‘Spread Through Air Spaces’ Predicts Poorer Prognosis in Stage 1 EGFR-Mutant Lung Adenocarcinoma

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A recent study from the National Cancer Centre Singapore highlights the prognostic impact and molecular characteristics of spread through air spaces (STAS) in stage 1 epidermal growth factor receptor-mutated (EGFRm) lung adenocarcinoma. The findings were presented during ASCO 2025.

While STAS is an established negative prognostic factor and has been incorporated into the 9th edition of the TNM staging system, its implications in EGFRm tumors had remained unclear until now, the researchers of the study explained.

The retrospective analysis included 300 patients with stage 1 lung adenocarcinoma and a minimum of three years of postoperative follow-up. Of these, 203 harbored EGFR mutations. STAS positivity (STAS+) was identified in nearly half of both EGFRm (49.8%) and EGFR-wildtype (EGFRwt) patients (56.7%), with no significant difference in incidence. However, the presence of STAS was associated with significantly worse 5-year disease-free survival (DFS) in the EGFRm group (67.8% vs. 93.2%, P=0.005), a relationship not observed in EGFRwt patients.

Importantly, the adverse prognostic role of STAS in EGFRm cases was independent of factors such as age, sex, smoking history, histological grade, lymphovascular invasion (LVI), and disease stage.

STAS+ EGFRm tumors were more likely to exhibit high histological grade (32.7% vs. 4.0%, P<0.001), LVI (20.8% vs. 3.9%, P<0.001), TP53 co-mutations (60.7% vs. 43.2%, P=0.020), whole genome doubling (34% vs. 17%, P=0.013), and PD-L1 expression ≥1% (42.3% vs. 21.2%, P=0.011). They also more frequently belonged to a non-terminal respiratory unit (non-TRU) transcriptomic subtype (55.9% vs. 22.2%, P<0.001), further suggesting a biologically aggressive phenotype.

These findings underscored the utility of STAS as a molecular and histologic marker of poor prognosis in stage 1 EGFRm lung cancer. As STAS independently predicts inferior outcomes, it should be considered in future risk stratification frameworks and potentially inform adjuvant treatment strategies in this population.

“Our findings highlight the molecular determinants of STAS+ and support STAS as a risk stratification factor for stage 1 EGFRm,” the authors concluded.