Patient-Derived Organoids to Functionally Characterize Chemotherapy Resistance in Breast Cancer (BC-PDO)

Functional Characterization of Neoadjuvant Chemotherapy Resistance in Breast Cancer Using Patient-Derived Organoid Models and Development of Drug Repurposing Strategies With Next-Generation Small Molecules

This prospective observational study aims to functionally characterize chemotherapy resistance in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. Despite standard molecular classification, significant heterogeneity in treatment response exists, and the biological mechanisms underlying chemoresistance remain incompletely understood.

In this study, patient-derived organoid (PDO) models will be established from tumor tissues obtained during routine clinical care. These three-dimensional models preserve the biological characteristics of individual tumors and enable ex vivo functional assessment of drug response. Chemotherapy sensitivity and resistance will be evaluated using quantitative parameters including Half-Maximal Inhibitory Concentration (IC50) values, cell viability, and apoptotic response.

Functional data obtained from PDO models will be correlated with clinical and pathological treatment outcomes, particularly pathological complete response (pCR), to assess the predictive value of PDO-based assays. In addition, apoptotic biomarkers such as Caspase-3/7 will be measured in serum samples collected during routine clinical evaluation and analyzed in relation to treatment response.

Furthermore, selected Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved small molecules will be tested in PDO models to evaluate their potential to reverse chemotherapy resistance, supporting drug repurposing strategies. This study aims to establish a functional, patient-specific platform for assessing chemoresistance and to contribute to the development of personalized therapeutic approaches in breast cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer; Locally Advanced Breast Cancer (LABC)

Detailed Description

Breast cancer is one of the most common malignancies worldwide, and neoadjuvant chemotherapy (NACT) is a standard treatment approach in patients with locally advanced disease. Achieving pathological complete response (pCR) after NACT is strongly associated with improved long-term outcomes. However, significant inter-patient variability in treatment response is observed, even among patients with similar molecular subtypes, highlighting the need for functional approaches to better understand and predict chemotherapy resistance.

Current predictive models based on molecular and genomic profiling are limited in their ability to capture the dynamic and functional behavior of tumors. Patient-derived organoid (PDO) models have emerged as a promising platform that preserves tumor architecture, heterogeneity, and biological characteristics, enabling patient-specific functional drug testing in a controlled ex vivo environment.

In this prospective observational study, 40 adult female patients diagnosed with locally advanced breast cancer and scheduled to receive neoadjuvant chemotherapy will be enrolled. Tumor tissues obtained during routine diagnostic or therapeutic procedures will be used to establish PDO cultures. No additional invasive procedures will be performed for research purposes.

PDO models will be subjected to standardized drug response assays to evaluate chemotherapy sensitivity and resistance. Quantitative endpoints will include dose-response curves (Half-Maximal Inhibitory Concentration (IC50) values), cell viability assays, and apoptotic activity measurements, particularly Caspase-3/7 activation. These functional parameters will be integrated to define resistance phenotypes at the individual patient level.

Clinical and pathological response data, including pCR status, will be collected and correlated with PDO-derived functional results to assess the predictive performance of the PDO platform. In parallel, serum samples obtained during routine clinical care will be analyzed for apoptotic biomarkers, and their association with treatment response will be evaluated.

In addition, selected Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved small molecules, particularly those not currently used in breast cancer treatment, will be tested on PDO models to investigate their potential to overcome chemotherapy resistance. This approach aims to identify candidate agents for drug repurposing and to generate a functional drug sensitivity profile for each patient.

The ultimate goal of this study is to develop a reproducible and clinically relevant functional assay system that integrates ex vivo drug response data with clinical outcomes. This platform may contribute to improved prediction of treatment response, identification of resistance mechanisms, and development of personalized therapeutic strategies in breast cancer.

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Emine Yildirim, MD; Phone Number: +905056234825; Email: emine.yildirim@atlas.edu.tr

Study Locations

• Turkey (Türkiye)
  • Istanbul, Turkey (Türkiye)
    • Istanbul Atlas University Faculty of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult female patients diagnosed with locally advanced breast cancer and scheduled to receive neoadjuvant chemotherapy at a tertiary academic center. All participants will be recruited prospectively and followed during the course of standard clinical treatment.

Description

Inclusion Criteria:

• Female patients aged 18 years or older
• Histologically confirmed locally advanced breast cancer
• Planned to receive neoadjuvant chemotherapy
• Availability of tumor tissue obtained during routine diagnostic or therapeutic procedures
• Availability of clinical and pathological treatment data
• Ability to provide written informed consent

Exclusion Criteria:

• Age under 18 years
• Metastatic breast cancer
• Prior systemic chemotherapy or targeted therapy for the current diagnosis
• Presence of another active malignancy
• Severe comorbid conditions that may interfere with study participation
• Insufficient biological sample for organoid generation or analysis
• Inability or unwillingness to provide informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Locally Advanced Breast Cancer Patients Cohort; Adult female patients diagnosed with locally advanced breast cancer and scheduled to receive standard neoadjuvant chemotherapy. Tumor tissue and blood samples obtained during routine clinical care will be used to generate patient-derived organoid models and to perform biomarker analyses. No experimental intervention will be applied to participants.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation Between PDO-Based Chemotherapy Response Metrics and Pathological Complete Response (pCR)	Assessment of the association between functional drug response parameters obtained from patient-derived organoid (PDO) models (including Half-Maximal Inhibitory Concentration (IC50) values, cell viability, and apoptotic response) and pathological complete response (pCR) following neoadjuvant chemotherapy.	At completion of neoadjuvant chemotherapy (approximately 6 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Apoptotic Biomarkers and Their Association With Treatment Response	Analysis of serum apoptotic biomarkers, including Caspase-3/7 levels, and their correlation with pathological treatment response and chemotherapy resistance.	At baseline, during neoadjuvant chemotherapy, and at completion of treatment (approximately 6 months)
Development of Functional Predictive Models for Chemotherapy Response	Integration of PDO-derived functional data and clinical parameters to develop predictive models for treatment response in breast cancer patients.	Within 12 months after completion of data collection
Association Between PDO-Derived Drug Sensitivity Metrics and Clinical Chemotherapy Resistance	Evaluation of chemotherapy resistance phenotypes in patient-derived organoid (PDO) models using quantitative measures such as Half-Maximal Inhibitory Concentration (IC50), cell viability, and apoptotic response, and their relationship with clinical treatment outcomes.	At baseline (prior to initiation of neoadjuvant chemotherapy) and at completion of treatment (approximately 6 months)
Evaluation of Drug Repurposing Strategies in PDO Models	Assessment of the effects of selected Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved small molecules on chemotherapy-resistant patient-derived organoid (PDO) models to evaluate their potential to reverse resistance.	Within 6 months after sample collection

Collaborators and Investigators

• Sponsor: Atlas University
• Investigators: Principal Investigator: Emine Yildirim, Istanbul Atlas University Faculty of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: April 1, 2026
• First Submitted That Met QC Criteria: April 1, 2026
• First Posted (Actual): April 8, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Neoadjuvant Chemotherapy; Locally Advanced Breast Cancer; Pathological Complete Response; Patient-Derived Organoids; Chemotherapy Resistance; Drug Repurposing; Ex Vivo Drug Testing
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: ATLAS-BC-PDO-2026-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The plan for sharing individual participant data (IPD) has not yet been finalized. Data sharing will be determined based on institutional policies, ethical approvals, and funding conditions. De-identified data may be made available upon reasonable request after completion of the study and publication of primary results.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No