Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Recurrence

Breast Neoplasms

Disease Attributes

Breast Diseases

Skin Diseases

MammaPrint

Michaela Tsai, MD

This is a prospective study that will assess the impact of MammaPrint on chemotherapy + endocrine versus endocrine alone treatment decisions in patients with an Oncotype Intermediate Score.

The frequency of chemotherapy + endocrine versus endocrine alone decisions in Oncotype DX intermediate score patients will be calculated before and after receiving the MammaPrint result.

Patients have the option to agree to the storage of excess samples at Agendia.

PRospective Study Of MammaPrint in Patients With an Intermediate Recurrence Score

The frequency of chemotherapy + endocrine versus endocrine alone decisions in Oncotype DX intermediate score patients will be calculated before and after receiving the MammaPrint result. A Chi-square test will be performed for the comparison of the two proportions.

Agendia

Carcinoma

Thijs van Dalen, Dr

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.

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. For further information: www.agendia.com or www.symphonytripleA.nl.

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

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

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.

The percentage treatment change will be calculated for the whole study group and for the three predefined subgroups.

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.

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.

The concordance between the ER, PR and Her2 results as assessed by the TargetPrint and local ICH/FISH techniques will be assessed.

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

Diakonessenhuis, Utrecht

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Reproductive Control Agents

Docetaxel

Cyclophosphamide

Letrozole

Leuprolide

Aromatase Inhibitors

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

1. MammaPrint high risk :

   * Neoadjuvant chemotherapy : Adriamycin/Cyclophosphamide #4 followed by Docetaxel #4
2. MammaPrint low risk :

   * Premenopausal women : Letrozole 2.5mg PO QD + leuprorelin acetate 3.6mg SQ every 4weeks during 16 weeks (if needed, maximum for 24 weeks)
   * Postmenopausal women : Letrozole 2.5mg PO QD during 16 weeks (if needed, maximum for 24 weeks)

In premenopausal women, 3.75mg of leuprorelin acetate is subcutaneously administered once every 4 weeks for 16 weeks. (if needed, maximum for 24 weeks)

Leuprorelin acetate

2.5 mg tablet is orally administered once a day, without regard to meals, for 16 weeks (if needed, maximum for 24 weeks)

In this study, patients with MammaPrint test is performed, neoadjuvant chemotherapy is conducted to genomic High Risk patients, and neoadjuvant endocrine therapy is conducted to Low Risk patients.

Wonshik Han

In ER+ and HER2- breast cancer(BC) patients for whom BCS is not feasible, we investigate the rate of BCS can be increased while decreasing unnecessary chemotherapy thru selective neoadjuvant chemotherapy or neoadjuvant endocrine therapy using tools of nodal status, Ki-67, and multigene assay(Mammaprint)

In patients with resectable BC, the neoadjuvant chemotherapy is recognized as one of the standard therapy in order to control and prevent the micrometastasis.

Conducting neoadjuvant chemotherapy can lead to increased numbers of BCS compared with adjuvant chemotherapy and the prognosis of BC patients is known to be improved when there is pathological complete response (pCR) after neoadjuvant chemotherapy compared with no pCR.

The effect of neoadjuvant chemotherapy is different in breast cancer subtypes. The quasi-pCR in HR- HER2+ BC is reported as 67% while 37% and 13% in triple negative and HR+ HER2- BC, respectively and it indicates that neoadjuvant chemotherapy has only limited effect in HR+ BC and the declined quality of life and the fecundity loss due to chemotherapy is a serious socioeconomic loss, especially in young patients.

According to the SOFT trial, for high risk, pre-menopausal women, use of exmestane (AI, Aromatase Inhibitors) and ovarian suppression as adjuvant systemic therapy did improve the PFD compared with the use of tamoxifen and ovarian suppression.

Neoadjuvant hormonal therapy as well as neoadjuvant chemotherapy has benefits in making inoperable BC to operable BC and improving the possibility of BCS by reducing the tumor size with complete response or partial response. Although these neoadjuvant systemic therapies have an ultimate objective to reduce the recurrence rate and improve the survival rate, the overall survival and disease-free survival has been reported similar to adjuvant systemic therapies. The clinical response rate of neoadjuvant hormonal therapy ranged from 13.5% to 100%, the radiologic response rate by ultrasound ranged from 20% to 91.7%, and these are statistically similar to the response rate of the neoadjuvant chemotherapy in ER+ patients. Most studies where letrozole was tested among AIs showed that letrozole has a similar or a little better effect on clinical or radiological response rate over tamoxifen and there were statistically more patients who became operable or eligible for BCS after neoadjuvant chemotherapy. Comparison studies among AIs showed that the response rates have been best achieved in letrozole over anastrozole and exemestane and the BCS rate was lowest in letrozole without statistical significance. According to the standard treatment guideline suggesting the selective use of ovarian suppression along with tamoxifen in HR+, premenopausal patients, a study investigated the combined treatment of letrozole with reversible ovarian ablation using goserelin (luteinizing hormone-releasing hormone: LHRH). The results showed that the response rate of the combination treatment of goserelin and anastrozole for 24 weeks as neoadjuvant hormonal therapy was statistically superior to goserelin and tamoxifen in premenopausal BC patients and this was not observed in the adjuvant setting. The most commonly used agents in BC are goserelin and leuprorelin(Leuplin) and their mechanism of action is to desensitize the hypothalamus and suppress the ovarian function by reducing the secretion of LH and FSH.

MammaPrint, which analyses 70-gene expressed in breast cancer, can identify low risk patients who may safely forgo chemotherapy and high risk patients who can benefit from chemotherapy. Recent results from MINDACT trial have proved that 46.2% of HR+ and clinical high risk patients were classified into MammaPrint low risk and they could avoid unnecessary chemotherapy. In 2017 San Antonio breast cancer symposium, Dubsky et al. reported the analysis of correlation between neoadjuvant chemotherapy and score of Endopredict(EP) multigene assay in ER+ and HER2- patients treated on ABCSG 34. In neoadjuvant chemotherapy group, reduction of tumor size in patients with low EP score(Endopredict low risk group) was significantly low(NPV 100%). Meanwhile, in neoadjuvant hormonal therapy group, reduction of tumor size in patients with high EP score(Endopredict high risk group) was significantly low(NPV 92%). These results support the evidence that response of neoadjuvant chemotherapy or hormonal therapy can be predicted by the molecular score of tumor and selective treatment can maximize the effect.

Accordingly, in this study, patients with MammaPrint test is performed, neoadjuvant chemotherapy is conducted to genomic High Risk patients, and neoadjuvant endocrine therapy is conducted to Low Risk patients. Although adjuvant therapy is conducted after the completion of this study, in case there is progressive disease (PD) after neoadjuvant endocrine therapy, adjuvant chemotherapy is conducted.

PersonaLized neoAdjuvant Strategy ER Positive and HER2 Negative Breast Cancer TO Increase BCS Rate

Multi-institutional Study to Increase Breast Conserving Surgery (BCS) Rate With Personalized Neoadjuvant Strategy in ER Positive and HER2 Negative Breast Cancer Patients for Whom BCS is Not Feasible

Evaluate ipsilateral breast tumor recurrence

Evaluate response rate by Blueprint subtype

Evaluate the conversion rate from BCS-ineligible to BCS-eligible patients

Evaluate the actual performance rate of BCS

Evaluate the accomplished rate of targeted tumor size reduction which enable to make BCS possible at presentation

Seoul National University Hospital

Professor

Chemoendocrine therapy according to national guidelines.

BluePrint

TargetPrint

Nadia Harbeck, Prof. Dr.

Ulrike Nitz, Prof. Dr.

PRIMe is a prospective, case-only trial designed to measure the impact of MammaPrint on physician chemotherapy intention in the two discordant groups (ET/POOR, CT/GOOD) in stage 1 and 2 HR-positive HER2-negative breast cancer patients. The design also provides for assessment of several important secondary indicators. Eligible patients will have their tumor sample analyzed for MammaPrint, BluePrint and TargetPrint. Patients cannot start treatment before the MammaPrint result is received and taken into consideration for the adjuvant treatment plan.

PRospective Study to Measure the Impact of MammaPrint on Adjuvant Treatment in Hormone Receptor-positive HER2-negative Breast Cancer Patients (PRIMe)

Compliance, assessed in terms of the fraction of patients in each discordant group whose physicians switch their chemotherapy intention following MammaPrint test disclosure is used to measure the impact of MammaPrint on adjuvant treatment decisions.

The planned analysis includes assessment of the incremental cost-effectiveness (ICER) of MammaPrint within a health economic context (i.e., taking cost and quality-adjusted life years into account).

West German Study Group

Kikuya Kato, MD, PhD, Prof

By using gene-expression profiling, Van't Veer and colleagues developed a 70-gene prognosis profile, MammaPrint, to identify breast cancer patients who are at low risk of developing distant metastases and therefore might safely be spared chemotherapy. The aim of this study is to evaluate the prognostic value of the 70-gene Mammaprint profile in Japanese women with node-negative breast cancer.

Frozen tumor samples from 140 node-negative, breast cancer patients aged between 29 and 70 years at diagnosis are hybridized on MammaPrint array. Patients were treated with breast conserving therapy or mastectomy with axillary lymph node dissection between December 1998 and August 2001 at Osaka Medical Center for Cancer and Cardiovascular Diseases. Samples are evaluated by gene expression profiling for the 70-gene MammaPrint profile and classified as genomic high risk or genomic low risk.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PRospective Study Of MammaPrint in Patients With an Intermediate Recurrence Score	NCT01617954	Hormone Recepto...	MammaPrint	18 Years - 90 Years	Agendia
The Symphony Triple A Study: Using Symphony in Treatment Decisions Concerning Adjuvant Systemic Therapy	NCT02209857	Breastcancer Invasive Breast...		18 Years -	Diakonessenhuis, Utrecht
PersonaLized neoAdjuvant Strategy ER Positive and HER2 Negative Breast Cancer TO Increase BCS Rate	NCT03900637	Breast Cancer	Leuprorelin ace... Letrozole MammaPrint	19 Years -	Seoul National University Hospital
PRospective Study to Measure the Impact of MammaPrint on Adjuvant Treatment in Hormone Receptor-positive HER2-negative Breast Cancer Patients (PRIMe)	NCT02269813	Breast Cancer	MammaPrint BluePrint TargetPrint	18 Years -	West German Study Group
The Symphony Triple A Study: Using Symphony in Treatment Decisions Concerning Adjuvant Systemic Therapy	NCT02209857	Breastcancer Invasive Breast...		18 Years -	Diakonessenhuis, Utrecht
PRospective Study Of MammaPrint in Patients With an Intermediate Recurrence Score	NCT01617954	Hormone Recepto...	MammaPrint	18 Years - 90 Years	Agendia
Validation of 70-gene MammaPrint Profile in Japanese Population	NCT00904566	Breast Cancer		29 Years - 70 Years	Agendia
PRospective Study to Measure the Impact of MammaPrint on Adjuvant Treatment in Hormone Receptor-positive HER2-negative Breast Cancer Patients (PRIMe)	NCT02269813	Breast Cancer	MammaPrint BluePrint TargetPrint	18 Years -	West German Study Group

Spots Global Cancer Trial Database for mammaprint

Every month we try and update this database with for mammaprint cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for mammaprint

Every month we try and update this database with for mammaprint cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for mammaprint cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.