The primary objective of this study is to assess the outcome of taxane- based chemotherapy in ER-positive MBC HER2-negative patients with progression after receiving endocrine therapy (with at least an AI) who have an ESR1 mutation measured in…
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 endpoint for this study will be the progression free survival rate
at 6 months (PFS6mnths) in ESR1 mutated MBC patients treated with taxane-based
chemotherapy.
Secondary outcome
Outcome to taxane-based chemotherapy in ESR1 mutated and wild-type patients
measured as progression free-rate at 6 months, progression free survival and
overall survival.
The relation between serial measurement of ESR1 mutations and clinical
follow-up data (i.e. survival and efficacy).
The relation between different activating ESR1 mutations (e.g. D538G and Y537S)
and treatment outcome measured as progression free- and overall survival.
The assessment of baseline and progression ESR1 mutational status, in order to
learn whether ESR1 mutations can be lost during treatment.
Background summary
Endocrine treatment is the mainstay of treatment for ER- positive metastatic
breast cancer (MBC). Unfortunately, 40% of patients have no clinical benefit
from first-line endocrine therapy due to intrinsic resistance, whereas the
remainder of patients initially responding will eventually develop resistance
during therapy (1). Importantly, once the tumor develops resistance to
endocrine therapy, the tumor becomes more aggressive, leading to a poor
prognosis (2). Recently, mutations in the gene encoding ERα, ESR1, have
attracted particular interest as a mechanism for endocrine resistance in MBC.
Functional studies have shown that somatic mutations in the ligand-binding
domain (LBD) of ESR1 result in constitutive activity of ERα in absence of its
ligand estrogen (3). This indicates a mechanism that directly leads to
endocrine resistance. These functional studies have been supported by clinical
data of the SoFEA and BOLERO-2 trials. Both studies showed an impaired
progression-free survival (PFS) in ESR1 mutated patients versus wild-type
patients treated with an aromatase inhibitor (AI) (4,5). In addition, in the
BOLERO-2 study, patients with an ESR1 mutation had overall an impaired overall
survival (OS) compared to wild-type patients, indicating a more aggressive
disease biology.
The impaired effectiveness of AIs in the ESR1 mutated patients raises the
question from which therapy these patients still could benefit and which is the
most effective. Therefore, we present here a biomarker study to investigate
whether ESR1 mutated patients could still benefit from taxane-based
chemotherapy.
Study objective
The primary objective of this study is to assess the outcome of taxane- based
chemotherapy in ER-positive MBC HER2-negative patients with progression after
receiving endocrine therapy (with at least an AI) who have an ESR1 mutation
measured in circulating tumor DNA (ctDNA). Secondary objectives include whether
serial measurement of ESR1 mutations can predict survival and/or efficacy of
taxane-based chemotherapy; investigate whether different activating ESR1
mutations result in differences in treatment efficacy and study if chemotherapy
can result in loss of ESR1 mutations.
Study design
This is a multicenter, prospective, biomarker study. From all patients, blood
will repeatedly be drawn at baseline and during treatment at 2-3 weeks, after 6
weeks, after 3 months, after completion of the chemotherapy, at 6 months and at
the time of disease progression.
Study burden and risks
Of all patients 2x10 mL will be drawn at baseline, and six additional time
points during treatment and at disease progression. The blood draws will be
taken when patients need to undergo blood draws for standard care as much as
possible. The risk of longitudinal blood collections by venipuncture is
negligible. Treatment response and disease progression will be assessed
according to current clinical guidelines. There will be no benefits for the
patients included in this study.
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Wytemaweg 80
Rotterdam 3015CN
NL
Wytemaweg 80
Rotterdam 3015CN
NL
Listed location countries
Age
Inclusion criteria
1. Female metastatic breast cancer patients with ER-positive, HER2- negative primary tumors;
2. Previous treatment with at least an aromatase inhibitor either in adjuvant and/or metastatic setting;
3. Failure to previous treatment with at least one type of aromatase inhibitor (non-steroidal/steroidal) for MBC;
4. Considered fit enough to receive taxane-based chemotherapy by the treating physician; either as a first line chemotherapy for metastatic breast cancer or as second line treatment if the time between completion of first line chemotherapy for metastatic breast cancer and inclusion is more than three years.
5. Intention to start with either paclitaxel and docetaxel;
6. Patient with measurable or clinically evaluable (bone only) disease on recent standard work-up for MBC;
7. CT chest and abdomen must not be older than 42 days on the day of the anticipated treatment start;
8. Age >=18 years old;
9. WHO performance status 0-2;
10. Signed written informed consent;
Exclusion criteria
1. Previous chemotherapy for metastatic disease, completed within three years before inclusion;
2. Patients with locally advanced disease, primary not amendable for resection or radiation therapy with curative intent;
3. (neo)adjuvant chemotherapy within 6 months prior to treatment start;
4. Anti-hormonal treatment for breast cancer within two weeks prior to treatment start;
5. Symptomatic CNS metastasis (the presence of at least one key symptom in combination with radiologic evidence (positive contrast-enhanced CT or MRI of the brain)
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL62417.078.17 |