Abstract 101P
Background
The proven success of combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy in estrogen receptor-positive (ER+) metastatic breast cancer has prompted evaluation of this therapeutic approach in patients with early-stage disease. Notably, the CDK4/6i abemaciclib and ribociclib, but not palbociclib, improved invasive disease-free survival in the adjuvant setting in clinical trials. These data suggest that complex assessment of breast tumor genomic, clinical and pathological characteristics, and CDK4/6i efficacy and toxicity profiles, will be required for a better refinement of indication for specific CDK4/6i in the early-stage setting. In the present study, we aimed to identify and characterize the early breast cancer patient population that will benefit the most from each CDK4/6i by using patient-derived breast cancer organoids.
Methods
We developed a repository of patient-derived organoids (PDOs) from ER+ primary breast tumor resections. RNA, DNA, and protein were purified from PDOs and paired fresh frozen tissue, for validation of organoids characteristics compared to the original tumor. To fully characterize our PDOs, we performed RNA sequencing (RNAseq), single nucleotide polymorphism/copy number variation (SNP/CNV) array, live-cell imaging, quantitative real-time PCR, and drug testing. Efficacy of CDK4/6i on selected PDOs was evaluated by viability and cytotoxicity assays, and gene expression profile in sensitive vs. resistant PDOs was compared by RNAseq.
Results
We found that various PDOs retained the main alterations of the original tumor, by SNP/CNV arrays. Furthermore, we were able to rank the organoids based on the response (IC50) to abemaciclib. By RNAseq and RT-qPCR we identified specific genes that might be linked with differential responses to CDK4/6i. Among these, we found concomitant CDK6 overexpression and, surprisingly, cyclin D1 downregulation in PDOs with higher IC50 towards CDK4/6i in both innate and acquired resistance models.
Conclusions
Our data suggest that high-CDK6 and low-cyclin D1 expression might be a biomarker for selection of patients with poor response to CDK4/6i abemaciclib in the adjuvant setting.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
Ethics Committee of the Region of Southern Denmark and Copenhagen and Frederiksberg Counties; Danish Data Protection Agency and the Danish Breast Cancer Cooperative Group.
Funding
Danish Cancer Society; Sygeforsikring Danmark; Danmarks 3R-Center.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
104P - Hypomethylated immune gene promoters as potential biomarkers in oral and oropharyngeal cancer
Presenter: Petra Anić
Session: Cocktail & Poster Display session
Resources:
Abstract
105P - Implementation of technical improvements in cfMeDIP-Seq library preparation
Presenter: Martina Dameri
Session: Cocktail & Poster Display session
Resources:
Abstract
106P - Clinical application of next-generation sequencing in metastatic colorectal cancer (mCRC): Experience from a comprehensive cancer centre
Presenter: David Lluís Garulo
Session: Cocktail & Poster Display session
Resources:
Abstract
107P - Unveiling mismatch repair deficiency (dMMR) and microsatellite-instability high (MSI-H) detection in cancer patients (pt) using a next-generation sequencing (NGS)-based molecular pre-screening program (MPP)
Presenter: Lucia Notario Rincon
Session: Cocktail & Poster Display session
Resources:
Abstract
108P - Validation and implementation of a large NGS panel to test liquid biopsies from patients with suspected advanced non-small cell lung cancer (NSCLC) in an NHS genomic laboratory for the QuicDNA biomarker study
Presenter: Rachel Dodds
Session: Cocktail & Poster Display session
Resources:
Abstract
109P - A multiomic, single-cell measurable residual disease (scMRD) assay for phasing DNA mutations and surface immunophenotypes
Presenter: Simone Formisano
Session: Cocktail & Poster Display session
Resources:
Abstract
110P - Multicellular three-dimensional tumor spheroid of nasopharyngeal carcinoma
Presenter: Shiau Chuen Cheah
Session: Cocktail & Poster Display session
Resources:
Abstract
111P - Development of digital PCR for accurate measurement of HER2 amplification in 184 gastric cancer patients
Presenter: So Young Kang
Session: Cocktail & Poster Display session
Resources:
Abstract
112P - A novel methylation-sensitive assay for early detection of hepatocellular carcinoma to improve surveillance
Presenter: Jeong Sil Ha
Session: Cocktail & Poster Display session
Resources:
Abstract
113P - Evaluation of effects of tissue preservation methods on the proteome abundance through deep proteomics of breast cancer tissue
Presenter: Shashwati parihari
Session: Cocktail & Poster Display session
Resources:
Abstract