Re-Evaluation of Tumor Samples From Women With Breast Cancer With the in Vitro Diagnostic Kit "MammaTyperTM"

• Sponsor: BioNTech Diagnostics GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02244580
• Collaborator: (none)
• Enrollment: 1,010
• Arm: 1

Study Details

Study Description

Brief Summary

This is a prospective examination of tumor material of breast cancer patients randomized into the FinHer-trial (= (= Comparison of vinorelbine and docetaxel and trastuzumab as adjuvant treatments of breast cancer patients wirh a high risk of cancer recurrence).

The formalin-fixed, paraffin-embedded tissue samples will be analysed for Estrogen receptor 1 (ESR1), progesterone receptor (PgR), Human epidermal growth factor receptor 2 (HER2) and Antigen Ki-67 (Ki-67) with the molecular in vitro diagnostic kit MammaTyper™.

According to the new subtyping the 5 year Distant disease free survival (DDFS) and Overall survival (OS) will be re-evaluated.

Condition or Disease	Intervention/Treatment	Phase
Invasive Breast Cancer	Device: MammaTyper™	N/A

Detailed Description

Despite the fact that reliable measures for the markers ESR1, PgR, HER2, Ki-67 are necessary with the currently used methods up to 20% of determinations are inaccurate and especially Ki67- measures are not very reproducible. Therefore new evaluation systems or new methods are necessary to improve diagnostic.

At least 4 subtypes can be distinguished to date depending on the expression of ESR, PgR,

Her2 and Ki-67:

• Luminal A-type

• Luminal B-type

• Her2-type

• Triple-negative-type

MammaTyper™ uses a new approach. Instead of detection of the marker proteins, the messenger ribonucleic adic (mRNA) of marker proteins is quantitated. This prospectively planned diagnostic study will investigate the potential of subgrouping of patients at baseline according to results of MammaTyper™ methodology for predicting survival.

Patients will be subgrouped according to the new marker determination and the DDFS and OS will be evaluated and compared to the DDFS and OS of subgrouping with former marker determination.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1010 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Evaluation of the MammaTyperTM Kit, Ref 90020/90021 Performed on Clinical Material Obtained From Patients With Breast Cancer: Re-Examination of Tumor Material and Re-Evaluation of Patient Data of the FinHer-Study
• Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MammaTyper™ MammaTyper™ kit will be used tio assess tumor material of patients enrolled into the FinHer trial.	Device: MammaTyper™; MammaTyper™ kit is a molecular in vitro diagnostic test for the quantitative detection of the ribonuclease acid (RNA) expression status of the genes for estrogen receptor (ESR1), progesterone receptor (PGR), human epidermal growth factor receptor 2 (HER2) and proliferation antigen KI 67.

Outcome Measures

Primary Outcome Measures

1. 5 Year Distant Disease Free Survival (DDFS) Assessed as Rate of Patients Without Distant Metastases in Subgroup Luminal A vs. Combined Subgroup (Luminal B, HER2 Positive, Triple Negative), Based on Subtyping With MammaTyper™ [5 year from the date of patient randomisation]

   Tumor material of breast cancer patients will be newly assessed by MammaTyper™ and 5 year DDFS will be calculated new according to new subgrouping (Luminal A vs. combined subgroup (Luminal B, HER2 positive, triple negative))

Secondary Outcome Measures

1. Number of Patients With High Ki-67 and Prognosis on Outcome for DDFS and OS (Measured by Hazard Ratio) [5 years]

   High Ki-67 is prognostic for worse outcome for DDFS and OS (measured by hazard ratio)

2. Number of Patients With Ki-67 Determined by MammaTyper™ Compared to Local Ki-67 Eyeballed Assessment for Luminal Tumors and Correlation to Rate of Patients With Regard to OS and DDFS [5 years]

   Superiority of outcome prediction for MammaTyper™ Ki-67 over local Ki-67 eyeballed assessment for Luminal tumors with regard to OS and DDFS

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Invasive breast cancer verified in a histological biopsy

• Age 65 or younger

• Estrogen receptor (ER), PgR and HER2 expression have been determined

• No distant metastases present (M0)

• The patient provides a written informed consent for study participation

• The estimated risk of breast cancer recurrence is high (25% or higher within the first 5 years from the date of the diagnosis, over >35% within the first 10 years from the diagnosis)

Exclusion Criteria:

• Patients with breast cancer with "a special histological type" (mucinous, papillary, medullary, or tubular type of breast cancer) when no metastases are present in the ipsilateral axillary lymph nodes

• The WHO performance status is moderate/poor, Z >1

• The peripheral blood leukocyte count is less than 3.0 x 109/L, the blood granulocyte count is less than 1.5 x 109/L, or the blood thrombocyte count is less than 120 x 109/L

• Any physical or mental disorder that is considered to prohibit administration of chemotherapy

• Cardiac failure; severe cardiac arrythmia requiring regular medication

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• BioNTech Diagnostics GmbH

Investigators

• Study Director: Michael Oed, Dr., BioNTech Diagnostics GmbH

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: BioNTech Diagnostics GmbH
• ClinicalTrials.gov Identifier: NCT02244580
• Other Study ID Numbers: MammaTyper-FinHer
• First Posted: Sep 19, 2014
• Last Update Posted: Nov 6, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by BioNTech Diagnostics GmbH: Subtyping of Invasive breast cancer
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Recruitment Details	The clinical data and breast tumour tissue samples were collected within the FinHer trial (identifier ISRCTN76560285), where 1010 women with axillary node-positive or high-risk axillary node-negative breast cancer were randomly assigned between October 2000 and September 2003.

Arm/Group Title	MammaTyper™
Arm/Group Description	MammaTyper™ kit will be used to assess tumor material of patients enrolled into the FinHer trial. MammaTyper™: MammaTyper™ kit is a molecular in vitro diagnostic test for the quantitative detection of the ribonuclease acid (RNA) expression status of the genes for estrogen receptor (ESR1), progesterone receptor (PGR), human epidermal growth factor receptor 2 (HER2) and proliferation antigen KI 67.
Period Title: Overall Study
STARTED	1010
COMPLETED	769
NOT COMPLETED	241

Baseline Characteristics

Arm/Group Title	FinHer Patients
Arm/Group Description	Of all patients, FFPE tumour block was processed with the RNXtract RNA extraction kit (BioNTech Diagnostics GmbH, Mainz) using a magnetic particle-based assay (Supplemental file 1A). RT-qPCR was done with the MammaTyper kit (BioNTech Diagnostics GmbH, Mainz) for ESR1, PGR, ERBB2 and MKI67.
Overall Participants	1010
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	50.9
Sex: Female, Male (Count of Participants)
Female	1010 100%
Male	0 0%
Region of Enrollment (participants) [Number]
Finland	1010 100%

Outcome Measures

1. Primary Outcome

Title	5 Year Distant Disease Free Survival (DDFS) Assessed as Rate of Patients Without Distant Metastases in Subgroup Luminal A vs. Combined Subgroup (Luminal B, HER2 Positive, Triple Negative), Based on Subtyping With MammaTyper™
Description	Tumor material of breast cancer patients will be newly assessed by MammaTyper™ and 5 year DDFS will be calculated new according to new subgrouping (Luminal A vs. combined subgroup (Luminal B, HER2 positive, triple negative))
Time Frame	5 year from the date of patient randomisation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Luminal A	Combined Subtype
Arm/Group Description	Patients subtyped as Luminal A with DDFS determined 5 years after randomisation	Patients subtyped as Luminal B, HER2 positive, triple negative with DDFS determined 5 years after randomisation
Measure Participants	769	769
Number [percentage of analyzed participants]	92 9.1%	82 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luminal A, Combined Subtype
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.423
	Confidence Interval	(2-Sided) 95%; 0.246 to 0.726
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Patients With High Ki-67 and Prognosis on Outcome for DDFS and OS (Measured by Hazard Ratio)
Description	High Ki-67 is prognostic for worse outcome for DDFS and OS (measured by hazard ratio)
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With MKI67 mRNA Determination
Arm/Group Description	Patients with low MKI67 mRNA
Measure Participants	769
Number (95% Confidence Interval) [Hazard ratio]	0.42

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luminal A
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; 0.25 to 0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Patients With Ki-67 Determined by MammaTyper™ Compared to Local Ki-67 Eyeballed Assessment for Luminal Tumors and Correlation to Rate of Patients With Regard to OS and DDFS
Description	Superiority of outcome prediction for MammaTyper™ Ki-67 over local Ki-67 eyeballed assessment for Luminal tumors with regard to OS and DDFS
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DDFS According to MKI67 mRNA and Ki-67 Protein (IHC) Levels	OS According to MKI67 mRNA and Ki-67 Protein (IHC) Levels
Arm/Group Description	Determination of DDFS of patients according to MKI67 mRNA (RT-qPCR) and Ki-67 protein (IHC) levels	Determination of OS of patients according to MKI67 mRNA (RT-qPCR) and Ki-67 protein (IHC) levels
Measure Participants	769	769
DDFS (MKI67 mRNA positive - negative)	0.42	0.45
DDFS (Ki-67 protein positive - negative)	0.56	0.43

Adverse Events

Arm/Group Title
Arm/Group Description	Since only tumor material was used, adverse events were not documented within the MammaTyper Study
All Cause Mortality
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.