Abstract 3174: Genomic alterations of TGFβ signaling genes as novel biomarkers for immunotherapy in patients with non-small cell lung cancer
Authors: Li Shuben , Zhou Chengzhi , Huang Jian , Zhang Shiyue , He Jiqiang , Chen Hui , Yuan Shaohua , Shi Weiwei 
Published: September 2020

Abstract
Background: Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), have shown remarkable effects in non-small cell lung cancer (NSCLC), but a limited number of patients derive durable benefit from it. Therefore, more accurate biomarkers are highly needed. The transforming growth factor β (TGFβ) signaling signature was associated with a lack of response to ICIs in metastatic urothelial cancer. Genomic alterations (GAs) of the TGFβ signature were frequently detected by targeted next-generation sequencing (NGS) in NSCLC, but their correlation with recognized immune biomarkers and predictive value for ICIs response remains unclear.
Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and matched blood samples of 3433 NSCLC patients (2859 lung adenocarcinoma (LUAD), 406 lung squamous cell carcinoma (LUSC), and 168 other histologic subtypes) from OrigiMed were collected for targeted NGS panel sequencing from December 2017 to January 2019. GAs including single nucleotide variations, short and long insertions/deletions, copy number variations, and gene rearrangements were assessed. PD-L1 expression positive was defined as ≥1% of tumor cells with membranous staining (22C3, DAKO). Genomic data and ICIs treatment outcome of a cohort of 240 NSCLC patients were derived from cBioPortal (MSKCC, J Clin Oncol 2018).
Results: GAs of the TGFβ signaling genes were found in 7.1% of patients (244/3433) in the OrigiMed database, including TGFBR1 (n = 34), TGFBR2 (n = 40), SMAD2 (n = 24), SMAD3 (n = 23), and SMAD4 (n = 130). TGFβ signaling GA sites were found scattered throughout the genes, and no significant difference was observed in the frequency of these GAs within the histologic subtypes. TGFBR1, TGFBR2, SMAD2, and SMAD4 GAs were associated with a significantly higher tumor mutational burden (TMB) compared with wild-type (WT) cases in LUAD (p&lt;0.01, respectively), while SMAD3 GAs were associated with a significantly higher TMB in LUAD and LUSC (p=0.019 and p=0.038, respectively). PD-L1 expression was detected in 32.4% of patients (1111/3433), including 73 patients with TGFβ signaling gene GAs. TGFβ signaling gene GAs were not correlated with PD-L1 expression. Survival analysis from an independent cohort confirmed that patients with SMAD4 GAs had a poor clinical benefit to ICIs compared with WT in both progression free survival (PFS) (1.97 months vs 3.5 months, respectively, p=0.02) and durable clinical benefit (DCB) (0% vs 32.5%, respectively, p=0.03). Furthermore, SMAD4 GAs were independent risk factors of PFS (HR: 2.01, 95%CI: 1.05-3.86, p=0.036).
Conclusion: This study's findings revealed that the GAs of SMAD4 occurred in a subgroup of patients with LUAD and were associated with an unfavorable response to ICIs. This suggests that GAs of SMAD4 may have implications as a biomarker for guiding ICI treatment.
Keywords: non-small cell lung cancer, SMAD4, tumor mutational burden, immunotherapy
Citation Format: Shuben Li, Chengzhi Zhou, Jian Huang, Shiyue Zhang, Jiqiang He, Hui Chen, Shaohua Yuan, Weiwei Shi. Genomic alterations of TGFβ signaling genes as novel biomarkers for immunotherapy in patients with non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3174.