Minimally Interventional Study on Prevalence of Emerging ESR1 Mutations in Liquid Biopsy in Three Cohorts of Patients With Breast Cancer in Comparison With Patient's Baseline ESR1 Mutation Status as Defined by Tissue Profiling. (Pangeia-2)

Minimally Interventional Study on Prevalence of Emerging ESR1 Mutations in Liquid Biopsy in Three Cohorts of Patients With Breast Cancer (With and Without Prior Therapies in Metastatic Setting, and During First-line Aromatase Inhibitor Plus CDK4/6 Inhibitor Therapy) in Comparison With Patient's Baseline ESR1 Mutation Status as Defined by Tissue Profiling.

Minimally interventional study on prevalence of emerging ESR1 mutations in liquid biopsy in three cohorts of patients with breast cancer (with and without prior therapies in metastatic setting, and during first-line aromatase inhibitor plus CDK4/6 inhibitor therapy) in comparison with patient's baseline ESR1 mutation status as defined by tissue profiling.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Breast Cancer

Detailed Description

This is a prospective minimally interventional biomarker cohort study.

Biomarkers:

1. GS Focus Liquid Breast (liquid biopsy sequencing test, covering mutations in ESR1, PIK3CA, AKT1, PTEN, ERBB2, BRCA1, BRCA2, PALB2);
2. GS Focus Breast (tissue sequencing assay performed on basal tissue biopsy from the primary tumour or metastatic lesion not exposed to any systemic therapy, covering the same gene panel);
3. ESR1 mutation by πCode (PlexBioTM), which covers hotspot variants (K303R, E380Q, S463P, P535H, L536P, L536H, L536Q, L536R, Y537S, Y537N, Y537C and D538G), with analytical sensitivity ranging from 0.1% to 0.5%, depending on the variant;
4. PTEN analysis by IHC (VENTANA SP218). Biomarker assessment will be carried out by NGS methodology in both liquid biopsy and baseline tissue biopsy. Both strategies consider a custom panel covering PIK3CA, AKT1, PTEN, ESR1, BRCA1, BRCA2, PALB2, ERBB2 genes.

NGS panels were internally validated and presented sensitivity, specificity and accuracy of 100,00% with a limit of detection of 0,5% VAF for liquid biopsy panel and sensitivity, specificity and accuracy of 100,00% with a limit of detection of 5% VAF for tissue panel.

Cohort 3 will be recruited in two phases. The pilot phase will include 30 patients to assess the complexity of recruitment, sample logistics and laboratory operations using the new πCode liquid biopsy assay. If approved by the investigators and the sponsor, recruitment will continue with a further 70 patients for full-scale implementation.

For the detection of ESR1 mutations in Cohort 3, πCode microdisc technology (PlexBio™) will be used with the IntelliPlex™ ESR1 Mutation cfDNA Kit. This assay covers hotspot mutations in ESR1 in exons 4, 5, 7 and 8 (12 variants), with a DNA input of 10 ng and a detection limit ranging from 0.1% to 0.5%.

In Cohort 3, an initial liquid biopsy NGS assay (GS Focus Liquid) will be collected 6 months after the start of treatment, followed by ctDNA analyses using GS Focus Liquid and the πCode assay every 3 months for each patient, provided there is no evidence of clinical/radiological progression or the emergence of an ESR1 mutation. In parallel, if archived paraffin blocks are available, tissue NGS (GS Focus) and PTEN IHC (see below) will be performed to assess alterations present in primary tissue or metastatic lesions prior to exposure to AI plus CDK4/6i.

PTEN IHC will be analyzed in samples from prospective cohorts 1, 2, and 3 with valid NGS results from tissue and residual paraffin blocks. For PTEN staining by IHC, the VENTANA SP218 antibody will be used, which binds to the PTEN protein in FFPE sample sections (OptiView DAB IHC detection kit) run on the Roche-Ventana Benchmark Ultra platform, according to the manufacturer's instructions.

• Study Type: Observational
• Enrollment (Estimated): 170

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Brazil
  • São Paulo, Brazil, 04513-020
    • Recruiting
    • Research Site
  • São Paulo, Brazil, 01.509-900
    • Not yet recruiting
    • Fundação Antonio Prudente - A.C. Camargo Cancer Center
  • São Paulo, Brazil, 01401-002
    • Not yet recruiting
    • Instituto D'Or de Pesquisa E Ensino - São Paulo
  • São Paulo, Brazil, 05652-000
    • Not yet recruiting
    • Sociedade Beneficente Israelita Brasileira Hospital Albert Eisntein
  • Estado de Bahia
    • Salvador, Estado de Bahia, Brazil, 41.950-640
      • Not yet recruiting
      • Ensino E Terapia de Inovação Clínica Amo - Ética
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90020-090
      • Not yet recruiting
      • Irmandade da Santa Casa de Misericordia de Porto Alegre

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

3 parallel cohorts:

1. Locally advanced/metastatic HR-positive/HER2-negative breast cancer, either treatment-naïve or having previously received adjuvant therapy, without prior palliative therapy, eligible for first-line hormonal therapy, with primary tumour tissue available;
2. Locally advanced/metastatic HR+/HER2- breast cancer, progression during treatment with hormone therapy plus a CDK inhibitor; with primary tumour tissue available;
3. Locally advanced/metastatic HR+/HER2- breast cancer, with no disease progression during 6 months of hormonal therapy plus a CDK4/6 inhibitor; with archived tumour tissue available. Patients will be enrolled from the start of therapy with AI plus CDK4/6i in the metastatic setting (index date) up to 6 months into this first-line therapy, provided they have no clinical or radiological evidence of progressive disease. Patients will be followed up until disease progression.

Description

Inclusion Criteria:

Cohort 1:

• BC patients, male and female, 18 years old and older, pre or post menopausal, with HR+ (ER and/or PR positive), Her-2 negative (confirmed centrally) locally advanced irresectable and/or metastatic disease
• Confirmation of HR and Her-2 status may be performed in the primary tumor or in the metastatic lesion (patients with discordant results may be included)
• Patients must be candidates to CDK4/6i therapy in combination with endocrine therapy in the first line setting (with or without ovarian suppression)
• Patients may have received one previous line of chemotherapy in the metastatic setting, but no endocrine therapy in the metastatic setting is allowed
• Patients may have received chemotherapy in the neo/adjuvant setting
• Patients may have received endocrine therapy (with or without ovarian suppression) in the neo/adjuvant setting
• Patients may have received a CDK4/6i in the adjuvant setting, provided they are still candidates for CDK4/6i therapy in the metastatic setting
• Patients must be able to undergo a liquid biopsy procedure before starting their first line treatment
• All patients must fill and sign an informed consent form.

Cohort 2:

• BC patients, male and felame, 18 years old and older, pre or post menopausal, with HR+ (ER and/or PR positive), Her-2 negative (confirmed centrally) locally advanced irresectable and/or metastatic disease who have progressed on a CDK4/6i in combination with endocrine therapy (with or without ovarian suppression) in the first or second line setting
• All other non-conflicting inclusion criteria for cohort 1 apply.

Cohort 3:

Patients with breast cancer, both men and women, aged 18 years or older, pre- or post-menopausal, with HR+ (ER and/or PR positive), HER2-negative (centrally confirmed) locally advanced unresectable and/or metastatic disease.

Confirmation of HR and HER2 status may be performed on the primary tumour or the metastatic lesion (patients with discordant results may be included).

Patients must be on first-line hormonal therapy with an aromatase inhibitor plus a CDK4/6 inhibitor (with or without ovarian suppression) for at least 6 months with no clinical or radiological evidence of progressive disease.

Patients may have received a prior line of chemotherapy in the metastatic setting; however, prior endocrine therapy in the metastatic setting is not permitted.

Patients may have received chemotherapy in the neoadjuvant/adjuvant setting. Patients may have received endocrine therapy (with or without ovarian suppression) in the neoadjuvant/adjuvant setting.

Patients may have received a CDK4/6 inhibitor in the adjuvant setting, provided they are still eligible for CDK4/6 inhibitor therapy in the metastatic setting.

Patients must be able to undergo a liquid biopsy procedure before starting their first-line treatment.

All patients must read and sign an Informed Consent Form.

Exclusion Criteria:

Patients WITHOUT HR+ (ER- and/or PR-positive)/HER2-negative disease Patients without radiological and/or pathological confirmation of locally unresectable and/or metastatic breast cancer.

Patients who are NOT candidates for further systemic treatment following a diagnosis of metastatic disease or disease progression.

Patients who have already started a CDK4/6 inhibitor in combination with endocrine therapy (with or without ovarian suppression) for first-line metastatic disease (for Cohort 1); and patients who have already started a new line of treatment for metastatic disease following progression on a CDK4/6 inhibitor in combination with endocrine therapy (with or without ovarian suppression) (for Cohort 2); and patients with any suspicion of clinical or radiological disease progression at the time of the first liquid biopsy collection (for Cohort 3).

Patients who are NOT able to undergo a liquid biopsy procedure. Patients who are NOT able to provide informed consent.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Cohort 1 (N=30); Locally-advanced/metastatic HR+/HER2- breast cancer, either treatment naive or previously exposed to adjuvant therapies, no prior palliative therapy, candidates to receive first-line hormone therapy, primary tumor tissue available.
Cohot 2 (N=40); Locally-advanced/metastatic HR+/HER2- breast cancer, progression during hormone therapy plus CDK inhibitor; primary tumor tissue available.
Cohort 3 (N=100); Locally advanced/metastatic HR+/HER2- breast cancer, with no disease progression during 6 months of hormonal therapy plus a CDK4/6 inhibitor; with archived tumour tissue available. Patients will be enrolled from the start of therapy with AI plus CDK4/6i in the metastatic setting (index date) up to 6 months into this first-line therapy, provided they have no clinical or radiological evidence of progressive disease. Patients will be followed up until disease progression.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of emerging ESR1 mutations	Primary objective A (Cohorts 1 and 2): to determine the prevalence of emerging ESR1 mutations in liquid biopsy samples from two cohorts of breast cancer patients (with and without prior treatment in the metastatic setting) and to compare this with the baseline ESR1 mutation status as determined by the patient's tissue profile. Primary objective B (Cohort 3): to determine the overall prevalence of emerging ESR1 mutations during first-line treatment with AI plus CDK4/6i in patients without clinical or radiological evidence of progressive disease, using a highly sensitive ctDNA assay.	Through study completation, an avarege 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Define the prevalence of PIK3CA, AKT1, PTEN, BRCA1, BRCA2, PALB2, ERBB2 mutations.	To determine the prevalence of mutations in PIK3CA, AKT1, PTEN, BRCA1, BRCA2, PALB2 and ERBB2 in liquid biopsy samples and compare these with the patient's baseline status. To determine the prevalence of ESR1 mutations at different time points during treatment with AI plus CDK4/6i; to validate a highly sensitive and specific ctDNA assay for common ESR1 variants using πCode technology (PlexBioTM).	Through study completation, an avarege 2 years

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Rodrigo Dienstmann, Oncoclínicas; Principal Investigator: Vladmir C. de Lima, Fundação Antonio Prudente - A.C. Camargo Cancer Center; Principal Investigator: Tomas Reinert, Irmandade da Santa Casa de Misericordia de Porto Alegre; Principal Investigator: Renata Bonadio, Instituto D'Or de Pesquisa E Ensino - São Paulo; Principal Investigator: Mayana Lopes, Ensino E Terapia de Inovação Clínica Amo - Ética; Principal Investigator: Leandro Jonata C. de Oliveira, Sociedade Beneficente Israelita Brasileira Hospital Albert Eisntein

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2024
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: May 13, 2024
• First Submitted That Met QC Criteria: May 13, 2024
• First Posted (Actual): May 16, 2024

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; ER-positive; ESR-1 mutation
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: D3612L00003

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 approved.

• 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 refer 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. A 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