Clinical trial NCT06129786: Overcoming Therapy Resistance in ER+ Breast Cancer Patients: a Translational Project (OVERTuRE)
Official title: Overcoming Therapy Resistance in ER+ Breast Cancer Patients: a Translational Project (OVERTuRE)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Breast Cancer
Lead sponsor: Centro di Riferimento Oncologico - Aviano
Sponsor class: OTHER
First posted: 2023-11-13
Enrollment: 74
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Women with hormone receptor-positive ABC, considered eligible for endocrine therapy as first line endocrine treatment

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: up to 3 years
measure: 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.
timeFrame: up to 3 years
Secondary outcomes:
measure: To explore the impact of ctDNA-based biomarkers in terms of treatment resistance
timeFrame: from first biomarker assessment until objective PD or end of follow-up, up to 3 years
measure: To explore the impact of ctDNA-based biomarkers in terms of survival
timeFrame: from beginning of the therapy until objective PD, death or end of follow-up, up to 3 years
measure: To explore the impact of ctDNA-based biomarkers in terms of survival
timeFrame: from beginning of the therapy until death from any cause or end of follow-up, up to 3 years
measure: Mean difference in mean VAF in most frequently mutated gene found at baseline, between baseline and progression in non-responders (PD, Progressive Disease)
timeFrame: up to 3 years
Other outcomes:
Locations:
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico (CRO) di aviano-IRCCS
state: Pordenone
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria del Friuli Centrale(ASUFC)
Study officials:
affiliation: Centro di Riferimento Oncologico di Aviano (CRO) - IRCCS
name: Fabio Puglisi, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centro di Riferimento Oncologico di Aviano (CRO) - IRCCS
name: Barbara Belletti, PhD
role: PRINCIPAL_INVESTIGATOR
References: