Tissue or liquid rebiopsy? A prospective study for simultaneous tissue and liquid NGS after first-line EGFR inhibitor resistance in lung cancer

Yen-Ting Lin; Chao-Chi Ho; Wei-Hsun Hsu; Wei-Yu Liao; Ching-Yao Yang; Chong-Jen Yu; Tzu-Hsiu Tsai; James Chih-Hsin Yang; Shang-Gin Wu; Chia-Lin Hsu; Min-Shu Hsieh; Yen-Lin Huang; Chia-Ling Wu; Jin-Yuan Shih

doi:10.1002/cam4.6870

Tissue or liquid rebiopsy? A prospective study for simultaneous tissue and liquid NGS after first-line EGFR inhibitor resistance in lung cancer

Cancer Med. 2023 Dec 22;13(1):e6870. doi: 10.1002/cam4.6870. Online ahead of print.

Authors

Yen-Ting Lin^{1

2

3}, Chao-Chi Ho³, Wei-Hsun Hsu⁴, Wei-Yu Liao³, Ching-Yao Yang³, Chong-Jen Yu^{3

5}, Tzu-Hsiu Tsai³, James Chih-Hsin Yang^{6

7

8}, Shang-Gin Wu^{2

3}, Chia-Lin Hsu³, Min-Shu Hsieh^{9

10}, Yen-Lin Huang¹⁰, Chia-Ling Wu¹¹, Jin-Yuan Shih^{1

3}

Affiliations

¹ Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
² Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan.
³ Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁴ Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
⁵ Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan.
⁶ Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
⁷ Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
⁸ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
⁹ Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
¹⁰ Department of Pathology, National Taiwan University Cancer Center, Taipei, Taiwan.
¹¹ ACT Genomics, Taipei, Taiwan.

Abstract

Introduction: According to current International Association for the Study of Lung Cancer guideline, physicians may first use plasma cell-free DNA (cfDNA) methods to identify epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant mechanisms (liquid rebiopsy) for lung cancer. Tissue rebiopsy is recommended if the plasma result is negative. However, this approach has not been evaluated prospectively using next-generation sequencing (NGS).

Methods: We prospectively enrolled patients with lung cancer with first-line EGFR-TKI resistance who underwent tissue rebiopsy. The rebiopsied tissues and cfDNA were sequenced using targeted NGS, ACTDrug®+, and ACTMonitor®Lung simultaneously. The clinicopathological characteristics and treatment outcomes were analyzed.

Results: Totally, 86 patients were enrolled. Twenty-six (30%) underwent tissue biopsy but the specimens were inadequate for NGS. Among the 60 patients with paired tissue and liquid rebiopsies, two-thirds (40/60) may still be targetable. T790M mutations were found in 29, including 14 (48%) only from tissue and 5 (17%) only from cfDNA. Twenty-four of them were treated with osimertinib, and progression-free survival was longer in patients without detectable T790M in cfDNA than in patients with detectable T790M in cfDNA (p = 0.02). For the 31 T790M-negative patients, there were six with mesenchymal-epithelial transition factor (MET) amplifications, four with ERBB2 amplifications, and one with CCDC6-RET fusion. One with MET amplification and one with ERBB2 amplification responded to subsequent MET and ERBB2 targeting agents respectively.

Conclusions: NGS after EGFR-TKI resistance may detect targetable drivers besides T790M. To do either liquid or tissue NGS only could miss patients with T790M. To do tissue and liquid NGS in parallel after EGFR-TKI resistance may find more patients with targetable cancers.

Keywords: EGFR mutation; EGFR-TKI resistance; NSCLC; next-generation sequencing.

Grants and funding

ACT Genomics