ctDNA Holds Potential to Guide Management of EGFR-Mutated NSCLC

Circulating tumor DNA (ctDNA) liquid biopsies can help direct the evaluation and management of EGFR-mutated non–small cell lung cancer (NSCLC), according to a review published in Cancers, although more work is needed to address its current limitations.

Blood samples | Image credit: © Daniel CHETRONI – stock.adobe.com

EGFR mutations are observed in approximately 15% of NSCLC cases in the US, and they occur more often in nonsmokers. Genomic testing, either via solid tissue biopsies or liquid biopsies, helps detect these mutations, thus allowing clinicians to use EGFR tyrosine kinase inhibitors (TKIs) in these patients. One liquid biopsy type growing in popularity as the technology evolves is ctDNA, which consists of DNA fragments shed by tumor cells into the plasma.

“ctDNA can provide a complementary or alternative approach to tissue-based genomic testing and is now increasingly incorporated into clinical practice,” the authors wrote.

Their review synthesized the existing literature in this area to discuss the role of ctDNA and its application to the treatment of patients with EGFR-mutated NSCLC, both in early and advanced stages. It also explored the remaining questions and ongoing research that will help solidify the role of ctDNA in guiding treatment recommendations.

Research has explored ctDNA’s performance vs traditional tissue next-generation sequencing (NGS), with some finding that plasma-based NGS testing was associated with higher rates of guideline-recommended treatment and shorter time to receiving first treatment for NSCLC. Study results also appear to show a faster testing turnaround with liquid biopsy than tumor tissue. Specifically for EGFR-mutated NSCLC, ctDNA is being used for molecular profiling to guide treatment decision-making, such as identifying mechanisms of resistance to EGFR TKIs. However, false-negative results can be a problem because approximately 15% to 32% of patients with EGFR-mutated NSCLC shed insufficient ctDNA to be detected, making the gold standard of tissue biopsy still necessary.

In the early stages of EGFR-mutated NSCLC, ctDNA testing after surgical resection has shown success in helping risk-stratify patients, assess their response to treatment, and detect any potential relapse earlier than standard imaging. However, research still needs to answer questions about the optimal timing of ctDNA testing post-surgery and the timing of samples to guide treatment escalation or reduction. The authors also noted the need to ensure the benefits of ctDNA are not outweighed by financial toxicity to patients.

ctDNA also has a place in the management of advanced EGFR-mutated NSCLC, via its ability to detect mechanisms of resistance to targeted agents. For instance, one trial found that serial ctDNA monitoring in this setting was feasible and allowed for the timely transition of patients from gefitinib to osimertinib, which was associated with improved progression-free survival and overall survival outcomes. It also has impressive prognostic capabilities, with one study showing prolonged progression-free survival in patients whose plasma ctDNA results were negative. ctDNA levels as early as 3 weeks into a treatment regimen can serve as a predictive marker of response, results showed. On the other hand, ctDNA has also been used to show comutations associated with poorer prognosis, thus guiding a more aggressive treatment approach.

Despite these promising data, the review authors noted ample room for improvement. The minimal residual disease assays currently available have limited or variable sensitivity, so work is ongoing to improve accuracy and assess implementation into clinical practice. Simultaneously, the integration into routine practice will necessitate the creation of mechanisms to refer patients for genetic consultation and counsel them on the results.

Nonetheless, the authors concluded that ctDNA plays a crucial role in managing EGFR-mutated NSCLC, including in its diagnosis, prognosis, resistance, response monitoring, and therapeutic decision-making.

“Furthermore, the emerging potential of ctDNA analysis in informing treatment escalation and de-escalation strategies offers promising avenues for enhancing treatment efficacy and reducing adverse effects,” they wrote.

Reference

Desai A, Vázquez TA, Arce KM, et al. ctDNA for the evaluation and management of EGFR-mutant non-small cell lung cancer. Cancers (Basel). 2024;16(5):940. doi:10.3390/cancers16050940