Copy number aberrations in ctDNA enables prognosis prediction and molecular characterization of breast cancer
Menée à partir d'une technique de séquençage de l'ADN tumoral circulant issu de 207 patientes atteintes d'un cancer métastatique du sein puis validée sur 465 patientes atteintes d'un cancer du sein triple négatif de stade II-III et ayant reçu une chimiothérapie néoadjuvante dans le cadre d'un essai de phase III, cette étude met en évidence une association entre la présence d'anomalies au niveau du nombre de copies géniques et le pronostic
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.
Journal of the National Cancer Institute , résumé, 2022