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

Abstract

Backgrounds 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 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 (+)/Low I-score and non-pCR/High I-score patients, respectively. The locus-level ctDNA CNA profile classified MBC patients into five 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 (HRD) 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.

Identification and Analysis of Sex-Biased Copy Number Alterations

“…Chromosomal aberrations are closely associated with the prognosis of cancer patients [ 30 , 31 ]. Correspondingly, we supposed that the impact of CNA regions with sex bias would be reflected in the divergent survival outcomes of male patients and female patients.…”

Liquid biopsy for human cancer: cancer screening, monitoring, and treatment

“… 54 ctDNA carries genetic alterations in the tumor, including point mutations, insertions/deletions, copy number variations, and chromosomal rearrangements. 55 , 56 , 57 Analyzing these genetic alterations in ctDNA can provide information about the tumor's mutational profile, heterogeneity, and potential therapeutic targets. ctDNA analysis is employed in various clinical applications, such as cancer diagnosis, prognosis, treatment selection, and monitoring.…”