Circulating DNA-Based Sequencing Guided Anlotinib Therapy in Non-Small Cell Lung Cancer

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Anlotinib is a multitargeted antiangiogenic drug for non-small cell lung cancer (NSCLC).
• Predicting patient response to anlotinib remains a clinical challenge.
• Identifying reliable biomarkers is crucial for optimizing NSCLC treatment.

Purpose of the Study:

• To develop a predictive model for anlotinib response in NSCLC patients.
• To identify genetic markers in circulating DNA associated with treatment benefit.
• To establish a noninvasive method for stratifying NSCLC patients for anlotinib therapy.

Main Methods:

• Circulating DNA was profiled using tumor-specific target capture in NSCLC patients receiving anlotinib.
• Genetic profiling included ARID1A, BRCA2, germline and somatic mutation burden (G+S MB), and nonsynonymous and synonymous mutation burden (N+S MB).
• A tumor mutation index (TMI) was developed by integrating multiple predictors, including IDH1 exon 4 mutation status.

Main Results:

• ARID1A and BRCA2 profiling can exclude non-responding patients.
• G+S MB, N+S MB, and unfavorable mutation scores were identified as predictors for durable benefit.
• The TMI model effectively identified patients likely to benefit from anlotinib, with IDH1 exon 4 mutation as an unfavorable factor.

Conclusions:

• Circulating DNA sequencing offers a noninvasive method to identify anlotinib responders in NSCLC.
• The TMI model, incorporating IDH1 exon 4 status, improves prediction of anlotinib efficacy.
• This approach has the potential to enhance clinical outcomes for NSCLC patients undergoing third-line therapy.