PROJECT SUMMARY/ABSTRACT Radiation (RT) therapy remains a mainstay in the treatment of women with breast cancer (BC), but locoregional disease recurrence remains a significant clinical issue that compromises survival, with locoregional recurrence rates ~20-25% at 10 years in women with >3 lymph nodes (LNs) ER+ BC or TNBC. As over 280,000 women are diagnosed with breast cancer in the US each year and 37% have N+ breast cancer at diagnosis, this population includes >100,000 women in the US each year who have either >3 LN or have TNBC each year. A 25% risk of recurrence in this number of potentially curable women represents a greater mortality risk than many other cancers and underscores the potential impact of these studies. Evaluation of clinical agents that function as radiosensitizers is an area of active yet understudied interest. Cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6i) are used as frontline therapy to treat women with metastatic estrogen receptor positive (ER+) breast cancers and ongoing studies continue to refine their utility in the upfront, non-metastatic setting for women with high-risk ER+ breast cancers. Despite these promising studies, CDK4/6 inhibitors are not yet given in combination with the radiation therapy that patients receive as part of the standard of care, and there currently is no indication for women with triple-negative breast cancer (TNBC) which disproportionately affects African American women. We previously showed that CDK4/6 inhibition leads to the radiosensitization of multiple Rb-intact ER+ breast cancer cell lines as well as TNBC models. This radiosensitization occurs to a similar degree with palbociclib, ribociclib, and abemaciclib, the three clinically approved CDK4/6 inhibitors. Our data suggests a novel association between CDK 4/6 inhibition and the DNA damage response. Indeed, we have demonstrated that short term CDK4/6 inhibition leads to a decrease in expression of DNA repair proteins like CHK1 and RAD51 that play a role in homologous recombination and leads to radiosensitization in ER+ breast cancer models. This has not, however, ever been demonstrated in TNBC. Although we have demonstrated that all three CDK4/6 inhibitors lead to the radiosensitization of ER+, the mechanism of this radiosensitization remains unclear as does the utility of this approach in women with TNBC. We hypothesize that women with locally advanced multiple node positive Rb intact breast cancer (including most ER+ and up to 70% of TNBC) will benefit from combination treatment with CDK4/6 inhibitor with radiation. Furthermore, we hypothesize that the combination of CDK 4/6i with RT is safe, tolerable, and effective in women at high risk of local recurrence of BC. In this proposal, we will 1) determine the mechanism of CDK4/6 inhibitor-mediated radiosensitization in ER+ and TNBC models; 2) determine the sequencing and efficacy of CDK4/6 inhibitor-mediated radiosensitization in in vivo models of ER+ and TNBC and 3) determine the safety and efficacy of this combination approach in women with locally advanced ER+ and TNBC in a phase I clinical trial.

NARRATIVE (Project 3) Locoregional control for women with locally advanced ER-positive (ER+) and triple-negative (TN) breast cancer (BC) remains a significant clinical challenge despite standard radiation therapy, which could be addressed by radiosensitization. This study will determine the mechanism of CDK 4/6 inhibitor-mediated radiosensitization, the efficacy of this combination in vivo in ER+ and TNBC models and will allow for a first-in-human phase I trial establishing the safety and efficacy of such an approach in women with locally advanced breast cancer.