PALOMA 3: Elucidating Resistance Mechanisms to Palbociclib and Fulvestrant
It is important to understand mechanisms of resistance with these inhibitors to determine future treatment strategies.
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Based on data from PALOMA 3, the combination of palbociclib and fulvestrant has been approved for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer following progression on endocrine therapy.
Palbociclib is one of three cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors that is standard of care for the treatment of advanced estrogen receptor-positive breast cancer. It is important to understand mechanisms of resistance with these inhibitors to determine future treatment strategies.
Data reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, identified mutations that emerged in a longitudinal analysis from samples obtained from patients in PALOMA 3.1
PALOMA 3 was a randomized trial that included 521 patients whose breast cancer had progressed on endocrine therapy. Patients received palbociclib and fulvestrant or placebo and fulvestrant.
Plasma samples were collected from patients at baseline and at the end of treatment. Using driver mutation targeted sequencing on circulating tumor DNA (ctDNA) from plasma samples, investigators conducted an analysis on 193 pairs of baseline and end-of-treatment (EOT) plasma samples — 125 of these paired samples came from patients receiving the palbociclib combination and 68 from those who received fulvestrant alone.
Mutations in the retinoblastoma gene, RB1, were found in 4.8% of EOT samples of patients on the palbociclib combination and none in those receiving fulvestrant alone. However, new driver mutations in PIK3CA and ESR1, especially in ESR1 Y537S, were found in EOT samples, with similar frequencies in both groups of patients.
PIK3CA is a gene associated with the phosphatidylinositol 3-kinase (PI3K) pathway and ESR1 is a gene associated with estrogen receptor alpha.
The conclusion is that driver mutation landscapes are similar in patients that have received the palbociclib combination or fulvestrant alone and that PIK3CA and ESR1 Y537S mutations likely contribute to fulvestrant resistance.
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- Turner NC, O'Leary B, Cutts R, et al. Genetic landscape of resistance to CDK4/6 inhibition in circulating tumor DNA (ctDNA) analysis of the PALOMA3 trial of palbociclib and fulvestrant versus placebo and fulvestrant. J Clin Oncol. 2018: 36, (suppl; abstr 1001). Presented at 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL.