Overcoming Therapy Resistance in ER+ Breast Cancer Patients: a Translational Project (OVERTuRE)
Study Details
Study Description
Brief Summary
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.
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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 Design
Outcome Measures
Primary Outcome Measures
- 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. [up to 3 years]
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)
- 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. [up to 3 years]
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)
Secondary Outcome Measures
- To explore the impact of ctDNA-based biomarkers in terms of treatment resistance [from first biomarker assessment until objective PD or end of follow-up, up to 3 years]
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.
- To explore the impact of ctDNA-based biomarkers in terms of survival [from beginning of the therapy until objective PD, death or end of follow-up, up to 3 years]
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.
- To explore the impact of ctDNA-based biomarkers in terms of survival [from beginning of the therapy until death from any cause or end of follow-up, up to 3 years]
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.
- 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]
Mean difference in mean VAF in most frequently mutated gene found at baseline, between baseline and progression in non-responders (PD, Progressive Disease)
Eligibility Criteria
Criteria
Inclusion Criteria:
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Histologically proven diagnosis of adenocarcinoma of the breast with evidence of metastatic disease.
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ER positive tumor ≥ 1%
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HER2 negative breast cancer by FISH or IHC (IHC 0,1+, 2+ and/or FISH HER2: CEP17 ratio < 2.0)
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Females, 18 years of age or older
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Candidate to first-line endocrine therapy (LH-RH analogue for pre-menopausal women is allowed)
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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.
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Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
Exclusion Criteria:
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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.
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Prior endocrine therapy for metastatic disease
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Prior chemotherapy for metastatic disease
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Patients unwilling to or unable to comply with the protocol.
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Known CNS metastases
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Centro di Riferimento Oncologico (CRO) di aviano-IRCCS | Aviano | Pordenone | Italy | 33081 |
| 2 | Azienda Sanitaria Universitaria del Friuli Centrale(ASUFC) | Udine | Italy | 33100 |
Sponsors and Collaborators
- Centro di Riferimento Oncologico - Aviano
Investigators
- Principal Investigator: Fabio Puglisi, MD,PhD, Centro di Riferimento Oncologico di Aviano (CRO) - IRCCS
- Principal Investigator: Barbara Belletti, PhD, Centro di Riferimento Oncologico di Aviano (CRO) - IRCCS
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CRO-2023-10