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Published on: March 21, 2018
Molecular Profiling Across 80,000 Patients With Lung Cancer
Alessandro Russo1, Manana Javey2, Richard S P Huang3
1Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Medical Oncology Department, Humanitas Istituto Clinico Catanese, Misterbianco, Catania, Italy.
Introduction:
Biomarker testing is an essential component of optimal therapeutic management in NSCLC, enabling the use of both Food and Drug Administration-approved and emerging targeted therapies. Despite well-established biomarker testing guidelines and the availability of many approved targeted therapies, a substantial proportion of patients with advanced NSCLC are not benefiting from precision oncology. In this study, we analyze the distribution of actionable genomic alterations across histologic subtypes and clinicodemographic subgroups of NSCLC using data in 82,328 samples profiled with a single comprehensive genomic profiling assay, aiming to support universal molecular testing across all NSCLC subtypes to ensure equitable access to available therapeutics.
Methods:
This is an observational retrospective analysis on histologically confirmed NSCLC cases tested with comprehensive genomic profiling by next-generation sequencing between 2014 and 2022 using Foundation One/Foundation CDx. All cases were centrally reviewed by board-certified anatomic pathologist to determine histologic type and subtype.
Results:
A total of 82,328 patients with NSCLC were included. An actionable genomic alteration (GA) was found in 35.1% of the cases. Lung adenocarcinoma (LUAD) and adenosquamous carcinoma were more frequently associated with actionable GA (45.8% and 40.9%, respectively) as compared with sarcomatoid (29.1%), not otherwise specified (27.6%), large cell (21.1%), and squamous cell (6.5%) histologies. Sarcomatoid histology had the highest METex14 skipping mutation (mut) frequency (9.95% versus 2.43% in LUAD). Tumor mutation burden more than or equal to 10 mut/Mb was associated with histology (50.91% in large cell, 40.79% in not otherwise specified, 39.08% in squamous cell, and 36.30% in sarcomatoid versus 31.22% in LUAD and 29.22% in adenosquamous carcinoma). Patients with actionable GA had usually a low tumor mutation burden (80.88%). A significant correlation (p < 0.005) between age and actionable GA was reported for BRAF/ERBB2 muts, ALK/RET/ROS1 rearrangements, and MET amplification. EGFR actionable muts and KRAS G12C were more frequently observed in females, whereas no significant correlation between sex and other GA was observed. Finally, genetic ancestry analyses revealed a strong correlation for EGFR actionable muts and South/East Asia and America, but not for other GA.
Conclusions:
This is the largest NSCLC data set analyzed for biomarker distribution across histologies, age, sex, and genetic ancestry. This data set confirms sufficient enough biomarker prevalence across many histologic subtypes of NSCLC, providing reassurance that all NSCLC cases should be considered for biomarker workup.
Insights
Actionable genomic alterations are prevalent across most Non-Small Cell Lung Cancer (NSCLC) subtypes, supporting universal biomarker testing for all patients. This ensures equitable access to targeted therapies for improved outcomes.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Biomarker testing is crucial for Non-Small Cell Lung Cancer (NSCLC) treatment selection.
- Despite guidelines, many advanced NSCLC patients do not receive precision oncology due to testing disparities.
- This study investigates actionable genomic alteration distribution across NSCLC subtypes.
Purpose of the Study:
- To analyze the prevalence of actionable genomic alterations in NSCLC across various histologic subtypes and demographic groups.
- To support universal molecular testing for all NSCLC patients to ensure equitable access to targeted therapies.
Main Methods:
- Retrospective analysis of 82,328 NSCLC cases tested with comprehensive genomic profiling (CGP) via next-generation sequencing (NGS).
- Histologic subtypes were confirmed by Board Certified Anatomic Pathologists.
- Data collected between 2014-2022.
Main Results:
- Actionable genomic alterations were found in 35.1% of NSCLC cases.
- Lung adenocarcinoma (LUAD) and adenosquamous (ASC) had higher rates of actionable alterations (45.8%, 40.9%) compared to other histologies.
- Specific alterations like METex14 skipping mutations were more frequent in sarcomatoid histology (9.95%).
- Tumor mutation burden (TMB) varied by histology, with higher rates in large cell (LCC) and not otherwise specified (NOS).
- Actionable alterations were generally associated with low TMB (80.88%).
- Correlations were observed between age and specific mutations/rearrangements (BRAF/ERBB2, ALK/RET/ROS1, MET).
- EGFR mutations and KRAS G12C were more common in females.
- EGFR alterations showed a strong correlation with South/East Asian and American ancestry.
Conclusions:
- This large-scale analysis confirms significant biomarker prevalence across diverse NSCLC histologies.
- The findings support comprehensive biomarker workup for all NSCLC patients.
- Ensuring universal testing can improve access to precision therapies for a broader patient population.
