Breastcancer Clinical Trial
Official title:
The Symphony Triple A Study: Using Symphony as an Adjunct to Histopathologic Parameters When the Doctor is Ambivalent About the Administration and Type of Adjunctive Systemic Therapy
Rationale:
Prediction of prognosis in patients with breast cancer is important to determine the
indication for adjuvant chemo-, endocrine- and immunotherapy. Apart from the
clinicopathological parameters incorporated into the Adjuvant!Online predictive model, the
validated 70-gene signature MammaPrint® is predictive of outcome too. MammaPrint® is advised
in the current Dutch CBO guideline (2012) for hormone receptor positive, invasive ductal
breast cancer in individual cases when there is 'doubt' about the indication for adjuvant
chemotherapy based on traditional prognostic factors. In the present study MammaPrint® is
used in this CBO 2012 guideline defined group of patients as an additional test for
decision-making for adjuvant chemotherapy.
Objective:
To assess the impact of MammaPrint® on clinical decision making regarding the administration
of adjuvant chemotherapy in the CBO 2012 guideline defined group of hormone receptor
positive invasive ductal carcinoma patients when there is doubt about the indication for
adjuvant chemotherapy based on traditional prognostic factors. The influence of various
factors and the impact of MammaPrint® in predefined subgroups will be analyzed too. Data
from a national registry regarding adjuvant systemic treatment in patients with similar
clinicopathological characteristics in whom MammaPrint® was not used will be obtained to
provide a control group.
Hypothesis:
In the group of patients where national guidelines advocate using systemic therapy but
doctors are ambivalent in treating patients with adjuvant chemotherapy, it is hypothesized
that using MammaPrint® as an additional test will change the indication for adjuvant therapy
in a substantial proportion of patients resulting in at least 10% less patients who receive
adjuvant chemotherapy. Thus, in the study group at least 10% less patients will receive
chemotherapy when compared to a contemporary group of patients with similar
clinicopathological characteristics but without using MammaPrint®
Study population:
Hormone receptor positive, invasive ductal breast cancer patients when there is doubt about
the indication for adjuvant chemotherapy based on traditional prognostic factors.
Study design:
This is a prospective multicentre impact study.
1. INTRODUCTION AND SCOPE During the last decade treatment guidelines for the
administration of adjuvant chemotherapy in patients with breast cancer have changed,
today advising chemotherapy in the majority of patients having a >1cm invasive cancer.
Prognostic factors used to determine the need for adjuvant chemotherapy are axillary
lymph node status, tumour size and grade, patients' age, and HER2 over expression. In
addition, HER2 status and ER/PR are also predictive of the effect of particular
adjuvant systemic therapies.
Besides predictive models based on histopathologic factors, gene expression arrays have
recognized four different molecular subtypes of breast cancer (Luminal A, Luminal B
HER2 +, Luminal B HER2 - and Triple negative). In addition, a number of gene expression
profiles have been designed and validated in its capacity to predict the risk of
dissemination. One of the gene expression profiles is the 70-gene MammaPrint®
signature. The 70-gene MammaPrint® has been validated in different retrospective
studies, and in a prospective community-based feasibility study (RASTER). A
considerable discrepancy in risk estimations among different clinicopathologic
guidelines and MammaPrint was observed. In the RASTER study, addition of MammaPrint to
standard clinic-pathological factors led to a change in adjuvant systemic treatment
advice in 19% of patients. The 5-year metastases free survival rates for MammaPrint Low
Risk (n=219) and High Risk (n=208) patients were 97,0% and 91,7%.
The recent Dutch CBO guideline (2012) for breast cancer suggests using validated gene
expression profiles in individual cases in patients with an invasive ductal carcinoma
with positive hormonal receptor when there is doubt about the indication for adjuvant
chemotherapy based on the traditional prognostic factors.
2. OBJECTIVES Primary objectives Assess the impact of MammaPrint® on clinical decision
making regarding the administration of adjuvant chemotherapy in the CBO 2012 guideline
defined group of hormone receptor positive invasive ductal carcinoma patients when
there is doubt about the indication for adjuvant chemotherapy based on traditional
prognostic factors.
Secondary objectives
- To document the influence of primary tumour characteristics (size, Bloom and
malignancy grade and Her-2 status) and N-status (N0 vs N1mi) with respect to the
(Mammaprint-dependent) decision to give adjuvant chemotherapy in predefined
subgroups
- To address doctor and patient influence on the eventual decision to give adjuvant
chemotherapy.
Hypothesis In the group of patients where contemporary national guidelines advocate
using systemic therapy but doctors are ambivalent in treating patients with adjuvant
chemotherapy, it is hypothesized that using MammaPrint® as an additional test will
change the indication for adjuvant therapy in a substantial proportion of patients
resulting in at least 10% less patients who receive adjuvant chemotherapy. Thus, in the
study group at least 10% less patients will receive chemotherapy when compared to a
contemporary group of patients with similar clinicopathological characteristics but
without using MammaPrint®
3. STUDY POPULATION
Population (base) The study population is the CBO 2012 guideline defined group of
hormone receptor positive, invasive ductal breast cancer patients when there is doubt
about the indication for adjuvant chemotherapy based on traditional prognostic factors.
Doubt about the indication for adjuvant chemotherapy based on traditional prognostic
factors is an ill-defined criterion. Potential differences in the individual judgement
of medical oncologists deciding on adjuvant systemic therapy are conceivable, which
will translate in differences in the tendency to use MammaPrint®. Based on the
CBO-guideline 2012, we expect that the tendency to use MammaPrint® in small, low-grade
tumours as well as in patients with lymph node macrometastases will be relatively low.
Based on the aforementioned assumptions the expected proportional composition of the
study group 'of hormone receptor positive, invasive ductal breast cancer patients when
there is doubt about the indication for adjuvant chemotherapy based on traditional
prognostic factors' is as follows:
N0, BR 1, > 2 cm : 10-15% (60-90 patients) N0, BR 2, > 1 cm : 50-60% (300-350 patients)
N1mi, grade 1,2 : 15-20% (90-120 patients)
Her+, N0, <2c, grade I: <5% (<30 patients) NI: <5% (<30 patients) N0, BR 1, 1-2 cm: <5%
(<30 patients)
Control group
For comparison, data regarding adjuvant chemotherapy in patients in whom no MammaPrint®
was used will be obtained from a national registry Netherlands Cancer Registry (NKR)
and matched with the MammaPrint® group to date of diagnosis and clinicopathological
characteristics. The control group will enable analysis of the impact of Mammaprint on
the proportion of patients receiving adjuvant chemotherapy.
4. STUDY DESIGN
This is a prospective multicentre impact study of MammaPrint® on clinical decision making in
a predefined group of patients where doctors and patients are ambivalent about adjuvant
chemotherapy. MammaPrint® is offered in addition to standard histopathology tests for
decision-making regarding adjuvant systemic therapy. The advised adjuvant systemic therapy
will be recorded before and after disclosure of the MammaPrint® result.
Logistical planning:
Post-surgery:
1. Every patient is discussed in a multidisciplinary team meeting for further treatment
advice. After definitive pathological assessment of tumour size, Bloom and Richardson
grade, confirmation of ER/PR- and HER2 status, potential inclusion of a patient is
assessed.
2. In the surgical outpatient clinic, patients are seen postoperatively and the
histopathological results are discussed. The surgeon informs the patient about the
conclusion of the multidisciplinary team and the patient is informed about existing
uncertainty of adjuvant treatment and the added value of the MammaPrint. Study
information is supplied including an Informed Consent form.
3. The pathologist sends the MammaPrint kit to Agendia for analyses. The attending surgeon
and/or research nurse register patients by completing electronic Case Report Form (CRF)
1.
4. MammaPrint® result is emailed to the surgeon, medical oncologist and mammacare nurse
within 10 working days.
5. Within two weeks the patient is seen in the outpatient clinic by the oncologist to
discuss the result of the MammaPrint®. A final decision concerning adjuvant
chemotherapy is made with the patient. CRF 2 is completed by the oncologist.
The study is expected to enrol 600 patients in approximately 25 hospitals in two and a half
years. The follow up regarding the advice of adjuvant treatment is estimated to be two
months, just after the start of the adjuvant chemotherapy.
5. TISSUE COLLECTION AND 'CLASSIC' HISTOPATHOLOGICAL EXAMINATION
After patients' approval and signed consent forms, samples can be sent to Agendia for
MammaPrint® analysis. The tissue specimen for MammaPrint® analysis consists of a tumour
block or 10 unstained slides with 5µm section on each slide. The tissue can be shipped as
formalin fixed paraffin embedded (FFPE) tissue.
6. STATISTICAL ANALYSIS
Descriptive statistics The primary endpoint is defined as the group of patients who receive
adjuvant systemic therapy and will be compared to the proportion of patients who were
advised to receive chemotherapy before knowledge of the MammaPrint® result. In addition,
using NKR/NBCA data as controls, the absolute difference in the proportion of patients
receiving adjuvant chemotherapy is evaluated. This absolute difference is evaluated for the
whole group as well as for the three expectedly largest subgroups.
Statistical analysis Baseline characteristics will be summarized by an incidence table. The
frequency of chemotherapy + endocrine versus endocrine alone decisions will be addressed
before and after receiving the MammaPrint result in the study group. A McNemars test will be
performed for the comparison of the two proportions treated (before and after), both
expressed as a percentage. When the p- value for this McNemars test is less than 0.05, the
conclusion will be that the two proportions indeed differ significantly.
Chi-square tests (binary variables), non-parametric Mann-Whitney test (for continuous
variables - 2 groups) and non-parametric Kruskall-Wallis tests (continuous variables - more
groups) will be used for the comparison of population characteristics in different
subgroups. When the p- values are less than 0.05, the conclusion will be that there is a
significant difference between the subgroups for these variables.
The percentage treatment change will be calculated for the whole study group and for the
three predefined subgroups. The distribution of MammaPrint test results will be summarized
in a frequency table. With a predefined sample size for the whole group (n=600), and a
control group consisting of at least 1800 patients the minimal detectable difference in the
proportion of patients receiving chemotherapy is 6.6% for the whole group and 9.3% for a
subgroup of 300 patients (2-sided alpha 0.05, Power 80). After inclusion of the first 150
patients, additional sample size calculation will be conducted based on the actual
proportions of the subgroups.
7. ETHICAL CONSIDERATIONS
Regulation statement This study is conducted according to the principles of the Declaration
of Helsinki (version 6, February 2008) and in accordance with the Medical Research Involving
Human Subjects Act (WMO) and other legal and regulatory frameworks.
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