Predictive Algorithm Demonstrates Association With Progression-Free and Overall Survival in Patients With Metastatic Breast Cancer

One of the most common breast cancer subtypes is hormone receptor-positive (HR+) and HER2-negative (HER2–) which is characterized by an estrogenic signaling dependence.1 Endocrine therapy has been the mainstay of treatment for the last 3 decades which delays the progression of metastatic disease but most patients progress on endocrine therapy alone.1 The addition of CDK4/6 inhibitors with endocrine therapy has been found to extend the progression-free survival (PFS) of patients.1 When compared to use of monotherapy with endocrine therapy CDK4/6 inhibitors have been found to generally double the progression-free survival (PFS) of patients.1 Although CDK4/6 inhibitors delay the need for chemotherapy and enhance patient quality of life they are not generally considered curative.1

CDK4/6 inhibitors work by inhibiting retinoblastoma protein phosphorylation, which induces G1 cell cycle arrest in the tumor cells.2 Despite knowledge of the mechanism of action of CDK4/6 inhibitors, biomarkers can help select patients with HR+/HER– breast cancer for treatment with these agents.1 To help determine biomarkers that can predict PFS with the use of CDK4/6 inhibitors, a study enrolling 300 patients with metastatic HR+/HER2– breast cancer was conducted. The patients received standard of care with CDK4/6 inhibitors combined with either aromatase inhibitors or fulvestrant. Both patient groups had a duration of PFS comparable to that found in randomized clinical trials. In this trial, duration of PFS was related to prior endocrine therapy, progesterone receptor-status, visceral disease, and endocrine therapy type.

To search for biomarkers, gene expression analysis was performed on 313 tumor samples collected from more than 200 patients. Gene expression analysis was performed to develop biomarkers. Pre-treatment metastatic biopsies were used to established signatures which were associated with prognosis in HR+/HER2– breast cancer to determine the association with response to combination therapy. Shorter PFS was associated with proliferation-associated signatures. For both aromatase inhibitors and fulvestrant, an established RB loss was found to be associated with PFS in treated patients. Signatures employed in the clinical setting had variable associations with patient outcomes. Random Survival Forest feature selection was applied to individual and combined prognostic signatures and resulted in a classifier for PFS. In an attempt to enable broader applicability to the various disease manifestations various pathological variables were incorporated into the algorithm resulting in a predictive algorithm which was found to be strongly associated with overall survival.


Witkiewicz A, Wang J, Knudsen E, et al. Composite biomarkers for the prediction of progression-free survival with CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer. Poster presented at: San Antonio Breast Cancer Symposium. December 6, 2023; San Antonio, TX. Abstract # PO2-27-05.


  1. Knudsen ES, Schultz E, Hamilton D, et al. Real-world experience with CDK4/6 inhibitors for metastatic HR+/HER2- breast cancer at a single cancer center. Oncologist. 2022;27:646-654.
  2. Zhou FH, Downton T, Freelander A, et al. CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective. Front Cell Dev Biol. 2023;11:1148792.

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