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.

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.