Genetic evolution to tyrosine kinase inhibitory therapy in patients with EGFR-mutated non-small-cell lung cancer.

BACKGROUND: Tumour heterogeneity impacts the efficacy of metastatic cancer treatment even if actionable mutations are identified. Clinicians need to understand if assessing one lesion provides reliable information to drive a therapeutic decision in non-small-cell lung cancer (NSCLC) patients. METHODS: We analysed inter-tumour heterogeneity from five autopsied individuals with NSCLC-harbouring mutations in the epidermal growth factor receptor (EGFR), treated with EGFR tyrosine kinase inhibitors (TKIs). Through a comprehensive next-generation sequencing (NGS) oncopanel, and an EGFR panel for digital droplet PCR (ddPCR), we compared metastases within individuals, longitudinal biopsies from the same lesions and, whenever possible, the primary naive tumour. RESULTS: Analysis of 22 necropsies from five patients revealed homogeneity in pathogenic mutations and TKI-resistance mechanisms within each patient in four of them. In-depth analysis by whole-exome sequencing from patient 1 confirmed homogeneity in clonal mutations, but heterogeneity in passenger subclonal alterations. Different resistance mechanisms were detected depending on the patient and line of treatment. Three patients treated with a c-MET inhibitor in combination with TKI lost MET amplification upon progression. CONCLUSION: At a given point and under selective TKI pressure, a single metastasis biopsy in disseminated tumours from EGFR-mutated NSCLC patients could provide a reasonable assessment of actionable alterations useful for therapeutic decisions.

Analysis of PM10 and PM2.5 Concentrations in an Urban Atmosphere in Northern Spain.

This work analyses levels of particles PM10 and PM2.5 recorded at four air-quality monitoring stations located in the urban area of Valladolid (Spain) during 2015-2016. To achieve this, the evolution of particle concentrations at different time scales was determined. Average concentrations ranged from 15.3 to 17.6 µg m-3 for PM10 and between 8.9 and 14.8 µg m-3 for PM2.5. The highest monthly means were recorded in autumn and winter. The difference between mean concentrations at weekends and on weekdays for PM10 was around 3 µg m-3 at most of the measuring stations and was 1 µg m-3 for PM2.5. Two concentration peaks were found during the day, one in the morning and the other in the evening, which evidenced the influence of traffic and other anthropogenic activities on PM concentrations. Their mean values were approximately 21 and 17-21 µg m-3, respectively, for PM10. Mean maximum values for PM2.5 were 12 µg m-3, except at one of the measuring sites, with 17 µg m-3 for the morning maximum and 1 µg m-3 more for the nocturnal peak. In addition, the impact of long-distance transport of air masses in the study area was analysed by applying a HYSPLIT trajectory model, taking into account backward trajectories of European, African, and Atlantic origins as well as local conditions. In particular, high concentration events due to Saharan dust intrusions are presented. Finally, background levels of particle concentrations estimated at most sampling areas were around 15 and 7.7 µg m-3 for the PM10 and PM2.5 particle fractions, respectively.

The influence of meteorological variables on CO2 and CH4 trends recorded at a semi-natural station.

CO2 and CH4 evolution is usually linked with sources, sinks and their changes. However, this study highlights the role of meteorological variables. It aims to quantify their contribution to the trend of these greenhouse gases and to determine which contribute most. Six years of measurements at a semi-natural site in northern Spain were considered. Three sections are established: the first focuses on monthly deciles, the second explores the relationship between pairs of meteorological variables, and the third investigates the relationship between meteorological variables and changes in CO2 and CH4. In the first section, monthly outliers were more marked for CO2 than for CH4. The evolution of monthly deciles was fitted to three simple expressions, linear, quadratic and exponential. The linear and exponential are similar, whereas the quadratic evolution is the most flexible since it provided a variable rate of concentration change and a better fit. With this last evolution, a decrease in the change rate was observed for low CO2 deciles, whereas an increasing change rate prevailed for the rest and was more accentuated for CH4. In the second section, meteorological variables were provided by a trajectory model. Backward trajectories from 1-day prior to reaching the measurement site were used to calculate distance and direction averages as well as the recirculation factor. Terciles of these variables were determined in order to establish three intervals with low, medium and high values. These intervals were used to classify the variables following their interval widths and skewnesses. The best correlation between pairs of meteorological variables was observed for the average distance, in particular with horizontal wind speed. Sinusoidal relationships with the average direction were obtained for average distance and for vertical wind speed. Finally, in the third section, the quadratic evolution was considered in each interval of all the meteorological variables. As regards the main result, the greatest increases were obtained for high potential temperature for both gases followed by low and medium boundary layer height for CO2 and CH4, respectively. Combining both meteorological variables provided increases of 22 ± 9 and 0.070 ± 0.019 ppm for CO2 and CH4, respectively, although the number of observations affected is small, around 7%.

Outcome prognostic factors in inoperable malignant bowel obstruction.

PURPOSE: Inoperable malignant bowel obstruction (MBO), a severe complication of peritoneal carcinomatosis, has a low desobstruction rate (30-40 %) and end-of-life decision-making is hampered by the lack of known prognostic factors. This study aimed to explore prognostic factors for desobstruction in MBO. METHODS: All patients with inoperable MBO admitted in our large oncology hospital between 2010 and 2013 were treated following a clinical protocol based on antiemetics, steroids and two antisecretories, octreotide, and hyoscine butylbromide. Two prognostic factor analyses using logistic regressions were performed, one based on data from day 1 of admission and the other on data from day 8. RESULTS: Forty-five patients were included. Frequency of desobstruction was 48.9 %. In the analysis of prognostic factors on day 1, MBO episodes derived from functional physiopathologic mechanisms (vs. mechanic or mixed) were more prone to resolve (p < 0.001 corrected for multiple comparisons). Considering patients alive with persistent obstruction on day 8, a better clinical condition was the variable more associated with desobstruction, but without statistical significance after correction for multiple comparisons. CONCLUSIONS: A functional physiopathologic mechanism of MBO development may be an early prognostic factor for desobstruction. A high proportion of desobstruction was observed, suggesting that the combination of antisecretories with different mechanism of action warrants further investigation.

CH4 continuous measurements in the upper Spanish plateau.

Continuous methane, CH4, concentrations were measured in a rural area of the upper Spanish plateau from June 2010 to May 2012 by cavity ring-down spectroscopy technique. The results obtained have proven the local impact of anthropogenic nearby sources on CH4 concentrations, and evidence a significant influence on the overall mean, averaged daily and seasonal patterns recorded at the measuring site. The positive anomalies in CH4 concentrations, statistically significant at 95 %, in the southeast sector, defined here as ESE, SE, SSE and S sectors, have been attributed to the contribution of the Valladolid urban plume and the urban landfill. Based on this finding, CH4 background levels were associated to the concentrations recorded in the remaining un-disturbed sectors. CH4 means of the overall data set, the southeast sector and background sectors yielded average means of 1,894.1, 1,927.9 and 1,887.1 ppb, respectively. The diurnal and seasonal patterns of the overall data set and background concentrations have shown that CH4 concentrations are mainly dominated by its reaction with OH radicals. Maximum hourly concentrations were reached during night-time and early morning, 5-7 h, whereas minimum concentrations were recorded at 16 h. Maximum and minimum monthly means were recorded in January and July, respectively. The diurnal and seasonal amplitudes, namely, peak-to-peak means, of background concentrations were 25.1 and 48.1 ppb, respectively. These values were significantly lower than those obtained for the overall data set, 42.9 and 58.1 ppb, revealing the significant role of local influences on CH4 concentrations despite the low frequency of southeast winds recorded at the measuring site, 16.9 %.

Connection between Weather Types and Air Pollution Levels: A 19-Year Study in Nine EMEP Stations in Spain.

This study focuses on the analysis of the distribution, both spatial and temporal, of the PM10 (particulate matter with a diameter of 10 µm or less) concentrations recorded in nine EMEP (European Monitoring and Evaluation Programme) background stations distributed throughout mainland Spain between 2001 and 2019. A study of hierarchical clusters was used to classify the stations into three main groups with similarities in yearly concentrations: GC (coastal location), GNC (north-central location), and GSE (southeastern location). The highest PM10 concentrations were registered in summer. Annual evolution showed statistically significant decreasing trends in PM10 concentration in all the stations covering a range from -0.21 to -0.50 µg m-3/year for Barcarrota and Víznar, respectively. Through the Lamb classification, the weather types were defined during the study period, and those associated with high levels of pollution were identified. Finally, the values exceeding the limits established by the legislation were analyzed for every station assessed in the study.

Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy.

Malignant pleural mesothelioma (MPM) is a locally aggressive disease related to asbestos exposure with a median survival for untreated patients of 4-8 months. The combination of chemotherapy based on platinum and antifolate is the standard treatment, and the addition of bevacizumab adds two months to median survival. Recently, in first-line treatment, immunotherapy combining nivolumab with ipilimumab has been shown to be superior to chemotherapy in the CheckMate-743 study in terms of overall survival (18.1 months), leading to its approval by the FDA and EMA. The positive results of this study represent a new standard of treatment for patients with MPM; however, not all patients will benefit from immunotherapy treatment. In an effort to improve the selection of patient candidates for immunotherapy for different tumors, biomarkers that have been associated with a greater possibility of response to treatment have been described. MPM is a type of tumor with low mutational load and neo-antigens, making it a relatively non-immunogenic tumor for T cells and possibly less susceptible to responding to immunotherapy. Different retrospective studies have shown that PD-L1 expression occurs in 20-40% of patients and is associated with a poor prognosis; however, the predictive value of PD-L1 in response to immunotherapy has not been confirmed. The purpose of this work is to review the state of the art of MPM treatment in the year 2023, focusing on the efficacy results of first-line or subsequent immunotherapy studies on patients with MPM and possible chemo-immunotherapy combination strategies. Additionally, potential biomarkers of response to immunotherapy will be reviewed, such as histology, PD-L1, lymphocyte populations, and TMB.

Dynamic changes in circulating tumor DNA assessed by shallow whole-genome sequencing associate with clinical efficacy of checkpoint inhibitors in NSCLC.

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis are the main therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) without a druggable oncogenic alteration. Nevertheless, only a portion of patients benefit from this type of treatment. Here, we assessed the value of shallow whole-genome sequencing (sWGS) on plasma samples to monitor ICI benefit. We applied sWGS on cell-free DNA (cfDNA) extracted from plasma samples of 45 patients with metastatic NSCLC treated with ICIs. Over 150 samples were obtained before ICI treatment initiation and at several time points throughout treatment. From sWGS data, we computed the tumor fraction (TFx) and somatic copy number alteration (SCNA) burden and associated them with ICI benefit and clinical features. TFx at baseline correlated with metastatic lesions at the bone and the liver, and high TFx (≥ 10%) associated with ICI benefit. Moreover, its assessment in on-treatment samples was able to better predict clinical efficacy, regardless of the TFx levels at baseline. Finally, for a subset of patients for whom SCNA burden could be computed, increased burden correlated with diminished benefit following ICI treatment. Thus, our data indicate that the analysis of cfDNA by sWGS enables the monitoring of two potential biomarkers-TFx and SCNA burden-of ICI benefit in a cost-effective manner, facilitating multiple serial-sample analyses. Larger cohorts will be needed to establish its clinical potential.

Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients.

MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.

Spatial analysis of CO2 concentration in an unpolluted environment in northern Spain.

CO(2) transport in the low atmosphere near the surface at night was analysed using spatial procedures applied to back trajectories. Concentration and meteorological data were obtained at a rural site during a seven and a half month campaign. Daily evolution of CO(2) skewness showed positive values during the night and negative values during the day. One concentration and one recirculation factor, an indicator of local recirculation, were associated with each back trajectory calculated during the night to study source and meteorological influences on concentrations recorded. Moreover, four procedures were used to analyse the trajectories, and their strengths and weaknesses were also investigated. (1) The nonparametric trajectory analysis applied with two weight functions successfully marked the most contributing region. (2) Hexagonal cells were used to account for radial distribution of trajectories. The potential source contribution function calculated in these cells highlighted the influence of the source against meteorology, this procedure therefore proving the best to mark the source direction. (3) Trajectory sector analysis revealed the most contributing wind sector and emphasised the role of recirculation in the E-S sectors. (4) Cluster analysis grouped neighbouring trajectories and was the most flexible procedure to classify them, providing a contrast of around 12 ppm between medians obtained in the SE cluster and the least contributing group.

Trend analysis and outlier distribution of CO2 and CH4: A case study at a rural site in northern Spain.

CO2 and CH4 outliers may have a noticeable impact on the trend of both gases. Nine years of measurements since 2010 recorded at a rural site in northern Spain were used to investigate these outliers. Their influence on the trend was presented and two limits were established. No more than 23.5% of outliers should be excluded from the measurement series in order to obtain representative trends, which were 2.349 ± 0.012 ppm year-1 for CO2 and 0.00879 ± 0.00004 ppm year-1 for CH4. Two types of outliers were distinguished. Those above the trend line and the rest below the trend line. Outliers were described by skewed distributions where the Weibull distribution figures prominently in most cases. A qualitative procedure was presented to exclude the worst fits, although five statistics were considered to select the best fit. In this case, the modified Nash-Sutcliffe efficiency is prominent. Finally, three symmetrical distributions were added to fit the observations when outliers are excluded, with the Gaussian and beta distributions providing the best fits. As a result, certain skewed functions, such as the lognormal distribution, whose use is frequent for air pollutants, could be questioned in certain applications.

Hepatic Rupture as the Initial Presentation of an EGFR-Mutated Lung Adenocarcinoma: A Case Report.

Hepatic rupture is a rare complication of solid tumor malignancies, notably in lung adenocarcinomas, and carries an extremely poor overall prognosis. Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma predict benefit with tyrosine kinase inhibitors (TKIs). This case report describes a female patient who presented with a metastatic hepatic rupture and was subsequently diagnosed with EGFR-mutated lung adenocarcinoma. The tumor had an impressive response to TKI inhibitor treatment, reversing her extremely poor, short-term prognosis. We believe this unique case sheds light on the treatment management of hepatic ruptures and supports the high response rate seen with TKIs in EGFR-mutated lung cancers, regardless of the patient's performance status.

Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer.

In recent years, immunotherapy-based regimens have been included into the treatment's algorithm of several cancer types. Programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) interact with their ligands found on the surface of antigen presenting cells (APC) or tumor cells (PD-L1/2 and CD80/86). Through these interactions, stimulatory or inhibitory signals are established. Immune checkpoint inhibitors (ICIs), block these interactions, and when administered not only as monotherapy but also as part of combination regimens, have shown to improve survival results in multiple advanced cancers leading to an increasing number of patients treated with ICI and, as a consequence, a rise in the number of patients developing immune-related adverse events (irAEs). Presence of irAEs has been associated with greater benefit from treatment, especially when blocking PD-L1. Recent data suggests that treatment benefit persists after discontinuation of ICIs due to a treatment related adverse event, regardless of the grade. Patients experiencing grade 3-4 irAEs are at risk of toxicity recurrence after reintroducing immunotherapy and therefore, the decision to resume the treatment is challenging. In these cases, a multidisciplinary approach is always needed and several factors should be considered. Management of severe toxicities may require systemic corticosteroids which can impact on T-cell function. Due to their immunosuppressive properties, it is necessary to deeper determine how corticosteroids influence responses. In terms of overall survival (OS), the use of steroids as therapy for irAEs seems not to reduce OS and several studies have reported durable responses in patients experiencing autoimmune toxicities treated with corticosteroids.

High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC.

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1/programmed death-ligand 1 axis have transformed the management of advanced non-small cell lung cancer (NSCLC). However, many patients do not benefit from this type of treatment, and thus several molecular biomarkers of benefit have been explored. The value of somatic copy number alterations (SCNAs) burden remains elusive. PATIENTS AND METHODS: We assembled a cohort of 109 patients with NSCLC treated with ICIs and available tumor samples. We performed shallow whole-genome sequencing on 89 patients to determine genome-wide SCNAs and targeted gene expression analysis on 63 patients to study immune infiltration. We analyzed SCNAs burden in different ways (ie, the fraction of the genome altered or number of events) and studied their association with ICIs benefit based on survival analysis. We correlated SCNAs burden and immune infiltration on 35 patients of our cohort and on patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RESULTS: High SCNAs burden, computed in diverse ways, is negatively associated with ICIs progression-free survival (PFS), with the fraction of the genome altered (FGA) by arm and chromosome events showing the strongest association with PFS (p=0.002) (n=77). Nevertheless, we found differences in SCNAs across some clinicopathological features (sample site origin). A multivariate analysis adjusted for relevant characteristics showed that the FGA of arm and chromosome alterations was strongly associated with PFS (HR=2.21, p=3.3 x 10-5). Finally, we confirmed that SCNAs burden negatively correlates with tumor immune infiltration (n=35), although this correlation was not found for the males studied. Similar results were observed in the TCGA cohort. CONCLUSIONS: SCNAs burden is a potential biomarker of benefit to ICIs in patients with NSCLC, although there appear to be some nuances worth consideration. Further studies will be needed to establish its role as a biomarker of benefit to ICIs.

Propranolol for infantile hemangiomas.

Propranolol has been used successfully in a limited number of children with infantile hemangiomas. This multicenter retrospective study describes the efficacy and adverse effects of propranolol in infantile hemangioma. Seventy-one infants with infantile hemangiomas were treated with oral propranolol, 1 mg/kg/12 hours, for at least 12 weeks. A photograph based severity scoring assessment was performed by five observers to evaluate efficacy, utilizing a scoring system of 10 as the original infantile hemangioma before treatment and 0 as completely normal skin. The mean of the five independent measurements was used in the analysis. Propranolol was a rapid and effective treatment for infantile hemangiomas at 4 weeks (p < 0.001), at 8 weeks (p < 0.001 compared to the 4 wks value), at 12 weeks (p < 0.05 compared to the 8 wks value), and thereafter up to 32 weeks (p < 0.01 compared to the 16 wks value). The response of infantile hemangiomas to propranolol was similar regardless of sex, age at onset of treatment, type of involvement (segmental and nonsegmental), facial segments affected, special locations (eyelid, nasal tip, and parotid region), ulceration, and depth of infantile hemangiomas. Very few side effects were reported; mainly agitated sleep in 10 of 71 patients. In the series of patients in this study, oral propranolol 2 mg/kg/day was a well-tolerated and effective treatment for infantile hemangiomas. Prospective studies are needed to establish the exact role of propranolol in the treatment of infantile hemangiomas.

Influence of Wind Speed on CO2 and CH4 Concentrations at a Rural Site.

Meteorological variables have a noticeable impact on pollutant concentrations. Among these variables, wind speed is typically measured, although research into how pollutants respond to it can be improved. This study considers nine years of hourly CO2 and CH4 measurements at a rural site, where wind speed values were calculated by the METEX model. Nine wind speed intervals are proposed where concentrations, distribution functions, and daily as well as annual cycles are calculated. Contrasts between local and transported concentrations are around 5 and 0.03 ppm for CO2 and CH4, respectively. Seven skewed distributions are applied, and five efficiency criteria are considered to test the goodness of fit, with the modified Nash-Sutcliffe efficiency proving to be the most sensitive statistic. The Gumbel distribution is seen to be the most suitable for CO2, whereas the Weibull distribution is chosen for CH4, with the exponential function being the worst. Finally, daily and annual cycles are analysed, where a gradual decrease in amplitude is observed, particularly for the daily cycle. Parametric and nonparametric procedures are used to fit both cycles. The latter gave the best fits, with the agreement being higher for the daily cycle, where evolution is smoother than for the annual cycle.

Spatial analysis and evolution of four air pollutants in England and Wales.

Pollution control is based on an exhaustive knowledge of concentration distributions. This study analyses a detailed database of NO2, O3, PM10 and PM2.5 in England and Wales over the period 2007-2011. Daily and annual means were considered in a 1-km spatial resolution. Histograms revealed a shape like a sawtooth. The interval was wide for NO2 and O3, although with a gap, whilst the particulate matter range was narrow. Spring provided the peak for the O3 annual cycle, whereas minima for the other pollutants were reached in summer. A trend for the annual medians of particulate matter was observed, with a minimum in the period analysed. However, the pattern was uniform for NO2 and O3. Cities appeared as NO2 hot spots and O3 cold spots. Wales stood out as an NO2 clean country, although with high O3 levels. Sources or sinks of particulate matter were not observed, suggesting that more detailed analysis is required. Two NO2 pollution axes were sometimes seen, one in the south from London to Bristol, and the second in the north, from Liverpool to Kingston Upon Hull. No annual spatial pattern was seen for the remaining pollutants beyond the contrast between cities and country sites for O3. Consequently, spatial analysis allows the real impact of pollutant sources be known, although it must be performed with a detailed temporal resolution in order to investigate the extension, quantity, and length of the concentrations calculated.

Interrelations between Patients' Clinicopathological Characteristics and Their Association with Response to Immunotherapy in a Real-World Cohort of NSCLC Patients.

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment. Unfortunately, only some patients benefit from these therapies. Thus, certain clinicopathological characteristics of the patients have been proposed as biomarkers of ICIs response. We assembled a retrospective cohort of 262 NSCLC patients treated with ICIs, compiled relevant clinicopathological characteristics, and studied their associations with treatment outcome using Cox proportional-hazards survival models. Additionally, we investigated the interrelations between clinicopathological features and devised a method to create a compendium associated with ICIs response by selecting those that provide non-redundant information. In multivariate analyses, ECOG performance status (hazard ratio (HR) 1.37 (95% CI 1.11 to 1.68), p < 0.005), LDH (HR 1.24 (95% CI 1.03 to 1.48), p = 0.02)) and PD-L1 negativity were associated with decreased PFS (HR 1.92 (95% CI 1.03 to 3.58), p < 0.04), whereas presentation of immune-related adverse events (irAEs) (HR 0.35 (95% CI 0.22 to 0.55, p < 0.005) or females (HR 0.52 (95% CI 0.33 to 0.80, p < 0.005) had longer progression-free survival. Additionally, numerous clinicopathological indicators were found to be interrelated. Thus, we searched for features that provide non-redundant information, and found the combination of LDH levels, irAEs, and gender to have a better association with ICIs treatment response (cross-validated c-index = 0.66). We concluded that several clinicopathological features showed prognostic value in our real-world cohort. However, some are interrelated, and compendiums of features should therefore consider these interactions. Joint assessment of LDH, irAEs, and gender may be a good prognostic compendium.

Efficacy of chemotherapy for malignant pleural mesothelioma according to histology in a real-world cohort.

CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line in MPM with some differences in the efficacy of chemotherapy according to histology. The objective of this study is to characterize the impact of chemotherapy according to histology in patients diagnosed with MPM at our institution. Clinical records of all MPM patients diagnosed at Vall d'Hebron University Hospital between November 2002 and April 2020 were reviewed. Associations between clinical variables and outcomes were assessed with Cox regression models. Survival data were calculated by the Kaplan-Meier method. 189 patients were included with 76% of tumors classified as epithelioid subtype. First line chemotherapy was offered to 85% of patients. Median survival in overall population was 21.3 months (95% CI 17.2-24.3). We found that patients with epithelioid tumors had better overall survival (OS) and progression free survival (PFS). Median OS of epithelioid patients treated with first line chemotherapy was 26.7 months versus 15.0 months in non-epithelioid patients (HR 2.25 CI 95% 1.4-3.4; p < 0.001). Median PFS for patients with epithelioid tumors treated with chemotherapy was 4.8 months versus 3.6 months in non-epithelioid (HR 1.5 CI 95% 1.0-2.3; p = 0.03). The improvement of outcomes in patients with epithelioid histology was detected in patients treated with cisplatin or carboplatin. Histology was not a predictive factor for the platinum agent sensitivity (p of interaction PFS = 0.09, p of interaction OS = 0.65). In our series, patients with non-epithelioid tumors presented worse prognosis. Although epithelioid tumors exposed to cisplatin had higher PFS, histology was not a clear predictor of chemotherapy efficacy.

Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs.