Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative advanced and metastatic breast cancer in Japan (KBCSG-TR-1316)

Breast Cancer. 2023 Nov;30(6):943-951. doi: 10.1007/s12282-023-01485-y. Epub 2023 Jul 24.

Abstract

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative advanced/metastatic breast cancer (HR+/HER2- mBC). However, some cancers show resistance to CDK4/6i and have a poor prognosis. The non-luminal disease score (NOLUS) was developed to predict non-luminal disease using immunohistochemical analysis.

Methods: The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including real-world progression-free survival (rw-PFS) and overall survival (OS). Real-world data of patients with HR+/HER2- mBC who received CDK4/6i therapy [palbociclib or abemaciclib] as first- or second-line endocrine treatments was obtained. NOLUS was calculated using the formula: NOLUS (0-100) = - 0.45 × estrogen receptor (ER) (%) - 0.28 × progesterone receptor (PR) (%) + 0.27 × Ki67(%) + 73, and the patients were divided into two groups: NOLUS-positive (≥ 51.38) and NOLUS-negative (< 51.38).

Results: Of the 300 patients, 28 (9.3%) were NOLUS-positive, and 272 (90.7%) were NOLUS-negative. The expression rates (%) of ER and PgR in NOLUS-positive patients were lower than those in NOLUS-negative patients (p < 0.001). Ki67 expression was higher in NOLUS-positive patients. There were statistically significant differences in prognosis (rw-PFS and OS) between the two groups. Moreover, NOLUS-negative patients showed statistically better rw-PFS with first-line therapy than second-line therapy. However, NOLUS-positive patients showed poor prognoses with both the first and second therapeutic lines, suggesting CDK4/6i inefficacy for NOLUS-positive patients.

Conclusions: The efficacy and prognosis of CDK4/6i significantly differed between the NOLUS-positive and NOLUS-negative patients. This feasible method can predict patients with HR+/HER2- mBC resistant to CDK4/6i and help select a better therapeutic approach to overcome resistance.

Keywords: CDK4/6 inhibitor; Luminal; Metastatic breast cancer; NOLUS; Resistant.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Female
  • Humans
  • Japan
  • Ki-67 Antigen
  • Progression-Free Survival
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Receptor, ErbB-2
  • Receptors, Estrogen

Substances

  • Ki-67 Antigen
  • Receptors, Estrogen
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Protein Kinase Inhibitors
  • Receptor, ErbB-2
  • CDK4 protein, human