Background: Combination treatments of endocrine therapy (ET) with CDK4 & 6 inhibitors have improved outcomes in patients with HR+ advanced breast cancer, both as initial therapy and after progression on ET. Abemaciclib is a selective inhibitor of CDK4 & 6 approved on a continuous dosing schedule for the treatment of HR+, HER2- MBC patients (pts), alone or in combination with ET. However, biomarkers that predict benefit from this class of agents remain elusive. We previously reported in the phase II neoadjuvant neoMONARCH study (NCT02441946), after 2 weeks of treatment, abemaciclib, alone or in combination with anastrozole (ANZ), led to a significantly higher rate of complete cell cycle arrest (CCCA, defined as Ki67 ≤2.7%) compared to ANZ alone in early stage HR+, HER2- breast cancer (Martin et al. SABCS 2017). As an exploratory aim of this trial, we evaluated the gene expression analyses in order to determine markers of sensitivity and resistance to therapy.
Methods: Serial biopsies were collected at 3 time points: Baseline (BL) - prior to treatment, Early – after 2 weeks of therapy with abemaciclib, ANZ, or abemaciclib+ANZ, and Late – after 2 weeks of initial therapy followed by 14 weeks of abemaciclib+ANZ. RNA was extracted from FFPE tumor biopsies at each timepoint and subjected to a Cell Cycle Associated Gene (CCAG) expression panel using the Modaplex® platform and whole transcriptome RNA sequencing. Ki67 was measured at each time point by immunohistochemistry (IHC). Tumors were categorized by the post-treatment Ki67 expression as either sensitive (Ki67 ≤2.7) or resistant (Ki67 ≥7.4), based upon the IMPACT and POETIC studies. Additionally, tumors intrinsically resistant/sensitive to therapy were also identified.
Results: ANZ-treated tumors that did not achieve CCCA at 2 weeks (N= 8) displayed higher expression of the cell cycle associated genes FOXM1, E2F1, TOPO2A, and RRM2. The addition of abemaciclib to ANZ decreased gene expression in a majority of the tumors (N=5, 62.5%). Tumors intrinsically resistant to treatment with abemaciclib+ANZ displayed persistently elevated levels of cell cycle associated genes compared to sensitive tumors. Finally, gene expression signature of Rb loss-of-function (Rbsig) and RB1 gene expression levels were associated with sensitivity to abemaciclib.
Conclusion: On-treatment Ki67 indicated treatment sensitivity and correlated with cell cycle associated gene expression in sensitive and resistant tumors. These exploratory analyses suggest that gene expression analyses may identify genomic markers for abemaciclib and ET treatment sensitivity and may help inform in which tumors to use abemaciclib.
Citation Format: Hurvitz S, Martin M, Wijayawardana S, Brahmachary M, Ebert PJ, Young S, Jansen V, Slamon D. Markers of response to CDK4 & 6 inhibition from neoMONARCH: A phase II neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive, HER2 negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-08.