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PURPOSE: Brain metastasis is common in lung cancer, and treatment of brain metastasis can lead to significant morbidity. Although early detection of brain metastasis may improve outcomes, there are no prediction models to identify high-risk patients for brain magnetic resonance imaging (MRI) surveillance. Our goal is to develop a machine learning-based clinicogenomic prediction model to estimate patient-level brain metastasis risk. METHODS: A penalized regression competing risk model was developed using 330 patients diagnosed with lung cancer between January 2014 and June 2019 and followed through June 2021 at Stanford HealthCare. The main outcome was time from the diagnosis of distant metastatic disease to the development of brain metastasis, death, or censoring. RESULTS: Among the 330 patients, 84 (25%) developed brain metastasis over 627 person-years, with a 1-year cumulative brain metastasis incidence of 10.2% (95% CI, 6.8 to 13.6). Features selected for model inclusion were histology, cancer stage, age at diagnosis, primary site, and RB1 and ALK alterations. The prediction model yielded high discrimination (area under the curve 0.75). When the cohort was stratified by risk using a 1-year risk threshold of > 14.2% (85th percentile), the high-risk group had increased 1-year cumulative incidence of brain metastasis versus the low-risk group (30.8% v 6.1%, P < .01). Of 48 high-risk patients, 24 developed brain metastasis, and of these, 12 patients had brain metastasis detected more than 7 months after last brain MRI. Patients who missed this 7-month window had larger brain metastases (58% v 33% largest diameter > 10 mm; odds ratio, 2.80, CI, 0.51 to 13) versus those who had MRIs more frequently. CONCLUSION: The proposed model can identify high-risk patients, who may benefit from more intensive brain MRI surveillance to reduce morbidity of subsequent treatment through early detection.
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Neoplasias Encefálicas , Neoplasias Pulmonares , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Receptores Proteína Tirosina Quinases , Estudos RetrospectivosRESUMO
Introduction: Paraneoplastic autoimmune diseases (ADs) are a hallmark of thymic epithelial tumors (TETs) and affect treatment management in patients with advanced-stage tumors, yet the risk factors for development of AD in advanced TET remain poorly understood. Methods: All patients with advanced TET treated at Stanford University between 2006 and 2020 were included. Charts were retrospectively reviewed for the presence of AD, demographic information, and treatment history. Next-generation sequencing was performed on available TET tissue. Multivariate regression was used to evaluate variables associated with AD. Results: A total of 48 patients were included in the analysis with a median follow-up of 5.4 years. One-third (n = 16, 33%) were diagnosed with having ADs, with 28 distinct ADs identified. The only significant difference observed in the AD cohort compared with the non-AD cohort was a higher proportion of thymoma histotype (81% versus 47%, p = 0.013). The most common AD events were myasthenia gravis (n = 7, 44%) followed by pure red cell aplasia (n = 5, 31%). In the multivariate models, there were no independent factors associated with AD, either at TET diagnosis or subsequent to TET diagnosis. Genomic data were available on 18 patients, and there were no overlapping mutations identified in the nine patients with AD. Conclusions: ADs are common in patients with advanced TETs. Prior total thymectomy does not affect the development of subsequent AD. Patients who developed AD other than myasthenia gravis were more likely to do so several years after TET diagnosis. Additional work, including multiomic analyses, is needed to develop predictive markers for AD in advanced TET.
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BACKGROUND: In most studies, patients with EGFR L858R mutant non-small cell lung cancer (NSCLC) have a shorter duration of response to EGFR tyrosine kinase inhibitor (TKI) therapy than do patients with EGFR exon 19 deletion NSCLC. The role that co-mutations play in this observation is unknown. METHODS: We performed a single-institution retrospective analysis of patients with EGFR-mutant NSCLC (exon 19 deletion or L858R mutation) who received frontline EGFR TKI for metastatic disease between 2014 and 2019, and who had STAMP next-generation sequencing (NGS), a 130-gene platform. Time to treatment failure (TTF) and overall survival were calculated using Cox models adjusted for age, race, and brain metastases. Co-mutations in key tumor suppressor genes (TP53, RB1, KEAP1, CDKN2A, or CTNNB1) were identified and their effects on outcomes were evaluated. Analyses were stratified according to receipt of osimertinib versus nonosimertinib as frontline EGFR TKI. RESULTS: Of 137 patients, 72 (57%) had EGFR exon 19 deletions and 65 (43%) had EGFR L858R mutations. Median TTF and OS on frontline TKI was shorter for the L858R cohort versus the exon 19 deletion cohort in univariate analysis. In adjusted models, this difference persisted for TTF but was no longer significant for OS. The difference in TTF in L858R mutant tumors was driven by the presence of co-mutations in key tumor suppressor genes. CONCLUSION: Patients with metastatic NSCLC with mutations in EGFR L858R had shorter TTF on frontline TKI compared to patients with EGFR exon 19 deletions. Co-mutations in tumor suppressor genes may play an important role in the differential response to TKI therapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Éxons/genética , Genes Supressores de Tumor , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Fator 2 Relacionado a NF-E2/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estudos RetrospectivosAssuntos
Anticorpos Monoclonais/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas , Quimioterapia de Consolidação , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genéticaRESUMO
Further characterization of thymic epithelial tumors (TETs) is needed. Genomic information from 102 evaluable TETs from The Cancer Genome Atlas (TCGA) dataset and from the IU-TAB-1 cell line (type AB thymoma) underwent clustering analysis to identify molecular subtypes of TETs. Six novel molecular subtypes (TH1-TH6) of TETs from the TCGA were identified, and there was no association with WHO histologic subtype. The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed. The IU-TAB-1 cell line was noted to be resistant to everolimus (mTORC1 inhibitor) and sensitive to nelfinavir (AKT1 inhibitor) across the endpoints measured. Sensitivity to nelfinavir was due to the IU-TAB-1 cell line's gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease.
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In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2-the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.This article is highlighted in the In This Issue feature, p. 1601.
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Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Acrilamidas/farmacologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , CamundongosRESUMO
INTRODUCTION: Despite the recent advance of consolidation durvalumab in the treatment of unresectable stage III NSCLC, not every patient benefits from durvalumab and the predictive markers of response have been difficult to identify. METHODS: We performed a retrospective analysis of patients with unresectable stage III NSCLC treated with consolidation durvalumab after definitive chemoradiation from January 2018 to March 2020. RESULTS: A total of 36 patients with unresectable stage III NSCLC were treated with consolidation durvalumab. Of these patients, 14 had tumor mutations in the ERBB family including 11 EGFR and 3 ERBB2. The ERBB2/EGFR tumor mutation cohort was more likely to be nonsmokers; otherwise, the two groups were similar in age, sex, programmed death-ligand 1 expression, and type of previous chemotherapy regimen. Patients in the ERBB2/EGFR cohort had a significantly shorter disease-free survival compared with the EGFR or ERBB2 wild-type cohort (7.5 mo versus not reached, p = 0.04). CONCLUSIONS: Consolidation durvalumab seems to be less efficacious in patients with ERBB2/EGFR-mutant tumors. Future work should seek to evaluate this in the prospective setting and provide insight into the optimal treatment of ERBB2/EGFR-mutant stage III NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Prospectivos , Estudos RetrospectivosRESUMO
INTRODUCTION: In 2018, durvalumab was approved by the U.S. Food and Drug Administration as consolidation immunotherapy for patients with stage III NSCLC after definitive chemoradiotherapy (CRT). However, whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown. METHODS: We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab. RESULTS: Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab owing to progression and five owing to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and eight completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKIs). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank p = 0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 mo) compared with CRT and durvalumab or CRT alone (log-rank p = 0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib. CONCLUSIONS: In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction or consolidation EGFR TKIs further investigated as definitive treatment.
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Neoplasias Pulmonares , Anticorpos Monoclonais , Quimiorradioterapia , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
The KEAP1-NFE2L2 pathway is an important modulator of cell homeostasis. Mutations in this pathway are common in NSCLC and have been associated with enhanced tumor growth and aggressiveness. In addition, tumors with mutations in the KEAP1-NFE2L2 pathway have been reported in preclinical and clinical studies to convey refractoriness to cancer-directed therapy such as radiation, chemotherapy, and targeted therapy. The role of immunotherapy in this patient population is less clear, and there are conflicting studies on the efficacy of immune checkpoint inhibitors in KEAP1-NFE2L2-mutant NSCLC. Here, we review the current clinical evidence on several classes of anticancer therapeutics in KEAP1-NFE2L2-mutant tumors. Furthermore, we provide an overview of the landscape of the current clinical trials in this patient population, highlighting the work being done with mTORC1, mTORC2, and glutaminase inhibition.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Fator 2 Relacionado a NF-E2/genéticaRESUMO
INTRODUCTION: There is emerging evidence to support the use of mTOR inhibitor everolimus in patients with advanced, relapsed-refractory thymic epithelial tumors (TETs). However, patient selection and identifying predictive biomarkers of response remains a challenge. Here, we describe a single-center experience with everolimus in patients with TETs and provide detailed molecular analysis of their thymic tumors. MATERIALS AND METHODS: Data on all patients with advanced TETs who were prescribed everolimus at Stanford University were retrospectively assessed. Time to treatment failure (TTF) and overall survival (OS) were calculated. STAMP, a 130-gene targeted next generation sequencing (NGS) panel, was performed on each tumor sample. RESULTS: Twelve patients with thymoma (T) and three with thymic carcinoma (TC) treated with everolimus were included. Patients had been heavily pre-treated with an average of three prior lines of therapy. Three patients discontinued treatment due to adverse events. The average TTF was 14.7 months in T and 2.6 months in TC with median OS of 27.6 months in the entire cohort (NR T and 5.3 months TC). Two patients with paraneoplastic autoimmune diseases had improvement in autoimmunity on everolimus. Pathogenic mutations were observed in 4/15 (27 %) of patients and includedTP53, KEAP1 and CDKN2A. Several variants of unknown significance in key genes responsible for modulating tumor response to mTOR inhibition were also found. CONCLUSION: As previously reported in a prospective trial, patients with previously treated advanced TETs appear to benefit from everolimus in this single institution cohort. Moreover, there was a manageable toxicity profile and no cases of everolimus-induced pneumonitis. A targeted NGS panel revealed several pathogenic mutations but there was no association between detectable tumor mutations and time to treatment failure in this cohort.
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Neoplasias Pulmonares , Neoplasias Epiteliais e Glandulares , Neoplasias do Timo , Everolimo/uso terapêutico , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/genéticaRESUMO
Five-year survival rates for patients with early-stage non-small cell lung cancer have room for improvement. Adjuvant chemotherapy results in a small but significant increase in overall survival at 5 years. Efforts to improve outcomes by intensifying adjuvant treatment, utilizing cancer-specific vaccines or tyrosine kinase inhibitors in unselected patients, have been unsuccessful. In addition to research with immune checkpoint inhibitors that are addressed in a separate article, ongoing studies to personalize adjuvant therapy either by selecting only patients with evidence of minimal residual disease or targeting tumor driver mutations are promising.
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Carcinoma Pulmonar de Células não Pequenas , Quimioterapia Adjuvante , Neoplasias Pulmonares , Terapia de Alvo Molecular/métodos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/tendências , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Estadiamento de Neoplasias , Medicina de PrecisãoRESUMO
PURPOSE: Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations that activate NFE2L2, including mutations in NFE2L2, KEAP1, or CUL3, have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored. EXPERIMENTAL DESIGN: We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC with KEAP1, NFE2L2, or CUL3 mutations and a matched cohort of 52 wild-type patients. Time to treatment failure after first-line platinum doublet chemotherapy and overall survival was compared between the two groups. RESULTS: Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In patients with NSCLC, median time to treatment failure (TTF) after first-line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared with 8.3 months in the control group (P < 0.0001). Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (P = 0.006). CONCLUSIONS: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter TTF and OS after first-line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of patients with NSCLC are therefore needed.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/patologia , Mutação , Fator 2 Relacionado a NF-E2/genética , Idoso , Animais , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Esferoides Celulares , Taxa de SobrevidaRESUMO
OBJECTIVES: There are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor. MATERIALS AND METHODS: This was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40â¯mg/m2 IV days 1-3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35â¯mg/m2 for the final 15 patients. RESULTS: A total of 33 patients (14â¯T/19â¯TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%-32.8%; Tâ¯=â¯4/14 (29%), TCâ¯=â¯2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient. CONCLUSION: Amrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted.
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Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Terapia de Salvação , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Seleção de Pacientes , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Timoma/patologia , Neoplasias do Timo/patologiaRESUMO
OBJECTIVES: For patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), frontline EGFR-tyrosine kinase inhibitor (TKI) therapy compared to chemotherapy improves outcomes. However, resistance to these agents uniformly develops. Recently, mutations in the KEAP1-NFE2L2 pathway have been implicated as a potential mechanism of acquired EGFR TKI resistance. MATERIALS AND METHODS: We examined all patients with metastatic NSCLC with mutations in both EGFR and KEAP1/NFE2L2/CUL3 identified on next generation sequencing from 2015 - 2018. These patients were compared to a NSCLC control cohort with mutations in EGFR and wild type in KEAP1/NFE2L2/CUL3 matched on the basis of sex, smoking status, age and race. Time to treatment failure on EGFR TKI therapy and overall survival were examined. RESULTS: Among 228 EGFR mutant NSCLCs, 17 (7%) also carried mutations in KEAP1, NFE2L2, or CUL3. The most common co-mutation in both the KEAP1/NFE2L2/CUL3 mutant and wild-type cohort was TP53. Patients with KEAP1/NFE2L2/CUL3 mutations had a shorter median time to treatment failure on EGFR TKI (4.7 months) compared with the wild-type matched cohort (13.0 months), p= 0.0014. There was no difference in overall survival. CONCLUSION: For NSCLC patients with mutations in EGFR, co-mutations in KEAP1/NFE2L2/CUL3 are associated with significantly decreased time to treatment failure. Our results suggest that these mutations represent a mechanism of intrinsic resistance to TKI treatment.
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Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Culina/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/genética , Mutação , Fator 2 Relacionado a NF-E2/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Falha de Tratamento , Resultado do TratamentoRESUMO
The introduction of programmed death receptor ligand-1 (PD-L1) and programmed death receptor-1 (PD-1) inhibitors into the field of non-small cell lung cancer (NSCLC) was practice changing. The pivotal trials consistently showed a clinically meaningful improvement in overall survival (OS) for patients with driver mutation-negative NSCLC, a field in which outcomes had been stagnant for decades. The success of immune checkpoint inhibitor (ICI) therapy in NSCLC has led to enthusiasm to expand the reach of these drugs into other thoracic malignancies such as thymic epithelial tumors (TETs), mesothelioma, and small cell lung cancer (SCLC). Unfortunately, the improvement in outcomes with ICI therapy in these rarer thoracic tumors has been somewhat modest, and in the case of thymoma, rates of adverse events are too high to routinely justify their use. Although the response rates seen in ICI therapy in these tumor types are similar to those seen with other available single-agent therapies for advanced disease, ICIs do present another option for clinicians treating patients with mesothelioma, small cell carcinoma, and thymic carcinoma (TC), diseases in which approved treatment options are limited. Here we review the latest trials of ICI therapy in mesothelioma, SCLC, and TETs.
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Imunoterapia , Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Neoplasias Epiteliais e Glandulares/terapia , Carcinoma de Pequenas Células do Pulmão/terapia , Neoplasias do Timo/terapia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Mesotelioma/diagnóstico , Mesotelioma/imunologia , Mesotelioma Maligno , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Epiteliais e Glandulares/imunologia , Recidiva , Terapia de Salvação , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/imunologia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/imunologiaRESUMO
PURPOSE: Defects in the homologous recombination (HR) DNA repair pathway sensitize tumors to therapeutics that target this pathway. A significant proportion of triple-negative breast cancers (TNBC) carry HR defects. The HRD assay is highly associated with sensitivity to neoadjuvant platinum-based chemotherapy in TNBC. Standard chemotherapy consists of some combination of an anthracycline, cyclophosphamide, and taxane. This study assesses the association of HR deficiency status with response to standard neoadjuvant chemotherapy in TNBC or BRCA1/2 mutation-associated breast cancer. METHODS: Tumor samples were retrospectively obtained from 45 TNBC patients and 2 BRCA1/2 mutant, hormone receptor-positive/HER2-negative breast cancer patients who received anthracycline- and/or taxane-based neoadjuvant chemotherapy at Stanford University or Cedars-Sinai Medical Centers. The HRD score and tumor BRCA1/2 mutation status were determined from baseline tumor biopsies. HR deficient tumors were those with a HRD score of ≥ 42 or a tumor BRCA1/2 mutation. Response was categorized by the residual cancer burden (RCB) index. RESULTS: HR deficient patients were more likely to achieve a pathologic complete response (pCR) compared with non-deficient patients (OR 13.06, CI 1.52-11.241, p = 0.0028). Among BRCA1/2 mutation wild-type patients, HR deficient patients were more likely to achieve a pCR (OR 16, 95% CI 1.65-160.41, p = 0.0041) compared with HR non-deficient patients. Further, HRD scores were highly concordant pre- and post-therapy (Spearman correlation > 99%). CONCLUSIONS: HR deficiency status is significantly associated with response to standard neoadjuvant chemotherapy in TNBC. This observation is consistent with the mechanisms of action of doxorubicin and cyclophosphamide as DNA damaging agents.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Recombinação Homóloga/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Antraciclinas/administração & dosagem , Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
OBJECTIVE: To evaluate warfarin prescription, quality of international normalised ratio (INR) monitoring and of INR control in patients with atrial fibrillation (AF) and chronic kidney disease (CKD). METHODS: We performed a retrospective cohort study of patients with newly diagnosed AF in the Veterans Administration (VA) healthcare system. We evaluated anticoagulation prescription, INR monitoring intensity and time in and outside INR therapeutic range (TTR) stratified by CKD. RESULTS: Of 123â 188 patients with newly diagnosed AF, use of warfarin decreased with increasing severity of CKD (57.2%-46.4%), although it was higher among patients on dialysis (62.3%). Although INR monitoring intensity was similar across CKD strata, the proportion with TTR≥60% decreased with CKD severity, with only 21% of patients on dialysis achieving TTR≥60%. After multivariate adjustment, the magnitude of TTR reduction increased with CKD severity. Patients on dialysis had the highest time markedly out of range with INR <1.5 or >3.5 (30%); 12% of INR time was >3.5, and low TTR persisted for up to 3â years. CONCLUSIONS: There is a wide variation in anticoagulation prescription based on CKD severity. Patients with moderate-to-severe CKD, including dialysis, have substantially reduced TTR, despite comparable INR monitoring intensity. These findings have implications for more intensive warfarin management strategies in CKD or alternative therapies such as direct oral anticoagulants.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Acidente Vascular Cerebral/prevenção & controle , Varfarina/administração & dosagem , Idoso , Anticoagulantes/administração & dosagem , Fibrilação Atrial/complicações , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/tratamento farmacológico , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Warfarin prevents stroke and prolongs survival in patients with atrial fibrillation and flutter (AF, collectively) but can cause hemorrhage. The time in international normalized ratio (INR) therapeutic range (TTR) mediates stroke reduction and bleeding risk. This study sought to determine the relation between baseline stroke, bleeding risk, and TTR. Using data from The Retrospective Evaluation and Assessment of Therapies in Atrial Fibrillation (TREAT-AF) retrospective cohort study, national Veterans Health Administration records were used to identify patients with newly diagnosed AF from 2003 to 2012 and subsequent initiation of warfarin. Baseline stroke and bleeding risk was determined by calculating CHA2DS2-VASc and HAS-BLED scores, respectively. Main outcomes were first-year and long-term TTR and INR monitoring rate. In 167,190 patients, the proportion of patients with TTR (>65%) decreased across increasing strata of CHA2DS2-VASc and HAS-BLED. After covariate adjustment, odds of achieving TTR >65% were significantly associated with high CHA2DS2-VASc or HAS-BLED score. INR monitoring rate was similar across risk strata. In conclusion, increased baseline stroke and bleeding risk is associated with poor INR control, despite similar rates of INR monitoring. These findings may paradoxically limit warfarin's efficacy and safety in high-risk patients and may explain observed increased bleeding and stroke rates in this cohort.
Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Hemorragia/etiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Varfarina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
[This corrects the article DOI: 10.1055/s-0036-1593443.].