RESUMO
PURPOSE: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB (R2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424). CONCLUSION: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/uso terapêutico , Proteoma , ProteômicaRESUMO
PURPOSE: The combination of DNA methylation inhibitors and histone deacetylase inhibitors is synergistic in gene expression activation and may overcome platinum resistance. Sequential treatment with azacitidine and valproic acid (VPA) in combination with carboplatin may overcome resistance to platinum-based therapy, and we conducted a phase I trial to assess safety, maximum tolerated dose (MTD), and clinical correlates. Experimental Design Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received azacitidine for 5 days from days 1 to 5, VPA for 7 days from days 5 to 11, and carboplatin starting in the second cycle on days 3 and 10. Clinical correlates included evaluation of epigenetic changes, methylation patterns, and histone acetylation levels in peripheral blood mononuclear cells. RESULTS: Thirty-two patients were treated. The MTD was 75 mg/m(2) azacitidine, 20 mg/kg VPA, and AUC 3.0 carboplatin. Minor responses or stable disease lasting ≥ 4 months were achieved by six patients (18.8 %), including three with platinum-resistant or platinum-refractory ovarian cancer. The most common adverse events grade ≥ 3 were fatigue (81 %) and neutropenia (69 %). Dose-limiting toxicity occurred in six patients (18.8 %), including four patients with grade 3 altered mental status. Death receptor 4 (DR4) methylation was shown to decrease in a subset of patients, but there was no relationship with tumor response or number of cycles received. CONCLUSIONS: Combination of azacitidine, VPA, and carboplatin demonstrates decreased DR4 methylation and modest evidence of antitumor activity in patients with heavily treated advanced malignancies.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Acetilação/efeitos dos fármacos , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ácido Valproico/administração & dosagem , Ácido Valproico/efeitos adversosRESUMO
The Ras family of genes is involved in the cellular regulation of proliferation, differentiation, cell adhesion and apoptosis. The K-ras gene is mutated in over 90% of pancreatic cancer cases. Salirasib (S-trans,trans-farnesylthiosalycilic acid [FTS]) is a synthetic small molecule that acts as a potent Ras inhibitor. It is a farnesylcysteine mimetic that selectively disrupts the association of active RAS proteins with the plasma membrane. Animal studies demonstrated that salirasib inhibited tumor growth, downregulated gene expression in the cell cycle and Ras signaling pathways. In a clinical study of salirasib combined with standard doses of gemcitabine, it was demonstrated that the two drugs have no overlapping pharmacokinetics. The salirasib recommended dose was 600 mg twice daily and the progression-free survival was 4.7 months. Future studies will determine whether salirasib adds to the anti-tumor activity of drugs approved by the US FDA for pancreatic cancer.
Assuntos
Antineoplásicos/uso terapêutico , Farneseno Álcool/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Salicilatos/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ensaios Clínicos Fase I como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Intervalo Livre de Doença , Ensaios de Seleção de Medicamentos Antitumorais , Farneseno Álcool/administração & dosagem , Farneseno Álcool/efeitos adversos , Farneseno Álcool/farmacocinética , Farneseno Álcool/uso terapêutico , Farnesiltranstransferase/antagonistas & inibidores , Galectinas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias Pancreáticas/enzimologia , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Salicilatos/administração & dosagem , Salicilatos/efeitos adversos , Salicilatos/farmacocinética , Transdução de Sinais/efeitos dos fármacos , GencitabinaRESUMO
A 28-year-old female with history of chest wall extraskeletal myxoid chondrosarcoma (EMC) presented to the emergency department complaining of two weeks of lightheadedness and fatigue. Laboratories showed hemoglobin of 7.6 g/dL and a positive hemoccult test. Upper and lower endoscopies were unremarkable, and the patient was discharged after blood transfusion. The next day she returned to the ED with left-sided weakness and perioral numbness. Brain CT scan revealed a 6 cm right frontal mass with midline shift and edema that required urgent craniotomy with resection of a hemorrhagic tumor. The patient continued dropping her hemoglobin, and CT scans showed a rounded 3 cm small bowel mass in the mid ileum. Repeat upper endoscopy revealed a 2 × 2 cm ulcerated mass in the fourth portion of the duodenum. The patient was taken to the operating room and was found to have two lesions; one in the distal duodenum and a second one in the mid ileum causing small bowel intussusception. Pathology was consistent with metastatic EMC grade 2/3, involving the bowel and mesenteric fat. Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft-tissue sarcoma with unique features that distinguishes, it from other sarcomas. It has been often described as a low-grade sarcoma although there are certain characteristics like high mitotic activity and the presence of focal regions of Ki67 staining above 25% that correlate with aggressive behavior of the tumor. This is the first case of EMC metastatic to the small bowel to be reported to the medical community.
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We report the case of an African American male with no significant past medical history presenting with recurrent, rapidly relapsing episodes of thrombotic thrombocytopenic purpura (TTP) despite aggressive treatment with several lines of treatment. Incidentally, these episodes were associated with severe abdominal pain which eventually developed into acute abdomen and prompted exploratory laparotomy, revealing diffuse carcinomatosis with a tumor located on the left pelvis that was encasing the distal sigmoid colon. Pathology made a final diagnosis of peritoneal mesothelioma. TTP-like syndrome (TTP-LS) has been described as a paraneoplastic phenomenon in several malignancies but never before in the setting of malignant mesothelioma. Paraneoplastic TTP-like syndrome has historically been associated with a dismal prognosis and particular clinical and laboratory abnormalities described in this paper. It is of utmost importance to make a prompt determination whether TTP is idiopathic or secondary to an underlying condition because of significant differences in their prognosis, treatment, and response. This paper also reviews the current literature regarding this challenging condition.