Case Western Reserve School of Medicine Cleveland, OH
R. Abou Zeidane1, S. Lichtman-Mikol1, A. Pesch2, N. Hirsh3, B. Hauk1, D. Gurdak1, C. E. Pisano1, M. Tao1, V. Mercer1, E. Cobain3, J. Lyons1, and C. Speers1; 1Department of Radiation Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, 2Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 3University of Michigan, Ann Arbor, MI
Purpose/Objective(s): Radiation therapy (RT) remains a staple in the treatment of women with breast cancer (BC). Locoregional disease recurrence remains a substantial clinical concern that compromises survival in both estrogen receptor-positive (ER+) and triple-negative (TN) BC with >3 involved lymph nodes. Currently, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) abemaciclib and ribociclib are indicated for the adjuvant treatment of women with locally advanced ER+ BC. We previously demonstrated that concurrent CDK4/6i and RT radiosensitizes in vitro and in vivo models of ER+ BC. The optimal treatment sequencing, however, remains unclear, and this information would inform future clinical trial design. Materials/
Methods: ER+ MCF-7 and T47D cells were treated in vitro with FDA-approved CDK4/6i abemaciclib or ribociclib in three treatment sequences: concurrent, adjuvant, and neoadjuvant (with a 48-hour window) and clonogenic survival assays were used to determine the most effective sequence. Neoadjuvant treatment consisted of drug for 48 hours then RT, concurrent consisted of drug 1 hour prior to RT, and adjuvant treatment consisted of RT followed by drug 48 hours later. IC50 values for CDK4/6i were used. Results: Concurrent administration of abemaciclib and ribociclib led to clinically meaningful radiosensitization, with radiation enhancement ratios (rER) ranging from 1.62-2.23 with abemaciclib: 1.62-2.23 and 2.21-3.24 with ribociclib. Similar effects were observed with adjuvant CDK4/6i (rER abemaciclib: 1.52-1.93, ribociclib: 1.74-2.33). In contrast, no significant radiosensitization was noted with the neoadjuvant sequence as compared to the controls (rER: abemaciclib: 0.93-1.01, ribociclib: 0.96-1.13).Mechanistically, this effect was not dependent on cell cycle rearrangements and was mediated, at least in part, by impaired homologous recombination. Conclusion: Our data suggest that RT is most effective when used concurrently with, or prior to, CDK4/6i administration. These data will inform ongoing in vivo studies as part of a federally funded SPORE grant and provide the basis for treatment sequencing in the recently opened phase IB safety and efficacy trial that is treating women with locally advanced ER+ BC who are at high risk of locoregional recurrence (NCT05996107). Ongoing efforts are exploring the efficacy and sequencing of models of TNBC as well.
