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Gene-based breast cancer diagnostic test in the spotlight

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Last June Prof. Laura van ’t Veer from the Netherlands Cancer Institute (NKI) and her team received the prestigious European Inventor Award 2015 for the invention of ‘MammaPrint’. This gene-based diagnostic test predicts the risk of recurrence for patients with breast cancer after initial surgery and helps doctors to identify which women do need chemotherapy due to the tumour aggressiveness and which women can be spared this additional treatment and its side-effects. Interview with the inventor:

How did the idea of this 70 breast cancer genes test – or MammaPrint – come about? What was your primary objective?

Early 2000 at the Netherlands Cancer Institute, we had the opportunity to work with a small start-up company based in Seattle, US, that had developed a technology where one could analyse the activity of all genes of a cell in just one experiment. This microarray technology has revolutionised molecular biology research and we took upon us to see if we could use it for pre-menopausal breast cancer to find the genes whose activity would be related to either ‘no breast cancer recurrence’ or ‘recurrence within 5 years’. We wanted to use this knowledge to understand who needed chemotherapy, and for whom the risk of recurrence was so low that they could safely forego chemotherapy and not suffer from the side effects without benefits.

 

What challenges did you and your team encounter in developing this test?

No one had ever done such a study before so we had to develop all the analytical tools, now widely used in bioinformatics, to find the gene pattern related to recurrence. It was also interesting to see, when working with physicists and clinical statisticians, that the best mathematical answer is not the same as the best clinically useful answer. I found it exciting to be in the middle of those groups and make them aware of what we were really after, the best predictor for a patient.

'We are looking at the true biology of the disease, unperturbed by drug treatments.'

The MINDACT study, sponsored and run by the EORTC under the BIG umbrella, aims to evaluate the added value of the MammaPrint test to the traditional method of assessing risk of breast cancer recurrence, and consequently the need for chemotherapy after surgery. The results are expected either later this year or at the beginning of next year.  Why was it so important to do this trial?

MINDACT will be the first prospective clinical validation of a genomic tool ever, putting the test through the comparison with standard of care in the ‘real clinical world’. In addition, MINDACT is a goldmine for translational research. Beyond MammaPrint, we are building a biospecimen bank, and with full genome expression microarrays we could even learn more. The MINDACT study group, which was created 10 years ago, includes experts from various disciplines representing the 9 participating countries.

In a few words, how does the MammaPrint test work?

The MammaPrint test is done on a small part of the tumor tissue, either fresh frozen, or embedded in paraffin. We extract the active genes, the RNAs, and measure their level of activity on a microarray that includes the 70 genes that constitute MammaPrint. We compare the activity of these genes with the prognostic gene activity pattern that was discovered in the original tumor series. If the current tumor 70 gene expression looks like the original pattern where patients did not get a recurrence we call it ‘low risk’. If it resembles the activity pattern of patients who did develop a recurrence, we call it ‘high risk’. There is a lot more bioinformatics involved, but basically it is nothing more than comparing the tumor tissue to the first established patterns of MammaPrint.

What is unique about this test, when compared to others?

The 70 genes were identified without including any predefined knowledge, we could thus find the most optimal predictive gene set. Furthermore, the patients whose tumors we analysed had not received any adjuvant treatment (chemotherapy or hormonal therapy given after surgery), which means that we are looking at the true biology of the disease, unperturbed by drug treatments.

'I truly hope that all the publicity around it will make more breast cancer patients aware that this type of test is available and that they can benefit from it.'

Did your invention lead to the development of similar tests for other types of cancers?

To be able to provide the MammaPrint test to patients we founded out of the Netherlands Cancer Institute the start-up company Agendia in 2004. There we developed a test that recognizes subtypes in colon cancer and offers guidance to patients regarding the type of chemotherapy to receive. This is currently being tested in Horizon 2020 EU-supported clinical trials.

Since the introduction of MammaPrint on the market in 2004, we have seen the emergence of other technologies, such as next-generation sequencing, which enable an in-depth analysis of the human genome.  How do these technologies impact on the development of novel diagnostic tests in breast cancer?

It is my (maybe a bit biased) view that for now gene expression microarrays are still more robust and represent thus a more suitable diagnostic test. Next generation sequencing for gene expression is a great new discovery technique. It is used as a diagnostic tool for DNA gene mutation testing and is useful, for example, in metastatic breast cancer.

Finally, congratulations on being a recipient of the European Inventor Award 2015 (SMEs category). How did this make you feel and what is special about this for you and your team?

I am thrilled and honored to have been awarded the European Inventor Award 2015. It is the biggest honor one can get in the world for an invention. I truly hope that all the publicity around it will make more breast cancer patients aware that this type of test is available and that they can benefit from it.


Prof. van ’t Veer is affiliated with the Netherlands Cancer Institute (NKI) as visiting scientist and now fulfills a position of Professor at the Department of Laboratory Medicine at the University of California in San Francisco, where she lives.  

Read more on the European Patent Office (EPO) website : https://www.epo.org/learning-events/european-inventor/finalists/2015/vantveer.html

Read more on the MINDACT trial