RESUMEN
Liquid biopsy is now considered a valuable diagnostic tool for advanced metastatic non-small cell lung cancer (NSCLC). In NSCLC, circulating tumor DNA (ctDNA) analysis has been shown to increase the chances of identifying the presence of targetable mutations and has been adopted by many clinicians owing to its low risk. Serial monitoring of ctDNA may also help assess the treatment response or for monitoring relapse. As the presence of detectable plasma ctDNA post-surgery likely indicates residual tumor burden, studies have been performed to quantify plasma ctDNA to assess minimal residual disease (MRD) in early-stage resected NSCLC. Most data on utilizing liquid biopsy for monitoring MRD in early-stage NSCLC are from small-scale studies using ctDNA. Here, we review the recent research on liquid biopsy in NSCLC, not limited to ctDNA, and focus on novel methods such as micro RNAs (miRNA) and long non-coding (lncRNA).
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Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Ácidos Nucleicos Libres de Células/sangre , Biopsia Líquida/métodos , Neoplasias Pulmonares/patología , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Humanos , Neoplasias Pulmonares/sangreRESUMEN
Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.
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Antineoplásicos/farmacología , Carioferinas/antagonistas & inhibidores , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/farmacología , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/tratamiento farmacológico , Transcriptoma/efectos de los fármacos , Quinasas p21 Activadas/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Quimioterapia Combinada , Proteínas Activadoras de GTPasa/metabolismo , Humanos , Carioferinas/metabolismo , Ratones Endogámicos ICR , Ratones SCID , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/uso terapéutico , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/efectos de los fármacos , Carcinoma Anaplásico de Tiroides/metabolismo , Neoplasias de la Tiroides/metabolismo , Transcriptoma/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas p21 Activadas/metabolismo , Proteína Exportina 1RESUMEN
Cancer cachexia is a debilitating metabolic syndrome accounting for fatigue, an impairment of normal activities, loss of muscle mass associated with body weight loss eventually leading to death in majority of patients with advanced disease. Cachexia patients undergoing skeletal muscle atrophy show consistent activation of the SCF ubiquitin ligase (F-BOX) family member Atrogin-1 (also known as MAFBx/FBXO32) alongside the activation of the muscle ring finger protein1 (MuRF1). Other lesser known F-BOX family members are also emerging as key players supporting muscle wasting pathways. Recent work highlights a spectrum of different cancer signaling mechanisms impacting F-BOX family members that feed forward muscle atrophy related genes during cachexia. These novel players provide unique opportunities to block cachexia induced skeletal muscle atrophy by therapeutically targeting the SCF protein ligases. Conversely, strategies that induce the production of proteins may be helpful to counter the effects of these F-BOX proteins. Through this review, we bring forward some novel targets that promote atrogin-1 signaling in cachexia and muscle wasting and highlight newer therapeutic opportunities that can help in the better management of patients with this devastating and fatal disorder.
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Caquexia/etiología , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Atrofia Muscular/etiología , Neoplasias/genética , Neoplasias/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Caquexia/tratamiento farmacológico , Caquexia/metabolismo , Proteínas F-Box/antagonistas & inhibidores , Regulación Leucémica de la Expresión Génica , Humanos , Espacio Intracelular/metabolismo , Terapia Molecular Dirigida , Complejos Multiproteicos/metabolismo , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/metabolismo , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Unión Proteica , Transporte de Proteínas , Proteínas Ligasas SKP Cullina F-box/metabolismo , Transducción de SeñalRESUMEN
With the rapid development of precision medicine, next-generation sequencing (NGS) has provided the ability to uncode tumors at the DNA level. Identifying EGFR mutations and other molecular changes has become more crucial in the management of non-small cell lung cancer (NSCLC) than ever before. Although the histologic subtypes in patients with advanced NSCLC remain valid in determining treatment options, the detection of specific molecular signatures such as de novo T790M with sensitizing EGFR mutations could be more useful than the histologic subtype itself. Germline T790M mutation should be suspected and tested for when multiple biopsies show de novo T790M mutations or when de novo T790M is found in patients with a family history of lung cancer. This case report presents a 60-year-old woman with bilateral NSCLC with 3 different distinct histologic diagnoses. Evaluating the molecular profile using NGS completely changed the diagnosis, prognosis, and management of this rare presentation of NSCLC.
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Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutación , Alelos , Sustitución de Aminoácidos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Femenino , Pruebas Genéticas , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/tratamiento farmacológico , Imagen por Resonancia Magnética , Persona de Mediana Edad , Estadificación de Neoplasias , Medicina de Precisión , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor ß superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was to evaluate the activity of dalantercept in RM-SCCHN. METHODS: Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments. RESULTS: Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia. CONCLUSIONS: In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016;122:3641-9. © 2016 American Cancer Society.
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Receptores de Activinas Tipo II/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Ligandos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del TratamientoRESUMEN
BACKGROUND: AT-101 is a BCL-2 Homolog domain 3 mimetic previously demonstrated to have tumoricidal effects in advanced solid organ malignancies. Given the evidence of activity in xenograft models, treatment with AT-101 in combination with docetaxel is a therapeutic doublet of interest in metastatic head and neck squamous cell carcinoma. PATIENTS AND METHODS: Patients included in this trial had unresectable, recurrent, or distantly metastatic head and neck squamous cell carcinoma (R/M HNSCC) not amenable to curative radiation or surgery. This was an open label randomized, phase II trial in which patients were administered AT-101 in addition to docetaxel. The three treatment arms were docetaxel, docetaxel plus pulse dose AT-101, and docetaxel plus metronomic dose AT-101. The primary endpoint of this trial was overall response rate. RESULTS: Thirty-five patients were registered and 32 were evaluable for treatment response. Doublet therapy with AT-101 and docetaxel was well tolerated with only 2 patients discontinuing therapy due to treatment related toxicities. The overall response rate was 11 % (4 partial responses) with a clinical benefit rate of 74 %. Median progression free survival was 4.3 months (range: 0.7-13.7) and overall survival was 5.5 months (range: 0.4-24). No significant differences were noted between dosing strategies. CONCLUSION: Although met with a favorable toxicity profile, the addition of AT-101 to docetaxel in R/M HNSCC does not appear to demonstrate evidence of efficacy.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Gosipol/análogos & derivados , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Taxoides/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Docetaxel , Esquema de Medicación , Femenino , Gosipol/administración & dosificación , Gosipol/efectos adversos , Gosipol/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Taxoides/administración & dosificación , Taxoides/efectos adversos , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Cetuximab/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Metotrexato/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Michigan , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICI) have profoundly impacted survival among patients with metastatic non-small cell lung cancer (NSCLC). However, population-based studies evaluating this impact on survival by race and socioeconomic factors are lacking. METHODS: We utilized the SEER-Medicare database to identify patients with metastatic NSCLC diagnosed between 2015 and 2019. The primary study outcomes were the receipt of an ICI and overall survival (OS). Chi-square tests and logistic regression were utilized to identify demographic factors associated with receipt of ICI. The Kaplan-Meier method was used to calculate 2-year OS rates, and log-rank tests were used to compared survival by race/ethnicity. RESULTS: Out of 17,134 patients, approximately 39% received an ICI. Those diagnosed with cancer recently (in 2019), who are relatively younger (<85 years old), non-Hispanic white, non-Hispanic Asian, or Hispanic, living in high socioeconomic status or metropolitan areas, not Medicaid eligible, and with adenocarcinoma histology were more likely to receive ICI. The 2-year OS rate from diagnosis was 21% for the overall population. The 2-year OS rate from ICI initiation was 30%, among those who received at least one cycle and 11% among those who did not receive ICI. The 2-year OS rates were higher among non-Hispanic whites (22%) and non-Hispanic Asians (23%) compared to non-Hispanic Blacks (15%) and Hispanics (17%). There was no significant racial differences in survival for those who received ICI. CONCLUSION: ICI utilization rates and the resulting outcomes were inferior for certain vulnerable groups, mandating the need for strategies to improve access to care.
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BACKGROUND: About 75% of medullary thyroid cancers (MTCs) are sporadic with 45% to 70% being driven by a RET mutation. Selpercatinib is an approved treatment for RET-mutated (mut RET ) MTC; however, treatments are needed for wild-type RET MTC (wt RET ). Genomic alterations and transcriptomic signatures of wt RET MTC may reveal new therapeutic insights. STUDY DESIGN: We did a retrospective analysis of MTC samples submitted for DNA/RNA sequencing and programmed cell death ligand 1 expression using immunohistochemistry at a Clinical Laboratory Improvement Amendments/College of American Pathologists-certified laboratory. Tumor microenvironment immune cell fractions were estimated using RNA deconvolution (quanTIseq). Transcriptomic signatures of inflammation and MAP kinase pathway activation scores were calculated. Mann-Whitney U, chi-square, and Fisher's exact tests were applied (p values adjusted for multiple comparisons). RESULTS: The 160-patient cohort included 108 mut RET and 52 wt RET MTC samples. wt RET tumors frequently harbored mitogen-activated protein kinase (MAPK) pathway mutations, including HRAS (42.31%), KRAS (15.7%), NF1 (6.7%), and BRAF (2%), whereas only 1 MAPK pathway mutation ( NF1 ) was identified among mut RET MTC. Recurrent mutations seen in wt RET MTC included MGA , VHL, APC , STK11 , and NFE2L2 . Increased transcriptional activation of the MAPK pathway was observed in patients with wt RET harboring mutations in MAPK genes. Although the frequency of programmed cell death ligand 1 expression was similar in wt RET and mut RET (10.2% vs 7%, p = 0.531), wt RET tumors were more often tumor mutational burden high (7.7% vs 0%, p = 0.011), and wt RET MTC exhibited higher expression of immune checkpoint genes. CONCLUSIONS: We identified molecular alterations and immune-related features that distinguish wt RET from mut RET MTC. Although RET mutation drives MTC in the absence of other alterations, we showed that wt RET MTC frequently harbors MAPK pathway mutations. These findings may indicate a potential basis for MAPK-targeted therapy, possibly in combination with immuno-oncology agents for selected patients with wt RET MTC.
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Carcinoma Neuroendocrino , Mutación , Proteínas Proto-Oncogénicas c-ret , Neoplasias de la Tiroides , Transcriptoma , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Estudios Retrospectivos , Proteínas Proto-Oncogénicas c-ret/genética , Femenino , Persona de Mediana Edad , Masculino , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/tratamiento farmacológico , Adulto , Anciano , Terapia Molecular Dirigida , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética , Microambiente Tumoral , Anciano de 80 o más Años , Genómica , Adulto JovenRESUMEN
PURPOSE: Adenoid cystic carcinoma (ACC) is an uncommon salivary gland cancer with no approved therapies available to treat advanced, incurable disease. Recent molecular profiling efforts have identified two important subtypes: the more aggressive ACC-I is characterized by Notch pathway alterations and MYC amplification whereas ACC-II demonstrates a more indolent phenotype and TP63 overexpression. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved de-identified samples from 438 patients with ACC with tumor samples sent for commercially-available molecular profiling (Caris Life Sciences). Next-generation whole-exome and whole-transcriptomic sequencing was performed on primary and metastatic samples. Immunostaining for PD-L1 and RNA deconvolution (quanTIseq) was used to explore the tumor immune microenvironment (TME). Real-world clinical and survival outcome metrics were extracted from insurance claims data. RESULTS: MYC expression was 1.61-fold higher (39.8 vs. 24.7; P < 0.0001) among NOTCH1-mutant ACC-I tumors, whereas MYB/L1 fusion rates were similar among ACC-I/II. The median B-cell fraction in the TME was higher among ACC-II (7.1% vs. 5.8%; P < 0.01), although infiltrating T cells subsets were low among either ACC subgroup (both <1%). When pooling systemic treatment categories, ACC-I patients had worse outcomes with available therapies (HR, 3.06; 95% confidence interval, 1.65-5.68; P < 0.01), with no significant difference in overall survival between ACC-I/II based on chemotherapy or VEGFR tyrosine kinase inhibitor exposure in smaller subsets. CONCLUSIONS: We confirmed the previously reported associations with MYC and TP63 in the prognostically relevant subgroups of ACC-I and -II, respectively, and report immunologic differences among these subtypes. Survival outcomes are comparatively worse in ACC-I regardless of treatment type.
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Biomarcadores de Tumor , Carcinoma Adenoide Quístico , Neoplasias de las Glándulas Salivales , Microambiente Tumoral , Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Carcinoma Adenoide Quístico/mortalidad , Carcinoma Adenoide Quístico/tratamiento farmacológico , Carcinoma Adenoide Quístico/inmunología , Carcinoma Adenoide Quístico/terapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/mortalidad , Neoplasias de las Glándulas Salivales/inmunología , Neoplasias de las Glándulas Salivales/terapia , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Biomarcadores de Tumor/genética , Estudios Retrospectivos , Adulto , Resultado del Tratamiento , Perfilación de la Expresión Génica , Proteínas Proto-Oncogénicas c-myc/genética , Pronóstico , Antígeno B7-H1/genética , Receptor Notch1/genética , Regulación Neoplásica de la Expresión Génica , Anciano de 80 o más Años , MutaciónRESUMEN
In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non-small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1-6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1-negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1-negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy. Significance: Autologous tumor-infiltrating lymphocyte therapy lifileucel was administered to 28 patients with heavily pretreated metastatic non-small cell lung cancer (mNSCLC). Responses were observed in patients with driver mutations, and various tumor mutational burdens and PD-L1 expression, potentially addressing an unmet medical need in patients with mNSCLC refractory to prior therapy. See related commentary by Lotze et al., p. 1366.
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Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Linfocitos Infiltrantes de Tumor , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplanteRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) are the newest class of anticancer drugs. Pneumonitis is increasingly being recognized as a potential complication of these agents. METHODS: We conducted a retrospective study of patients who received ICIs at a comprehensive cancer center. We collected data on demographics, type of malignancy, type of ICI agent, incidence of pneumonitis up to 6 weeks after receiving ICI agent, clinical characteristics, and risk factors for overall survival in patients who develop pneumonitis. RESULTS: A total of 654 patients received ICIs during the study period. The most common type of cancer for which ICI was given was adenocarcinoma of the lung (29%), followed by renal cell cancer (12%) and squamous cell lung cancer (12%). Among the study patients, 41% received nivolumab and 32% received pembrolizumab. Other patients in the study received combination of ICIs or ICI plus chemotherapeutic agent, or were part of clinical trial involving ICI. Overall 42 (6.4%) patients developed pneumonitis within 6 weeks after the last dose of treatment of any ICI agent. Of these, 81% of patients had Grade ≥ 2 pneumonitis and 45% of these required hospital admission for pneumonitis, with 10% of them requiring admission to intensive care unit. Overall, patients who received pembrolizumab-containing regimen, had prior chemotherapy, or who never had cancer-related surgery had increased risk of death. CONCLUSION: Our large retrospective study shows real-life data of incidence of pneumonitis in patients who are treated with ICIs for cancer treatment. Our data indicate that the incidence of pneumonitis is overall lower than that reported previously with relatively good outcomes.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neumonía , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Incidencia , Estudios Retrospectivos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neumonía/inducido químicamente , Neumonía/epidemiología , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
PURPOSE: Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18-associated HNSCC. PATIENTS AND METHODS: In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS). RESULTS: Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7-47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. <25%). DCR-16 was 44.8% (95% CI, 26.5-64.3). Median PFS was 3.5 months (95% CI, 1.9-9.0); median OS was 29.2 months (15.2-not calculable). Twenty-eight (80.0%) patients had treatment-related adverse events [grade 3: 5 (14.3%); no grade 4/5], resulting in discontinuation in 2 (5.7%) patients. HPV-16/18-specific T cells increased on treatment; 4 of 8 evaluable patients had a >2-fold increase in tumor-infiltrating CD8+ T cells. CONCLUSIONS: MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.
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Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Virus del Papiloma Humano , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Infecciones por Papillomavirus/complicaciones , Papillomavirus Humano 16/genética , Antígeno B7-H1/genética , Papillomavirus Humano 18RESUMEN
BACKGROUND: We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored. METHODS: We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (Tcellinf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS). RESULTS: Two hundred and fifty-seven patients (KEYNOTE-012, n = 106; KEYNOTE-055, n = 151) had TMB data available; of these, 254 had PD-L1 and 236 had Tcellinf GEP. TMB, PD-L1, and Tcellinf GEP were each significantly associated with ORR (p < 0.01). Kaplan-Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD-L1 or Tcellinf GEP (Spearman ρ = -0.03 and ρ = -0.13, respectively); PD-L1 and Tcellinf GEP were moderately correlated (Spearman ρ = 0.47). In multivariate models, TMB, PD-L1, and Tcellinf GEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD-L1 or TMB and Tcellinf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcellinf GEP) were associated with response. HPV detection by p16-immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method. CONCLUSIONS: TMB and the inflammatory biomarkers PD-L1 and Tcellinf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC.
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Antineoplásicos Inmunológicos , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Antígeno B7-H1 , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/inducido químicamente , Infecciones por Papillomavirus/complicaciones , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Biomarcadores de Tumor/genéticaRESUMEN
Mammary analog secretory carcinoma (MASC) is a newly described carcinoma with a molecular hallmark of ETV6-NTRK3 fusion that promotes oncogenesis. While MASC histopathology was well-studied in the literature, clinical behavior remains unstudied. We present a 22-year-old man with painless parotid mass, which was diagnosed as salivary gland cancer, MASC subtype.
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Although treated appropriately, bladder cancer can recur and metastasize. We are reporting the case of a patient with a well-cured bladder cancer who presented after 14 months with femoral pain which turned out to be a bony metastasis. The patient underwent surgical excision followed by chemotherapy.
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BACKGROUND: Initial primary head and neck cancer (IPHNC) is associated with second primary lung cancer (SPLC). We studied this association in a population with a high proportion of African American (AA) patients. METHODS: Patients with IPHNC and SPLC treated between 2000 and 2017 were reviewed for demographic, disease, and treatment-related characteristics and compared to age-and-stage-matched controls without SPLC. Logistic and Cox regression models were used to analyze the relationship of these characteristics with the development of SPLC and overall survival (OS). RESULTS: Eighty-seven patients and controls were compared respectively. AA race was associated with a significantly higher risk of developing SPLC (OR 2.92, 95% CI 1.35-6.66). After correcting for immortal time bias, patients with SPLC had a significantly lower OS when compared with controls (HR 0.248, 95% CI 0.170-0.362). CONCLUSIONS: We show that AA race is associated with an increased risk of SPLC after IPHNC; reasons of this increased risk warrant further investigation.
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Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares , Neoplasias Primarias Secundarias , Negro o Afroamericano , Neoplasias de Cabeza y Cuello/complicaciones , Humanos , Neoplasias Primarias Secundarias/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is a frequently devastating cancer that affects more than a half million people annually worldwide. Although some cases arise from infection with human papillomavirus (HPV), HPV-negative HNSCC is more common, and associated with worse outcome. Advanced HPV-negative HNSCC may be treated with surgery, chemoradiation, targeted therapy, or immune checkpoint inhibition (ICI). There is considerable need for predictive biomarkers for these treatments. Defects in DNA repair capacity and loss of cell-cycle checkpoints sensitize tumors to cytotoxic therapies, and can contribute to phenotypes such as elevated tumor mutation burden (TMB), associated with response to ICI. Mutation of the tumor suppressors and checkpoint mediators TP53 and CDKN2A is common in HPV-negative HNSCC. EXPERIMENTAL DESIGN: To gain insight into the relation of the interaction of TP53 and CDKN2A mutations with TMB in HNSCC, we have analyzed genomic data from 1,669 HPV-negative HNSCC tumors with multiple criteria proposed for assessing the damaging effect of TP53 mutations. RESULTS: Data analysis established the TP53 and CDKN2A mutation profiles in specific anatomic subsites and suggested that specific categories of TP53 mutations are more likely to associate with CDKN2A mutation or high TMB based on tumor subsite. Intriguingly, the pattern of hotspot mutations in TP53 differed depending on the presence or absence of a cooccurring CDKN2A mutation. CONCLUSIONS: These data emphasize the role of tumor subsite in evaluation of mutational profiles in HNSCC, and link defects in TP53 and CDKN2A to elevated TMB levels in some tumor subgroups.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neoplasias de Cabeza y Cuello/genética , Humanos , Mutación , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
PURPOSE: ARRY-382 (PF-07265804) is a selective inhibitor of colony-stimulating factor-1 receptor. We evaluated the safety and preliminary efficacy of ARRY-382 plus pembrolizumab in patients with advanced solid tumors. PATIENTS AND METHODS: This was an open-label, multicenter, Phase 1b/2 study (NCT02880371) performed over September 1, 2016 to October 24, 2019. In the Phase 1b dose-escalation, patients with selected advanced solid tumors received ARRY-382 [starting dose 200 mg once daily (QD) orally] plus pembrolizumab [2 mg/kg intravenously (IV) every 3 weeks (Q3W)]. Phase 2 patients had: Pancreatic ductal adenocarcinoma (PDA); programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitor-refractory (PD-1/PD-L1 IR) advanced solid tumors; or platinum-resistant ovarian cancer (prOVCA). Patients received ARRY-382 at the maximum tolerated dose (MTD) of 300 mg QD plus pembrolizumab 200 mg IV Q3W. RESULTS: Primary endpoints of dose-limiting toxicities (DLT; Phase 1b) and objective response rate (Phase 2) were met. In Phase 1b, 19 patients received ARRY-382 200-400 mg. Three patients reported DLTs. The MTD of ARRY-382 (plus pembrolizumab) was 300 mg QD. In Phase 1b, 2 patients (10.5%) had confirmed partial response (PR): 1 with PDA and 1 with ovarian cancer, lasting 29.2 and 3.1 months, respectively. In Phase 2, there were 27, 19, and 11 patients in the PDA, PD-1/PD-L1 IR, and prOVCA cohorts, respectively. One patient (3.7%) with PDA had a PR lasting 2.4 months. The most frequent ARRY-382-related adverse events were increased transaminases (10.5%-83.3%) and increased creatine phosphokinase (18.2%-50.0%). CONCLUSIONS: Although limited clinical benefit was observed, ARRY-382 plus pembrolizumab was well tolerated.
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Neoplasias Ováricas , Receptor de Muerte Celular Programada 1 , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1 , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas QuinasasRESUMEN
BACKGROUND: HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. METHODS: We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. RESULTS: Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004). CONCLUSION: A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.