p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor–positive breast cancer

Abstract

Biomarker; Hormone receptor-positive; Breast cancer

Biomarcador; Cáncer de mama; Receptor hormonal positivo

Biomarcador; Càncer de mama; Receptor hormonal positiu

CDK4/6 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.

MM is supported by the Spanish Ministry of Science and Innovation (RTI2018-095582-B-100; PLEC2021-007892 and RED2018-102723-T), AES (DTS21/00132) and Comunidad de Madrid (B2017/BMD-3884 and Y2020/BIO-6519). MQF is a recipient of the following grants: AES—PI 19/00454 funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF), and B2017/BMD3733 (Immunothercan-CM) – Call for Coordinated Research Groups from the Madrid Region—Madrid Regional Government—ERDF funds. This study was also funded by a donation from CRIS Contra El Cancer Foundation.