Circulating tumor DNA mutational landscape and dynamics after progression on a CDK4/6 inhibitor in the PACE phase II trial for metastatic HR-positive/HER2-negative breast cancer

Authors

R Jeselsohn, Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Center, Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA.
J Fu, Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Center, Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA.
Y Ren, Division of Biostatistics, Dana-Farber Cancer Institute, Boston, USA.
R Mahtani, Department of Medical Oncology, Miami Cancer Institute, Miami, USA.
C Ma, Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, USA.
A DeMichele, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.
M Cristofanilli, Department of Medical Oncology, Weill Cornell Medicine, New York, USA.
J Meisel, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
K D. Miller, Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, Indianapolis, USA.
Y Abdou, Department of Medicine, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, USA.
E C. Riley, Department of Medicine, Brown Cancer Center, University of Louisville Health, Louisville, USA.
Rubina Qamar, Advocate Health - MidwestFollow
P Sharma, Department of Medical Oncology, University of Kansas Medical Center, Westwood, USA.
S Reid, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, USA.
N Ko, Department of Medical Oncology, Boston Medical Center, Boston, USA.
Y Liu, Pfizer, La Jolla, USA.
E Gauthier, Pfizer, La Jolla, USA.
H J. Burstein, Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Center, Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA.
M DeMeo, Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Center, Dana-Farber Cancer Institute, Boston, USA.
M Regan, Harvard Medical School, Boston, USA; Division of Biostatistics, Dana-Farber Cancer Institute, Boston, USA.
S M. Tolaney, Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Center, Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA.
E L. Mayer, Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Center, Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA. Electronic address: Erica_Mayer@dfci.harvard.edu.

Recommended Citation

Jeselsohn R, Fu J, Ren Y, Mahtani R, Ma C, DeMichele A, Cristofanilli M, Meisel J, Miller KD, Abdou Y, Riley EC, Qamar R, Sharma P, Reid S, Ko N, Liu Y, Gauthier E, Burstein HJ, DeMeo M, Regan M, Tolaney SM, Mayer EL. Circulating tumor DNA mutational landscape and dynamics after progression on a CDK4/6 inhibitor in the PACE phase II trial for metastatic HR-positive/HER2-negative breast cancer. ESMO Open. 2025 Aug;10(8):105506. doi: 10.1016/j.esmoop.2025.105506. Epub 2025 Jul 25. PMID: 40714513; PMCID: PMC12314381.

Affiliations

Aurora Cancer Care Milwaukee

Abstract

Background: Genomic determinants of response and resistance to endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer are not well characterized. We analyzed serial circulating tumor DNA from the PACE trial in which patients who progressed on ET and CDK4/6i were randomized to fulvestrant, fulvestrant plus palbociclib, or fulvestrant, palbociclib, and avelumab.

Materials and methods: Plasma samples from 200 of 220 PACE participants were collected for circulating tumor DNA analysis using the Guardant360 assay. Samples included baseline (n = 200), cycle 3, day 1 (C3D1; n = 124), and end of treatment (n = 137). The fulvestrant and fulvestrant + palbociclib arms were combined given similar clinical outcomes. The log-rank test was used to test associations between genomic alterations and progression-free survival (PFS).

Results: The most common baseline genomic alterations beyond progression on CDK4/6i plus ET, were mutations in ESR1 (54.0%), TP53 (35.5%), PIK3CA (34.0%), GATA3 (18.5%), and RB1 (10.0%). Among 150 patients treated with fulvestrant or fulvestrant + palbociclib, baseline mutations in TP53, PIK3CA, RB1, and the Y537S ESR1 mutation, were associated with shorter PFS. Mutations within the PI3K and cell cycle pathways were associated with significantly decreased PFS. We also observed increases in the allelic fractions of the ESR1, PIK3CA, and TP53 mutations at progression.

Conclusions: Several mutations within genes and biological pathways are associated with CDK4/6i resistance beyond progression. Additional studies are needed to optimize treatment after resistance to CDK4/6i using genomic biomarkers.

Type

Article

PubMed ID

40714513