Resistance to KRAS inhibition in advanced non-small cell lung cancer.

Lung cancer remains the leading cause of cancer death globally. More than 50% of new cases are diagnosed in an advanced or metastatic stage, thus contributing to the poor survival of such patients. Mutations in the KRAS (Kirsten rat sarcoma virus) gene occur in nearly a third of lung adenocarcinoma and have for decades been deemed an 'undruggable' target. Yet, in recent years, a growing number of small molecules, such as the GTPase inhibitors, has been investigated in clinical trials of lung cancer patients harboring KRAS mutations, yielding promising results with improved outcomes. Currently, there are only two approved targeted therapies (adagrasib and sotorasib) for advanced or metastatic KRAS-mutated NSCLC from the second-line setting onwards. In this narrative review, we will focus on KRAS, its molecular basis, the role of its co-mutations, clinical evidence for its inhibition, putative mutation to resistance, and future strategies to overcome resistance to KRAS inhibition.

ERS International Congress 2023: highlights from the Thoracic Oncology Assembly.

Lung cancer is the leading cause of cancer mortality in the world. It greatly affects the patients' quality of life, and is thus a challenge for the daily practice in respiratory medicine. Advances in the genetic knowledge of thoracic tumours' mutational landscape, and the development of targeted therapies and immune checkpoint inhibitors, have led to a paradigm shift in the treatment of lung cancer and pleural mesothelioma. During the 2023 European Respiratory Society Congress in Milan, Italy, experts from all over the world presented their high-quality research and reviewed best clinical practices. Lung cancer screening, management of early stages of lung cancer, application of artificial intelligence and biomarkers were discussed and they will be summarised here.

ERS International Congress 2022: highlights from the Thoracic Oncology Assembly.

Thoracic malignancies are associated with a substantial public health burden. Lung cancer is the leading cause of cancer-related mortality worldwide, with significant impact on patients' quality of life. Following 2 years of virtual European Respiratory Society (ERS) Congresses due to the COVID-19 pandemic, the 2022 hybrid ERS Congress in Barcelona, Spain allowed peers from all over the world to meet again and present their work. Thoracic oncology experts presented best practices and latest developments in lung cancer screening, lung cancer diagnosis and management. Early lung cancer diagnosis, subsequent pros and cons of aggressive management, identification and management of systemic treatments' side-effects, and the application of artificial intelligence and biomarkers across all aspects of the thoracic oncology pathway were among the areas that triggered specific interest and will be summarised here.

Pharmacogenetics of advanced lung cancer: Predictive value of functional genetic polymorphism AGXT Pro11Leu in clinical outcome?

INTRODUCTION: AGXT gene codes for the enzyme alanine glyoxylate aminotransferase, which is involved in hepatic peroxisomal metabolism of platinum-based chemotherapeutic agents. The association of genetic variant AGXT rs34116584 on the clinical outcome and response to chemotherapy of patients with non-small cell lung cancer (NSCLC) remains to be established. Our aim was to evaluate the association of functional AGXT gene polymorphism in NSCLC progression, considering as primary and secondary endpoint, progression free survival (PFS) and overall survival (OS), respectively. METHODS: Genotyping of theAGXT rs34116584 genetic polymorphism was performed by mass spectrometry on 168 DNA samples from patients with NSCLC (stages IIIA-IVB). Univariate survival analysis included the study of Kaplan-Meier curves with the Log-Rank test, while Cox regression was used as a multivariate analysis. RESULTS: Multivariate analysis showed shorter PFS for T carriers [HR=2.0, 95% CI, 1.4-3.0, p<0.0001] and shorter OS [HR=1.8, 95% CI, 1.1-3.0, p=0.017] globally, as well as in a subgroup of patients (n=144) treated with first line platinum-based chemotherapy [HR=2.0, 95% CI, 1.3-3.1, p=0.001] and [HR=1.8, 95% CI, 1.1-3.1, p=0.026], respectively. CONCLUSION: This polymorphism seems to have an impact on NSCLC progression, opening new perspectives for its inclusion as a pharmacogenetic predictor of response to platinum-based chemotherapy.

Outcomes of Airway Stents in the Palliative Care of Patients With Cancer.

INTRODUCTION: A significant proportion of patients with advanced primary or metastatic intrathoracic malignancy will eventually develop central airway obstruction. The morbidity associated with malignant airway obstruction (MAO) is considerable and the management is difficult. Our aim was to evaluate the outcomes of tracheobronchial stenting in patients with MAO and its role in palliative care. MATERIAL AND METHODS: This retrospective study involved a consecutive case series of patients with advanced cancer with MAO who underwent tracheobronchial stenting between August 2014 and August 2019. The European Cooperative Oncology Group (ECOG) scale was used to evaluate patient functional status before and after tracheobronchial stenting. Univariate survival analysis included Kaplan-Meier curves with Log-Rank test, while Cox regression was used as a multivariate analysis. RESULTS: We included 28 patients with median age of 55.0 years (interquartile range = 49.3-66.5) and 89.3% male. The most frequent primary tumour was the esophagus followed by lungs. The majority of the patients (75%) expressed immediate symptom relief after stenting and there was a significant improvement in the mean ECOG performance status (PS; P = .005). There was no intraprocedure mortality and complications were observed in 6 patients. The median survival after airway stenting was 39.0 days (95% CI = 32.2-45.8) with poorer PS after stent insertion associated with lower overall survival (hazard ratio = 2.3 [95% CI = 1.1-4.9], P = .030) on multivariate analysis. CONCLUSION: Airway stent is a safe and effective procedure that offers rapid palliation of symptoms with no major complications. Therefore, stent placement should be considered as part of the treatment of patients with terminal cancer.

Germline Genetic Variants of the Renin-Angiotensin System, Hypoxia and Angiogenesis in Non-Small Cell Lung Cancer Progression: Discovery and Validation Studies.

INTRODUCTION: The renin-angiotensin system (RAS) is involved in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. Our aim was to study the association of putatively functional genetic polymorphisms in genes coding for proteins involved in RAS, hypoxia and angiogenesis with non-small cell lung cancer (NSCLC) prognosis. METHODS: Genotyping of 52 germline variants from genes of the RAS and hypoxic/angiogenic factors/receptors was performed using MassARRAY iPLEX Gold in a retrospective cohort (n = 167) of advanced NSCLC patients. Validation of the resulting genetic markers was conducted in an independent group (n = 190), matched by clinicopathological characteristics. RESULTS: Multivariate analysis on the discovery set revealed that MME rs701109 C carriers were protected from disease progression in comparison with homozygous T (hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.2-0.8, p = 0.010). Homozygous A and T genotypes for KDR rs1870377 were at increased risk for disease progression and death compared to heterozygous (HR = 1.7, 95% CI = 1.2-2.5, p = 0.005 and HR = 2.1, 95% CI = 1.2-3.4, p = 0.006, respectively). Carriers of homozygous genotypes for ACE2 rs908004 presented increased risk for disease progression, only in the subgroup of patients without tumour actionable driver mutations (HR = 2.9, 95% CI = 1.3-6.3, p = 0.010). Importantly, the association of homozygous genotypes in MME rs701109 with risk for disease progression was confirmed after multivariate analysis in the validation set. CONCLUSION: This study provides evidence that MME polymorphism, which encodes neprilysin, may modulate progression-free survival in advanced NSCLC. Present genetic variation findings will foster basic, translational, and clinical research on their role in NSCLC.

Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions.

The mechanistic involvement of the renin-angiotensin system (RAS) reaches beyond cardiovascular physiopathology. Recent knowledge pinpoints a pleiotropic role for this system, particularly in the lung, and mainly through locally regulated alternative molecules and secondary pathways. Angiotensin peptides play a role in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. This manuscript reviews the literature supporting a role for the renin-angiotensin system in the lung tumor microenvironment and discusses whether blockade of this pathway in clinical settings may serve as an adjuvant therapy in lung cancer.

Patient-physician discordance in assessment of adherence to inhaled controller medication: a cross-sectional analysis of two cohorts.

OBJECTIVE: We aimed to compare patient's and physician's ratings of inhaled medication adherence and to identify predictors of patient-physician discordance. DESIGN: Baseline data from two prospective multicentre observational studies. SETTING: 29 allergy, pulmonology and paediatric secondary care outpatient clinics in Portugal. PARTICIPANTS: 395 patients (≥13 years old) with persistent asthma. MEASURES: Data on demographics, patient-physician relationship, upper airway control, asthma control, asthma treatment, forced expiratory volume in one second (FEV1) and healthcare use were collected. Patients and physicians independently assessed adherence to inhaled controller medication during the previous week using a 100 mm Visual Analogue Scale (VAS). Discordance was defined as classification in distinct VAS categories (low 0-50; medium 51-80; high 81-100) or as an absolute difference in VAS scores ≥10 mm. Correlation between patients' and physicians' VAS scores/categories was explored. A multinomial logistic regression identified the predictors of physician overestimation and underestimation. RESULTS: High inhaler adherence was reported both by patients (median (percentile 25 to percentile 75) 85 (65-95) mm; 53% VAS>80) and by physicians (84 (68-95) mm; 53% VAS>80). Correlation between patient and physician VAS scores was moderate (rs=0.580; p<0.001). Discordance occurred in 56% of cases: in 28% physicians overestimated adherence and in 27% underestimated. Low adherence as assessed by the physician (OR=27.35 (9.85 to 75.95)), FEV1 ≥80% (OR=2.59 (1.08 to 6.20)) and a first appointment (OR=5.63 (1.24 to 25.56)) were predictors of underestimation. An uncontrolled asthma (OR=2.33 (1.25 to 4.34)), uncontrolled upper airway disease (OR=2.86 (1.35 to 6.04)) and prescription of short-acting beta-agonists alone (OR=3.05 (1.15 to 8.08)) were associated with overestimation. Medium adherence as assessed by the physician was significantly associated with higher risk of discordance, both for overestimation and underestimation of adherence (OR=14.50 (6.04 to 34.81); OR=2.21 (1.07 to 4.58)), while having a written action plan decreased the likelihood of discordance (OR=0.25 (0.12 to 0.52); OR=0.41 (0.22 to 0.78)) (R2=44%). CONCLUSION: Although both patients and physicians report high inhaler adherence, discordance occurred in half of cases. Implementation of objective adherence measures and effective communication are needed to improve patient-physician agreement.