The Symphony Triple A Study: Using Symphony in Treatment Decisions Concerning Adjuvant Systemic Therapy

Sponsor

Diakonessenhuis, Utrecht (Other)

Overall Status

Completed

CT.gov ID

NCT02209857

Collaborator

Agendia (Industry)

660

Enrollment

Locations

Duration (Months)

19.4

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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 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.

Condition or Disease	Intervention/Treatment	Phase
Breastcancer Invasive Breast Carcinoma by Gene Expression Profile

Detailed Description

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.

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®

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.

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:

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.
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.
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)
MammaPrint® result is emailed to the surgeon, medical oncologist and mammacare nurse within 10 working days.
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.

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.

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.

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 Design

Study Type:

Observational

Actual Enrollment :

660 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

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

Study Start Date :

Jan 1, 2013

Actual Primary Completion Date :

Mar 1, 2016

Actual Study Completion Date :

May 1, 2016

Outcome Measures

Primary Outcome Measures

Frequency of adjuvant chemotherapy [Within one month after surgery]
We will measure and compare the proportion of patients receiving adjuvant chemotherapy in the group of patients receiving MammaPrint and the group who doesn't receive MammaPrint. In addition we'll record the type of chemotherapy given.

Secondary Outcome Measures

Changes in adjuvant systemic treatment decisions due to MammaPrint use [Within one month after (initial) surgery]
The percentage treatment change will be calculated for the whole study group and for the three predefined subgroups.
Influence of BluePrint and TargetPrint on adjuvant systemic treatment decisions [Within one month after (initial) surgery]
The percentage of adjuvant systemic treatment changes due to the use of BluePrint and/or TargetPrint for the whole studygroup, and the various subgroups will be calculated.
Clinical utility of MammaPrint in multicentric/contralateral disease. [Within one month after (initial) surgery]
Of patients included in the Symphony Triple A study with multicentric or contralateral breast cancer two tissue samples will be collected and a MammaPrint will be performed on both samples. In this subgroup of patients, MammaPrint, BluePrint and TargetPrint results of both tumors will be compared to evaluate the clinical utility of MammaPrint in multicentric and contralateral disease.
Concordance of TargetPrint results with locally assessed ICH/FISH ER, PR and Her2 results [Within one month after (initial) surgery]
The concordance between the ER, PR and Her2 results as assessed by the TargetPrint and local ICH/FISH techniques will be assessed.
Comparison of clinical subtype with BluePrint molecular subtype [Within one month after (initial) surgery]
Based on the ER, PR and Her2 results as assessed by local pathologist patients can be categorized in clinical molecular subtypes. Concordance between these clinical subtypes and the molecular subtype as assessed by the BluePrint will be assessed

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion criteria

Oestrogen receptor positive, invasive ductal and female breast cancer patients where the benefit of adjuvant chemotherapy is uncertain based on traditional prognostic factors
Written informed consent
Patients with multicentric or contralateral disease

Exclusion criteria

Patients with a previous history of malignancy (in the five years before breast cancer diagnosis), excluding basal cell carcinoma.
Patients with confirmed distant metastasis.
Patients who undergo neoadjuvant systemic treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jeroen Bosch ziekenhuis	Den Bosch	Brabant	Netherlands	5301EH
2	Whilhelmina ziekenhuis	Assen	Drenthe	Netherlands	9041RK
3	Medisch Centrum Zuiderzee	Lelystad	Flevoland	Netherlands	8233AA
4	Nij Smellinghe ziekenhuis	Drachten	Friesland	Netherlands	9202 NN
5	Tjongerschans	Heerenveen	Friesland	Netherlands	8441PW
6	Antoniusziekenhuis	Sneek	Friesland	Netherlands	8601ZK
7	Gelre ziekenhuis	Apeldoorn	Gelderland	Netherlands	7334 DZ
8	Rijnstate	Arnhem	Gelderland	Netherlands	6815AD
9	Gederse Vallei	Ede	Gelderland	Netherlands	6716RP
10	Sint Jansdal	Harderwijk	Gelderland	Netherlands	3844DG
11	Ziekenhuis Rivierenland	Tiel	Gelderland	Netherlands	4000 HA
12	Gelre ziekenhuis	Zutphen	Gelderland	Netherlands	7207 AE
13	Medisch Centrum Alkmaar	Alkmaar	Noord-Holland	Netherlands	1815JD
14	Boven IJ ziekenhuis	Amsterdam	Noord-Holland	Netherlands	1034CS
15	Onze Lieve Vrouwe Gasthuis	Amsterdam	Noord-Holland	Netherlands	1091AC
16	Gemini ziekenhuis	Den Helder	Noord-Holland	Netherlands	1782GZ
17	Kennemer Gasthuis	Haarlem	Noord-Holland	Netherlands	2035RC
18	Spaarne ziekenhuis	Hoofddorp	Noord-Holland	Netherlands	2134TM
19	Westfriesgasthuis	Hoorn	Noord-Holland	Netherlands	1624NP
20	Waterland ziekenhuis	Purmerend	Noord-Holland	Netherlands	1441RN
21	Vlietland ziekenhuis	Schiedam	Noord-Holland	Netherlands	3118 JH
22	Zaans medisch centrum	Zaandam	Noord-Holland	Netherlands	1502DV
23	Deventer ziekenhuis	Deventer	Overijssel	Netherlands	7416SE
24	Ropcke Zweers ziekenhuis	Hardenberg	Overijssel	Netherlands	7772SE
25	Isale klinieken	Zwolle	Overijssel	Netherlands	8011 JW
26	Alexander Monro ziekenhuis	Bilthoven	Utrecht	Netherlands	3723 MB
27	Ter Gooi ziekenhuis	Hilversum	Utrecht	Netherlands	1201 DA
28	Sint Antoniusziekenhuis	Nieuwegein	Utrecht	Netherlands	3435CM
29	Zuwe Hofpoort ziekenhuis	Woerden	Utrecht	Netherlands	3447GN
30	IJsselland ziekenhuis	Capelle aan den IJssel	Zuid-Holland	Netherlands	2906ZC
31	Sint Fransiscus gasthuis	Rotterdam	Zuid-Holland	Netherlands	3045 PM
32	Lange Land ziekenhuis	Zoetermeer	Zuid-Holland	Netherlands	2700 KJ
33	Martini ziekenhuis	Groningen		Netherlands	9728NT
34	Diakonessenziekenhuis	Utrecht		Netherlands	3508 TG