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Genomic Profiling of Premenopausal HR+ and HER2- Metastatic Breast Cancer by Circulating Tumor DNA and Association of Genetic Alterations With Therapeutic Response to Endocrine Therapy and Ribociclib

 Aditya Bardia  ;  Fei Su  ;  Nadia Solovieff  ;  Seock-Ah Im  ;  Joohyuk Sohn  ;  Keun Seok Lee  ;  Saul Campos-Gomez  ;  Kyung Hae Jung  ;  Marco Colleoni  ;  Rafael Villanueva Vázquez  ;  Fabio Franke  ;  Sara Hurvitz  ;  Nadia Harbeck  ;  Louis Chow  ;  Tetiana Taran  ;  Karen Rodriguez Lorenc  ;  Naveen Babbar  ;  Debu Tripathy  ;  Yen-Shen Lu 
 JCO PRECISION ONCOLOGY, Vol.5 : 1408-1420, 2021-08 
Journal Title
Issue Date
Adolescent ; Adult ; Aminopyridines / administration & dosage* ; Antineoplastic Agents, Hormonal / administration & dosage* ; Antineoplastic Combined Chemotherapy Protocols / therapeutic use ; Biomarkers, Tumor / genetics ; Breast Neoplasms / drug therapy* ; Breast Neoplasms / genetics* ; Breast Neoplasms / mortality ; Breast Neoplasms / pathology ; Circulating Tumor DNA / genetics* ; Double-Blind Method ; Drug Resistance, Neoplasm / genetics ; Female ; Genomics ; Humans ; Middle Aged ; Premenopause / drug effects ; Progression-Free Survival ; Proportional Hazards Models ; Purines / administration & dosage* ; Receptor, ErbB-2 / genetics ; Transcription Factors / genetics ; Young Adult
Purpose: This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial.

Methods: Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib.

Results: Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status.

Conclusion: In this study-to our knowledge, the first large study of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer-multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Sohn, Joo Hyuk(손주혁) ORCID logo https://orcid.org/0000-0002-2303-2764
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