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

乳腺癌 医学 肿瘤科 内科学 癌症
作者
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,Kyung Sik Kim,Joon Jeong,Jieun Lee,Soonmyung Paik,Sang Woo Kim,Kyung Hae Jung,Eun Hae Cho,Joohyuk Sohn
出处
期刊:Journal of the National Cancer Institute [Oxford University Press]
卷期号:115 (9): 1036-1049
标识
DOI:10.1093/jnci/djad080
摘要

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.
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