SHIELD: Surveillance of HR+/HER2- : Implementing ESR1m Long-term Monitoring and Detection in 1L aBC (SHIELD)

A Multicenter Study to Describe the Frequency and Emergence of ESR1 Mutations in Patients With Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer Receiving First-Line Endocrine Based Therapy

This is a multicountry, multicenter, observational study in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer receiving first-line endocrine-based therapy with an aromatase inhibitor in combination with a CDK4/6 inhibitor. The study aims to describe the prevalence of ESR1 mutations at baseline and the emergence of ESR1 mutations over time using circulating tumor DNA testing in routine clinical practice.

Patients receiving first-line treatment for at least 6 months and no more than 18 months, without evidence of disease progression at study entry, may undergo baseline ESR1 mutation testing. Patients with a negative baseline result may undergo longitudinal monitoring approximately every 3 months, for up to 18 months or 6 testing timepoints, to assess emergence of ESR1 mutations. The study will also describe mutation subtypes, testing methods used in routine practice, selected clinical characteristics, and treatment patterns across participating countries.

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Other: Blood sampling

Detailed Description

This is a multicountry, multicenter, observational study designed to determine the prevalence of ESR1 mutations at baseline and to assess the emergence of ESR1 mutations during longitudinal surveillance in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- aBC) receiving first-line treatment with an aromatase inhibitor (AI) in combination with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.

Eligible patients are adults with histologically or cytologically confirmed HR+/HER2- advanced breast cancer who have been receiving first-line AI plus CDK4/6 inhibitor therapy for at least 6 months and no more than 18 months, without evidence of disease progression according to investigator assessment, and who are willing and able to provide blood samples for circulating tumor DNA (ctDNA) testing at predefined intervals.

Following informed consent, baseline data will be collected in electronic case report forms and will include sociodemographic characteristics, clinical and tumor history, testing methods, and treatment patterns. A baseline blood sample will be collected for ctDNA-based ESR1 mutation testing using testing methods applied in routine clinical practice, including but not limited to quantitative polymerase chain reaction (qPCR), digital polymerase chain reaction (dPCR), and next-generation sequencing (NGS), according to local availability and site capability. Testing will be performed in validated laboratories in accordance with local standard operating procedures.

Patients who are negative for ESR1 mutation at baseline will undergo longitudinal ctDNA monitoring approximately every 12 weeks (+/-4 weeks), for up to 18 months or 6 testing time points from initial testing, whichever occurs first. Patients who test positive for ESR1 mutation at baseline or during follow-up will discontinue further study surveillance and will continue to receive routine clinical care as determined by the treating physician. The date of first ESR1 mutation detection will be recorded.

The primary objectives are to determine the prevalence of ESR1 mutations at baseline and the emergence rate and time to emergence of ESR1 mutations during the surveillance period among patients who are ESR1 negative at initial testing. Secondary objectives include assessment of ESR1 mutation frequency by duration of first-line therapy and by testing method, distribution of specific ESR1 mutation subtypes, co-mutations with other clinically relevant biomarkers when available, patient clinical and sociodemographic characteristics, testing and treatment patterns, and associations between ESR1 mutation status and relevant patient or treatment factors.

Approximately 3,000 patients are planned to be enrolled at about 30 sites in 15 countries across Asia, Latin America, and the Middle East and Africa. The estimated recruitment period is 12 months.

• Study Type: Observational
• Enrollment (Estimated): 3000

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: +1877240-9479; Email: information.center@astrazeneca.com

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Adults with HR-positive/HER2-negative advanced breast cancer (aBC), receiving first-line aromatase inhibitor (AI) plus CDK4/6 inhibitor therapy for 6-18 months, without disease progression, and with unknown ESR1 status at baseline.

Description

Inclusion Criteria:

• Age 18 years or older at the time of informed consent and willing and able to provide informed consent before any study-related procedures.
• Histologically- or cytologically-confirmed hormone receptor-positive (ER- and/or progesterone receptor-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer.
• Receiving first-line therapy with an aromatase inhibitor in combination with a CDK4/6 inhibitor for at least 6 months and no more than 18 months, with no evidence of disease progression at study entry, as assessed by the investigator.
• Able and willing to provide a blood sample for circulating tumour DNA testing for ESR1 mutation assessment at approximately quarterly intervals.

Exclusion Criteria:

• Evidence of disease progression during first-line aromatase inhibitor plus CDK4/6 inhibitor therapy, based on investigator assessment.
• Known ESR1 mutation status at study entry.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Participants with HR-positive, HER2-negative advanced breast cancer; Adults with HR-positive, HER2-negative advanced breast cancer receiving first-line therapy with an aromatase inhibitor plus a CDK4/6 inhibitor for 6 to 18 months without disease progression at study entry. Participants undergo baseline ESR1 mutation testing using circulating tumour DNA; those with a negative baseline result may undergo follow-up testing approximately every 3 months for up to 18 months.

Other: Blood sampling; Blood sampling for ctDNA-based ESR1 mutation testing, which are associated with minimal additional risk and burden compared with routine clinical practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of ESR1 mutations in circulating tumour DNA	Number and proportion of patients with at least one ESR1 mutation	At baseline, approximately 3, 6, 9, 12, 15, and 18 months after initial testing
Emergence of ESR1 mutations during longitudinal ctDNA surveillance	Number and proportion of patients who are detected with ESR1 mutation	At approximately 3, 6, 9, 12, 15, and 18 months after initial testing
Time to first detection of an ESR1 mutation	Time in months from initiation of first-line treatment with AI and CDK4/6 inhibitors to first detection of ESR1mutation	From first-line AI plus CDK4/6 inhibitor initiation to first ESR1 mutation detection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of ESR1 mutations by duration of ongoing first-line AI plus CDK4/6 inhibitor therapy	Number and proportion of participants with ESR1 mutations by duration of ongoing first-line therapy with an aromatase inhibitor plus a CDK4/6 inhibitor	At baseline and at approximately 3, 6, 9, 12, 15, and 18 months after initial testing
Frequency of ESR1 mutation-positive results by testing method	Number and proportion of participants with ESR1 mutation-positive results according to the circulating tumour DNA testing method used.	At baseline and at approximately 3, 6, 9, 12, 15, and 18 months after initial testing
Distribution of ESR1 mutation subtypes and allele frequency	Number and proportion of participants with specific ESR1 mutation subtypes detected by circulating tumour DNA testing.	At baseline and at approximately 3, 6, 9, 12, 15, and 18 months after initial testing
Frequency of additional co-mutations among ESR1 mutation-positive participants	Number and proportion of participants with ESR1 mutations who have at least 1 additional clinically relevant co-mutation detected, where available.	At baseline and approximately every 3 months through study completion, up to approximately 18 months after initial ESR1 testing
Baseline and follow-up characteristics of the study population	Summary of selected sociodemographic, clinical, tumour, and testing characteristics of the study population.	At baseline and at approximately 3, 6, 9, 12, 15, and 18 months after initial testing
Relationship between ESR1 mutation status and selected participant and treatment characteristics	Assessment of the relationship between ESR1 mutation status and selected participant, disease, testing, and treatment characteristics.	At baseline and at approximately 3, 6, 9, 12, 15, and 18 months after initial testing
Treatment patterns for advanced breast cancer	Summary of first-line treatment regimens for advanced breast cancer, including endocrine therapy and CDK4/6 inhibitor use, and duration of therapy.	From enrolment through study completion, up to approximately 18 months after initial ESR1 testing
Prior treatment patterns for early-stage breast cancer	Summary of prior therapies received for early-stage breast cancer in participants who later developed advanced breast cancer, including duration of therapy and reasons for discontinuation, where available.	At baseline

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Food and Drug Administration (FDA)

Study record dates

Study Major Dates

• Study Start (Estimated): September 30, 2026
• Primary Completion (Estimated): March 30, 2029
• Study Completion (Estimated): March 30, 2029

Study Registration Dates

• First Submitted: July 8, 2026
• First Submitted That Met QC Criteria: July 8, 2026
• First Posted (Actual): July 14, 2026

Study Record Updates

• Last Update Posted (Actual): July 14, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: D9673L00023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org.

Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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