Dynamic characterization of circulating tumor DNA in HER2-altered advanced non-small cell lung cancer treated with pyrotinib and apatinib: Exploratory biomarker analysis from PATHER2 study.

Background: HER2 mutations are critical drivers of non-small cell lung cancer (NSCLC), affecting 2 %-3 % of patients and often leads to poor prognosis and limited response to conventional therapies. This study investigates the genomic characteristics and prognostic relevance of dynamic circulating tumor DNA (ctDNA) monitoring in advanced NSCLC patients with HER2 mutations treated with pyrotinib and apatinib.

Methods: The PATHER2 study included 33 advanced NSCLC patients harboring HER2 mutations or amplification, who received combination therapy of pyrotinib and apatinib. Among them, 27 patients had baseline blood samples available for analysis. Baseline blood samples (n = 27), follow-up samples after one treatment cycle (n = 13), and samples upon disease progression (n = 18) were collected. ctDNA was extracted and sequenced using a 556-gene panel.

Results: At baseline, HER2 mutations were detected in 21 of 27 patients through ctDNA, and 19 showed consistent results between tissue and blood sample testing. Patients with TP53 and DNMT3A alterations at baseline had significantly shorter progression-free survival (PFS). Dynamic ctDNA monitoring revealed that patients without detectable HER2 mutations after one treatment cycle had longer PFS and a trend toward longer overall survival (OS) compared to those with persistent HER2 mutations. The newly emerged mutations after resistance were infrequently found in HER2, instead primarily enriched in the chromatin remodeling pathway.

Conclusion: ctDNA holds significant value in guiding the treatment of patients with HER2 mutations. Baseline TP53 and DNMT3A alterations, along with persistent HER2 mutations after initial treatment, are associated with poorer prognosis. The primary mechanism of resistance to pyrotinib and apatinib in these patients may be attributed to chromatin remodeling rather than on-target alterations.