Circulating tumor DNA-based copy-number profiles enable monitoring treatment effects during therapy in high-grade serous carcinoma

• Published in: Biomedicine & pharmacotherapy 2023-12, Vol.168, p.115630-115630, Article 115630
• Main Authors: Nguyen, Mai T.N., Rajavuori, Anna, Huhtinen, Kaisa, Hietanen, Sakari, Hynninen, Johanna, Oikkonen, Jaana, Hautaniemi, Sampsa
• Format: Article
• Language: English
• Subjects: Copy-number alterations; CtDNA; High-grade serous carcinoma; Targeted sequencing; Treatment monitoring
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.115630

Circulating tumor DNA (ctDNA) analysis has emerged as a promising tool for detecting and profiling longitudinal genomics changes in cancer. While copy-number alterations (CNAs) play a major role in cancers, treatment effect monitoring using copy-number profiles has received limited attention as compared to mutations. A major reason for this is the insensitivity of CNA analysis for the real-life tumor-fraction ctDNA samples. We performed copy-number analysis on 152 plasma samples obtained from 29 patients with high-grade serous ovarian cancer (HGSC) using a sequencing panel targeting over 500 genes. Twenty-one patients had temporally matched tissue and plasma sample pairs, which enabled assessing concordance with tissues sequenced with the same panel or whole-genome sequencing and to evaluate sensitivity. Our approach could detect concordant CNA profiles in most plasma samples with as low as 5% tumor content and highly amplified regions in samples with ∼1% of tumor content. Longitudinal profiles showed changes in the CNA profiles in seven out of 11 patients with high tumor-content plasma samples at relapse. These changes included focal acquired or lost copy-numbers, even though most of the genome remained stable. Two patients displayed major copy-number profile changes during therapy. Our analysis revealed ctDNA-detectable subclonal selection resulting from both surgical operations and chemotherapy. Overall, longitudinal ctDNA data showed acquired and diminished CNAs at relapse when compared to pre-treatment samples. These results highlight the importance of genomic profiling during treatment as well as underline the usability of ctDNA. [Display omitted]