Journal of Thoracic Oncology最新文献

Introduction: Pyrotinib, a novel pan-HER tyrosine kinase inhibitor, has demonstrated substantial anti-tumor activity in patients with NSCLC harboring HER2 mutations. Nevertheless, the inevitable resistance to pyrotinib necessitates an in-depth understanding of the underlying mechanisms.

Methods: Resistance-associated mutations were identified through genomic sequencing of paired baseline and post-resistance samples from 40 patients. Integrated computational and experimental approach were utilized to validate the resistance mechanisms and explore strategies for overcoming resistance in vitro and in vivo.

Results: Analysis of novel mutations upon the development of resistance did not identify any predominant secondary HER2 mutations. Nevertheless, 12 secondary HER2 mutations (38.7%) occurred either as single nucleotide variations (75%) or insertions-deletions (25%), on the basis of HER2 p.Y772_P775dup mutation. Only two mutations led to HER2 autophosphorylation and IL3-independent proliferation of Ba/F3 cells from the in vitro experiments, implying that the remaining 10 secondary mutations were passenger mutations. Further in vivo and in vitro validation showed that the HER2 p.E770_A771insAYMM mutation diminished the sensitivity of murine HER2 mutant lung adenocarcinoma cell line to pyrotinib, with ineffective inhibition of HER2 and its downstream pathways. Drug screening indicated that mobocertinib and dacomitinib could effectively restrain the growth of tumors bearing the HER2 p.E770_A771insAYMM mutation.

Conclusions: Our findings unveil a new form of resistance-a secondary mutation superimposed on the original mutation-and offer insights into a potentially sequential strategy for overcoming resistance to pyrotinib.

Introduction: Low-dose computed tomography screening for lung cancer reduces lung cancer mortality, but there is a lack of international consensus regarding the optimal eligibility criteria for screening. The Yorkshire Lung Screening Trial was designed to evaluate lung cancer screening (LCS) implementation, and a primary objective was prospective evaluation of three predefined eligibility criteria.

Methods: Individuals who had ever smoked, aged 55 to 80 years, who responded to written invitation, underwent telephone risk assessment and if eligible by at least one criterion (PLCO_M2012 ≥ 1.51%, LLP_v2 ≥ 5%, USPSTF₂₀₁₃) were offered biennial low-dose computed tomography screening.

Results: Of 44,957 individuals invited, 22,814 responded and underwent eligibility assessment, of whom a total of 7826 were eligible according to any of the three LCS criteria. Comparing PLCO_M2012 ≥ 1.51%, LLP_v2 ≥ 5%, and USPSTF₂₀₁₃, the proportions of responders eligible for screening were 28.0%, 20.5%, and 18.9%, respectively (p < 0.0001 for each comparison), and the proportion of all cancers detected 91.1%, 77.0%, and 62.8%, respectively (p ≤ 0.0002 for each comparison). When risk thresholds were selected to result in equivalent numbers of people eligible for screening, cancer detection proportions were higher for PLCO_M2012 (74.5%) and LLP_v2 (71.3%) than USPSTF₂₀₁₃ (62.8%) (p = 0.0002 and p = 0.032, respectively), but there was no significant difference between the two risk models. Reducing the LLPv2 risk threshold from 5% to 2.5% (as currently used in the English LCS program) and reducing the pack-year requirement for the USPSTF₂₀₂₁ versus the USPSTF₂₀₁₃ criteria increased the numbers eligible for screening, but subsequent cancer yield was not measured in this study.

Conclusion: The PLCO_M2012 ≥ 1.51% criteria identified more people eligible for screening in Yorkshire Lung Screening Trial and resulted in more screen-detected lung cancers than LLP_v2 ≥ 5% or USPSTF₂₀₁₃. When compared in equivalent populations, there was no significant difference between risk models in terms of lung cancer detection and each appeared more efficient at screening population selection than USPSTF₂₀₁₃.

Objectives: Genomic profiling is a major component for first-line treatment decisions in patients with NSCLC and the timeliness of biomarker testing is essential to improve time to treatment initiation (TTI) or avoid inappropriate treatment.

Methods: The phase III LIquid Biopsy for the Early detection of LUng cancer Lesion trial (NCT03721120) included patients with radiological suspicion of advanced lung cancer. They were randomized (1:1), the control arm receiving diagnostic procedures according to each center's practice, and the liquid biopsy arm with additional testing performed at the first visit using the InVisionFirst-Lung assay. Treatment initiation and type were defined according to the European Society for Medical Oncology guidelines. Primary endpoint was the time from randomization to initiation of appropriate treatment on the basis of informative genomic and pathological results in the intention-to-treat population.

Results: A total of 319 patients were enrolled (liquid biopsy [LB]: 161; control: 158). The median age was 68 years, 28.8% were non-smokers, 18.1% had a performance status of 2 or higher, and 56.7% had adenocarcinoma. In the LB arm, 81% of patients had circulating tumor DNA findings. The mean TTI was not significantly reduced (LB: 29.0 d; control 34 d (p = 0.26)). Sensitivity analyses found a shorter TTI in patients from the LB arm who received systemic treatment (LB: 29.1 d; control: 38.8 d, p = 0.01), in patients with advanced non-squamous NSCLC (LB: 29.5 d; control: 40.3 d, p = 0.01), and in patients with first-line targetable alterations (LB: 21d; control 37.4 d) (p = 0.004). Time to contributory genomic results was significantly reduced (LB: 17.9 d; control: 25.6 d, p < 0.001).

Conclusion: Early liquid biopsy testing did not significantly shorten the TTI in unselected patients referred for suspected advanced lung cancer. Nevertheless, it could reduce the TTI in patients eligible for systemic treatment, particularly for those with actionable alterations.

Introduction: EGFR mutations are key oncogenic drivers in lung adenocarcinoma (LUAD), predominantly affecting Asian, nonsmoking, and female populations. Although common mutations, such as exon 19 deletions and L858R, respond well to tyrosine kinase inhibitors (TKIs), uncommon EGFR mutations and compound variants exhibit variable treatment responses. This study aims to compare clinical characteristics and molecular profiles of patients with common, uncommon, and compound EGFR mutations, assessing their implications for therapy outcomes.

Methods: We analyzed a multi-cohort genomic dataset of 19,163 patients with LUAD (5,212 with EGFR mutations), categorizing mutations into common, uncommon, and compound classes. Patient demographics, mutational signatures, and tumor microenvironment factors were assessed, with particular attention to smoking status and concomitant alterations in KRAS and TP53. Treatment outcomes were analyzed by time under treatment as a surrogate measure of TKI efficacy.

Results: Uncommon EGFR mutations, comprising 8.9% of EGFR-altered cases, were significantly more frequent among smokers and associated with tobacco-related mutational signatures. Compared with common EGFR-mutant cases, tumors harboring uncommon EGFR mutations reported higher rates of EGFR amplifications, KRAS, and TP53 mutations. Uncommon mutations also exhibited higher tumor mutational burden and distinct transcriptional profiles linked to cell cycle activity. Median time on treatment with TKIs was notably shorter in patients with uncommon mutations (4.1 mo) than those with common and compound mutations (10.9 mo and 12.4 mo, respectively).

Conclusions: This study underscores the clinical and molecular heterogeneity of EGFR mutation classes in LUAD, highlighting the unique profile of uncommon mutations, particularly their association with smoking and co-mutations in KRAS and TP53. Comprehensive molecular testing, including next-generation sequencing, is crucial to identify these uncommon mutations and inform therapeutic decisions. Further investigation into the role of immunotherapy in patients with uncommon EGFR mutations is warranted given the tobacco-related molecular signatures and high tumor mutational burden associated with this subgroup.

Background: To reduce the gap about the relevant heterogeneity of molecular testing and cancer care across Europe, Women Against Lung Cancer in Europe (WALCE) promoted the European Program for ROutine testing of Patients with Advanced lung cancer (EPROPA) and provided a free-of-charge molecular profiling platform for non-small cell lung cancer sample characterization with the aim of increasing the detection of targetable drivers and improving patients' access to clinical trials.

Methods: From January 2021 to December 2023, 20 centres located at 5 different European countries (Greece, Slovenia, Romania, Albania and Italy) joined EPROPA, with 555 advanced NSCLC patients registered into the program. Anonymized patients' clinical-pathological data were shared through the EPROPA web platform and tissue samples were collected to the Molecular Pathology Unit of the Reference Center (University of Turin) for molecular analyses. A comprehensive genomic profiling by targeted next-generation sequencing approach has been performed and molecular reports have been discussed within the molecular tumour board (MTB) in order to assess patients' eligibility for clinical trials.

Results: The average turnaround time was 8 days, with only 30 out of 555 (6%) tissue samples not suitable for molecular analysis. Among the 525 analyzed samples, a total of 570 molecular alterations have been identified, including 264 pathogenic targetable oncogenic alterations and 113 cases with co-occurring mutations. A total of 18 molecular alterations with potential germline and hereditary cancer syndrome implications have been reported. The identification of a clinical trial was considered for 205 patients. After MTB discussion, 30 patients were enrolled and treated in clinical studies available in Europe. Survival outcome were significantly improved in patients with targetable molecular alterations receiving a matched targeted therapy.

Conclusion: This data confirmed the feasibility and usefulness of the program in the real-world practice scenario, supporting the implementation of NGS-based molecular characterization of NSCLC samples, in order to reduce the unequal access to tests, drugs and clinical trials in Europe.

Objectives: The study aimed to assess the opinion of pathologists and thoracic surgeons of the International Association for the Study of Lung Cancer regarding the application and interpretation of the residual tumor (R) classification for lung cancer.

Methods: On the basis of their membership profiles, a total of 623 pathologists and thoracic surgeons were identified and contacted by email with a cover letter and a link to an online survey. The questionnaire consisted of 12 questions about various aspects of the application and interpretation of the R classification for lung cancer. The response rate (to at least one question) was 72% (144 pathologists and 303 surgeons).

Results: The frequency of use of the R classification varies by geographic region. Although R status is regularly reported in Europe and Asia, 70% of pathologists in the United States and Canada never include R status in reports. Similar variations exist about who assigns the R category for the resection-in Europe and the United Kingdom, it is mainly the pathologist, whereas in China, Japan and the United States, it is the surgeon. There are some good agreements about margins examined and how to manage staple lines. The category "uncertain resection" has not been practically implemented in most of the world, except at some centers in Japan and the United Kingdom.

Conclusion: This survey shows that surgical resection margins are part of routine reporting in most institutions; but the assignment of an R category is not always part of the pathology report, with considerable variation between countries. Despite the International Association for the Study of Lung Cancer proposals, the application of the uncertain resection category has not been taken up by most institutions, and further evidence is needed.

Introduction: Guideline-discordant low-dose computed tomography (LDCT) screening may cause lung cancer (LC) overdiagnosis, but its extent and consequences are unclear. This study aimed to investigate the prevalence of self-initiated, non-reimbursed LDCT screening in a predominantly non-smoking population and its impact on LC epidemiology and healthcare utilization.

Methods: This nationwide cohort study analyzed data from Korea's National Health Information Database and 11 academic hospital screening centers (1999-2022). The overall analysis encompassed the entire Korean population. For non-reimbursed LDCT screening prevalence, which the National Health Information Database does not capture, a separate analysis was conducted on a cohort of 1.7 million adults to extrapolate nationwide rates. Outcomes included trends in self-initiated, non-reimbursed LDCT screening, LC incidence, mortality, stage and age at diagnosis, 5-year survival, and LC-related healthcare utilization, including surgeries and biopsies. Joinpoint regression assessed trend changes.

Results: Self-initiated, non-reimbursed LDCT screening during health check-ups increased from 29% to 60% in men and 7% to 46% in women, despite only 2.4% of men and 0.04% of women qualifying for risk-based screening. In women, localized-stage LC incidence nearly doubled (age-standardized incidence rate: from 7.6 to 13.7 per 100,000), whereas distant-stage incidence decreased (age-standardized incidence rate: from 16.1 to 15.0 per 100,000). LC mortality declined (age-standardized mortality rate: from 23.3 to 19.8 per 100,000), whereas 5-year survival rates improved substantially. LC diagnoses in women shifted towards earlier stages and younger ages. Lung surgeries for both malignant and benign lesions, frequently lacking nonsurgical biopsies, increased sharply in women.

Conclusions: Widespread guideline-discordant LDCT screening correlates with LC overdiagnosis and increased healthcare utilization, particularly in women. Randomized controlled trials are needed to assess the risks and benefits of screening in low-risk populations to determine its efficacy and consequences.

Introduction: Investigator-assigned Subjective or Judgmental Efficacy and Toxicity (ISJET) reporting represents language used to contextualize efficacy or toxicity data in clinical trials that may be inappropriate or misleading. In addition, pooling of grade 1 and 2 adverse events (AEs) may reflect a practice based on acute chemotherapy treatments rather than the expansion of chronic treatments that are now commonplace for many patients with lung cancer. In this study, we set out to evaluate the use of ISJETs and combined grade 1 and 2 reporting in early phase clinical trials of lung treatments at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

Methods: Phase I and II clinical trials of systemic treatments in adults with at least one patient with lung cancer presented at the 2024 ASCO Annual Meeting were reviewed. Baseline information and toxicity/efficacy reporting were collected. ISJETs were captured based on predefined phrases such as "tolerable," "manageable," "acceptable," or "favorable."

Results: A total of 100 eligible studies were identified. The median sample size was 43 (interquartile range 29-73), and 61 studies (61%) were phase I trials. Most studies reported any-grade (99%) and grade 3 (96%) AEs. Only 12% of the studies distinguished between grade 1 and 2 AEs. ISJETs were used to report toxicity in 88% and efficacy in 41% of the studies, respectively.

Conclusion: Most early phase lung cancer clinical trials presented at the 2024 ASCO Annual Meeting included ISJETs and did not distinguish between grade 1 and 2 AEs. Initiatives to increase objective efficacy and toxicity reporting language and more fit-for-purpose toxicity reporting are warranted.