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BioNTech Gathering Data Supporting MammaTyper Over Manual, Digital IHC for Breast Cancer Subtyping


NEW YORK (GenomeWeb) – Supporting continued marketing of its breast cancer subtyping test MammaTyper, German MDx firm BioNTech Diagnostics published a study last month comparing the test for the first time with both visual and computer-assisted immunohistochemistry methods.

The company argued that the results, published online in the journal BMC Cancer, solidify MammaTyper's superiority over not only the standard manual methods for analyzing immnohistochemical staining, but also newer strategies for computer-assisted image analysis.

Importantly, the data also suggest that MammaTyper outperforms IHC in assessing Ki-67 status. This is where the company sees its "main advantage," Gerd Hempel, BioNTech's diagnostics marketing manager, said in an interview this week.

The results also hint that MammaTyper's more reliable Ki-67 measurement could be used to predict which patients are likely to have a pathologically complete response when treated with adjuvant chemotherapy.

MammaTyper uses quantitative RT-PCR to analyze four individual biomarkers — ERBB2, ESR1, PGR, and MKI67.

The St. Gallen International Breast Cancer Conference recommends these as the classifiers of choice for determining which molecular subtypes breast cancer patients fall into: luminal A-like, luminal B-like (HER2 negative), luminal B-like (HER2 positive), HER2-positive (non-luminal), and triple negative.

Each subtype is associated with different therapy recommendations and as well as differences in risk and prognosis.

Although there are other subtyping methods — for example, MDx Firm Agendia launched a test called BluePrint several years ago — Hempel said that MammaTyper offers a unique value to labs, because it much more narrowly reflects the St. Gallen recommendations and subtype definitions. Moreover, it precisely reflects the IHC methods that are already used widely by clinicians.

Ki-67 values specifically, are recognized by St. Gallen as useful for defining the luminal A vs luminal B subtypes, with additional data showing that the marker is associated with higher rates of pathological complete remission when patients are treated with neoadjuvant chemotherapy.

The current standard method for detecting Ki-67, as well as these other markers, is manual microscopic immunohistochemistry which is widely used but also widely known to suffer from intra- and inter-observer variability issues.

MammaTyper is a quantitative test, removing some of the variability that hinders IHC methods. In previous studies, BioNTech has shown that its assay corresponds well with IHC, but with added value due to the avoidance of inter-observer variability.

In the new study, by comparing MammaTyper results with patient outcomes, the company was also able to show not only that its calls for MKI67 differed from those made using IHC, but that they were actually better correlated with successful treatment.

In the study, researchers from BioNTech and the University of Heidelberg analyzed formalin-fixed, paraffin-embedded core needle biopsy samples from 101 breast cancer patients who had participated in a prior randomized neoadjuvant trial.

The team was able to successfully apply MammaTyper to 83 biopsy specimens that had full clinical data available. Out of this group, 12 patients had achieved complete pathological remission.

Investigators compared MammaTyper calls with both standard and computer-assisted IHC results, the company said.

Results of the determination of ER and PR status confirmed the high correlation between MammaTyper and immunohistochemistry results that BioNTech has seen in previous studies. The data also demonstrated a slightly higher correlation between MammaTyper and computer-assisted IHC versus standard IHC.

For both ESR1 and PGR there were four discordant cases — three of each were positive by IHC and negative by MammaTyper, while one case was negative by IHC and positive by the RT-qPCR test.

However, the authors wrote, several of these discrepancies could be resolved by looking at the quantitative IHC results, as these cases were also discrepant when comparing standard IHC with computer-assisted analysis.

Meanwhile, MammaTyper showed only moderate correlation with IHC in detecting Ki-67. When the researchers looked at how these results compared to patients' actual clinical progress data, it appeared that the MammaTyper results, not the IHC results, better predicted outcomes.

More specifically, the researchers arranged the data to reflect a high- versus low-MKI67 cutoff point with 100 percent sensitivity for predicting pathological completed response to neoadjuvant chemo. With this cutoff in place, RT-qPCR showed itself to be significantly more specific than IHC.

Although this data is only a first hint, the authors wrote that if validated it would signify that MammaTyper could help patients safely forego unnecessary treatment.

In recent years, a number of complex molecular tests like OncotypeDx, MammaPrint, and Prosigna have gained ground for guiding decisions on the use of neoadjuvant chemotherapy.

However, the Heidelberg and BioNTech researchers wrote, generalized use of these assays, at least outside the US, is limited by their cost and their requirement for sending samples to a centralized testing lab.

"Interestingly, proliferation genes, including MKI67, are often heavily weighted in multi-gene scores which serve as estimators of a patients’ risk of developing recurrences," the study authors wrote.

"This is perhaps one of the reasons why multi-gene tests do not always prove to be convincingly superior to conventional or less sophisticated methods for tumor risk stratification, leading some authors to question their cost-effectiveness," they added.

For example, while Genomic Health has published much data demonstrating that its 21-gene OncotypeDx test discriminates patients in a way standard clinicopathologic features cannot, some have questioned whether the added information the algorithm provides is necessary to accurately guide treatment.

For example, authors of a letter to the New England Journal of Medicine last year argued that standard clinicopathologic criteria are sufficient to spare the use of chemotherapy in a large majority of patients with breast cancer.

Researchers cited data showing that women who were spared chemotherapy based on low Ki-67 scores had survival outcomes on par with those reported for those with low recurrence risk as assessed by OncotypeDx in the pivotal TAILORx study.

Recent guidelines in the US by the American Society of Clinical Oncology, however, recommend against using Ki-67 levels to make decisions about treatments, though they say women with hormone-receptor-positive disease and no cancer in the lymph nodes could benefit from OncotypeDx to predict chemo benefit.

In its 2015 consensus publication on the primary therapy of early breast cancer, St. Gallen reports that of all the available molecular tests, only OncotypeDx commanded a majority in favor of its value in predicting chemotherapy benefit.

However, the report authors wrote, "tests which are prognostic but not specifically predictive of the efficacy of cytotoxic therapy, are commonly used to make decisions about such therapy … on the grounds that they may define a group of patients with a prognosis so good that even if chemotherapy were similarly proportionately effective as in higher risk patients the absolute benefit may be thought insufficient to justify such treatment."

On Ki-67, the St. Gallen authors wrote that while "there can be little doubt that Ki-67 scores carry robust prognostic information, and that high values predict the benefit of addition of cytotoxic chemotherapy … definition of a single useful cutoff point has proved elusive both because Ki-67 displays a continuous distribution and as a result of analytic and preanalytic barriers to standardized assessment."

BioNTech highlighted that the results of its recent study suggest that its PCR-based approach may be a way to overcome IHC's standardization challenges, potentially allowing testing of Ki-67 alone, without the other markers in tests like Oncotype, to help guide chemotherapy use.

This will require significant further validation though, the authors wrote.

Meanwhile, Hempel said that MammaTyper doesn't directly compete with risk tests like Oncotype or its brethren. Its main position is as an alternative to IHC for rapid and relatively inexpensive assessment of ER/PR, HER-2, and Ki-67 status.

As such, it's not something that clinicians are going to stop needing, he explained.

For example, tests like Oncotype are only indicated for specific subsets of patients. Even just to identify those patients, clinicians first need to test for the markers that MammaTyper or IHC cover.

According to Hempel, the firm is still working on moving from a mostly European market toward global distribution.

Though the process of gaining approval from the Chinese FDA — which BioNTech's partner Shuwen Biotech has been working on — is still ongoing, the company has solidified its position in Europe, Hempel said.

"Based on our distributors we are currently reaching about 40 different countries," he said. Plans to move into the US market are still in place, but that process will be longer-term, he said.