Biological Factors Affect CDK4/6 Inhibitor Response in Breast Cancer


Results from a new study could lead to the development of biomarkers for predicting treatment response and the implementation of strategies to address acquired resistance of CDK4/6 inhibitors in HR-positive/HER2-negative breast cancer.

Breast Cancer © Axel Kock -

Breast Cancer © Axel Kock -

Specific biological features of hormone-receptor (HR)-positive/HER2-negative breast cancer are associated with CDK4/6 inhibitor response, according to data from a prospective study (NCT04526587) recently published in NPJ Precision Oncology.1

In the study, investigators observed that biomarkers could be developed to predict response to CDK4/6 inhibitors and new strategies deployed to target acquired resistance. HR-positive/HER2-negative metastatic tumors of the luminal B, HER2, and basal subtypes resulted in shorter progression-free survival (PFS) with CDK4/6 inhibitor combination therapy.

However, these subtypes were not associated with overall survival (OS). In addition, changes in the cell cycle and estrogen signaling occurred during treatment, both of which were determinants for therapeutic efficacy.

“Physicians always welcome information that allows them to target their patients' cancer using a particular drug to produce a good outcome, not only to celebrate that success with their patients, but also to avoid the frustration of providing a drug that does not work and delays a more efficacious treatment,” said Ellis Levine, MD, chief of breast medicine, Roswell Park Comprehensive Cancer Center, in a press release.2

HR-positive/HER2-negative breast cancer is 1 the most common subtype of breast cancer reported in the United States each year, but with the emergence of CDK4/6 inhibitors, progression of disease has been limited among patients.

CDK4/6 are already FDA-approved and often used for treatment in this patient population. However, more research is warranted to continue understanding the clinical success of these agents.

“While CDK4/6 inhibitors have been considered a ‘game-changer’ in the treatment of breast cancer, more work is needed to utilize these agents with precision to further improve quality of life and outcomes for our patients,” said lead author Agnieszka Witkiewicz, MD, professor of Oncology and director of the Advanced Tissue Imaging Shared Resource at Roswell Park Comprehensive Cancer Center, in a press release.2

Focusing on this goal, researchers developed a study where over 280 patients were enrolled and evaluated with standard-of-care CDK4/6 inhibitor regimens as of December 2022 in the clinical trial.

Among those enrolled, most patients (n = 228) were aged 50 years and older, had an ECOG performance status of 0 (n =144), were European (n = 242), and female (n = 275).1 A total of 222 patients had postmenopausal status at the start of the CDK, 147 had non-visceral metastatic status, and 189 had recurrent metastatic status at presentation. The majority of patients had 1 metastatic site (n = 124), 86 had 2 sites, and 56 had 3 sites. Additionally, 183 patients received prior endocrine therapy, and 144 received prior chemotherapy.

In the patient population observed in the study, most patients (92%) were treated with palbociclib (Ibrance) along with either an aromatase inhibitor (AI) or fulvestrant. Among these patients, the PFS was 28.6 months for those treated with the AI vs 17.2 months for those given fulvestrant, respectively. Among clinical variables, visceral involvement, prior endocrine therapy, and recurrent disease correlated with shorter PFS rates.

The OS observed in this cohort was determined from either the initiation of treatment or the point of progression, and those treated with an AI had a longer OS. However, when using the point of progression on CDK4/6 inhibitor-based therapy as the starting point, each group had a veritably identical median OS of 19 months.

Investigators also assessed progesterone receptor (PR) and HER2 expressions to see if any standard pathological marker was associated with PFS. HER2 level determined by IHC scoring (0, 1+, or 2+/FISH non-amplified) was not linked with PFS in the combined cohort or in subgroup analysis of patients treated with AI or fulvestrant. PR status correlated with PFS, and PR negative/low status signified shorter PFS among those in the combined cohort.

Looking at subgroup analyses, the absence of PR was associated with PFS in the AI-treated patients. However, this was not the case among patients treated with fulvestrant. The majority of patients (n = 248) had tumor histologic grade assigned using the Nottingham modification of Scarff–Bloom–Richardson (SBR) scoring, and higher SBR scores were associated with shorter PFS in the combined cohort, as well as in the cohort of patients given AI. Again, this was not true for the fulvestrant-treated cohort.

Tissue obtaining procedures were also evaluated and did not significantly alter the PFS association. Several routine pathological features of breast cancer were associated with the duration of therapeutic response, and gene expression analyses of the tumors showed substantial changes during treatment and evolution of the tumors with acquired resistance.

Overall, this study identified pathological and biological features associated with therapeutic response in patients with HR-positive/HER2-negative breast cancer. These findings suggest potential treatment strategies for this subtype of breast cancer. Further research on this topic is warranted.

Witkiewicz AK, Schultz E, Wang J, et al. Determinants of response to CDK4/6 inhibitors in the real-world setting. NPJ Precis Oncol. 2023;7(1):90. Published 2023 Sep 13. doi:10.1038/s41698-023-00438-0
Roswell Park team reports new insights on treatment of metastatic breast cancer. News release. Rosewell Park Comprehensive Cancer Center. September 14, 2023. Accessed September 18, 2023.
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