The primary objective of this clinical study is to identify whether activating mutations in ESR1 detected in circulating tumor DNA (ctDNA) in peripheral blood are associated with resistance to endocrine therapy in patients with ER-positive, human…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary end point is to detect a difference in progression-free survival
(PFS) between patients with and without detectable ESR1 mutations in their
plasma.
Secondary outcome
Secondary, exploratory end points are to identify mutations emerging in ctDNA
during treatment and associated with progression to AI and/or everolimus and
exemestane treatment, to identify genetic markers in ctDNA explaining how
initially responding tumors escape drug sensitivity, and to compare the DNA
mutational landscape between primary tumors, metastatic lesions, if available,
and matching ctDNA at start and during treatment for metastatic disease.
Background summary
The efficacy of endocrine treatment in patients with estrogen receptor (ER)
positive metastatic breast cancer (MBC) is limited due to the presence of
intrinsic endocrine resistance as well as the occurrence of acquired therapy
resistance in initially responding patients. Important mechanisms whereby
resistance develops are mutations in the ESR1 gene and activation of parallel
signaling pathways. We hypothesize that evaluating the mutational status of a
set of pre-specified genes involved in endocrine resistance in the peripheral
blood of MBC patients may detect failure to endocrine treatment at an early
stage. If confirmed, this will improve our insight into mechanisms underlying
treatment failure, would allow to discontinue ineffective treatment earlier
than based on routine radiological assessments, thereby sparing patients from
toxicity and reducing costs, and lastly, would allow to explore switching to
other (combination) treatments based on the detected emerging mutations.
Study objective
The primary objective of this clinical study is to identify whether activating
mutations in ESR1 detected in circulating tumor DNA (ctDNA) in peripheral blood
are associated with resistance to endocrine therapy in patients with
ER-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC.
Further aims are to obtain detailed molecular information on emerging
(in)activating mutations in driver genes by targeted next generation sequencing
(NGS) of ctDNA from plasma taken before and during two subsequent treatment
lines and to determine which of the collected genetic information will be
informative to predict and monitor disease progression and to eventually guide
the choice of therapies. Also, the mutational landscapes of primary tumors and
metastatic lesions,
Study design
This concerns a prospective longitudinal study.
Study burden and risks
Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: the burden for patients participating to this
study is limited. Only one blood tube of 10 mL will be drawn every twelve
weeks, preferentially in combination with a routine blood draw and out-patient
visit. The risk of participation are negligible, since only blood draws per
venipuncture are asked. Participation to this study will not directly benefit
the patient herself, but may provide information to improve endocrine
treatments for patients with ER-positive, HER2-negative MBC in the near future.
Wytemaweg 80
Rotterdam 3015 CN
NL
Wytemaweg 80
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
• Age >=18 years
• Postmenopausal status, being defined as:
- Age >=60 years
- Age <60 years and last menstruation >=1 year ago when not treated with chemotherapy and/or endocrine treatment in the meantime
- Age <60 years and postmenopausal luteinizing hormone (LH), follicle stimulating hormone (FSH), and plasma estradiol levels
- Surgical or radiation-induced sterilization
• Histologically or cytologically confirmed diagnosis of metastatic breast cancer
• Histological confirmation of ER-positive (>10% of the tumor cells ER-positive), HER2-negative disease (1+ staining or 2+ non-amplified), preferentially of the primary tumor, but otherwise of a biopsied metastatic/recurrent site
• Radiologically evaluable disease according to RECIST version 1.1
• Willingness and capacity to follow the protocol specified visits for blood sampling for the total duration of the study
• Capacity of understanding and signing the informed consent brochure prior to the blood samplin
Exclusion criteria
• Prior treatment in the metastatic setting with any AI
• For the second part of blood sampling during everolimus/exemestane: other hormonal treatment in between the AI and combination everolimus/exemestane line. Chemotherapy to contain rapidly progressing before starting everolimus/exemestane is allowed.
• A secondary malignancy currently present or curatively treated within the last five years before registration, except for non-melanoma skin cancer, cervical carcinoma in situ, or bladder cancer in situ.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL53978.078.15 |