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Updated: Sep 5, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Clinical outcomes and immune phenotypes associated with STK11 co-occurring mutations in non-small cell lung cancer
Jyoti Malhotra1, Brid Ryan2, Malini Patel1
1Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Background:
STK11 mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis.
Methods:
Forty-one patients with STK11-mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis. Data from the Cancer Genome Atlas (TCGA) was used for survival and immune gene expression analysis. Overall and progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared using a log-rank test.
Results:
In the 41 patients included, common co-occurring alterations with STK11 were KRAS (54%), TP53 (44%), CDKN2A (37%) and KEAP1 (27%). Overall 17 patients received locoregional therapy with surgery or radiation with median OS of 8.6 years and there was no significant difference in clinical outcomes with KRAS and TP53 co-occurring mutations. Response to both chemotherapy and immunotherapy was poor across all co-occurring mutations. However, TP53 co-mutation was associated with improved clinical benefit with immunotherapy. Patients with higher TMB had longer PFS with immunotherapy. In TCGA survival analysis, tumors with STK11 mutation with or without KRAS co-mutation were associated with worse survival (P<0.05) but tumors with STK11/TP53 co-mutation did not have worst survival compared to STK11 wild type tumors. Moreover, co-occurring mutations had significant effect on intratumoral immune status with both STK11 alone and STK11/KRAS co-mutated tumors showing more enrichment for wound healing immune subtype while STK11/TP53 co-mutated tumors showed more enrichment for IFN-g immune subtype.
Conclusions:
Our retrospective analysis in patients with STK11-mutated NSCLC found that both TMB and co-occurring mutations may be predictors for response to immunotherapy with worse outcomes in patients with low TMB or KRAS co-mutation and improved outcomes with TP53 co-mutation. Patients with STK11-mutated NSCLC also demonstrate chemotherapy resistance but have similar outcomes with localized treatment compared to STK11 wild type tumors. Moreover, co-mutations with KRAS or TP53 significantly alter tumor immune landscape of STK11-mutated tumors and therefore response to immunotherapy.
Insights
STK11 mutations in non-small cell lung cancer (NSCLC) are linked to poor immunotherapy response. Co-occurring TP53 mutations may improve outcomes, while KRAS mutations and low tumor mutational burden (TMB) are associated with worse progression-free survival (PFS).
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- STK11 mutations in non-small cell lung cancer (NSCLC) correlate with diminished survival and primary resistance to PD-1/PD-L1 immunotherapy.
- The interplay between co-occurring mutations, tumor mutational burden (TMB), and therapeutic response in STK11-mutated NSCLC remains incompletely understood.
Purpose of the Study:
- To investigate the impact of co-occurring mutations and TMB on the prognosis and immunotherapy response in patients with STK11-mutated NSCLC.
- To analyze the association between specific co-mutations (KRAS, TP53) and TMB with survival and immune profiles.
Main Methods:
- Retrospective analysis of 41 patients with STK11-mutated NSCLC and available next-generation sequencing data.
- Utilized The Cancer Genome Atlas (TCGA) for survival and immune gene expression analysis.
- Kaplan-Meier method and log-rank test were employed for survival estimations.
Main Results:
- Common co-occurring mutations with STK11 included KRAS (54%), TP53 (44%), CDKN2A (37%), and KEAP1 (27%).
- STK11-mutated NSCLC showed poor response to chemotherapy and immunotherapy, though TP53 co-mutation was linked to improved immunotherapy benefit.
- Higher TMB correlated with longer progression-free survival (PFS) with immunotherapy. STK11/TP53 co-mutation was not associated with worse survival compared to STK11 wild-type tumors.
- Co-mutations significantly altered the tumor immune microenvironment, with STK11/KRAS tumors enriched for wound healing pathways and STK11/TP53 tumors for IFN-g pathways.
Conclusions:
- Co-occurring mutations and TMB are potential predictors of immunotherapy response in STK11-mutated NSCLC.
- KRAS co-mutation and low TMB are associated with worse outcomes, whereas TP53 co-mutation may indicate improved immunotherapy response.
- STK11-mutated NSCLC exhibits chemotherapy resistance but similar outcomes with localized treatment. Co-mutations critically influence the tumor immune landscape and immunotherapy efficacy.
