Genomic profiling uncovers distinct TP53 and PI3K pathways across tumor budding grades

A newly proposed International Association for the Study of Lung Cancer (IASLC) tumor budding-based grading system successfully identified patients with resected lung squamous cell carcinoma (SqCC) at higher risk of poor outcomes and showed potential to help guide selection for adjuvant chemotherapy, according to research presented at the IASLC 2026 World Conference on Lung Cancer on Lung Cancer. (WCLC).

The study independently validated the 2025 IASLC two-tier grading system, which classifies resected lung SqCC as low grade or high grade based solely on tumor budding. Investigators retrospectively reviewed 585 consecutive patients who underwent curative-intent upfront resection at Yonsei University Medical Center from 2015 through 2022.

Our findings show that the newly proposed IASLC tumor budding-based grading system can identify patients with resected lung squamous cell carcinoma who have a poorer prognosis, while also suggesting that high-grade patients may be the group most likely to derive benefit from adjuvant chemotherapy. Prospective multicenter validation will be important to confirm its potential role in treatment selection."

T.H. Hong, Yonsei University School of Medicine in Seoul, Republic of Korea

Among the 585 patients, 520 (88.9%) had low-grade tumors and 65 (11.1%) had high-grade tumors. High-grade disease was associated with a significantly more advanced pathologic stage distribution. High-grade tumors were independently associated with worse overall and disease-free survival on multivariable analysis.

Investigators also examined patients with pathologic stage IB–III disease who were eligible for adjuvant treatment. Across this subgroup, there was no overall disease-free survival benefit from adjuvant chemotherapy. When patients were stratified by tumor budding grade, however, low-grade patients showed no benefit, while high-grade patients demonstrated a clinically meaningful trend toward benefit from adjuvant chemotherapy. Exploratory genomic profiling in a case-matched subset (n = 100) showed no difference in global genomic instability between grades, but identified significant enrichment of PI3K pathway alterations in low-grade tumors and directional enrichment of truncating TP53 mutations in high-grade tumors, suggesting divergent oncogenic programs between grades.

The authors concluded that the IASLC tumor budding–based grading system provided independent prognostic stratification and was associated with distinct patterns of adjuvant chemotherapy outcomes and genomic alterations. These findings extend the clinical and biological relevance of the newly proposed grading system. Prospective multicenter validation is warranted to confirm its potential role in treatment stratification.