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PURPOSE: Histologic transformation to small cell lung cancer (SCLC) is a mechanism of treatment resistance in patients with advanced oncogene-driven lung adenocarcinoma (LUAD) that currently requires histologic review for diagnosis. Herein, we sought to develop an epigenomic cell-free (cf)DNA-based approach to non-invasively detect small cell transformation in patients with EGFR mutant (EGFRm) LUAD. EXPERIMENTAL DESIGN: To characterize the epigenomic landscape of transformed (t)SCLC relative to LUAD and de novo SCLC, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to profile the histone modifications H3K27ac, H3K4me3, and H3K27me3, methylated DNA immunoprecipitation sequencing (MeDIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA sequencing on 26 lung cancer patient-derived xenograft (PDX) tumors. We then generated and analyzed H3K27ac ChIP-seq, MeDIP-seq, and whole genome sequencing cfDNA data from 1 ml aliquots of plasma from patients with EGFRm LUAD with or without tSCLC. RESULTS: Analysis of 126 epigenomic libraries from the lung cancer PDXs revealed widespread epigenomic reprogramming between LUAD and tSCLC, with a large number of differential H3K27ac (n=24,424), DNA methylation (n=3,298), and chromatin accessibility (n=16,352) sites between the two histologies. Tumor-informed analysis of each of these three epigenomic features in cfDNA resulted in accurate non-invasive discrimination between patients with EGFRm LUAD versus tSCLC (AUROC=0.82-0.87). A multi-analyte cfDNA-based classifier integrating these three epigenomic features discriminated between EGFRm LUAD versus tSCLC with an AUROC of 0.94. CONCLUSIONS: These data demonstrate the feasibility of detecting small cell transformation in patients with EGFRm LUAD through epigenomic cfDNA profiling of 1 ml of patient plasma.
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The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens and found an association with beneficial response to PD-1 blockade. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcome. This hub is distinct from mature tertiary lymphoid structures and is enriched for stem-like TCF7+PD-1+CD8+ T cells, activated CCR7+LAMP3+ dendritic cells and CCL19+ fibroblasts as well as chemokines that organize these cells. Within the stem-immunity hub, we find preferential interactions between CXCL10+ macrophages and TCF7-CD8+ T cells as well as between mature regulatory dendritic cells and TCF7+CD4+ and regulatory T cells. These results provide a picture of the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.
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Neoplasias Pulmonares , Humanos , Linfocitos T CD8-positivos , Receptor de Muerte Celular Programada 1 , Quimiocinas/metabolismo , Inmunoterapia/métodos , Microambiente TumoralRESUMEN
Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SIGNIFICANCE: SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. This article is featured in Selected Articles from This Issue, p. 695.
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Resistencia a Antineoplásicos , Amplificación de Genes , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Resistencia a Antineoplásicos/genética , Ratones , Animales , Proteínas Proto-Oncogénicas c-myc/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability to identify the transcriptional programs that govern cancer phenotypes and their dynamic changes during the course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling of cancer from 1 ml of patient plasma. Using an immunoprecipitation-based approach targeting histone modifications and DNA methylation, we measured 1,268 epigenomic profiles in plasma from 433 individuals with one of 15 cancers. Our assay provided a robust proxy for transcriptional activity, allowing us to infer the expression levels of diagnostic markers and drug targets, measure the activity of therapeutically targetable transcription factors and detect epigenetic mechanisms of resistance. This proof-of-concept study in advanced cancers shows how plasma epigenomic profiling has the potential to unlock clinically actionable information that is currently accessible only via direct tissue sampling.
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ADN Tumoral Circulante , Neoplasias , Humanos , Epigenómica , Biomarcadores de Tumor/genética , Neoplasias/genética , ADN Tumoral Circulante/genética , Biopsia Líquida/métodos , MutaciónRESUMEN
Introduction: MET amplification is a potentially actionable resistance mechanism in ALK-rearranged (ALK+) lung cancer. Studies describing treatment outcomes of this molecular subgroup are lacking. Methods: We assembled a cohort of patients with ALK+ lung cancer and acquired MET amplification (identified by tissue or plasma) who received regimens targeting both ALK and MET. Efficacy and safety were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse Events version 4.03, respectively. Results: A total of 12 patients were included in the series. MET amplification was detected after a median of 1.5 (range 1-5) lines of therapy. Four distinct regimens were implemented to address MET amplification: crizotinib (n = 2), lorlatinib plus crizotinib (n = 6), alectinib plus capmatinib (n = 3), and alectinib plus crizotinib (n = 1). Partial responses were observed in five (42%) of 12 patients, including patients who received crizotinib (n = one of two), lorlatinib plus crizotinib (n = three of six), and alectinib plus capmatinib (n = one of three). Primary progression was observed in four patients (33%). Grades 1 to 2 peripheral edema, occurring in seven (58%) patients, was found with both crizotinib and capmatinib. One patient required dose reduction of capmatinib plus alectinib for persistent grade 2 edema. Across the regimens, one patient discontinued therapy for toxicity, specifically neurocognitive toxicity from lorlatinib plus crizotinib. At progression on ALK+ MET therapy, potential resistance mechanisms included MET copy number changes and ALK kinase domain mutations. Conclusions: Combined ALK and MET inhibition is associated with moderate antitumor activity in patients with ALK+ NSCLC with concurrent MET amplification. Prospective studies are indicated to confirm activity and identify individuals most likely to benefit from the treatment.
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AIMS: Small cell lung carcinoma (SCLC) can be classified into transcription factor-based subtypes (ASCL1, NeuroD1, POU2F3). While in-vitro studies suggest intratumoral heterogeneity in the expression of these markers, how SCLC subtypes vary over time and among locations in patients remains unclear. METHODS AND RESULTS: We searched a consecutive series of patients at our institution in 2006-22 for those with greater than one available formalin-fixed paraffin-embedded SCLC sample in multiple sites and/or time-points. Immunohistochemistry for ASCL1, NeuroD1 and POU2F3 was performed and evaluated using H-scores, with subtype assigned based on the positive marker (H-score threshold >10) with the highest H-score. The 179 samples (75, lung; 51, lymph nodes; 53, non-nodal metastases) from 84 patients (74 with two, 10 with more than two samples) included 98 (54.7%) ASCL1-dominant, 47 (26.3%) NeuroD1-dominant, 15 (8.4%) POU2F3-dominant, 17 (9.5%) triple-negative and two (1.1%) ASCL1/NeuroD1 co-dominant samples. NeuroD1-dominant subtype was enriched in non-lung locations. Subtype concordance from pairwise comparison was 71.4% overall and 89.7% after accounting for ASCL1/NeuroD1-dual expressors and technical factors including <500 cells/slide, H-score thresholds and sample decalcification. No significant difference in subtype concordance was noted with a longer time lapse or with extrathoracic versus intrathoracic samples in this cohort. CONCLUSIONS: After accounting for technical factors, transcription factor-based subtyping was discordant among multiple SCLC samples in ~10% of patients, regardless of sample locations and time lapse. Our findings highlighted the spatiotemporal heterogeneity of SCLC in clinical samples and potential challenges, including technical and biological factors, that might limit concordance in SCLC transcription factor-based subtyping.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/patología , Factores de Transcripción/genética , Neoplasias Pulmonares/patología , Pulmón/patología , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Factores de Transcripción de Octámeros/metabolismoRESUMEN
Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here we present a pre-clinical system that recapitulates acquired cross-resistance in SCLC, developed from 51 patient-derived xenografts (PDXs). Each model was tested for in vivo sensitivity to three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These functional profiles captured hallmark clinical features, such as the emergence of treatment-refractory disease after early relapse. Serially derived PDX models from the same patient revealed that cross-resistance was acquired through a MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that this was not unique to one patient, as MYC paralog amplifications on ecDNAs were recurrent among cross-resistant models derived from patients after relapse. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SIGNIFICANCE: SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC.
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Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Animales , Ratones , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/terapia , Adenocarcinoma del Pulmón/metabolismo , Lactatos/metabolismo , Lactatos/farmacología , Lactatos/uso terapéutico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Macrófagos , Mutación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
BACKGROUND: The role of adjuvant therapy in completely resected primary tumors that have components of both non-small cell lung cancer and small cell lung cancer (combined SCLC) is poorly understood. We sought to determine the potential benefits of adjuvant chemotherapy in patients who undergo complete resection for early-stage combined SCLC. METHODS: Overall survival of patients with pathologic T1-2 N0 M0 combined SCLC who underwent complete resection in the National Cancer Database from 2004 to 2017, stratified by adjuvant chemotherapy vs surgery alone, was evaluated by multivariable Cox proportional hazards modeling and propensity score-matched analysis. Patients treated with induction therapy and those who died within 90 days of surgery were excluded from analysis. RESULTS: Of 630 patients who had pT1-2 N0 M0 combined SCLC during the study period, 297 patients (47%) underwent complete R0 resection. Adjuvant chemotherapy was administered to 63% of patients (n = 188), and 37% of patients underwent surgery alone (n = 109). In unadjusted analysis, the 5-year overall survival was 61.6% (95% CI, 50.8-70.7) for patients who underwent surgery alone and 66.4% (95% CI, 58.4-73.3) for patients who underwent adjuvant chemotherapy. In multivariable and propensity score-matched analysis, there were no significant differences in overall survival between adjuvant chemotherapy and surgery alone (adjusted hazard ratio, 1.16; 95% CI, 0.73-1.84). These findings were consistent when limited to patients who underwent lobectomies or to healthier patients who have at most 1 major comorbidity. CONCLUSIONS: In this national analysis, patients with pT1-2 N0 M0 combined SCLC treated with surgical resection alone have similar outcomes to those who undergo adjuvant chemotherapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Quimioterapia Adyuvante , Terapia Combinada , Neumonectomía/efectos adversos , Estadificación de Neoplasias , Estudios RetrospectivosRESUMEN
Background and Objective: Lineage transformation is a known mechanism of acquired resistance to targeted therapies in non-small cell lung cancer (NSCLC). Transformation to small cell and squamous carcinoma and epithelial-to-mesenchymal transition (EMT) have all been identified as recurrent but rare events in ALK-positive NSCLC. However, centralized data informing our understanding of the biology and clinical implications of lineage transformation in ALK-positive NSCLC are lacking. Methods: We performed a narrative review by searching the PubMed and clinicaltrials.gov databases for articles published in English from August, 2007 until October, 2022 and reviewing the bibliographies of key references to identify important literature related to lineage transformation in ALK-positive NSCLC. Key Content and Findings: In this review, we aimed to synthesize the published literature describing the incidence, mechanism(s), and clinical outcomes of lineage transformation in ALK-positive NSCLC. Lineage transformation as a mechanism of resistance to ALK TKIs in ALK-positive NSCLC is reported at a frequency of <5%. Available data across molecular subtypes of NSCLC suggest that the process of lineage transformation is likely to be driven by transcriptional reprogramming rather than acquired genomic mutations. Retrospective cohorts including tissue-based translational studies together with clinical outcomes make up the highest level of evidence that exists to inform treatment approach for patients with transfomed ALK-positive NSCLC. Conclusions: The clinicopathologic features of transformed ALK-positive NSCLC as well as the biologic mechanisms underling lineage transformation remain incompletely understood. Prospective data are needed to develop improved diagnostic and treatment algorithms for patients with ALK-positive NSCLC that undergo lineage transformation.
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The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, and CXCL9/10/11 + macrophages that preferentially interact with CD8 T cells. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD-1+ CD8 T cells and activated CCR7 + LAMP3 + dendritic cells, as well as chemokines that organize these cells. These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.
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Plasma cell-free DNA (cfDNA) sequencing is a compelling diagnostic tool in solid tumors and has been shown to have high positive predictive value. However, limited assay sensitivity means that negative plasma genotyping, or the absence of detection of mutation of interest, still requires reflex tumor biopsy. METHODS: We analyzed two independent cohorts of patients with advanced non-small-cell lung cancer (NSCLC) with known canonical driver and resistance mutations who underwent plasma cfDNA genotyping. We measured quantitative features, such as maximum allelic frequency (mAF), as clinically available measures of cfDNA tumor content, and studied their relationship with assay sensitivity. RESULTS: In patients with EGFR-mutant NSCLC harboring EGFR T790M, detection of driver mutation at > 1% AF conferred a sensitivity of 97% (368/380) for detection of T790M across three cfDNA genotyping platforms. Similarly, in a second cohort of patients with EGFR or KRAS driver mutations, when the mAF of nontarget mutations was > 1%, sensitivity for driver mutation detection was 100% (43/43). Combining the two NSCLC patient cohorts, the presence of nontarget mutations at mAF > 1% predicts for high sensitivity (> 95%) for identifying the presence of the known driver mutation, whereas mAF of ≤ 1% confers sensitivity of only 26%-54% across platforms. Focusing on 21 false-negative cases where the driver mutation was not detected on plasma next-generation sequencing, other mutations (presumably clonal hematopoiesis) were detected at ≤ 1% AF in 14 (67%). CONCLUSION: Plasma cfDNA genotyping is highly sensitive when adequate tumor DNA content is present. The likelihood of a false-negative cfDNA genotyping result is low in a sample with evidence of > 1% tumor content. Bioinformatic approaches are needed to further optimize the assessment of cfDNA tumor content in plasma genotyping assays.
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Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Genotipo , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Humanos , Sensibilidad y EspecificidadRESUMEN
Approximately 10% of EGFR-activating mutations occur as in-frame insertion mutations in exon 20 of the EGFR kinase domain (EGFR ins20). EGFR ins20 mutations have not demonstrated the same sensitivity to early generations of EGFR tyrosine kinase inhibitors (TKI) as canonical activating EGFR mutations such as del19 and L858R. Development of effective therapies for this subset of patients has been challenging, but recent years have seen more rapid progress in these efforts. In this review, we describe the molecular and clinicopathologic features of EGFR ins20 mutations and summarize recent data on emerging therapies for patients with this subtype of EGFR-mutant non-small cell lung cancer (NSCLC). SIGNIFICANCE: When activating mutations in EGFR were first discovered in lung cancer, the lack of sensitivity of tumors harboring EGFR ins20 mutations to early-generation EGFR TKIs resulted in this subset of EGFR-mutant tumors being initially classified as an untargetable or intrinsically resistant subpopulation. In addition, the diversity of mutations within EGFR exon 20 and resultant challenges identifying them on routine clinical genotyping tests led to underestimation of their frequency. However, recent scientific progress in targeting EGFR ins20 mutations as well as more effective identification of this clinical cohort has enhanced our ability to develop effective therapies for patients with this subtype of EGFR-mutant NSCLC.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Exones , Humanos , Neoplasias Pulmonares/genética , Mutación , Medicina de PrecisiónRESUMEN
SUMMARY: Lineage plasticity is an important, and likely underappreciated, mechanism of treatment resistance in lung cancer. Here, Quintanal-Villalonga and colleagues integrate results from multiomic analyses to provide key new insights into the biology of lineage plasticity. See related article by Quintanal-Villalonga et al., p. 3028.
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Neoplasias Pulmonares , Biología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genéticaRESUMEN
INTRODUCTION: Lung cancer is associated with severe coronavirus disease 2019 (COVID-19) infections. Symptom overlap between COVID-19 and lung cancer may complicate diagnostic evaluation. We aimed to investigate the incidence, symptoms, differential diagnosis, and outcomes of COVID-19 in patients with lung cancer. METHODS: To determine an at-risk population for COVID-19, we retrospectively identified patients with lung cancer receiving longitudinal care within a single institution in the 12 months (April 1, 2019 to March 31, 2020) immediately preceding the COVID-19 pandemic, including an "active therapy population" treated within the last 60 days of this period. Among patients subsequently referred for COVID-19 testing, we compared symptoms, laboratory values, radiographic findings, and outcomes of positive versus negative patients. RESULTS: Between April 1, 2019 and March 31, 2020, a total of 696 patients received longitudinal care, including 406 (58%) in the active therapy population. Among 55 patients referred for COVID-19 testing, 24 (44%) were positive for COVID-19, representing a cumulative incidence of 3.4% (longitudinal population) and 1.5% (active therapy population). Compared with patients who were COVID-19 negative, those who were COVID-19 positive were more likely to have a supplemental oxygen requirement (11% versus 54%, p = 0.005) and to have typical COVID-19 pneumonia imaging findings (5 versus 56%, p = 0.001). Otherwise, there were no marked differences in presenting symptoms. Among patients who were COVID-19 negative, alternative etiologies included treatment-related toxicity (26%), atypical pneumonia (22%), and disease progression (22%). A total of 16 patients positive for COVID-19 (67%) required hospitalization, and seven (29%) died from COVID-related complications. CONCLUSIONS: COVID-19 was infrequent in this lung cancer population, but these patients experienced high rates of morbidity and mortality. Oncologists should maintain a low threshold for COVID-19 testing in patients with lung cancer presenting with acute symptoms.
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While significant advancements have been made in the available therapies for metastatic non-small cell lung cancer (NSCLC), acquired resistance remains a major barrier to treatment. We have not yet achieved the ability to cure advanced NSCLC with systemic therapy, despite our growing understanding of many of the oncogenic drivers of this disease. Rather, the emergence of drug-tolerant and drug-resistant cells remains the rule, even in the face of increasingly potent targeted therapies. In this review, we provide a broad overview of the mechanisms of resistance to targeted therapy that have been demonstrated across molecular subtypes of NSCLC, highlighting the dynamic interplay between driver oncogene, bypass signaling pathways, shifting cellular phenotypes, and surrounding tumor microenvironment.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Antineoplásicos/efectos adversos , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Linaje de la Célula , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Terapia Molecular Dirigida , Resultado del Tratamiento , Microambiente TumoralRESUMEN
BACKGROUND: Approximately 10% of patients with SCLC develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor-infiltrating lymphocytes and immune recognition. METHODS: We queried 2,512,042 medical records from a single institution to identify patients who have SCLC with and without PNS and performed manual, retrospective chart review. We then performed multiplexed fluorescence immunohistochemistry and automated quantitative analysis (AQUA Technology) on tumors to assess CD3, CD4, and CD8 T cell infiltrates and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interactions. T cell infiltrates and PD-1/PD-L1 interaction scores were compared among patients with neurologic PNS, endocrinologic PNS, and a control group without PNS. Clinical outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: We evaluated 145 SCLC patients: 55 with PNS (25 neurologic and 30 endocrinologic) and 90 controls. Patients with neurologic PNS experienced improved overall survival compared to patients with endocrinologic PNS and controls (median overall survival of 24 months versus 12 months versus 13 months, respectively). Of the 145 patients, we identified tumor tissue from 34 patients that was adequate for AQUA analysis. Among 37 specimens from these 34 patients, patients with neurologic PNS had increased T cell infiltrates (p = 0.033) and PD-1/PD-L1 interaction (p = 0.014) compared to tumors from patients with endocrinologic PNS or controls. CONCLUSIONS: Tumor tissue from patients with SCLC with neurologic PNS showed increased tumor-infiltrating lymphocytes and PD-1/PD-L1 interaction consistent with an inflamed tumor microenvironment.