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Short-term Preoperative Abemaciclib Shows a Significant Anti-Proliferative Effect in Early Breast Cancer

Abemaciclib treatment induces changes in the expression of several cell cycle biomarkers
20 Sep 2020
Anticancer agents & Biologic therapy;  Breast cancer;  Translational research

Patients receiving a short course of abemaciclib prior to surgery for early breast cancer demonstrated a statistically significant decrease in cell proliferation compared with untreated control patients according to findings from the ABC-POP study presented by Monica Arnedos of the Gustave Roussy Cancer Campus in Villejuif, France at the ESMO Virtual Congress 2020.

Dr Arnedos conducted this randomised, preoperative window of opportunity (WOO) study. Regarding the rationale for this investigation, she cited the encouraging results seen in their previous WOO study, wherein short-term treatment with the CDK4/6 inhibitor palbociclib resulted in inhibition of proliferation.

The ABC-POP trial reported at ESMO 2020 evaluated the anti-proliferative effect of abemaciclib, which also inhibits CDK4/6 but has a different pattern of CDK target inhibition than palbociclib. In addition, the study team compared differences in differential gene expression (GE) array pathway analyses between abemaciclib and palbociclib.

The primary objective of the study was the anti-proliferative response, which was defined as the natural logarithm of Ki67 expression at day 15<1.

The study randomised 103 patients with untreated early breast cancer in a 3:1 ratio to receive either abemaciclib at 150 mg twice daily for 14 days or no treatment.

The FFPE and frozen samples were obtained at baseline and upon surgery. Immunohistochemistry was performed for detection of Ki67, RB, pRB, p16, Cyclin D1, Cyclin E1, Cyclin E2, and the CD8+/FOXP3 ratio, as well as tumour infiltrating lymphocytes (TILs).

The investigators performed GE arrays pre- and post-treatment and pooled GE pathway analysis was done using GE arrays from the prior WOO trial of palbociclib to compare the two drugs.  

The ABC-POP trial uncovered significant differences in anti-proliferative effects between patients treated with abemaciclib and non-treated controls

Immunohistochemistry findings showed that the anti-proliferative effect in abemaciclib-treated patients was 71% compared with 8% in the control arm (p <0.0001).

Significant differences between the abemaciclib and control arms were also observed regarding changes in expression of Ki67 (p < 0.0001), pRB (p < 0.0001), Cyclin D1 (p = 0.047), and Cyclin E2 (p < 0.0001).

A significant (FDR < 0.005) effect on change in expression from baseline was noted primarily for genes associated with the cell cycle and proliferation; however, no genes were found to significantly associate with the anti-proliferative effect observed with abemaciclib and no significant predictive biomarkers for abemaciclib activity were identified.

Pooled samples of 149 patients with HR+/HER2- tumorus participating in the palbociclib and ABC-POP trials were used for the GE pathway analysis, which showed that CDK4/6 inhibition was associated with significant effects on the E2F, G2M, and mitotic spindle pathways. This combined set identified 23 potential genes significantly predictive of benefit from CDK4/6 inhibition but they require final validation.

A differential effect between treatment with abemaciclib and palbociclib on GE observed in 263 genes and further analyses are currently ongoing although no significant differences were observed between the two drugs when analysing for main GE pathways.

Conclusions

According to the authors, IHC and GE array data from the ABC-POP trial indicated that short-term pre-operative abemaciclib treatment was associated with a significant anti-proliferative effect as, well as changes in cell cycle biomarkers including pRb, Cyclin D1, and Cyclin E2. The study team found decrease in genes involved in cell proliferation, DNA replication and cell cycle, including CCNA2, CCNB1, CDK1, CCNE2. However, they could not identify any biomarkers predictive of abemaciclib benefit.

The GE pathway analyses using pooled samples obtained from abemaciclib and palbociclib treated patients showed significant effects on cell cycle pathways with both agents and identified some significant differences in GE array effect between palbociclib and abemaciclib but not in main GE pathways.

The ABC-POP study received funding from Eli Lilly and the Breast Cancer Research Foundation. The POP study received funding from Pfizer and the Breast Cancer Research Foundation.

Reference

161O – Arnedos A, Chaltiel D, Cheaib B, et al. Randomized preoperative window of opportunity (WOO) study with the CDK4/6 inhibitor abemaciclib in early breast cancer (EBC) patients and differential gene expression pathway analyses with palbociclib. ESMO Virtual Congress 2020.

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