Overcoming Therapy Resistance in ER+ Breast Cancer Patients: a Translational Project (OVERTuRE) (OVERTuRE)

Patients presenting with a de novo diagnosis of luminal-like advanced breast cancer (ABC) or with disease recurrence after >12 months from the end of adjuvant ET, are generally candidate to a first line therapy with an aromatase inhibitor in association with a CDK4/6i. Disease recurrence in <12 months from the end of adjuvant ET defines the disease as "endocrine resistant" and identifies patients that should receive a first line therapy with the selective estrogen receptor degrader (SERD) Fulvestrant in association with the CDK4/6i Ribociclib, according to the results of the MONALEESA-3 trial.

A significant percentage of ABC patients develops a primary resistance with disease progression within the first 6 months from the beginning of the treatment. Furthermore, another relevant percentage of patients initially responding to the therapy, will later develop a secondary resistance, thus progressing after a median of 2 years from the beginning of the treatment. Thereby, it is crucial to identify biomarkers that could be predictive of a response or a resistance to ET and/or CDK4/6i, to provide the best therapeutic strategy, tailored upon both clinico-pathological and molecular characteristics.

Numerous pathways associated with resistance to CDK4/6i have been investigated by means of liquid biopsy analysis. The aim of this study is to identify potential biomarkers predictive of a clinical benefit in patients receiving a first line therapy with AI/fulvestrant (+/- LH-RH analogue) in association with a CDK4/6i for luminal-like advanced breast cancer.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer

Detailed Description

Patients presenting with a de novo diagnosis of luminal-like advanced breast cancer (ABC) or with disease recurrence after >12 months from the end of adjuvant ET, are generally candidate to a first line therapy with an aromatase inhibitor (+/- LH-RH analogue depending from the menopausal status) in association with a CDK4/6i. Disease recurrence in <12 months from the end of adjuvant ET defines the disease as "endocrine resistant" and identifies patients that should receive a first line therapy with the selective estrogen receptor degrader (SERD) Fulvestrant in association with the CDK4/6i Ribociclib, according to the results of the MONALEESA-3 trial.

The choice of the endocrine backbone and of the CDK4/6i is mostly influenced by the patient's clinical characteristics and by disease factors.

However, a significant percentage of ABC patients develops a primary resistance with disease progression within the first 6 months from the beginning of the treatment. Furthermore, another relevant percentage of patients initially responding to the therapy, will later develop a secondary resistance, thus progressing after a median of 2 years from the beginning of the treatment. Thereby, it is crucial to identify biomarkers that could be predictive of a response or a resistance to ET and/or CDK4/6i, to provide the best therapeutic strategy, tailored upon both clinico-pathological and molecular characteristics.

Numerous pathways associated with resistance to CDK4/6i have been investigated by means of liquid biopsy analysis. The aim of this study is to identify potential biomarkers predictive of a clinical benefit in patients receiving a first line therapy with AI/fulvestrant (+/- LH-RH analogue) in association with a CDK4/6i for luminal-like advanced breast cancer.

• Study Type: Observational
• Enrollment (Estimated): 74

Contacts and Locations

• Study Contact: Name: Fabio Puglisi, MD, PhD; Phone Number: +39 0434 659253; Email: fabio.puglisi@cro.it

Study Locations

• Italy
  • Udine, Italy, 33100
    • Recruiting
    • Azienda Sanitaria Universitaria del Friuli Centrale(ASUFC)
    • Contact: Alessandro Marco Minisini, MD; Phone Number: 0432 552751; Email: alessandro.minisini@asufc.sanita.fvg.it
    • Principal Investigator: Alessandro Marco Minisini, MD
  • Pordenone
    • Aviano, Pordenone, Italy, 33081
      • Recruiting
      • Centro di Riferimento Oncologico (CRO) di Aviano-IRCCS
      • Principal Investigator: Barbara Belletti, PhD
      • Contact: Fabio Puglisi, MD, PhD; Email: fabio.puglisi@cro.it
      • Principal Investigator: Fabio Puglisi, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Women with hormone receptor-positive ABC, considered eligible for endocrine therapy as first line endocrine treatment

Description

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 pre-menopausal 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
• Prior chemotherapy for metastatic disease
• Patients unwilling to or unable to comply with the protocol.
• Known CNS metastases

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To identify potential biomarkers predictive of a clinical benefit in patients receiving a first line therapy with AI/fulvestrant (+/- LH-RH analogue) in association with a CDK4/6i for luminal-like ABC.	Mean difference in mean VAF in most frequently mutated gene found at baseline, with respect to first evaluation after 15 days between responders (CR-PR-SD, Complete Response - Partial Response - Stable Disease) and non-responders (PD, Progressive Disease)	up to 3 years
To identify potential biomarkers predictive of a clinical benefit in patients receiving a first line therapy with AI/fulvestrant (+/- LH-RH analogue) in association with a CDK4/6i for luminal-like ABC.	Mean difference in mean VAF in most frequently mutated gene found at baseline, with respect to 6 months evaluation between responders (CR-PR-SD, Complete Response - Partial Response - Stable Disease) and non-responders (PD, Progressive Disease)	up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To explore the impact of ctDNA-based biomarkers in terms of treatment resistance	Differences in time-to-progression (TTP) probability between patients with or without selected ctDNA-based biomarkers. TTP will be defined as the time from first biomarker assessment until objective PD or end of follow-up, whichever comes first.	from first biomarker assessment until objective PD or end of follow-up, up to 3 years
To explore the impact of ctDNA-based biomarkers in terms of survival	Differences in progression-free survival (PFS) between patients with or without selected ctDNA-based biomarkers. PFS will be defined as time from beginning of the therapy until objective PD, death or end of follow-up, whichever comes first.	from beginning of the therapy until objective PD, death or end of follow-up, up to 3 years
To explore the impact of ctDNA-based biomarkers in terms of survival	Differences in Overall survival (OS) between patients with or without selected ctDNA-based biomarkers. OS will be defined as time from beginning of the therapy until death from any cause or end of follow-up, whichever comes first.	from beginning of the therapy until death from any cause or end of follow-up, up to 3 years
Mean difference in mean VAF in most frequently mutated gene found at baseline, between baseline and progression in non-responders (PD, Progressive Disease)	Mean difference in mean VAF in most frequently mutated gene found at baseline, between baseline and progression in non-responders (PD, Progressive Disease)	up to 3 years

Collaborators and Investigators

• Sponsor: Centro di Riferimento Oncologico - Aviano
• Investigators: Principal Investigator: Barbara Belletti, PhD, Centro di Riferimento Oncologico di Aviano (CRO) - IRCCS; Principal Investigator: Fabio Puglisi, MD,PhD, Centro di Riferimento Oncologico di Aviano (CRO) - IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2023
• Primary Completion (Estimated): May 18, 2026
• Study Completion (Estimated): May 18, 2026

Study Registration Dates

• First Submitted: November 8, 2023
• First Submitted That Met QC Criteria: November 8, 2023
• First Posted (Estimated): November 13, 2023

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 8, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: CRO-2023-10

Drug and device information, study documents

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