Copy number aberrations in circulating tumor DNA enables prognosis prediction and molecular characterization of breast cancer
Authors
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
Citation
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, Vol.115(9) : 1036-1049, 2023-09
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
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.