Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology.

Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide. However, its incidence, mortality, and characteristics are not uniform across all regions worldwide. Understanding the factors contributing to this diversity is crucial in a prevalent disease where most cases are diagnosed in advanced stages. Hence, prevention and early diagnosis emerge as the most efficient strategies to enhance outcomes. In Western societies, tobacco consumption constitutes the primary risk factor for lung cancer, accounting for up to 90% of cases. In other geographic locations, different significant factors play a fundamental role in disease development, such as individual genetic predisposition, or exposure to other carcinogens such as radon gas, environmental pollution, occupational exposures, or specific infectious diseases. Comprehensive clinical and molecular characterization of lung cancer in recent decades has enabled us to distinguish different subtypes of lung cancer with distinct phenotypes, genotypes, immunogenicity, treatment responses, and survival rates. The ultimate goal is to prevent and individualize lung cancer management in each community and improve patient outcomes.

IPSOS trial: A "game changer" redefining first-line immunotherapy in platinum-ineligible NSCLC.

First-line therapy for advanced non-small cell lung cancer (NSCLC) involves immunotherapy with or without platinum-based chemotherapy; however, not all patients are fit enough. In the IPSOS trial, atezolizumab monotherapy demonstrated a clinical benefit in platinum-ineligible patients with advanced NSCLC, redefining first-line immunotherapy, and breaking barriers for unfit population in NSCLC.

Presentation and outcomes of KRASG12C mutant non-small cell lung cancer patients with stage IV disease at diagnosis (de novo) versus at recurrence.

Close monitoring after diagnosis of patients with stage I-III non-small cell lung cancer (NSCLC) may result in fitter patients with lower disease burden at the time of metastatic recurrence or progression compared to patients diagnosed initially as stage IV (de novo). We compared the presentation, treatments, and outcomes of patients with KRASG12C-mutated NSCLC with de novo versus recurrent stage IV disease. Of 109 patients, 94% had a smoking history. When compared to patients with KRASG12C-mutated NSCLC who developed stage IV disease at recurrence (n = 38), de novo stage IV patients (n = 71) had worse ECOG performance status (p = 0.007), greater numbers of extra-thoracic metastatic sites (p = 0.001), and were less likely to receive 2nd/3rd line systemic therapy (p = 0.05, p = 0.002) or targeted therapy (p = 0.001). De novo metastatic patients had shorter overall survival than metastatic patients at recurrence (9.1 versus 24.2 months; adjusted-hazard-ratio=1.94 (95% CI: 1.14-3.28; p = 0.01)). There is a critical need for well-tolerated targeted therapies in the first-line setting for metastatic patients with de novo, high-burden, stage IV KRASG12C-mutated NSCLCs.

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial.

Importance: Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. Objective: To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. Design, Setting, and Participants: This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. Interventions: Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. Main Outcome and Measures: The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. Results: Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. Conclusions and Relevance: This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing. Trial Registration: ClinicalTrials.gov Identifier: NCT04863924.

Respiratory and Cardiometabolic Comorbidities and Stages I to III NSCLC Survival: A Pooled Analysis From the International Lung Cancer Consortium.

INTRODUCTION: We explored the association of respiratory and cardiometabolic comorbidities with NSCLC overall survival (OS) and lung cancer-specific survival (LCSS), by stage, in a large, multicontinent NSCLC pooled data set. METHODS: On the basis of patients pooled from 11 International Lung Cancer Consortium studies with available respiratory and cardiometabolic comorbidity data, adjusted hazard ratios (aHRs) were estimated using Cox models for OS. LCSS was evaluated using competing risk Grey and Fine models and cumulative incidence functions. Logistic regression (adjusted OR [aOR]) was applied to assess factors associated with surgical resection. RESULTS: OS analyses used patients with NSCLC with respiratory health or cardiometabolic health data (N = 16,354); a subset (n = 11,614) contributed to LCSS analyses. In stages I to IIIA NSCLC, patients with respiratory comorbidities had worse LCCS (stage IA aHR = 1.51, confidence interval [CI]: 1.17-1.95; stages IB-IIIA aHR = 1.20, CI: 1.06-1.036). In contrast, patients with stages I to IIIA NSCLC with cardiometabolic comorbidities had a higher risk of death from competing (non-NSCLC) causes (stage IA aHR = 1.34, CI: 1.12-1.69). The presence of respiratory comorbidities was inversely associated with having surgical resection (stage IA aOR = 0.54, CI: 0.35-0.83; stages IB-IIIA aOR = 0.57, CI: 0.46-0.70). CONCLUSIONS: The presence of either cardiometabolic or respiratory comorbidities is associated with worse OS in stages I to III NSCLC. Patients with respiratory comorbidities were less likely to undergo surgery and had worse LCSS, whereas patients with cardiometabolic comorbidities had a higher risk of death from competing causes. As more treatment options for stages I to III NSCLC are introduced into the practice, accounting for cardiometabolic and respiratory comorbidities becomes essential in trial interpretation and clinical management.

Plasma-first: accelerating lung cancer diagnosis and molecular profiling through liquid biopsy.

Introduction: Molecular profiling of tumor tissue is the gold standard for treatment decision-making in advanced non-small cell lung cancer (NSCLC). Results may be delayed or unavailable due to insufficient tissue, prolonged wait times for biopsy, pathology assessment and testing. We piloted the use of plasma testing in the initial diagnostic workup for patients with suspected advanced lung cancer. Methods: Patients with ⩽15 pack-year smoking history and suspected advanced lung cancer referred to the lung cancer rapid diagnostic program underwent plasma circulating-tumor DNA testing using a DNA-based mutation panel. Tissue testing was performed per standard of care, including comprehensive next-generation sequencing (NGS). The primary endpoint was time from diagnostic program referral to cancer treatment in stage IV NSCLC patients (Cohort A) compared to a contemporary cohort not enrolled in the study (Cohort B) and an historical pre-COVID cohort referred to the program between 2018 and 2019 (Cohort C). Results: From January to June 2021, 20 patients were enrolled in Cohort A; median age was 70.5 years (range 33-87), 70% were female, 55% Caucasian, 85% never smokers, and 75% were diagnosed with NSCLC. Seven had actionable alterations detected in plasma or tissue (4/7 concordant). Fusions, not tested in plasma, were identified by immunohistochemistry for three patients. Mean result turnaround time was 17.8 days for plasma NGS and 23.6 days for tissue (p = 0.10). Mean time from referral to treatment initiation was significantly shorter in cohort A at 32.6 days (SD 13.1) versus 62.2 days (SD 31.2) in cohort B and 61.5 days (SD 29.1) in cohort C, both p < 0.0001. Conclusion: Liquid biopsy in the initial diagnostic workup of patients with suspected advanced NSCLC can lead to faster molecular results and shorten time to treatment even with smaller DNA panels. An expansion study using comprehensive NGS plasma testing with faster turnaround time is ongoing (NCT04862924).

Vaccine Therapy in Non-Small Cell Lung Cancer.

Immunotherapy using immune checkpoint modulators has revolutionized the oncology field, emerging as a new standard of care for multiple indications, including non-small cell lung cancer (NSCLC). However, prognosis for patients with lung cancer is still poor. Although immunotherapy is highly effective in some cases, not all patients experience significant or durable responses, and further strategies are needed to improve outcomes. Therapeutic cancer vaccines are designed to exploit the body's immune system to activate long-lasting memory against tumor cells that ensure tumor regression, with minimal toxicity. A unique feature of cancer vaccines lies in their complementary approach to boost antitumor immunity that could potentially act synergistically with immune checkpoint inhibitors (ICIs). However, single-line immunization against tumor epitopes with vaccine-based therapeutics has been disappointingly unsuccessful, to date, in lung cancer. The high level of success of several recent vaccines against SARS-CoV-2 has highlighted the evolving advances in science and technology in the vaccines field, raising hope that this strategy can be successfully applied to cancer treatments. In this review, we describe the biology behind the cancer vaccines, and discuss current evidence for the different types of therapeutic cancer vaccines in NSCLC, including their mechanisms of action, current clinical development, and future strategies.

Integrating circulating-free DNA (cfDNA) analysis into clinical practice: opportunities and challenges.

In the current era of precision medicine, the identification of genomic alterations has revolutionised the management of patients with solid tumours. Recent advances in the detection and characterisation of circulating tumour DNA (ctDNA) have enabled the integration of liquid biopsy into clinical practice for molecular profiling. ctDNA has also emerged as a promising biomarker for prognostication, monitoring disease response, detection of minimal residual disease and early diagnosis. In this Review, we discuss current and future clinical applications of ctDNA primarily in non-small cell lung cancer in addition to other solid tumours.

Plasma-Based Genotyping in Advanced Solid Tumors: A Comprehensive Review.

Molecular genotyping for advanced solid malignancies has transformed the clinical management of patients with metastatic disease. Treatment decisions in a growing number of tumors require knowledge of molecularly driven alterations in order to select optimal targeted therapy. Although genomic testing of tumor tissue is the gold standard for identifying targetable genomic alterations, biopsy samples are often limited or difficult to access. This has paved the way for the development of plasma-based approaches for genomic profiling. Recent advances in the detection of plasma-circulating tumor DNA (ctDNA) have enabled the integration of plasma-based molecular profiling into clinical practice as an alternative or complementary tool for genomic testing in the setting of advanced cancer, to facilitate the identification of driver mutations to guide initial treatment and diagnose resistance. Several guidelines now recommend the use of plasma where tumor tissue is limited to identify a targetable genomic alteration. Current plasma-based assays can evaluate multiple genes in comprehensive panels, and their application in advanced disease will be increasingly incorporated into standard practice. This review focuses on current and future applications of plasma ctDNA-based assays in advanced solid malignancies, while highlighting some limitations in implementing this technology into clinical practice.

Molecular Profiling and Targeted Therapy in Cholangiocarcinoma: An Observational, Retrospective Multicenter Study.

PURPOSE: Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy and overall prognosis remains poor, with a median survival of less than 24 months. Sequencing studies have revealed a high prevalence of genomic alterations in CCA, with multiple potential therapeutic targets. Next-generation sequencing (NGS) can identify actionable mutations such as FGFR, IDH, BRAF, ERBB2, ROS1, or microsatellite instability (MSI-H), among others. METHODS: We conducted a retrospective multicenter study in Spain in 2019. Thirty consecutive patients from 15 centers were included. All patients were diagnosed with advanced CCA and underwent NGS (FoundationOne®) in 2019. Twenty-four patients underwent tissue-based NGS (FoundationOne® CDx), and 6 patients underwent blood-based NGS (FoundationOne®Liquid) with sequencing panels of 324 and 70 genes, respectively RESULTS: We identified 12 patients (40%) with an actionable genetic alteration in tissue: 2 FGFR2 fusions, 6 IDH1 mutations, 1 ERBB2 mutation, 1 ROS1 fusion, 1 PIK3CA mutation, and 1 MSI-H. CONCLUSION: Comprehensive genomic profiling (CGP) in cholangiocarcinoma can identify, in a high proportion of patients, clinically relevant genomic alterations that can lead to targeted therapies, expanding treatment options.