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Multidimensional Coculture System to Model Lung Squamous Carcinoma Progression
Published on: March 17, 2020
Distinct Clinicogenomic Features and Immunotherapy Associations in Pulmonary Sarcomatoid Carcinoma: A Multicenter
Lingzhi Hong1, Alessandro Di Federico2, Bolun Liu3
1Department of Thoracic-Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Introduction:
Pulmonary sarcomatoid carcinoma (PSC) is a rare NSCLC subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared with other NSCLC subtypes.
Methods:
Patients from three institutions and the National Cancer Database (NCDB) with metastatic NSCLC treated with ICI alone or with chemotherapy were identified. Clinicogenomics and treatment outcomes were compared across PSC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC).
Results:
We analyzed 4841 patients including 165 PSC cases treated with ICI-based therapy from three institutions and 201 PSC from NCDB. In MDACC, 65 (4.3%) were PSC, 1138 (75.1%) LUAD, and 312 (20.6%) LUSC. Patients with PSC were older and more likely to present with metastatic disease. In both the MDACC and NCDB cohorts, ICIs resulted in better outcomes for patients with PSC compared with chemotherapy. In these patients, there was no difference in outcome between ICI-monotherapy and ICI-chemotherapy. Across the three institutional cohorts, 37% to 43% of patients with PSC who received ICIs were responders, compared with 26% to 29% in LUAD and 22% to 46% in LUSC (p < 0.05). Improved ICI outcomes in PSC appeared driven by high PD-L1 (≥50% in 73%-77% cases). Among patients with high PD-L1, response rates were similar across histologic subtypes. Conversely, TMB was similar in PSC compared with LUAD or LUSC and was not associated with ICI outcomes. Across cohorts, PSC tumors were enriched for TP53, NF1, NF2, and NRAS, with relative depletion of STK11 and KEAP1 compared with LUAD. Case observation revealed relatively better outcomes to ICI than targeted therapies in patients with PSC with MET exon 14 skipping or KRAS G12C.
Conclusion:
PSC exhibits improved outcomes to ICI relative to other therapies, potentially driven by high PD-L1 expression. Genomic analysis highlights a distinct genomic landscape of PSC when compared with LUAD.
Insights
Pulmonary sarcomatoid carcinoma (PSC) shows better outcomes with immune checkpoint inhibitors (ICIs) compared to chemotherapy. High PD-L1 expression is a key driver of this response in PSC, a rare non-small cell lung cancer subtype.
Area of Science:
- Oncology
- Pulmonology
- Genomics
Background:
- Pulmonary sarcomatoid carcinoma (PSC) is a rare non-small cell lung cancer (NSCLC) subtype with a generally poor prognosis.
- Outcomes with immune checkpoint inhibitors (ICIs) and the genomic characteristics of PSC are not well understood compared to other NSCLC subtypes.
Purpose of the Study:
- To compare the clinicogenomic features and treatment outcomes of PSC with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).
- To evaluate the efficacy of ICIs in patients with PSC.
Main Methods:
- Retrospective analysis of patients with metastatic NSCLC treated with ICIs or chemotherapy from three institutions and the National Cancer Database (NCDB).
- Comparison of clinicogenomic data and treatment outcomes across PSC, LUAD, and LUSC cohorts.
Main Results:
- Patients with PSC were older and more likely to have metastatic disease at diagnosis.
- ICIs demonstrated superior outcomes in PSC compared to chemotherapy, with no significant difference between ICI monotherapy and combination therapy.
- Response rates to ICIs in PSC (37%-43%) were higher than in LUAD (26%-29%) and comparable to LUSC (22%-46%), largely driven by high PD-L1 expression (73%-77% of PSC cases).
- Genomic analysis revealed distinct mutational profiles in PSC, with enrichment of TP53, NF1, NF2, and NRAS, and depletion of STK11 and KEAP1 compared to LUAD.
- PSC patients with MET exon 14 skipping or KRAS G12C mutations showed better responses to ICIs than targeted therapies.
Conclusions:
- PSC exhibits improved response to ICIs compared to other therapies, with high PD-L1 expression being a significant predictive factor.
- The distinct genomic landscape of PSC warrants further investigation and may inform therapeutic strategies.
