurrence; then a combination of these 2 proteins was analyzed. Combination of ATF6α(high) and p-p38(low) was strongly associated with a higher risk of recurrence (hazard ratio 2.918, Pâ=â0.013). This 2-protein model remained significant after multivariate adjustment.We proposed a 2-protein signature based on ATF6α(high) and p-p38(low) as a potential biomarker of risk of recurrence in resected biliopancreatic adenocarcinoma patients.