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Mutations in polymerase ε (POLE) confer favorable prognosis and outcomes in various cancer types, but their role in non-small cell lung cancer (NSCLC) is unknown. Utilizing the data of 513 patients with adenocarcinoma (LUAD) and 497 patients with squamous cell carcinoma (LUSC) from The Cancer Genome Atlas (TCGA) cohort, we tested the prognostic value of POLE mutations and programmed cell death ligand 1 (PD-L1) expression in the two main subtypes of NSCLC. POLE mutation is a favorable biomarker for the improved overall survival (OS) of the LUSC patients (P = 0.033, 28 mutant vs. 469 wildtype patients), but not that of the LUAD patients (P = 0.12, 31 mutant vs. 482 wildtype patients). POLE-mutant LUAD patients with high expression of PD-L1 (Mut-High, n = 6) exhibited improved OS (P = 0.024) when compared to POLE-mutant patients with low PD-L1 expression (Mut-Low, n = 24) and other patients without POLE mutation (n = 476). This benefit was not due to the high content of the tumor infiltrating lymphocytes. Instead, the antitumor immune response was activated in Mut-High patients so that these patients were likely responding more effectively to immuno-oncology (IO) treatments; whereas genes involved with metabolic pathways were enriched in Mut-Low group, which may cause the decreased OS of these patients. Our study sheds light on the molecular basis of NSCLC and adds to our understanding of responses to chemotherapy and IO therapy.
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Adenocarcinoma de Pulmão/genética , Antígeno B7-H1/genética , Carcinoma de Células Escamosas/genética , DNA Polimerase II/genética , Neoplasias Pulmonares/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Biomarcadores Tumorais/genética , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Mutação , Prognóstico , Análise de SobrevidaRESUMO
Tissue biopsy is the standard diagnostic procedure for cancer. Biopsy may also provide material for genotyping, which can assist in the diagnosis and selection of targeted therapies but may fall short in cases of inadequate sampling, particularly from highly heterogeneous tumors. Traditional tissue biopsy suffers greater limitations in its prognostic capability over the course of disease, most obviously as an invasive procedure with potential complications, but also with respect to probable tumor clonal evolution and metastasis over time from initial biopsy evaluation. Recent work highlights circulating tumor DNA (ctDNA) present in the blood as a supplemental, or perhaps an alternative, source of DNA to identify the clinically relevant cancer mutational landscape. Indeed, this noninvasive approach may facilitate repeated monitoring of disease progression and treatment response, serving as a means to guide targeted therapies based on detected actionable mutations in patients with advanced or metastatic solid tumors. Notably, ctDNA is heralding a revolution in the range of genomic profiling and molecular mechanisms to be utilized in the battle against cancer. This review will discuss the biology of ctDNA, current methods of detection and potential applications of this information in tumor diagnosis, treatment, and disease prognosis. Conventional classification of tumors to describe cancer stage follow the TNM notation system, heavily weighting local tumor extent (T), lymph node invasion (N), and detectable metastasis (M). With recent advancements in genomics and bioinformatics, it is conceivable that routine analysis of ctDNA from liquid biopsy (B) may make cancer diagnosis, treatment, and prognosis more accurate for individual patients. We put forward the futuristic concept of TNMB tumor classification, opening a new horizon for precision medicine with the hope of creating better outcomes for cancer patients.
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Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Biópsia Líquida/métodos , Estadiamento de Neoplasias/métodos , Neoplasias/sangue , Humanos , Neoplasias/classificação , Neoplasias/diagnósticoRESUMO
Importance: Small cell lung cancer (SCLC) is an aggressive disease that is characterized by rapid growth and the early development of metastases. Patients typically respond to initial chemotherapy but quickly experience relapse, resulting in a poor long-term outcome. Therapeutic innovations that substantially improve survival have historically been limited, and reliable, predictive biomarkers are lacking. Observations: This review examines the biologic characteristics of SCLC, the current treatment landscape, and ongoing efforts to identify novel therapeutic targets. Ongoing research has advanced the understanding of molecular categories and the immunologic microenvironment of SCLC, which in turn has helped improve disease classification and staging. Recently, immunotherapy-based regimens have become available for the management of SCLC, with 2 programmed cell death 1 ligand 1 inhibitors approved in combination with chemotherapy for first-line treatment of extensive-stage disease. For second-line treatment, a novel alkylating agent, lurbinectedin, which inhibits oncogenic transcription, has been approved for use in patients with metastatic SCLC. Furthermore, a wide variety of therapies and innovative combination regimens are being continuously evaluated. Potential therapeutic strategies, including aurora kinase A inhibitors, polyadenosine diphosphate-ribose polymerase inhibitors, ataxia telangiectasia and Rad3-related inhibitors, cyclin-dependent kinase 7 inhibitors, delta-like protein 3 agents, antiganglioside agents, CD47 inhibitors, and lysine-specific histone demethylase 1a inhibitors, are also being examined. Conclusions and Relevance: Therapeutic optimization of SCLC remains a challenge, but recent trial results and drug approvals are encouraging. Advances in research have revealed critical information regarding biologic characteristics of the disease, which may lead to the identification of vulnerabilities and the development of new therapies. Further research focused on identifying biomarkers and evaluating innovative therapies will be paramount to improving treatment outcomes for patients with SCLC.
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Produtos Biológicos , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia , Imunoterapia/métodos , Produtos Biológicos/uso terapêutico , Microambiente TumoralRESUMO
Despite therapeutic advancements, the prognosis of locally advanced non-small cell lung cancer (LANSCLC), which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes, remains poor. The emergence of immunotherapy with immune checkpoint blockade (ICB) is transforming cancer treatment. However, only a fraction of lung cancer patients benefit from ICB. Significant clinical evidence suggests that the proinflammatory tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression correlate positively with response to the PD-1/PD-L1 blockade. We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized (AeroNP-CDN) for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon (IFN) genes in macrophages and dendritic cells (DCs). Using a mouse model that recapitulates the clinical LANSCLC, we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype, activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+ T cells for adaptive anticancer immunity. Intriguingly, activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors, which, however, set a stage for response to anti-PD-L1 treatment. Indeed, anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice. Importantly, AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity. In conclusion, this study demonstrates a potential nano-immunotherapy strategy for LANSCLC, and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.
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Background and Objectives: This study describes patients' prognostic awareness and palliative care use in the setting of immunotherapy for metastatic non-small cell lung cancer (mNSCLC). Design: We surveyed 60 mNSCLC patients receiving immunotherapy at a large academic medical center; conducted follow-up interviews with 12 survey participants; and abstracted palliative care use, advance directive completion, and death within a year of survey completion from the medical record. Results: Forty seven percent of patients surveyed thought they would be cured; 83% were not interested in palliative care. Interviews suggested oncologists emphasized therapeutic options when discussing prognosis and that commonly used descriptions of palliative care may exacerbate misperceptions. Only 7% had received outpatient palliative care and 8% had an advance directive a year after the survey; only 16% of the 19 patients who died had received outpatient palliative care. Conclusions: Interventions are needed to facilitate prognostic discussions and outpatient palliative care during immunotherapy. Clinical Trial Registration Number NCT03741868.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Cuidados Paliativos , Prognóstico , Pacientes Ambulatoriais , ImunoterapiaRESUMO
BACKGROUND: One-half of all people who undergo lung cancer screening (LCS) currently use tobacco. However, few published studies have explored how to implement effective tobacco use treatment optimally during the LCS encounter. RESEARCH QUESTION: Was the Optimizing Lung Screening intervention (OaSiS) effective at reducing tobacco use among patients undergoing LCS in community-based radiology facilities? STUDY DESIGN AND METHODS: The OaSiS study (National Cancer Institute [NCI] Protocol No.: WF-20817CD) is an effectiveness-implementation hybrid type II cluster randomized trial of radiology facilities conducted in partnership with the Wake Forest National Cancer Institute Community Oncology Research Program research base. We randomly assigned 26 radiology facilities in 20 states to the intervention or usual care group. Staff at intervention facilities implemented a variety of strategies targeting the clinic and care team. Eligible patient participants were aged 55 to 77 years undergoing LCS and currently using tobacco. Of 1,094 who completed a baseline survey (523 intervention group, 471 control group) immediately before the LCS appointment, 956 completed the 6-month follow-up (86% retention rate). Fifty-four percent of those who reported not using tobacco at 6 months completed biochemical verification via mailed cotinine assay. Generalized estimating equation marginal models were used in an intention-to-treat analysis to predict 7-day tobacco use abstinence. RESULTS: The average self-reported abstinence among participants varied considerably across facilities (0%-27%). Despite a significant increase in average cessation rate over time (0% at baseline to approximately 13% at 6 months; P < .0001), tobacco use did not differ by trial group at 14 days (OR, 0.96; 95% CI, 0.46-1.99; P = .90), 3 months (OR, 1.17; 95% CI, 0.69-1.99; P = .56), or 6 months (OR, 0.97; 95% CI, 0.65-1.43; P = .87). INTERPRETATION: The OaSiS trial participants showed a significant reduction in tobacco use over time, but no difference by trial arm was found. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03291587; URL: www. CLINICALTRIALS: gov.
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Neoplasias Pulmonares , Abandono do Hábito de Fumar , Abandono do Uso de Tabaco , Humanos , Abandono do Hábito de Fumar/métodos , Detecção Precoce de Câncer , Neoplasias Pulmonares/diagnóstico , PulmãoRESUMO
Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Carcinoma de Pequenas Células do Pulmão/patologia , Topotecan/efeitos adversos , Neoplasias Pulmonares/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , RecidivaRESUMO
BACKGROUND: In a phase I study of angiotensin-(1-7) [Ang-(1-7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations. The current study examines Ang-(1-7) induced changes in biomarkers according to cancer type and investigates mechanisms of action engaged in vitro. METHODS: Plasma biomarkers were measured prior to Ang-(1-7) administration as well as 1, 2, 3, 4, and 6 hours after treatment. Tests for interaction were performed to determine the impact of cancer type on angiogenic hormone levels. If a positive interaction was detected, treatment-induced biomarker changes for individual cancer types were assessed. To investigate mechanisms of action, in vitro growth assays were performed using a murine endothelioma cell line (EOMA). PCR arrays were performed to identify and statistically validate genes that were altered by Ang-(1-7) treatment in these cells. RESULTS: Tests for interaction controlled for dose cohort and clinical response indicated a significant impact of cancer type on post-treatment VEGF and PlGF levels. Following treatment, PlGF levels decreased over time in patients with sarcoma (P = .007). Treatment of EOMA cells with increasing doses of Ang-(1-7) led to significant growth suppression at doses as low as 100 nM. PCR arrays identified 18 genes that appeared to have altered expression after Ang-(1-7) treatment. Replicate analyses confirmed significant changes in 8 genes including reduction in PlGF (P = .04) and hypoxia inducible factor 1α (HIF-1α) expression (P < .001). CONCLUSIONS: Ang-(1-7) has clinical and pre-clinical activity for vascular sarcomas that is linked to reduced HIF-1α and PlGF expression.
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Angiotensina I/metabolismo , Biomarcadores Tumorais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias de Tecido Vascular/metabolismo , Fragmentos de Peptídeos/metabolismo , Sarcoma/metabolismo , Adulto , Idoso , Análise de Variância , Angiotensina I/genética , Animais , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/genética , Fator de Crescimento Placentário , Proteínas da Gravidez/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Malignant pleural effusion (MPE) is indicative of terminal malignancy with a uniformly fatal prognosis. Often, two distinct compartments of tumour microenvironment, the effusion and disseminated pleural tumours, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumour-associated myeloid cells with the tumour-promoting phenotype, impairing antitumour immunity. Here we developed a liposomal nanoparticle loaded with cyclic dinucleotide (LNP-CDN) for targeted activation of stimulators of interferon genes signalling in macrophages and dendritic cells and showed that, on intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both effusion and pleural tumours. Moreover, combination immunotherapy with blockade of programmed death ligand 1 potently reduced MPE volume and inhibited tumour growth not only in the pleural cavity but also in the lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.
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Antígeno B7-H1/farmacologia , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Derrame Pleural Maligno/tratamento farmacológico , Imunidade Adaptativa/efeitos dos fármacos , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/química , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunoterapia , Interferons/genética , Camundongos , Nanopartículas/uso terapêutico , Cavidade Pleural/efeitos dos fármacos , Cavidade Pleural/imunologia , Cavidade Pleural/patologia , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/imunologia , Derrame Pleural Maligno/patologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Long-term outcomes after external beam radiation therapy (EBRT) and radiofrequency ablation (RFA) for medically inoperable early-stage non-small cell lung cancer (NSCLC) are not well known. METHODS AND MATERIALS: Patients with medically inoperable early-stage NSCLC were enrolled in a prospective single-arm, phase 2 study between June 2007 and October 2008 and were treated with RFA followed by EBRT. Radiation was delivered using hypofractionated radiation therapy (HFRT; 70.2 Gy in 26 fractions) or stereotactic body radiation therapy (54 Gy in 3 fractions). RESULTS: Twelve patients were evaluable; 10 patients were treated with HFRT. The cumulative incidence of local progression at 5 years was 16.7% (95% confidence interval [CI], 0-37.8). Median progression-free survival was 37.8 months (95% CI, 11.1 to not reached) and median overall survival was 53.6 months (95% CI, 21.0 to not reached). There were no mortalities within 30 days after RFA and no grade ≥4 toxicity. CONCLUSIONS: The combination of RFA with EBRT appears feasible with favorable long-term local control. However, because SBRT alone has similar or better rates of control, we do not recommend routine combined RFA and EBRT.
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Carcinoma Pulmonar de Células não Pequenas/terapia , Ablação por Cateter/métodos , Neoplasias Pulmonares/terapia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Terapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVE: Preclinical studies with muscadineâ¯grape extract (MGE) show antitumor activity and decreased systemic inflammation. This phase I study (NCT02583269) assessed safety and tolerability of a proprietary MGE preparation in patients with advanced solid tumors. METHODS: Patients with metastatic orâ¯unresectableâ¯cancers who were progressing on standard therapiesâ¯were assignedâ¯toâ¯MGE in a standard 3+3â¯design. Five dose levels were tested (320 to 1600 mg totalâ¯phenolics/d). Safety and maximum-tolerated dose were assessed after 4 weeks.â¯Patients were evaluated for response at 8 weeks and continued on MGE if clinically stable. Secondary outcomes were response, survival, adherence, fatigue, and quality of life (QOL). RESULTS: In total, 23 patients (lung, n=7; gastrointestinal, n=7; genitourinary, n=6; other, n=3) received MGE capsules by mouth twice daily. The cohort [median age 72 years, 48% Eastern Cooperative Oncology Group (ECOG) 2] was heavily pretreated. After 4 weeks on MGE, possibly attributable adverse events grade 2 or higher were fatigue (n=1), decreased lymphocyte count (n=1), and constipation (n=2), including 1 dose-limiting toxicity for grade 3 constipation. Maximum-tolerated dose was not reached. No partial responses were observed. Median time on therapy was 8 weeks, with 29% of patients treated beyond 16 weeks and a median overall survival of 7.2 months. QOL and fatigue levels were stable from baseline to 8 weeks. Higher MGE dose was correlated with improvement in self-reported physical well-being QOL at 8 weeks (r=0.6; P=0.04). CONCLUSIONS: MGE is safe andâ¯well-toleratedâ¯in heavily pretreated and older cancer patients. â¯The potential anticancer properties and the effects of MGE on physical well-being and QOL metrics will be evaluated in future studies.
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Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacocinética , Extratos Vegetais/uso terapêutico , Vitis/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/patologia , Prognóstico , Distribuição TecidualRESUMO
When recruited to promoters, histone 3 lysine 4 (H3K4) methyltransferases KMT2 (KMT2A-D) activate transcription by opening chromatin through H3K4 methylation. Here, we report that KMT2 mutations occur frequently in non-small cell lung cancer (NSCLC) and are associated with high mutation loads and poor survival. KMT2C regulated DNA damage responses (DDR) through direct recruitment to DNA damage sites by Ago2 and small noncoding DNA damage response RNA, where it mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. Furthermore, by disrupting homologous recombination (HR)-mediated DNA repair, KMT2C/D mutations sensitized NSCLC to Poly(ADP-ribose) polymerase inhibitors (PARPi), whose efficacy is unclear in NSCLC due to low BRCA1/2 mutation rates. These results demonstrate a novel, transcription-independent role of KMT2C in DDR and identify high-frequency KMT2C/D mutations as much-needed biomarkers for PARPi therapies in NSCLC and other cancers with infrequent BRCA1/2 mutations. SIGNIFICANCE: This study uncovers a critical role for KMT2C in DDR via direct recruitment to DNA damage sites, identifying high-frequency KMT2C/D mutations as biomarkers for response to PARP inhibition in cancer.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Animais , Apoptose , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , Proteínas de Ligação a DNA/genética , Feminino , Recombinação Homóloga , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Immunotherapy or chemoimmunotherapy is now standard treatment for most patients with metastatic non-small-cell lung cancer (mNSCLC), yet patient supportive care needs (SCNs) on immunotherapy are not well defined. This study characterized the SCNs and financial hardship of patients with mNSCLC treated with immunotherapy or chemoimmunotherapy and examined the relationship between patient and caregiver cancer-related employment reductions and patient financial hardship. METHODS: Patients with mNSCLC on immunotherapy or chemoimmunotherapy from a single academic medical center completed the SCNs Survey-34, items indexing material, psychological, and behavioral financial hardship, and the Comprehensive Score for Financial Toxicity. Univariate and bivariate analyses examined care needs, financial hardship, and impact of cancer-related employment reductions on patient financial hardship. RESULTS: Sixty patients (40% male; 75% White, mean age = 62.5 years, 57% on immunotherapy alone) participated. Fifty-five percent reported unmet needs in physical or daily living and psychological domains. Financial hardship was common (33% material, 63% psychological, and 57% behavioral). Fifty-two percent reported hardship in at least two domains. Forty percent reported a caregiver cancer-related employment reduction. Caregiver employment reduction was related to patient financial hardship (68% of those reporting caregiver employment reduction reported at least two domains of hardship v 40% of those without reduction, P = .03) and patient financial distress (mean Comprehensive Score for Financial Toxicity = 19.6 among those with caregiver employment reduction v 26.8 without, P = .01). CONCLUSION: Patients with mNSCLC treated with immunotherapy or chemoimmunotherapy report multiple unmet care needs and financial hardship. Psychological, functional, financial, and caregiver concerns merit assessment and intervention in this population.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/terapia , Emprego , Feminino , Estresse Financeiro , Humanos , Imunoterapia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients received veliparib orally twice daily (BID) in escalating doses (60-240 mg, Day -3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120-240 mg BID, Days -2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. RESULTS: Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7-32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0-not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0-not reached). CONCLUSIONS: When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimiorradioterapia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêuticoRESUMO
INTRODUCTION: Immunotherapy and chemoimmunotherapy clinical trials for metastatic non-small-cell lung cancer (mNSCLC) have generally excluded patients with poor performance status (PS) and have utilized patient-reported measures that could miss some symptoms associated with immunotherapy. The goals of this study were to describe quality of life and symptom burden among mNSCLC patients receiving immunotherapy in clinical practice, and to examine burden by Eastern Cooperative Oncology Group performance status (ECOG PS) and age. PATIENTS AND METHODS: Between 2017 and 2018, mNSCLC patients receiving immuno/chemoimmunotherapy at an academic medical center completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) and the National Cancer Institute Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Univariate and bivariate analyses described EORTC-QLQ-C30 subscales and the proportion reporting at least moderate PRO-CTCAE symptoms, and compared scores by ECOG PS (0/1 vs. 2/3) and age (< 70 vs. ≥ 70 years). RESULTS: Sixty patients (60% female; 75% < 70 years old; 68% ECOG PS 0/1; 57% receiving single-agent immunotherapy) participated. The mean EORTC-QLQ-C30 global health score was 62.6; EORTC symptoms were highest for fatigue, insomnia, dyspnea, and financial concerns (all > 30). Global health and pain were worse in ECOG PS 2/3 patients. For PRO-CTCAE, 20% to 40% reported at least moderate gastrointestinal, respiratory, dermatologic, arthralgia, or myalgia symptoms. The PRO-CTCAE pain score was higher among ECOG PS 2/3 patients. CONCLUSION: In clinical practice, global health was largely comparable to published clinical trials, but PRO-CTCAE items indicated a higher symptom prevalence. Closer monitoring of symptoms is warranted in ECOG PS 2/3 patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/mortalidade , Neoplasias Pulmonares/mortalidade , Medidas de Resultados Relatados pelo Paciente , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Estudos Transversais , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
INTRODUCTION: When the Centers for Medicare and Medicaid Services announced coverage for low dose CT lung cancer screening, they also mandated that imaging centers offer smoking cessation services. We designed the Optimizing Lung Screening (OaSiS) trial to evaluate strategies to implement the Public Health Service Guidelines for Treating Tobacco Use and Dependence during CT screening for lung cancer. METHODS AND DESIGN: OaSiS was implemented using a pragmatic effectiveness-implementation hybrid design in 26 imaging clinics across the United States affiliated with the National Cancer Institute's National Community Oncology Research Program (NCORP). The 26 sites selected for participation in the OaSiS trial were randomized to receive either a compendium of implementation strategies to add or enhance smoking cessation services during lung screening or to usual care. Usual care sites were given the option to receive the full compendium of implementation strategies at the conclusion of data collection. We have evaluated both the effectiveness of the implementation strategies to improve smoking cessation at six months among patients undergoing LDCT screening as well as the adoption and sustainability of evidence-based tobacco cessation strategies in imaging clinics. DISCUSSION: The OaSiS trial was designed to identify opportunities for implementing evidence-based smoking cessation into LDCT lung cancer screening imaging facilities and to establish the effectiveness of these services. We report our study design and evaluation, including strengths of the pragmatic design and the inclusion of a diverse range of screening programs. Establishing these tobacco cessation services will be critical to reducing smoking related morbidity and mortality.
Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Abandono do Hábito de Fumar/métodos , Fatores Etários , Cotinina/análise , Nível de Saúde , Humanos , Capacitação em Serviço , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Tutoria/métodos , Grupo Associado , Projetos de Pesquisa , Fatores Sexuais , Fatores Socioeconômicos , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: Immunotherapy has become a key treatment for patients with advanced non-small-cell lung cancer (NSCLC). While a survival advantage has been proven for patients who are medically fit, it is unknown whether a benefit exists for patients with poor performance status (PS). PATIENTS AND METHODS: We performed a retrospective analysis of NSCLC patients who received immunotherapy in our health system. Age and PS at the time of initial immunotherapy administration were assigned based on physician documentation. Radiographic response and date of progression were assigned according to the treating physician's assessment and confirmed by the study team. Immune-related adverse events were extracted from records. RESULTS: We identified 285 NSCLC patients who received immunotherapy between January 2014 and April 2018. In this group, 153 patients (53.7%) had PS 0-1, 114 (40.0%) had PS 2, and 18 (6.3%) had PS 3. Response rates were similar across PS groups with 26.6% for PS 1, 25.2% for PS 2, and 23.1% for PS 3 (P = .95). Survival outcomes varied with pretreatment PS. For PS 0-1, PS 2, and PS 3, median overall survival was 14.7, 8.3, and 1.5 months (P < .001), and progression-free survival was 7.4, 5.1, and 1.3 months (P < .001). Patients aged < 70 had a lower rate (7.6%) of immune-related adverse events requiring steroids compared to patients ≥ 70 (15%) (P = .04). CONCLUSION: Patients with poor baseline PS demonstrate similar response rate but inferior progression-free survival and overall survival compared to medically fit patients. Prospective trials are needed to optimize treatment for this large population.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Imunoterapia/mortalidade , Neoplasias Pulmonares/mortalidade , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Mounting evidence suggests that the tumor microenvironment is profoundly immunosuppressive. Thus, mitigating tumor immunosuppression is crucial for inducing sustained antitumor immunity. Whereas previous studies involved intratumoral injection, we report here an inhalable nanoparticle-immunotherapy system targeting pulmonary antigen presenting cells (APCs) to enhance anticancer immunity against lung metastases. Inhalation of phosphatidylserine coated liposome loaded with STING agonist cyclic guanosine monophosphate-adenosine monophosphate (NP-cGAMP) in mouse models of lung metastases enables rapid distribution of NP-cGAMP to both lungs and subsequent uptake by APCs without causing immunopathology. NP-cGAMP designed for enhanced cytosolic release of cGAMP stimulates STING signaling and type I interferons production in APCs, resulting in the pro-inflammatory tumor microenvironment in multifocal lung metastases. Furthermore, fractionated radiation delivered to one tumor-bearing lung synergizes with inhaled NP-cGAMP, eliciting systemic anticancer immunity, controlling metastases in both lungs, and conferring long-term survival in mice with lung metastases and with repeated tumor challenge.
Assuntos
Células Apresentadoras de Antígenos/efeitos dos fármacos , Imunoterapia , Neoplasias Pulmonares/secundário , Pulmão/efeitos dos fármacos , Melanoma Experimental/secundário , Proteínas de Membrana/agonistas , Nanopartículas , Nucleotídeos Cíclicos/farmacologia , Radioterapia , Administração por Inalação , Animais , Células Apresentadoras de Antígenos/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Interferon Tipo I/efeitos dos fármacos , Interferon Tipo I/imunologia , Lipossomos , Pulmão/imunologia , Pulmão/efeitos da radiação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Nucleotídeos Cíclicos/administração & dosagem , FosfatidilserinasRESUMO
PURPOSE: Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases in patients with limited stage small cell lung cancer (LS-SCLC). However, PCI is associated with neurotoxicity. Previous studies have not consistently used pretreatment magnetic resonance imaging. Modern imaging improvements continue to enhance early metastasis detection, potentially decreasing the utility of PCI. We sought to determine whether PCI was associated with improved outcomes in LS-SCLC patients with modern imaging. METHODS AND MATERIALS: We identified LS-SCLC patients with no intracranial disease who were treated between 2007 and 2018. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated and multivariate Cox proportional hazards models were generated. The cumulative incidence of brain metastases was estimated using competing risks methodology. RESULTS: Ninety-two patients were identified without intracranial disease at initial staging, 39 of whom received PCI. Median follow-up was 56.7 months. The median OS for the cohort was 35.5 months (95% CI, 25.8-49.3), and median PFS was 19.1 months (95% CI, 12.3-30.5). Median OS with PCI versus observation was 37.9 months (95% CI, 31.8-not reached) versus 30.5 months (95% CI, 14.6-56.1; P = .07), whereas median PFS was 26.3 months (95% CI 19.1-not reached) versus 12.3 months (95% CI, 8.5-30.5; P = .02), respectively. Overall, at 2 years, the cumulative incidence of brain metastases was 10% with PCI and 29% without; this increased to 32% and 29% by 4 years (P = .66). In those patients who had negative magnetic resonance imaging of the brain after completing initial treatment, the 1-year cumulative incidence of brain metastasis was not significantly different at 8% versus 11% (P = .46) respectively. Both PCI and treatment response were independent predictors for PFS on multivariate analysis. Stratified by disease response, patients with a complete response did not benefit from PCI (P = .50), whereas those with partial response or stable disease experienced improved PFS (P = .01). CONCLUSIONS: Overall, PCI was associated with improved PFS and reduced early incidence of brain metastases. Patients achieving a complete response to initial therapy did not experience a PFS benefit with PCI. This may indicate that subsets of LS-SCLC patients can potentially be spared from PCI in the era of modern imaging.
Assuntos
Neoplasias Encefálicas/radioterapia , Irradiação Craniana/métodos , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/mortalidadeRESUMO
INTRODUCTION: RNA isolation from tumor tissue is used for biomarker analyses and validation. Limited diagnostic material from small volume biopsies combined with an increasing demand for standard histologic, molecular characterization, and next generation sequencing applications often leads to limited material for research. We sought to evaluate small volume sampling of lung cancer tissue collected from a single needle pass during a diagnostic procedure and determine if it can provide RNA of acceptable quantity and quality. METHODS: We enrolled 140 patients with probable primary bronchogenic carcinoma and collected RNA from a dedicated FNA aspiration. Total RNA (ηg), RNA integrity number (RIN), and %Mass in base pairs were evaluated from each patient sample. A customized nanoString nCounter® 95-gene panel was used to profile the expression patterns of feature NSCLC genes. We compared gene expression patterns that distinguish lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) in our cohort with a corresponding Cancer Genome Atlas (TCGA) NSCLC datasets. RESULTS: Of the 149 patients consented. RNA-extraction was performed in 101 eligible patients. A satisfactory total RNA mass and RIN was quantified for all samples with a similar distribution among cellular subtypes. Mean %-Mass over 300 base pairs was noted for all specimens and 96% of samples met criteria to perform genetic evaluation with our commercialized gene expression assay. The FNA-derived transcriptomic results showed excellent consistency with the TCGA counterparts, and the differential expression pattern of LUAD vs LUSC subtypes were highly similar. DISCUSSION: In this study, RNA retrieval from a single-pass FNA regardless of procedural approach showed equivalence and suitability for gene expression assessments. RNA extraction from small volume samples has the potential to provide valuable material for genetic profiling.