Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer

Abstract

Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or abemaciclib and antiestrogen therapy were identified. Patients were grouped into early (<6 months); intermediate (6–24 months for 0–1 lines; 6–9 months for ≥2 lines); or late progressors (>24 months for 0–1 lines; >9 months PFS for ≥2 lines). NGS and RNA sequencing data were analyzed in association with PFS, and survival analysis was stratified by prior lines of chemotherapy. A total of 795 patients with HR+ MBC treated with CDK 4/6i were identified. Of these, 144 (18%) patients had genomic data and 29 (3.6%) had RNA data. Among the 109 patients who received CDK4/6i as 1st- or 2nd-line therapy, 17 genes showed associations with PFS (p-value ≤ 0.15 and HR ≥ 1.5 or HR < 0.5). Whole transcriptome RNAseq was analyzed for 24/109 (22%) patients with 0–1 prior lines of therapy and 56 genes associated with PFS (HR ≥ 4 or HR ≤ 0.25 and FDR ≤ 0.15). In this retrospective analysis, genomic biomarkers including FGFR1 amplification, PTEN loss, and DNA repair pathway gene mutations showed significant associations with shorter PFS for patients receiving CDK4/6 inhibitor therapy.

Bone Marrow Only Metastases from Lobular Carcinoma: Insights into Responses to Endocrine Therapy

“…Treatment with everolimus was associated with an improved overall survival compared to chemotherapy while single agent fulvestrant was not. Lee et al [17] lookedfor genomic signals of resistance to CDK 4/6 inhibitor treatment in hormone receptor positive breast cancer. They noted FGFR1 amplification, PTEN loss and DNA repair pathway gene mutations showed significant associations with shorter progression free survival for patients receiving CDK 4/6 inhibitor therapy.…”

CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions

“…This study revealed the heterogeneous genomic landscape of resistance mechanisms, identifying multiple potential mediators such as Rb1 disruption, AKT1 activation, and alterations in AURKA, CCNE2, RAS, ERBB2, and FGFR2. Lastly, our group conducted a comprehensive analysis of broad-panel nextgeneration sequencing (NGS) data obtained from patients receiving any CDK4/6 inhibitors in a real-world clinical setting [48]. This retrospective study analyzed genomic biomarkers of CDK4/6 inhibitor resistance in patients with HR-positive MBC treated with palbociclib, ribociclib, or abemaciclib.…”

“…The genomic and transcriptomic profiling of tumor samples have provided valuable insight into the molecular alterations associated with CDK 4/6 inhibitor resistance. For example, studies have identified alterations in genes such as CCNE1, RB1, ERBB1, and ESR1 that contribute to resistance [28,46,48,49]. Genomic profiling using techniques like NGS has revealed the presence of specific mutations, amplifications, or deletions in these genes that can influence treatment response.…”

Biomarkers of Response and Resistance to CDK4/6 Inhibitors in Breast Cancer: Hints from Liquid Biopsy and microRNA Exploration

“…Moreover, in a retrospective study, Lee et al performed tumor tissue genomic and transcriptomic profiling in a cohort of patients with HR+/HER2- MBC treated with palbociclib, ribociclib, or abemaciclib and hormone therapy in different lines. Mutations in key genes involved in DDR, such as PALB2, BRCA1 , and ATRX , were associated with worse PFS [ 29 ].…”

“…Some of the most relevant mutations these contexts are those concerning the following genes: MLL3 , GPR124 , MAP2K4 , CREBBP , AURKA , and PTEN . Other genes confer resistance to CDK4/6 inhibitors after amplification, such as ZNF703 , FGFR1 , MDM2 , AURKA , and FRS2 [ 18 , 29 ]. This appears to be a particularly important aspect to be considered while searching for biomarkers in liquid biopsy and by microRNA profiling.…”