p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer
Menée à l'aide de lignées cellulaires et de données portant sur des patientes atteintes d'un cancer du sein HR+, cette étude met en évidence une association entre la protéine mutée p27Kip1 V109G et la réponse aux inhibiteurs des kinases CDK4/6
CDK4/6 inhibitors benefit a minority of patients that receive them in the breast cancer adjuvant setting. p27Kip1 is a protein that inhibits CDK/Cyclin complexes. We hypothesized that SNPs that impaired p27Kip1 function could render patients refractory to endocrine therapy but responsive to CDK4/6 inhibitors, narrowing-down the patient sub-population that requires CDK4/6 inhibitors. We found that the p27Kip1 V109G SNP is homozygous in ∼15% of hormone-positive breast cancer patients. Polymorphic patients experience rapid failure in response to endocrine monotherapy compared to wild-type/heterozygous patients in the first-line metastatic setting (progression-free survival: 92 versus 485 days; P < 0.001); when CDK4/6 inhibitors are added, the differences disappear (progression-free survival: 658 versus 761 days; P = 0.92). As opposed to wild-type p27Kip1, p27Kip1 V109G is unable to suppress the kinase activity of CDK4 in presence of endocrine inhibitors; however, palbociclib blocks CDK4 kinase activity regardless of the p27Kip1 status. p27Kip1 genotyping could constitute a tool for treatment selection.
JNCI Cancer Spectrum , article en libre accès, 2022