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Copy number aberrations in circulating tumor DNA enables prognosis prediction and molecular characterization of breast cancer

 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 
 JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, Vol.115(9) : 1036-1049, 2023-09 
Journal Title
Issue Date
Biomarkers, Tumor / genetics ; Circulating Tumor DNA* / genetics ; DNA Copy Number Variations ; Disease-Free Survival ; Humans ; Prognosis ; Triple Negative Breast Neoplasms* / drug therapy ; Triple Negative Breast Neoplasms* / genetics ; Triple Negative Breast Neoplasms* / pathology
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biomedical Systems Informatics (의생명시스템정보학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Gun Min(김건민) ORCID logo https://orcid.org/0000-0001-9167-8682
Kim, Min Hwan(김민환) ORCID logo https://orcid.org/0000-0002-1595-6342
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
Kim, Seul-gi(김슬기) ORCID logo https://orcid.org/0000-0003-1641-4059
Kim, Seung Il(김승일)
Kim, Jee Ye(김지예) ORCID logo https://orcid.org/0000-0003-3936-4410
Kim, Jee Hung(김지형) ORCID logo https://orcid.org/0000-0002-9044-8540
Park, Byeong Woo(박병우) ORCID logo https://orcid.org/0000-0003-1353-2607
Park, Se Ho(박세호) ORCID logo https://orcid.org/0000-0001-8089-2755
Park, Hyung Seok(박형석) ORCID logo https://orcid.org/0000-0001-5322-6036
Paik, Soon Myung(백순명) ORCID logo https://orcid.org/0000-0001-9688-6480
Sohn, Joo Hyuk(손주혁) ORCID logo https://orcid.org/0000-0002-2303-2764
Jeong, Joon(정준) ORCID logo https://orcid.org/0000-0003-0397-0005
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