Monitoring luminAl Breast Cancer Through the Evaluation of Mutational and epiGeNEtic alteraTIons of Circulating ESR1 DNA

Study Overview
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Brief Summary
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The purpose of the study is to determine the diagnostic role of ctDNA when used to monitor metastatic breast cancer (MBC) during first-line endocrine therapy.

Detailed Description
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Patients with hormone receptor-positive MBC are eligible for endocrine therapy (ET) as first line treatment which is based on strategies aimed to either block signaling pathways depending on the estrogen receptor (ESR1) or using ESR1 antagonists. Only a few accepted predictive factors are associated with treatment benefit for MBC (i.e., hormone receptor status and HER2 status). Furthermore, a standardized assessment evaluation for MBC is still lacking. Because of these unmet needs, ET is continued until disease progression, or if toxicity requiring discontinuation occurs. Resistance is frequent in the treatment of early BC and unavoidable in MBC. Recently, mutations in ESR1 have been described in MBC that had been previously exposed to aromatase inhibitors (AIs) and are rarely detectable in primary BC. Besides that, resistance phenomena have been also linked to ESR1 cisregulatory elements (CRE, i.e. enhancers and promoters) hypermethylation, both related to ESR1 silencing. According to the literature, the aim of the study is to detect tumor response with liquid biopsy technique compared to conventional clinical pratice algorithms.

Official Title
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Monitoring luminAl Breast Cancer Through the Evaluation of Mutational and epiGeNEtic alteraTIons of Circulating ESR1 DNA

Conditions
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Hormone Receptor Positive Breast Carcinoma, Breast Neoplasms, Neoplasms, Breast, Breast Diseases, Antineoplastic Agents, Aromatase Inhibitors, ESR1 Gene Mutation

Intervention / Treatment
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* Diagnostic Test: Liquid biopsy and CT scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven diagnosis of adenocarcinoma of the breast with evidence of metastatic disease. ER positive tumor ≥ 1% HER2 negative breast cancer by FISH or IHC (IHC 0,1+, 2+ and/or FISH HER2: CEP17 ratio < 2.0) Females, 18 years of age or older Candidate to first-line endocrine therapy (LH-RH analogue for premenopausal women is allowed) Signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. Exclusion Criteria: Diagnosis of any secondary malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. Prior endocrine therapy for metastatic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hormone-receptor positive MBC<br>Women with hormone receptor-positive MBC, that will be eligible for endocrine therapy as first line treatment | Diagnostic Test: Liquid biopsy and CT scan<br>* CT scan and liquid biopsy blood sample are performed at baseline, after 8 weeks from baseline and, then, every 12 weeks. Between two subsequent CT scan another liquid biopsy blood sample is performed. CEA and CA 15.3 will be performed at baseline and then concomitantly to the radiological evaluation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liquid-biopsy in monitoring treatment response in luminal breast cancer | The primary objective of this study is to evaluate whether liquid-biopsy technique is able to detect treatment response in luminal breast cancer through the quantification of ESR1 ctDNA mutations | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ctDNA/miRNA based follow-up | To characterize the clinical implications of deploying a ctDNA/miRNA based follow-up both in terms of outcome and health systems management. | 3 years | 
| Treatment resistance mechanisms | To investigate treatment resistance mechanisms and their detectability through ctDNA/miRNA analysis. | 3 years | 
| Specificity | The proportion of patients correctly classified with a stable or response disease through the genetic and epigenetic analysis of ESR1 ctDNA among those without clinicoradiological relapse. | From baseline until disease progression | 
| Positive predictive value | The proportion of patients correctly classified with a progressive disease through the genetic and epigenetic analysis of ESR1 ctDNA (i.e. those patients with molecular progression that is confirmed by clinic-radiological progression) among all patients with molecular progression (i.e. patients who show molecular progression irrespectively of clinic-radiological progression). | 3 years | 
| Negative predictive value | The proportion of patients correctly classified with a stable or response among those without clinico-radiological relapse. | 3 years | 
| Accuracy | Accuracy of the ESR1 ctDNA test in respect to correctly classify the patients with clinicoradiological relapse and without clinico-radiological relapse at 6 months. | 6 months | 
| Lead time (for PFS) | The time elapsed between the molecular detected progression and the imaging assessed one. | 3 years | 
| Number of futile diagnostic imaging | The number of imaging evaluations negative for progression and that could be avoided with the liquid biopsy technique. | 3 years | 
| Time to Progression (TTP) | The time from first biomarker assessment until objective tumor progression. | 3 years | 
| Progression Free Survival (PFS) | The time from first biomarker assessment until objective tumor progression or death for any cause, whichever comes first. | 3 years | 
| Overall Survival (OS) | The time from first biomarker assessment until death from any cause. | 3 years | 
| Overall Response Rate (ORR) | The sum of partial responses (PR) and complete responses (CR) evaluated from the time of first biomarker assessment to documented disease progression. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epigenetics, Liquid biopsy, ctDNA, ESR1 Gene Mutation, Biomarker, HR-positive HER2-negative, Advanced breast cancer, CDK4/6, Antineoplastic Agents Hormonal