Determinants of Resistance to Endocrine Therapy and a Cyclin-dependent Kinases 4 and 6 (CDK4/6) Inhibitor for HR+ MBC

Prospective Evaluation of Determinants of Resistance to Endocrine Therapy and a Cyclin-dependent Kinases 4 and 6 (CDK4/6) Inhibitor in Hormone Receptor (HR) Positive Metastatic Breast Cancer (MBC)

The goal of this research study is to determine if the investigators can predict which participants will respond to endocrine therapy and a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor for metastatic breast cancer and which participants will not. Investigators will use information from the tumor tissue and serial blood samples. Investigators hope that a deeper understanding of which participants will respond to this combination and how resistance emerges will allow the investigators to better tailor therapies for metastatic breast cancer.

Subjects will have archived tissue or new biopsy collected at study enrollment. This tissue will undergo special molecular testing. Subjects will also have blood collected at study enrollment and periodically thereafter. This blood will also undergo special molecular testing. Information from this testing will not be available to subjects or their treating physicians as the investigators do not know how this information should impact treatment.

The investigators will collect information about which treatment the subjects receive and how their cancer responds.

Any man or woman being seen at Johns Hopkins for treatment of newly diagnosed estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) metastatic breast cancer may be eligible.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Endocrine Therapy and a CDK 4/6 inhibitor; Drug: Endocrine Therapy and a CDK 4/6 inhibitor

Detailed Description

Resistance to endocrine therapy (ET) invariably develops in patients with estrogen and/or progesterone receptor (ER/ PR) positive metastatic breast cancer (MBC). Data regarding primary resistance and patterns of emergence of acquired resistance in patients treated with endocrine therapy (ET) and cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors are limited. Understanding these mechanisms could result in improved selection of treatment options and provide new targets for therapy development. In this study, we aim to identify and characterize determinants of intrinsic and acquired resistance to endocrine therapy in patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative MBC treated with the combination of endocrine therapy (aromatase inhibitor or fulvestrant) and a CDK4/6 inhibitor.

Investigators will determine the prevalence of genomic alterations at baseline in the primary tumor, metastatic tissue and plasma tumor DNA (ptDNA), including in the gene encoding estrogen receptor- alpha (ESR1). The mutational tumor burden in the primary tumor, metastatic tumor and blood will be assessed. Blood samples will be collected at several time points, allowing the detection of changes in molecular markers over time. We will further characterize tissue markers associated with progression and duration of response by evaluating these markers in available tissue obtained at progression. Investigators goal is to evaluate the prevalence and role of known alterations determining endocrine resistance in patients with metastatic disease, as knowledge regarding this population remains limited.The investigators also hope to unveil novel markers of endocrine resistance.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or Female
• 18 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Metastatic (stage IV) breast cancer or locally advanced breast cancer
• Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive, HER2- negative
• Treatment naïve in metastatic or locally advanced setting and planning to undergo treatment with endocrine therapy (ET) and palbociclib OR receiving first-line ET and palbociclib for metastatic or locally advanced disease.
• Premenopausal women and men must be treated with concurrent luteinizing hormone-releasing hormone (LHRH) agonist as would be standard-of-care.
• Evaluable or measurable disease.
• Tissue from a metastatic site must be available within past 6 months prior to therapy initiation.
• Ability to give voluntary informed consent

Exclusion Criteria:

• Any pregnant or nursing woman
• No history of another primary malignancy within past 5 years. Patients with prior history of in situ cancer or basal or localized squamous cell skin cancer are eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A: Participants with untreated metastatic disease receiving ET and a CDK 4/6; Participants will undergo blood collection (intervention) at time of initiating treatment with endocrine therapy and palbociclib, at 4 weeks after initiating this treatment, and every 3-4 months while on treatment. If a participant progresses on this treatment, they will have a blood collection at that time.	Drug: Endocrine Therapy and a CDK 4/6 inhibitor; Participants with untreated metastatic disease receiving ET and a CDK 4/6 i as first line therapy.; Other Names: ET and CDK4/6i; Drug: Endocrine Therapy and a CDK 4/6 inhibitor; Participants initiating a CDK 4/6 i after progression on ET.; Other Names: ET and CDK4/6i
Experimental: Cohort B: Participants initiating a CDK 4/6 i after progression on ET.; Participants will undergo blood collection (intervention) at time of initiating treatment with endocrine therapy and palbociclib, at 4 weeks after initiating this treatment, and every 3-4 months while on treatment. If a participant progresses on this treatment, they will have a blood collection at that time.	Drug: Endocrine Therapy and a CDK 4/6 inhibitor; Participants with untreated metastatic disease receiving ET and a CDK 4/6 i as first line therapy.; Other Names: ET and CDK4/6i; Drug: Endocrine Therapy and a CDK 4/6 inhibitor; Participants initiating a CDK 4/6 i after progression on ET.; Other Names: ET and CDK4/6i

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genetic Mutation	The number of participants who have an ESR1 mutation prior to receiving endocrine therapy and palbociclib.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genetic Mutation	The amount of time from receiving palbociclib and endocrine therapy to the first detectable ESR1 mutation	4 years
Genetic Mutation	Percentage of participants with an ESR1 mutation at the time of progression for those who received treatment with endocrine therapy and palbociclib.	3 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Safeway Foundation; Biovica International AB
• Investigators: Principal Investigator: Jessica Tao, M.D., Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2018
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: December 8, 2017
• First Submitted That Met QC Criteria: February 13, 2018
• First Posted (Actual): February 20, 2018

Study Record Updates

• Last Update Posted (Actual): August 12, 2025
• Last Update Submitted That Met QC Criteria: August 7, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Breast Cancer; Metastatic Breast Cancer; Aromatase Inhibitors; Palbociclib; Hormone Receptor Positive Metastatic Breast Cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: J17118; IRB00143030 (Other Identifier: JHM-IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes