905MO - Synergistic combination of clinical, imaging and DNA methylation biomarkers improves the classification of pulmonary nodules

Background

Clinical unmet needs still abound for an accurate noninvasive test to facilitate early detection of lung cancer. Here, we describe a novel combination of clinical, imaging and DNA methylation biomarkers to improve the classification of pulmonary nodules.

Methods

We conducted a prospective collection and retrospective blinded evaluation trial comprising 1,380 subjects in 24 sites. We developed a 10-feature combined clinical and imaging biomarkers model (CIBM) for the classification of malignant and benign pulmonary nodules in a cohort (n=839) and validated it in 2 cohorts (n₁=258, n₂=283). Then we integrated CIBM model with our previously established ctDNA methylation model (PulmoSeek) to create a new combined model (n=258), PulmoSeek Plus, and verified it independently (n=283). Meanwhile, a 12-feature imaging biomarker model for invasiveness differentiation (IBMI) of lung adenocarcinoma were established (n=624) and validated (n₁=202, n₂=193). Clinical utility of the models was evaluated using a decision curve analysis.

Results

The CIBM model achieved improved AUCs (0.85 [95% CI 0.80-0.89]; 0.85 [0.81-0.89]) over Mayo model (0.60 [0.52-0.68]; 0.57 [0.50-0.64]) and Brock model (0.70 [0.63-0.77]; 0.67 [0.60-0.73]) in the two validation cohorts, respectively. PulmoSeek Plus had AUC of 0.90 [0.88-0.93] in the combined set (n=541), significantly outperforming both CIBM (0.85 [0.82-0.88]) and PulmoSeek (0.85 [0.82-0.88]). The overall sensitivity was 98.0% [0.97-1.00] at a fixed specificity of 50.0% for rule out. High sensitivity of 98.0% [0.96-0.99] was maintained in early-stage lung cancer (0-I, n=390) and 99.2% [0.96-1.00] in 5-10 mm nodules (n=123). The IBMI model had AUCs of 0.87 [0.82-0.92], 0.89 [0.84-0.93] and 0.89 [0.85-0.92] in the two validation sets and the combined set. At a risk score of 0.54, PulmoSeek Plus improved net benefit by 60.8%, equivalent to detecting additional 82.4% of lung cancers. Using two cut-offs of PulmoSeek Plus scores to reclassify would have reduced 46.0% unnecessary surgeries and reduced 73.2% delayed treatment.

Conclusions

PulmoSeek Plus model improves the early detection and classification of pulmonary nodules, potentially worth using in clinical decision-making.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Anchordx Medical Co., Ltd., Guangzhou, China.

Funding

Anchordx Medical Co., Ltd., Guangzhou, China.

Disclosure

All authors have declared no conflicts of interest.