NICE Develops a Medtech Innovation Briefing on the MammaTyper In Vitro Diagnostic Test

Technology used for determining molecular subtypes of breast cancer

In January 2018, NICE published a Medtech innovation briefing [MIB135] on the MammaTyper in Vitro Diagnostic Test. The technology described in this briefing is used for determining different molecular subtypes of breast cancer to decide on systemic therapy.

The MammaTyper (BioNTech Diagnostics GmbH) test is a molecular in vitro diagnostic test for the relative gene expression quantification of the genes ERBB2, ESR1, PGR and MKI67 in human breast cancer tissue. It is used as a diagnostic test on biopsy samples of invasive breast cancer tissue from surgical resection or pre-operative core needle biopsies. The test is based on reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). MammaTyper classifies breast cancer into 4 subtypes that have different treatments according to St Gallen (2017) guidelines:

  • Luminal A-like (oestrogen receptor [ER]-positive and generally human epidermal growth receptor 2 [HER2]-negative); treated with endocrine therapy.
  • Luminal B-like subdivided according to the ERBB2 expression into:HER2-positive (non-luminal); treated with anti-HER2 therapy and chemotherapy.
    • luminal B-like (ER-negative and HER2-positive); treated with anti-HER2 therapy and chemotherapy
    • luminal B-like (ER-positive and generally HER2-negative); treated with endocrine therapy.
  • Triple-negative (generally ER, progesterone receptor [PR]- and HER2-negative); treated with chemotherapy.

The MammaTyper test uses a standard formalin-fixed paraffin-embedded (FFPE) biopsy sample, which is processed using RNXtract to extract ribonucleic acid (RNA). The sample is then run through a RT-qPCR machine with the MammaTyper test and controls supplied with the test.

MammaTyper measures ER and HER2 status on routinely collected FFPE material. It offers an objective, sensitive, and precise test, based on measuring the upregulation of genes on standard RT-qPCR equipment. It would be an alternative to immunohistochemistry (IHC), which is a subjective test that has no defined cut off and may have inter-observer and inter-laboratory variability for some measures, such as those relating to MKI67.

MammaTyper would be done in secondary care on a surgical resection of the breast cancer tissue (or the initial diagnostic core biopsy) so results are available to guide post-surgical chemotherapy or initial treatment. It would be used in the same place in the care pathway as IHC, to identify patients likely to have a low-risk subgroup of ER-positive luminal A-like or B-like disease and to avoid using chemotherapy in these groups. It would provide additional information on luminal B-like tumour subtypes that cannot be assessed using IHC. Luminal B-like tumour subtypes are associated with different prognoses and therapy recommendations. Knowing the luminal B-like subtype is designed to enable treatment to be optimised, which may avoid over- or under-treatment. Information about hormone-receptor status and ERBB2 expression can also be used to identify people for whom further multigene testing is not needed. This may avoid the unnecessary use of expensive multigene tests.

NICE is aware of the following CE-marked device that appears to fulfil a similar function as MammaTyper: IHC4 AQUA (Genoptix Inc) – assesses risk (low, intermediate, high) and subtype.

The main points from the evidence summarised in this briefing are from randomised controlled trials (RCTs) and diagnostic reproducibility studies (UK, US and Europe) including a total of 1,460 adults (1,138 evaluable tumour samples) with early-stage breast cancer in secondary care. It shows that MammaTyper is more effective than IHC in defining breast cancer subtype to guide chemotherapy.

Key uncertainties around the evidence include the need for further studies on clinical outcomes after MammaTyper-guided therapy and on the relative utility of MammaTyper compared with other gene-based tests.

The company state the price per patient of MammaTyper is 400 GBP, including RNXtract to extract RNA. It states that there is potential for preferential NHS pricing. The test can be run on a range of industry-standard RT-PCR devices and needs 45 minutes of technician time (about 16 GBP).

IHC tests are done using standard pathology laboratory techniques and cost about 152 GBP per test. This includes 30 to 45 minutes of a consultant pathologist's time to do the test (117 GBP), and the costs of consumables (35 GBP).

The MammaTyper test would add costs compared with the standard IHC test in initial testing and treatment of breast cancer. It has the potential to make resource savings in avoiding unnecessary chemotherapy, optimising treatment regimens and potentially avoiding the need for more expensive multigene testing. As MammaTyper is an objective test, it does not need expert histopathology clinicians to read the result, and so can release staff time.

MammaTyper test uses industry-standard RT-PCR machines (including Roche LightCycler, Versant kPCR Cycler, cobas z480 Analyzer and others) and is done on routine clinical samples such as FFPE material, so additional training is not needed.

The test runs on a range of standard PCR devices and would need no changes to infrastructure beyond buying the relevant technology.