3122 - Optimal Treatment Sequence for CDK4/6 Inhibitors and Radiation Combination Therapy in Triple Negative and Estrogen Receptor Positive Breast Cancer

05:00pm - 06:00pm PT

Hall F

Screen: 4

POSTER

Presenter(s)

Courtney Pisano, DO, MS, MPH - UH Seidman Cancer Center Case Western Reserve University, Cleveland, OH

C. E. Pisano¹, R. Abou Zeidane², E. Hochmuth³, B. Hauk¹, S. Lichtman-Mikol², P. Rana⁴, M. Tao¹, V. Mercer¹, B. McBean⁵, A. Pesch⁶, N. Hirsh⁷, J. Rae⁷, L. J. Pierce⁶, E. Cobain⁷, J. Lyons⁸, and C. Speers⁹; ¹Department of Radiation Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, ²Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, ³Case Western Reserve University, School of Medicine, Cleveland, OH, ⁴Case Western Reserve University, School of Medicine, University Hospitals Seidman Cancer Center, Cleveland, OH, ⁵Department of Human Genetics, University of Michigan, Ann Arbor, MI, ⁶Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, ⁷University of Michigan, Ann Arbor, MI, ⁸15University Hospitals Seidman Cancer Center / Case Western Reserve University / University Hospitals of Cleveland, Cleveland, OH, ⁹University of Alabama-Birmingham, Department of Radiation Oncology,, Birmingham, AL

Purpose/Objective(s): Radiation therapy (RT) remains an effective treatment for breast cancer (BC), though locoregional recurrence remains an issue for women with locally advanced estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC). Ongoing clinical trials are exploring whether cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), such as abemaciclib and ribociclib, can improve the efficacy of RT in women with ER+ and TNBC, though the optimal sequencing of drug and RT has not been explored. Building on our prior findings that CDK4/6i enhances RT effectiveness in vitro and in vivo, we investigate the optimal sequencing of CDK4/6i with RT in multiple ER+ and TNBC models.

Materials/Methods: The TNBC cell lines MDA-MB-231 and CAL-51 and ER+ cell lines MCF7 and T47D (all RB wt) were treated with CDK4/6i (abemaciclib, ribociclib) in 3 sequences: neoadjuvant (48 hrs before RT), concurrent (1 hr before RT), and adjuvant (48 hrs after RT). Clonogenic survival assays evaluated the effectiveness of each sequence Radiation enhancement ratios (rER) calculated. Assays were conducted at least in triplicate.

Results: The concurrent administration of CDK4/6i with RT significantly enhanced radiosensitivity across all tested cell lines, with rERs exceeding 1.2 (ER+ rER 1.58-1.8, TNBC rER 1.37-1.5). TNBC cells also responded to neoadjuvant sequencing, showing notable radiosensitization (rER 1.3-1.53), whereas adjuvant sequencing was less effective (rER 1.14-1.25). Conversely, ER+ cells demonstrated substantial radiosensitization with adjuvant CDK4/6i (rER 1.52-1.8) but showed limited response to neoadjuvant treatment (rER 0.78-1.0).

Conclusion: Our data suggest that RT is most effective when used concurrently with, or following, CDK4/6i administration in TNBC cells. Additionally, there was radiosensitization in TNBC cells using the adjuvant sequence, but to a lesser degree than the other two sequences. In comparison, ER+ cell lines showed that RT is most effective when used concurrently with, or prior to, CDK4/6i administration, with no meaningful radiosensitization using the neoadjuvant sequence. These insights continue to inform ongoing in vivo studies and a phase IB clinical trial (NCT05996107), supported by a federally funded SPORE grant.

Abstract 3122 - Table 1: Median rER (range) for TNBC and ER+ Cell Lines, according to treatment sequence

		ER+		TNBC
RIBO		T47D	MCF-7	CAL-51	MDA-MB231
	NAC	0.78 (0.60-.96)	0.96 ( 0.9-1.13)	1.3 (1.2-1.4)	1.3 (1.1-1.4)
	CON	1.6 (1.2-2.0)	1.8 (1.2-2.3)	1.4 (1.2-1.6)	1.37 (1.2-1.58)
	ADJ	1.73 (1.2-2.3)	1.8 (1.3-2.3)	1.14 (1.1-1.18)	1.19 (1.14-1.2)
ABEMA	NAC	0.8 (0.6-1.0)	1.0 (0.9-1.01)	1.52 (1.38-1.6)	1.53 (1.4-1.6)
	CON	1.58 (1.2-2.0)	1.6 (1.2-2.2)	1.5 (1.38-1.6)	1.5 (1.4-1.6)
	ADJ	1.52 (1.2-1.91)	1.8 (1.3-2.3)	1.25 (1.2-1.3)	1.25 (1.1-1.3)
CON: Concurrent; ADJ: Adjuvant; NAC: Neoadjuvant.