Mouron, SilvanaBueno, Maria JMuñoz, ManuelTorres, RaulRodríguez, SandraApala, Juan VSilva, JorgeSánchez-Bayona, RodrigoManso, LuisGuerra, JuanRodriguez-Lajusticia, LauraMalon, DiegoMalumbres Martinez, MarcosQuintela Fandino, Miguel Angel2024-06-122024-06-122023-03-01JNCI Cancer Spectr . 2023;7(2):pkad014.http://hdl.handle.net/20.500.12105/19749CDK4/6 inhibitors benefit a minority of patients who receive them in the breast cancer adjuvant setting. p27Kip1 is a protein that inhibits CDK/Cyclin complexes. We hypothesized that single-nucleotide polymorphisms that impaired p27Kip1 function could render patients refractory to endocrine therapy but responsive to CDK4/6 inhibitors, narrowing the patient subpopulation that requires CDK4/6 inhibitors. We found that the p27Kip1 V109G single-nucleotide polymorphism is homozygous in approximately 15% of hormone-positive breast cancer patients. Polymorphic patients experience rapid failure in response to endocrine monotherapy compared with wild-type or heterozygous patients in the first-line metastatic setting (progression-free survival: 92 vs 485 days, P < .001); when CDK4/6 inhibitors are added, the differences disappear (progression-free survival: 658 vs 761 days, P = .92). As opposed to wild-type p27Kip1, p27Kip1 V109G is unable to suppress the kinase activity of CDK4 in the presence of endocrine inhibitors; however, palbociclib blocks CDK4 kinase activity regardless of the p27Kip1 status. p27Kip1 genotyping could constitute a tool for treatment selection.engBreast NeoplasmsFemaleHumansBiomarkersCyclin-Dependent Kinase 4Protein Kinase Inhibitorsp27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer.otherAttribution-NonCommercial-NoDerivatives 4.0 Internacional368069427210.1093/jncics/pkad0142515-5091JNCI cancer spectrumopen access