Comprehensive Genomic Profiling at the Cusp of Modern Precision Oncology: Interview with Dr. Nicolas Martin 

Genetic testing has forayed into various therapeutic areas and it is starting to influence the field of oncology in a big way. “Roche’s acquisition of Foundation Medicine and its vision for personalized medicine shares its origin in the realization that in the last hundred years anatomical and histological classification of tumors is going through paradigm shift toward a pan tumor molecular classification. It is now clear that cancer originates from an accumulation of genetic alterations over a period of time and it is important to identify targetable driver mutations” says Dr. Nicolas Martin, International Scientific Lead at Roche Foundation Medicine. He firmly believes that comprehensive genomic profiling is the future and it definitely outperforms existing technologies.

Current trends in genetic testing around the world

Dr. Nicolas Martin started the conversation by giving his perspective on the current trends in cancer clinical practice. He observes that there is an increasing appetite among physicians to get a clearer picture of the tumor they are treating, and the standard methodologies available to them such as immunohistochemistry, FISH, and PCR have both pros and cons. Next Generation Sequencing (NGS) opened up new avenues, especially in the last ten years with the ability to perform a single test and obtain data of over 300 genes. However, Dr. Martin feels that FoundationOne CDx, Foundation Medicine’s Comprehensive Genomic Profiling (CGP) test could be a potential game changer because it’s really getting embedded into clinical practice in the USA. The genomic biomarker assay is the first FDA-approved broad companion diagnostic and it also received initial National Coverage Determination (NCD) from the Centers for Medicare & Medicaid Services (CMS). 

Secondly, liquid biopsy is becoming more common in practice, especially in lung cancer, and in fact last year the company launched its new liquid biopsy for solid-tumors, FoundationOne Liquid. Now the challenge ahead for his company is to make these technologies accessible to patients around the world. “In Asia Pacific like most places around the world, the test is paid out of pocket by the patients. In countries like Taiwan and Australia, which have a central government healthcare system, we are working with all the stakeholders toward making CGP available for patients with advanced cancers. In some countries, private insurance companies are open to cover CGP testing. At the end of the day, we all want to get the best outcome for cancer patients,” he explained.

When the conversation was steered more towards the trends in Asia, Dr. Martin said like everywhere else, single-molecule testing is widely prevalent. In Southeast Asia, especially in the case of lung cancer, people prefer screening for EGFR mutations using standard technologies, because it has captured 60% – 70% of the patients. But if that does not yield results, given the opportunity, some people have been fortunate to avail the services of comprehensive genomic profiling tests. He says that they have observed an increase in the use of Foundation’s products in the region over the past three years since the launch.

Comprehensive Genomic Panel (CGP) in clinical practice and its advantage over existing technology

When asked to elaborate on the CGP technology, Dr. Martin explained that, although there can be different perceptions of genetic profiling among people, their company sees comprehensive genomic profiling as a test examining all the different classes of cancer-relevant mutations taking the entire coding region into account. He uses an interesting analogy to describe the evolution of molecular profiling methodologies by classifying them into three different categories. Standard methodologies such as IHC, FISH or PCR belong to the first category, which tests for a known mutation with specifically designed primers. He compares it to using a single flashlight inside a dark room. The hot spot NGS panels belong to the second category where one could identify multiple pre-specified mutations occurring in a limited area. This is similar to using multiple flashlights and one learns more about the genome. However, CGP belongs to the more comprehensive third category, in which the entire coding region of the gene is tested. It is an unbiased approach to find new clinically relevant genetic alterations that were previously unknown. Therefore, CGP is not a flashlight, but it’s more akin to switching on the ceiling light and seeing everything. “This gives a much clearer picture of your environment and what you have to deal with” he added.

When prodded about its use in clinical practice, Dr. Martin emphasizes that Foundation Medicine is a very academic-oriented company that has published more than 400 peer-reviewed publications in collaboration with premier research institutions such as the Memorial Sloan Kettering Center. He points out that, there have been studies involving patients with lung adenocarcinoma, where CGP has helped them find some clinically relevant mutations that were previously unknown and has aided in their understanding of resistance mechanisms.

However, he recognizes that establishing newly identified mutations to be clinically relevant is another challenge. Although CGP is the first step, the second step is to link it to an outcome. The field of oncology has recently adopted clinical trials called basket studies that include patients with a certain genetic mutation regardless of the site of origin of cancer in the body. “An umbrella screening protocol is performed initially, and then based on the mutations identified, you get a small basket to see proof of principle. But as we learn about it, we might find more and more mutations which can be extremely rare” he added. Nevertheless, he accepts that the way forward to confirm clinically relevant rare mutations is the use of real world data that links genomic data with patient outcome data.

Validation of new technologies and their importance

When probed about the importance of validations, Dr. Martin, mentioned the high standard to which FoundationOne CDx adheres. Validations are of two types, analytical validation, which refers to finding alterations that are claimed, and clinical validation, which is solid data that demonstrates that patients with certain biomarkers undergoing targeted treatments are likely to respond to it. The latter is the highest level of validation. 

It is really hard for any new drug in the market to get approved by the FDA or any regulatory body. Eventually, when it does, it is often linked to a recommended diagnostic test. Therefore, there is a certain quality that is expected of companion diagnostics. According to the New York state guidelines, it is required that a service provision is validated with a minimum of 50 patient samples and a minimum of 10 positive samples for each type of variant. FoundationOne CDx has significantly raised the bar and has been FDA approved based on stringent analytical and clinical validations of more than 6,300 samples. It is important that diagnostic tests are maintained at high quality as the drugs themselves, so it can be relied upon day after day. “Foundation Medicine has been very transparent, publishing everything, and the methodology has been published in Nature Biotechnology a few years back, and similarly the validation data of Foundation liquid was published last year as well”. At the moment, FoundationOne CDx has been approved as a companion diagnostic for 18 FDA-approved targeted therapies.

The crucial role of bioinformatics in NGS data

Dr. Martin acknowledges that high throughput technology produces a huge amount of data, and defining different variants other than the usual substitutions and indels, requires some expertise. Foundation Medicine has been the pioneer in terms of using Formalin-fixed, paraffin-embedded (FFPE) samples, and applying it to the CGP, and have developed the whole pipeline of translating the data from wet lab to bioinformatics. The clinicians today want a clear, thorough report with information about mutations that can be targeted. So, we have perfected our methodologies in the past ten years and one needs to be specialized to use CGP.

He also clarified the technology is quite different from whole genome sequencing, because it mostly sequences the coding and some intronic regions of genes identified to play a role in cancer biology. He states that some commercial providers address their NGS hot spot technology as comprehensive profiling but their technical specifications mention that they sequence thousands of hotspots. It still means that many important regions could be missed while Foundation’s CGP technology is truly comprehensive without blank spots.

Actionability in comprehensive genomic profiling

Dr. Martin concluded the interview by saying that it’s a very exciting time to be in the field of oncology. Earlier there only existed a single gold standard chemo regimen for cancer treatment, but now one can use comprehensive genomic profiling. Besides, there is this concept of actionability, which helps in informed clinical decision-making by providing molecular insights. In some instances, these insights can identify suitable targeted therapies or immunotherapies, and in others inform on the prognosis.

Dr. Martin predicts CGP becoming a standard diagnostic option in the future by giving an example of a recently published precision oncology trial. The I-PREDICT study conducted at the University of California, San Diego subjected 83 cancer patients to genomic profiling. Subsequently, a Molecular Tumor Board (MTB) comprising of a team of experts helped physicians in tailoring combinatorial therapies that targeted as many mutations as possible. The study proved to be very promising for most patients, reiterating that comprehensive genomic profiling technologies are here to stay. In the future, it would not be a surprise if clinicians suggest such tests for every patient.

code : PM-TW-3340-12-2019 

Edits by Rajaneesh K. Gopinath

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