Ignite Creation Date:
2024-05-06 @ 3:06 AM
Last Modification Date:
2024-10-26 @ 11:28 AM
Study NCT ID:
NCT02209857
Status:
COMPLETED
Last Update Posted:
2017-02-15
First Post:
2014-07-24
Brief Title:
The Symphony Triple A Study Using Symphony in Treatment Decisions Concerning Adjuvant Systemic Therapy
Sponsor:
Diakonessenhuis Utrecht
Organization:
Diakonessenhuis Utrecht
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2017-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Symphony
Brief Summary:
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 AdjuvantOnline 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
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 AdjuvantOnline 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
Detailed Description:
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 ERPR 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 n219 and High Risk n208 patients were 970 and 917
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 12 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 ERPR- 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 andor 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 NKRNBCA 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 005 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 005 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 n600 and a control group consisting of at least 1800 patients the minimal detectable difference in the proportion of patients receiving chemotherapy is 66 for the whole group and 93 for a subgroup of 300 patients 2-sided alpha 005 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
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 n219 and High Risk n208 patients were 970 and 917
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 12 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 ERPR- 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 andor 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 NKRNBCA 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 005 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 005 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 n600 and a control group consisting of at least 1800 patients the minimal detectable difference in the proportion of patients receiving chemotherapy is 66 for the whole group and 93 for a subgroup of 300 patients 2-sided alpha 005 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None