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Insights from the European Cancer Congress 2015 (Vienna, 25-29 Sept.): Dr. Alexandre Irrthum on "Breast Cancer and Molecular Screening"

Intro text: 

 

During the European Cancer Congress, which took place in Vienna from 25 to 29 September 2015, Breast Cancer and Molecular Screening were high on the agenda. Alexandre Irrthum, PhD, ‎Bioinformatician and Cancer Geneticist at the Breast International Group (BIG) Headquarters, participated as an expert to the panel discussion “Molecular Screening Board: Breast Cancer” and he shares his views on the topics that were discussed and their link with the BIG AURORA research programme for metastatic breast cancer.

The session in which you participated was entitled “Molecular Screening Board: Breast Cancer”. Could you explain what this was about?

Sure. The management of cancer has traditionally encompassed multiple medical specialities, and multidisciplinary tumour board reviews, where specialists such as medical oncologists, radiation oncologists and surgeons discuss the best treatment options for their patients, are well established. What is new now is that the falling costs of tumour DNA sequencing have made this technology increasingly applicable in the clinic. Obtaining the mutation profile of a tumour gives the opportunity to use some of the newer targeted therapies that act on specific aberrations (often in the context of clinical trials) but it requires bringing additional expertise in genetics, genomics and bioinformatics to the “molecular tumour board” or the “molecular screening board”. It also comes with new challenges.
 

What are some of these challenges that molecular tumour boards are facing?

The first challenge is to identify the molecular aberrations, known as drivers that confer to the tumour cells their aggressiveness. Some of the genes that are mutated and can be targeted in breast cancer, such as PIK3CA, are almost always mutated in a very limited number of positions, known as hotspots, in the DNA sequence. As these mutations have been observed very frequently, a lot is known about them. By contrast, some other genes that are clinically actionable in breast cancer can be mutated all over their length, and many of the mutations that we found in tumours have not been observed before, and nothing is known about them. One must determine if these variants of uncertain significance are drivers, or just passengers, mutations that accumulate in the genome because the cancer cell has lost its ability to repair DNA accurately but play no active role in the disease. We have a certain number of bioinformatics tools to differentiate the drivers from the passengers based on sequence evolutionary conservation, protein structure and physico-chemistry, and on what is already known about oncogenic drivers. These tools can be very useful, but they are often not sufficiently accurate and must be perfected and validated.
 

Is knowledge about the molecular drivers of a tumour sufficient to decide which targeted therapy a patient might receive?

No. As discussed during this session, knowing the driver mutations is only part of the equation.
Of course, one must first have targeted drugs available for the driver aberrations that are detected in the tumour, and currently there are not enough drugs to propose a targeted therapy to all patients.

Furthermore, inter-tumour and intra-tumour heterogeneity significantly complicates the situation. Some mutations will be observed in all cells of the primary tumour and, for patients with metastatic disease in all the metastatic lesions, but we frequently see sub-clonal mutations that are only present in a fraction of the primary tumour, or are restricted to certain metastatic lesions. At this stage, we know that tumour heterogeneity plays an important role in the response to treatment, but the detailed mechanisms and clinical implications must still be elucidated.

Another complication is that knowing that a specific mutation is a drug response biomarker in a specific tumour type by no means guarantees that the drug will work on the same mutation in another tumour type. A well-known example is the BRAF V600E mutationthat confers exquisite sensitivity to some targeted drugs in melanoma but not in other cancer types. The context where a mutation occurs, including the cancer type and the co-occurring mutations, matters enormously, and sometimes our understanding of tumour biology is just too fragmentary to adequately integrate all these aspects.
 

What other aspects of implementing molecular screening in the clinic were discussed?

The need for standardisation was also addressed. For example, one still needs to agree on a common nomenclature for the levels of evidence of genetic biomarkers in oncology, in other words how we communicate our confidence in the reliability of genetic biomarker information. Different people use different scales for these levels of evidence, making it more difficult to develop a global discussion and reach consensus.

Another aspect that was discussed in the session is that the current DNA-centric approach, while very powerful and very useful, doesn’t give the full picture. Ultimately, it’s at the level of the proteins, the molecular pathways, the cells and the tissues where most of the action happens. If we want to achieve reliable personalised cancer medicine, we will probably have to incorporate more information on the protein level, microenvironment, metabolism, immune system and even tumour architecture. Systems biology and mathematical modelling will also become increasingly important to make sense of this bewildering complexity.
 

What impact will the AURORA programme have on the way molecular information is used in the clinic?

AURORA is innovating in the way the molecular tumour board is implemented. Having more than 80 sites that will ultimately participate in the programme prompted us to establish a central molecular tumour board that comprises more than fifteen experts in oncology, genetics and genomics, pathology and bioinformatics. This board seeks to provide additional information on the functional and clinical consequences of the molecular aberrations. It meets every two weeks via a conference call to discuss the findings and seek consensus on the information that should be reported to the clinicians. I think that this is an interesting model for molecular tumour boards in the future.

Even more importantly, the basic knowledge about metastatic breast cancer biology coming out of AURORA will be very useful to guide the decisions of molecular tumour boards in the future. In particular, a better understanding of how tumour heterogeneity and tumour evolution impacts treatment will be a major advance. And lastly, the clinical trials for targeted therapies that will be associated with AURORA will generate important information about the clinical utility of specific genetic biomarkers.

The final take home message of the session was that the enthusiasm for molecular screening is fully warranted, but also that one should keep in mind that its clinical implementation comes with many challenges and still largely belongs to the investigative realm. Ambitious initiatives such as AURORA will be crucial to bridge the remaining gap with the clinic.