Copy number aberrations in circulating tumor DNA enables prognosis prediction and molecular characterization of breast cancer
- Abstract
- Background: Low-pass whole-genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis is a versatile tool for somatic copy number aberration (CNA) detection, and this study aims to explore its clinical implication in breast cancer.
Methods: We analyzed LP-WGS ctDNA data from 207 metastatic breast cancer (MBC) patients to explore prognostic value of ctDNA CNA burden and validated it in 465 stage II-III triple-negative breast cancer (TNBC) patients who received neoadjuvant chemotherapy in phase III PEARLY trial (NCT02441933). The clinical implication of locus level LP-WGS ctDNA profiling was further evaluated.
Results: We found that a high baseline ctDNA CNA burden predicts poor overall survival and progression-free survival of MBC patients. The post hoc analysis of the PEARLY trial showed that a high baseline ctDNA CNA burden predicted poor disease-free survival independent from pathologic complete response (pCR), validating its robust prognostic significance. The 24-month disease-free survival rate was 96.9% and 55.9% in [pCR(+) and low I-score] and [non-pCR and high I-score] patients, respectively. The locus-level ctDNA CNA profile classified MBC patients into 5 molecular clusters and revealed targetable oncogenic CNAs. LP-WGS ctDNA and in vitro analysis identified the BCL6 amplification as a resistance factor for CDK4/6 inhibitors. We estimated ctDNA-based homologous recombination deficiency status of patients by shallowHRD algorithm, which was highest in the TNBC and correlated with platinum-based chemotherapy response.
Conclusions: These results demonstrate LP-WGS ctDNA CNA analysis as an essential tool for prognosis prediction and molecular profiling. Particularly, ctDNA CNA burden can serve as a useful determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients.
- Author(s)
- Min Hwan Kim; Gun Min Kim; Jin Mo Ahn; Won-Ji Ryu; Seul-Gi Kim; Jee Hung Kim; Tae Yeong Kim; Hyun Ju Han; Jee Ye Kim; Hyung Seok Park; Seho Park; Byeong Woo Park; Seung Il Kim; Joon Jeong; Jieun Lee; Soonmyung Paik; Sangwoo Kim; Kyung Hae Jung; Eun Hae Cho; Joohyuk Sohn
- Issued Date
- 2023
- Type
- Article
- Keyword
- LP-WGS ctDNA analysis; copy number aberrations; breast cancer; prognosis; molecular profiling
- DOI
- 10.1093/jnci/djad080
- URI
- https://oak.ulsan.ac.kr/handle/2021.oak/16593
- Publisher
- JOURNAL OF THE NATIONAL CANCER INSTITUTE
- Language
- 영어
- ISSN
- 0027-8874
- Citation Volume
- 115
- Citation Number
- 9
- Citation Start Page
- 1036
- Citation End Page
- 1049
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- Medicine > Nursing
- 공개 및 라이선스
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