Abstract P5-13-35: Mechanisms of CDK4/6 inhibitor resistance in hormone receptor positive metastatic breast cancer: Single institution retrospective analysis
Authors: Lee Jin Sun , Yost Susan , Cui Yujie , Frankel Paul , Li Sierra Min , Yuan Yate-Ching , Morse Denise , Wong-Toh Judy , Bosserman Linda , Mortimer Joanne , Yuan Yuan 
Published: March 2022

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are the standard of care for hormone receptor positive (HR+) metastatic breast cancer (MBC). Mechanisms of intrinsic and acquired resistances have been proposed but are poorly understood in the real-world setting. The current study aims to study the association of genomic biomarkers and CDK 4/6i resistance mechanisms utilizing genomic data acquired through routine clinical practice. Methods: Tumor genomic data from patients with HR+ MBC who received FDA-approved CDK4/6i (palbociclib, ribociclib, and abemaciclib) were obtained by chart review. Progression free survival (PFS) was determined from the first day of treatment until date of disease progression. Patients were divided by number of lines of treatment (first line vs. ≥ 2 lines of therapy) and subcategorized into early progressors (&lt; 6 months PFS), intermediate progressors (6-24 months PFS for first line and 6-9 months PFS for ≥ 2 lines of therapy), and late progressors (&gt;24 months PFS for first line and &gt; 9 months PFS for ≥ 2 lines of therapy). Genomic alterations from next-generation sequencing (NGS) were analyzed with PFS. PFS stratified by first vs. &gt;2 lines of treatment were performed using a Cox proportional hazards model with hazard ratios and 95% confidence intervals reported. Results: Among 795 patients with HR+ MBC treated with CDK 4/6i between 2015 and 2020 including 673 patients from a main campus and 122 patients from community sites, a total of 131 patients had genomic data available for the analysis. The obtaining rate of genomic data was 18% (122 out of 673 patients) from the main campus and 7% (9 out of 122 patients) from community sites. Seventy-one patients were treated with CDK4/6i as the first line of MBC, and 60 were treated as second or sequential lines. 35 patients had early progression, 40 patients had intermediate progression, 44 patients had late progression, and 12 patients were indeterminate. The distribution of genomic alterations was not significantly different between each group. The genomic alterations that were associated with impaired PFS were ZNF703(hazard ratio, HR 2.1, N=13), ERBB2 (HR 1.9, N=12), MDM2 (HR 3.3, N=6), PALB2 (HR 3.8, N=5), ARFRP1 (HR 3.1, N=4), FRS1 (HR 2.9, N=4), IRS2 (HR 6.9, N=2), and JAK2 (HR 6, N=2). RNA seq analysis is currently underway. Conclusion: Tumor genomic tests are not routinely performed for patients with HR+ MBC, particularly less performed from community practices. In this single institution retrospective analysis, we identified genomic alterations, such as ZNF703, ERBB2, PALB2, and MDM2, as potential resistance mechanisms of CDK4/6i. Tumor genomics through standard clinical practice are essential to understand resistance mechanisms to CDK4/6i.

Citation Format: Jin Sun Lee, Susan Yost, Yujie Cui, Paul Frankel, Sierra Min Li, Yate-Ching Yuan, Denise Morse, Judy Wong-Toh, Linda Bosserman, Joanne Mortimer, Yuan Yuan. Mechanisms of CDK4/6 inhibitor resistance in hormone receptor positive metastatic breast cancer: Single institution retrospective analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-35.