Clinicopathologic and molecular characteristics of small-scale ROS1-mutant non-small cell lung cancer (NSCLC)
Moritz Glaser1, Anna Rasokat2, Darinka Prang2
1University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, Department I of Internal Medicine, Germany; Lung Cancer Group Cologne, Cologne, Germany.
Background:
ROS1 fusions are well treatable aberrations in NSCLC. Besides solvent-front mutations (SFM) in resistance to targeted therapy, small-scale ROS1 mutations are largely unknown. We exploratively analyzed the clinical and molecular characteristics of small-scale ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs.
Methods:
Next-generation sequencing was performed on tissue samples from NSCLC patients within the Network Genomic Medicine. Patients with ROS1 fusions and SFMs were excluded. We analyzed clinical characteristics of patients harboring small-scale ROS1-mutations, ROS1- and co-occurring mutations, and their response to systemic therapy.
Results:
Of 10,396 patients analyzed, 101 (1.0%) patients harbored small-scale ROS1 mutations. Most patients were male (73.3%) and smokers (96.6%). Nearly half of the patients presented with squamous-cell carcinoma (SqCC, 40.4%). Most mutations were transversions (50.5%), and 66% were in the kinase domain. Besides TP53 mutations (65.3%), KRAS (22.8%), EGFR (5.9%), PIK3CA (9.9%) and FGFR1-4 mutations (8.9%) co-occurred. In 10 (9.9%) patients, ROS1 mutation was the only aberration detected. Median overall survival (mOS) differed significantly in patients with or without KRAS co-mutations (9.7 vs 21.5 months, p = 0.02) and in patients treated with or without immune-checkpoint blockade (ICB) during treatment (21.5 vs 4.4 months, p = 0.003).
Conclusion:
The cohort's clinical characteristics contrasted ROS1-fused cohorts. Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.
Insights
Small ROS1 mutations in non-small cell lung cancer (NSCLC) are not strong drivers. Co-occurring KRAS mutations shorten survival, while immune checkpoint blockade (ICB) benefits patients with these ROS1 mutations.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Small-scale ROS1 mutations in non-small cell lung cancer (NSCLC) are poorly understood, unlike treatable ROS1 fusions.
- This study investigates the clinical and molecular landscape of small-scale ROS1 mutations in NSCLC patients, excluding those with fusions or solvent-front mutations (SFMs).
Purpose of the Study:
- To explore the clinical and molecular characteristics of small-scale ROS1 mutations in NSCLC.
- To determine the impact of co-occurring mutations and treatment strategies on patient survival.
Main Methods:
- Next-generation sequencing of tissue samples from 10,396 NSCLC patients.
- Exclusion of patients with ROS1 fusions and SFMs.
- Analysis of clinical data, mutation profiles, and treatment responses.
Main Results:
- 1.0% of patients (101) had small-scale ROS1 mutations, predominantly in male smokers with squamous-cell carcinoma.
- Common co-occurring mutations included TP53, KRAS, PIK3CA, and FGFR1-4.
- KRAS co-mutations significantly shortened overall survival (9.7 vs 21.5 months), while immune checkpoint blockade (ICB) improved survival (21.5 vs 4.4 months).
Conclusions:
- Small-scale ROS1 mutations in NSCLC appear to be bystanders rather than primary oncogenic drivers.
- KRAS co-mutations negatively impact survival in patients with small-scale ROS1 mutations.
- ICB demonstrates a survival benefit for NSCLC patients with small-scale ROS1 mutations.
