11P - Multimodal analysis of methylation and fragmentomic profiles in plasma cell-free DNA for differentiation of benign and malignant breast tumors

Background

Breast cancer is the second leading cause of cancer deaths in women worldwide. Early detection of breast cancer has been demonstrated to improve patients' treatment outcomes and survival. Liquid biopsy based on detecting DNA shed by breast tumors into the circulation, known as circulating tumor DNA (ctDNA), has emerged as a promising non-invasive approach. However, differentiating benign breast lumps from malignant tumors remains a challenge in current clinical practice, and inaccurate detection may result in unnecessary invasive procedures.

Methods

To address this challenge, we employed a multimodal analysis approach, namely SPOT-MAS (Screen for the Presence of Tumor by DNA Methylation and Size) to profile alterations in methylation and fragment length patterns of cell free DNA (cfDNA) from 133 breast cancer patients and 59 patients with benign breast lumps comprising cysts and fibroadenomas.

Results

We identified multiple distinct end motifs, differential methylation and fragment length patterns across 22 chromosomes, which were further exploited as input features to build machine learning models to discriminate early-stage breast cancer patients from patients with benign lesions. The models achieved an area under the curve of 0.87 (95% CI: 0.79 – 0.94) and a sensitivity of 64.1% at 90% specificity in detecting patients with malignant tumors.

Conclusions

Therefore, our findings demonstrated that cancer-specific methylation and fragmentomic patterns in plasma cfDNA could serve as novel biomarkers for accurately differentiating malignant breast cancer patients from those with benign lesions.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Medical Genetics Institute and Gene Solutions Joint Stock Company, Vietnam.

Funding

Gene Solutions Joint Stock Company.

Disclosure

All authors have declared no conflicts of interest.