To investigate prospectively how the "TAMRO-profile" performs in a pre-operative treatment setting. In addition we can examine whether the profile is specific for tamoxifen or is predictive for endocrine resistance in general. Also the…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in tumor cell proliferation. Proliferation will be measured by (change
in) Ki67 expression and Cyclin A, apoptosis by the TUNEL assay. We will try to
correlate the "TAMRO-profile", the phospho-PKA expression, and the
phosphorylation extent of Serine305 with these parameters.
Secondary outcome
- Investigate different gene-profiles with proven predictive value for
endocrine resistance
• Compare the changes in gene expression in the different study arms with
changes in proliferation index
• To collect blood samples of all patients for research on SNPs in CYP450
sequences in normal and tumor DNA.
• To collect tumor material for research on downregulation of ER and PgR.
• To collect blood samples to evaluate whether (a change in) estrogen serum
levels correlate with outcome.
• To study the relationship among concentrations of tamoxifenmetabolites in
serum and tumormaterial and expression levels of CYP450 sequences in the tumor.
- Investigate paired tumor samples by ChIP-sequencing for response-predicting
changes in estrogen-receptor binding sites
- To collect blood samples to evaluate the effect of endocrine therapy on the
immune system.
Background summary
It is unclear how the recently validated, predictive gene expression profile
for tamoxifen resistance in metastatic breast cancer (*TAMRO profile*) performs
in the pre-operative or adjuvant setting. Nor is it clear whether this profile
predicts endocrine therapy resistance in general, or is specific for tamoxifen
treatment. In addition, we hypothetize that after short-term exposure of breast
cancer patients to endocrine treatment a change in the molecular profile of the
tumor will take place. This change could be predictive for endocrine therapy
resistance.
Recently it has been shown PKA-mediated phosphorylation of Ser305 confers
resistance to tamoxifen in vitro. Our group revealed a correlation between
highly expressed phospho-PKA in combination with a high extent of Ser305
phosphorylation and worse outcome after first line palliative tamoxifen for
metastatic disease. We will try to validate these findings prospectively.
Study objective
To investigate prospectively how the "TAMRO-profile" performs in a
pre-operative treatment setting. In addition we can examine whether the profile
is specific for tamoxifen or is predictive for endocrine resistance in general.
Also the correlation between phospho-PKA in combination with phospho-Serine305
and tamoxifen resistance can be confirmed in a prospective study. These results
will be correlated with changes in proliferation index induced by different
short-term endocrine therapies. We anticipate this will enable us to identify
an *endocrine-resistance-breast-cancer-profile*. Additionally we will compare
the changes in gene expression in the different study arms; collect blood
samples of all patients for research on SNPs in CYP450 sequences; collect blood
samples to evaluate whether a change in estradiol concentration correlates with
outcome; study the relationship among concentrations of tamoxifenmetabolites in
serum/ tumormaterial and expression levels of CYP450 sequences in the tumor;
and study changes in estrogenbindingsites induced by short-term endocrine
treatment; investigate the effects of IGF-1R and levels of IGF*s on treatment
effect; explore the role of DC-SCRIPT in tumor material in relation to
preoperative endocrine exposure. Furthermore, the effect of endocrine therapy
on the immunesystem (CD4+ and CD8+ T cells) will be evaluated.
Study design
We will perform a randomized, open-label, multi-institution study. It will
compare the efficacy of three different endocrine treatment regimens
(Anastrozole, Fulvestrant or Tamoxifen) in changing proliferation-index during
a 3 (+/- 1 week) week pre-operative treatment period in breast cancer patients.
These results will be correlated to gene expression profiles, phosphorylation
status of the ER, SNPs in CYP450 sequences, tamoxifen metabolite
concentrations, changes in estrogen serum levels and protein expression
patterns.
Intervention
Endocrine therapy during a 3 (+/-1 week) weeks pre-operative treatment period.
Study burden and risks
Once the first informed consent is signed core needle biopsies will be taken of
the primary tumor. This biopsy is an extra burden for the participating
patient.
The reliability of the sentinel lymph node procedure (SLNP) after pre-operative
endocrine therapy is unknown. A false negative rate after full-dose neoadjuvant
cytotoxic treatment is around 10%, which is comparable to SLNP without
neoadjuvant treatment. As the therapies proposed in this protocol are less
intense and shorter in duration we expect no clinical significant risks.
Another potential risk could be degradation of ER, due to fulvestrant. To
prevent possible tamoxifen insensitivity, all fulvestrant patients shall
receive adjuvant an aromatase inhibitor, whenever indicated.
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
• Patients with proven invasive adenocarcinoma of the breast
• Any tumor with a size >= 1cm (NOT inflammatory breast cancer)
Patients with a tumor diameter > 0.5 and < 1.0 cm are eligible when a biopsy can be performed, however for very small tumors leaving behind a radiologic marker need to be discussed.
• WHO-performance score 0 or 1
• Written informed consent
Exclusion criteria
• Clues of metastatic disease by clinical examination according to most recent NABON guidelines
• Multicentric breast cancer
• Inflammatory breast cancer
• Hormone replacement during the last 12 months
• Other systemic treatment during waiting time till surgery
• Already planned date for surgery within the next 2 weeks
• Any psychological, familial, sociological or geographical condition potentially hampering adequate informed consent or compliance with the study protocol
• Patient*s refusal to undergo a core biopsy procedure of the primary tumor before the start of treatment
NB: a concomitant malignancy within the last five years is not an exclusion criterium, because survival is not the primary endpoint. Just as prior invasive breast cancer or DCIS within the last 15 years is not an exclusion criterium.
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EudraCT | EUCTR2008-000644-13-NL |
| CCMO | NL21855.031.08 |