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Vol 22, No. 01, January 2018   |   Issue PDF view/purchase
The genomic landscape of cancer
Cancer is an incredibly complex series of diseases and the emerging fields of comprehensive genomic profiling and molecular information are set to play a fundamental role in how cancer medicines and diagnostics solutions are developed and used, says Roche and Foundation Medicine at a global media event. Lim Guan Yu reports from Boston.

As we see how cancer is developing in the world, we are starting to realise cancer is impacting all of us. We may not receive a cancer diagnosis personally, but we all know someone who has been impacted by cancer. We have made tons of progress on cancer treatment, and while we haven’t cured cancer, we have more people living and surviving with cancer now. But this comes with another set of challenges. Josh Lauer, lifecycle leader, Roche said, “For some patients, cancer is not just an acute disease, but also becoming a chronic disease”.

Which is why we’re here in Boston, US, to learn more about cancer. Organised by Roche and Foundation Medicine, the event attracted journalists all around the world. This year’s theme centered on transforming and shaping cancer care, with a focus on personalised healthcare and the pioneering science of genomics and comprehensive genomic profiling in oncology.

At the 13th Annual Personalized Medicine Conference, organised by the Personalized Medicine Coalition and held concurrently at the Harvard Medical School, Edward Abrahams, president of the Personalized Medicine Coalition defined personalised medicine. He said, “Personalised medicine is an evolving field in which physicians use molecular diagnostic tests to determine which medical treatments will work best for patients. By combining the data from those tests with an individual’s medical history, circumstances, and values, healthcare providers and patients can develop targeted treatment and prevention plans”.

Evolution of genomic science

In the past, cancer was viewed simply. Tumours were diagnosed by the origin of the organ in the body they came from. There were no personalised treatment options for patient. Chemotherapy was essentially the standard treatment and there would be differences in chemotherapies for different tumour types, with no real personalisation, no real biomarkers.

Cancer is no longer seen as just one disease, but a collection of hundreds of diseases, each with unique characteristics and genetic make-up (genomic profile). The number of disease-driving mutations that can now be detected and potentially treated has increased greatly over the years due to our greater understanding of cancer biology and treatment. For example, lung cancer was once thought of as a single disease, but now can be categorised into over 10 distinct subtypes based on the molecular alternations (mutations) that drive its growth.

This shift in understanding has been in a large part due to the progress made in the field of DNA sequencing over the last three decades. With the emergence of DNA sequencing techniques in the late 1970s, led by Prof Frederick Sanger, scientists gained the ability to sequence a full genome in a reliable and reproducible manner. ‘Sanger sequencing’ became the most widely used sequencing method for the next two decades, and, in fact, is still in use today for smaller scale projects.

Then in the early 2000s, the Human Genome Project necessitated a ‘next-generation’ transformation in the way scientists tackled DNA sequencing due to the massive volumes of DNA involved and deadlines associated with the Project. In 2003, it took over two years and three billion Swiss Francs to sequence the human genome. Today, an individual’s full genetic sequence of three billion DNA base pairs (genome) can be achieved in a few hours for a fraction of the cost, using a method called ‘next generation sequencing’.

In the past decade or so, we had been living in a paradigm – one cancer population, one biomarker, one drug. Now, with the advancement of sequencing and other technologies, there is an increased complexity in cancer care. We learned about biomarkers that identified subsets of cancer populations and these subsets would respond differently to treatments because their cancer was driven by different underlying factors. It is a major advancement for patients as this means there is a lot more options for treatments.

But this is also a challenge. Josh commented, “We can no longer operate in the traditional paradigm of making large drugs for large populations. It requires pharmaceutical companies to tailor their business models to deliver personalised treatments to smaller populations. It is a great opportunity for patients, but it is a challenge to make it work in practice”.

DNA sequencing in cancer care today

There are four types of genomic alterations that drive cancer development and growth.

Analysis of an individual’s cancer to establish what unique DNA alterations drive their disease is key to the diagnosis and optimal management across many types of cancers. This knowledge impacts on treatment decisions and can lead to more personalised care for patients. There are several types of tests currently available to help identify these alterations and deliver more personalised care:

  • Single marker tests identify one or two classes of alterations across a single pre-specified gene commonly associated with cancer. These tests are often cancer type-specific. In colorectal cancer, for example, one test may detect mutations in K-Ras and a second test may detect mutations in BRAF. These routine molecular tests have been used for decades and will continue to play an important role in cancer diagnosis.

However, a limitation is the lower sensitivity of certain molecular testing platforms can often lead to false negative results. This results in preventing the consideration of life-extending, genomically-matched treatment and/or clinical trial participation.

  • Hot spot tests utilise next generation sequencing to identify a limited range of pre-specified mutations across several genes, but may not detect all classes of genomic alterations. For example, these tests may simultaneously detect K-Ras and BRAF mutations in a single test. However, many clinically-relevant genomic alterations may still be missed by single marker and/or hot spot assays. Because they examine a narrow set of genes, they are unable to detect all four types of alterations (base substitutions, insertions/deletions, copy number alterations, and rearrangements).
  • Comprehensive genomic profiling utilises next generation sequencing to identify all four classes of alterations across hundreds of genes known to drive cancer. Therefore, these tests are often described as ‘pan-cancer’, or applicable for use across any type of cancer. Continuing with the example of colorectal cancer, the test may simultaneously identify K-Ras and BRAF mutations, as well as all other clinically relevant genomic alterations (such as MET or mTOR), in a single test. It helps resolve the unmet need for a comprehensive, high quality diagnostic tool, and this comprehensive profiling is what will enable precision medicine.

As our knowledge continually evolves and further new molecular drivers of cancer are found year on year, due to its sensitivity, accuracy and complete approach, comprehensive genomic profiling offers cancer patients the best chance of truly personalised cancer care as it identifies an increased number of relevant targeted treatment therapies, and clinical trials, compared to other methods.

A partnership to fight cancer

In 2015, Foundation Medicine (FMI) and Roche entered into a strategic collaboration to transform and improve patient care in oncology. Roche acquired majority interest in FMI, but FMI still maintains independent operations. This collaboration will help to commercialise future co-developed products outside of the US and enhance R&D capabilities. The collaboration also includes development of diagnostic assays based on next generation sequencing, which enables multiple tests to be performed on limited amounts of cancer tissue. New product development collaborations include circulating tumour cell (ct) DNA, cancer immunotherapy and companion diagnostics. ctDNA, and other product developments are really products of collaboration. FMI develops products independently and Roche is primarily involved in commercialising FMI's service outside the US.

A key focus of this partnership is the commercialisation of FMI products outside of the US. FMI’s comprehensive genomic sequencing assays: FoundationOne and FoundationOne Heme, have been launched to patients in the US and several other countries. FoundationACT, a blood based (liquid) biopsy or ctDNA assay, is currently available in the US and a few other countries including Singapore and Hong Kong in the Asia Pacific region..

Using a small biopsy sample from patients, FoundationOne applies next generation sequencing and a proprietary analysis pipeline to identify all four classes of genomic alterations across 315 cancer-related genes known to be drivers of solid tumours. FoundationOne Heme is designed to analyse and interpret DNA sequence information from 406 genes and RNA sequence information from 265 commonly rearranged genes in haematologic malignancies and sarcomas. FoundationACT uses next generation sequencing to analyse 62 cancer-related genes within a blood sample.

By analysing all four of the genomic alterations known to be associated with cancer, FMI services can identify up to three times as many targeted therapy options for patients, compared to standard hotspot assays, which typically identify just one or two types of clinically relevant alterations. To date, more than 160,000 patients have had the opportunity to benefit from FMI services.

What’s next

Cancer is undergoing a transformation shift, from being a disease of the anatomy, to being a disease of the genome. The advances in cancer science are driving a future where cancer care is becoming increasingly personalised. In the past, where they were few targeted therapy trials and little knowledge of immunotherapies in precision medicine, there are now about 600 targeted therapies in development, with thousands of clinical trials, and a rapid adoption of immunotherapies. Where oncology clinical trials used to be siloed within academia and biopharma companies, now collaborative basket, umbrella, J.I.T., and community based trials are emerging. No one organisation can make personalised healthcare happen on its own; there needs to be collaboration across the globe to make this a reality.

Genomically-driven targeted treatment is often less toxic, more efficacious, and potentially less costly than traditional cytotoxic chemotherapy. Josh concluded the session by saying, “Cancer is a disease of the genome, and profiling is the future”.

Dr Steven Kafka
President, chief operating officer, Foundation Medicine

Courtesy of Foundation Medicine, Inc.
Images by Jon Chomitz Photography

Walk the talk

Says Dr Steven Kafka, president and chief operating officer of Foundation Medicine, on what it means to be a leader.

As president and chief operating officer of Foundation Medicine, what are your current priorities?

One of the key things we're working on is a growing our core clinical business both in the US and globally, in partnership with Roche to advance the progress of personalized cancer care and drive access to precision medicine.

One of the key priorities for us is taking our flagship assay through the FDA approval process (it’s called the Parallel Review program). This will greatly impact how comprehensive genomic profiling is implemented into clinical care.

Another priority is the commercialization of FMI’s products outside of the US, like the FoundationOne (for solid tumours), FoundationOne Heme (for haematological cancers and sarcomas), and FoundationACT, a blood-based (liquid) biopsy. With this partnership with Roche, we can leverage on both companies’ strengths to improve clinical practice for the benefit of patients globally.

How do you manage to keep your employees keen and motivated?

We’re lucky to have a team that is incredibly passionate in their mission to transform cancer care. Most of the people in our company has been touched by cancer in some form or another, whether they know a family member or friend who has had cancer, and that keeps them motivated to have a big impact on others.

I think many people are also motivated by the innovative space that we work in. We have scientists who are probably excited by all these biology and technology, and all these can be part of creating the next generation of comprehensive genomic profiling.

What advice would you give someone going into a leadership position for the first time?

I think that the most important thing you can do as a leader is to create a sense of vision. A culture that really supports the individual’s aspirations and growth, and their ability to contribute to our organisation. We ask people to do difficult things at work, and work really hard, they need to know why, and where we're heading. I think that's one of the most empowering things as a leader, to be supportive.

Can you share one of your proudest moment in FMI since joining in 2013?

There are many, it's hard to choose one. I think one thing I’ll remember is creating this partnership with Roche. It's a unique and transformative partnership, it's having a tremendously accelerated impact on our ability to bring genomic profiling and its impact into the market place.

What is the best leadership advice you have received?

I'm going to say, 'walk the talk'. I have had mentors who have been great leaders by example. Effective leaders will readily jump in and help, both in creating the environment and helping to solve problems themselves, instead of expecting others to do so.

Can you name a person who has had a big impact on you?

My dad, who sadly passed away from small cell lung cancer three years ago. He was very sick, yet very keen on getting his tumour profiled using the FMI assay. We unfortunately didn't find anything that was going to be useful for him directly. But he said, "That's okay, what you're learning from my case, is going to help someone else." I think my dad was pretty much a selfless guy and that helps me to go through the hard days at FMI too, keeping in mind that there is always a bigger purpose in life.

Bonnie J. Addario
Founder, Bonnie J. Addario Lung Cancer Foundation.

A breath of hope

We spoke to Bonnie J. Addario, a lung cancer survivor and founder of the Bonnie J. Addario Lung Cancer Foundation, when she discovered she had lung cancer, her treatment process and how that changed her life.

“I had pain across my chest and was misdiagnosed for almost a year. No one offered a CT scan. I went out and paid for my own full body scan and they found my cancer. It was a relief and a shock to discover what was causing my pain”, said Bonnie J. Addario. The founder of the Bonnie J. Addario Lung Cancer Foundation (ALCF) discovered she had lung cancer in 2004. It took her almost two years to become a survivor of Stage 3B lung cancer. As part of her cancer treatment, she undergone many rounds of chemotherapy and radiation. All of that did not come without issues that she still lives with today. Bonnie elaborated, “One vocal chord, oesophagus issues, pulmonary hypertension and necrosis. At one point, the blood stopped flowing to my hip and femur which resulted in both bones fracturing. A titanium bar was placed from my hip to the femur with 9 bolts holding it in”. That left her with a 6-month recovery period. She then suffered two pulmonary embolisms from that surgery. It was not an easy period, but Bonnie was determined.

With the determination and time during her recovery phase, she researched on lung cancer. She was appalled and discouraged with the information associated to the disease. Bonnie feels strongly with the stigma associated to lung cancer, “Lung cancer patients are not any different than any other cancer patients. Smoking is the highest cause of heart disease and vascular disease, and also thirty other cancers. Lung cancer isn’t and always associated to smoking”. The lack of funding for lung cancer research is also far from other cancers (breast, colon and prostate), considering lung cancer affects the most number of people globally. Bonnie is struck by the injustice related to lung cancer and treatment and the amount of people dying because of the lack of concern, care and funding.

That drove her to start ALCF in 2006, to raise awareness and empower patients and their families in the fight against lung cancer. Today, ALCF is the largest lung cancer foundation in the world and has raised more than $30 million for lung cancer research and related programmes.

Bonnie’s foundation is constantly working on achieving their goals of eradicating lung cancer through research, early detection, education and treatment. Their work never stops. When Lung Cancer Awareness Month fell in November, Bonnie shared a programme organised by ALCF. ALCF carries out a program called ‘Bring Hope Home’ where they visit a lung cancer patient in 20 different cities in the US and do something for them during the Holidays, that they are unable to do themselves. It can be trimming a tree, cleaning the yard, cooking a holiday meal, etc.

More than 10 years after ALCF was established, we asked Bonnie whether her priorities have changed from 2006 to the present; she has this to say, “My priorities will not change until the survival rate for lung cancer in equal to breast, colon and prostate cancer. I am encouraged by Personalized Medicine and Comprehensive Genomic Profiling. These will change the way we think about all cancers in the next decade to a world of research that is entirely different. We will be looking at cancer and what causes it and can treat it in a very laser focused way rather than throwing spaghetti at the wall”.

Dr Vincent Miller
Chief medical officer, Foundation Medicine.

Courtesy of Foundation Medicine, Inc.
Images by Jon Chomitz Photography

Precision medicine is exhilarating

Dr Vincent Miller, chief medical officer of Foundation Medicine shares the future of precision medicine in oncology and whether it will become the standard care for patients.

You started your work in lung cancer and you're considered an expert in this field. Was there a defining moment that made you go into the study of lung cancer?

I chose oncology in general, and lung cancer specifically, because the field and disease respectively were so challenging - even a modest contribution would be meaningful. I also recognized oncology was a young discipline and DNA sequencing was in its infancy so there was reason to hope we would have opportunities for progress.

In your opinion, what are the current, major unmet needs in lung cancer research/therapy?

In the past several years, treatments such as targeted therapies and immunotherapy have fundamentally changed how we approach treatment in lung cancer. While we have seen dramatic survival outcomes in many people, we also recognize that these treatments only work in a subset of patients and many treatments which are often initially successful ultimately fail. Therefore, we need more ways to identify those most likely to benefit from these approaches to care.

A major step towards this goal occurred recently when the US Food and Drug Administration (FDA) approved our diagnostic test called FoundationOne CDx, the first and only broad-based genomic profiling test for all solid tumors incorporating multiple companion diagnostics.

FoundationOne CDx is designed to identify certain patients with non-small cell lung cancer (NSCLC), melanoma, colorectal cancer, ovarian cancer, or breast cancer who may benefit from one of 17 on-label targeted therapies. In addition, it is a comprehensive genomic profiling (CGP) test that includes genomic biomarkers to help inform the use of other targeted oncology therapies, including immunotherapies and provides relevant clinical trial information to help guide the decisions of treating physicians.

Precision oncology has many genomic alterations and targeted-therapy combinations which cannot be addressed with historical clinical trial designs. What is Roche/FMI's strategy in designing clinical trials for precision oncology?

Novel clinical trial design is critical in the development of targeted therapeutics tied to cancer genomics. Historically, most Phase III trials in oncology compared various chemotherapy regimens with little or no biomarker driven treatment selection. As such, effect size was often quite modest and large trials were needed.

More recently, with the use of predictive biomarkers such as BRAF mutations in melanoma or ALK rearrangements in non-small cell lung cancer and respective targeted therapeutics, agents have been approved on far smaller sample sizes and in some cases even on the basis of high response rates and long PFS seen I Phase I trials.

Thus, in the era of precision medicine, smaller more nimble trials with routine use of robustly validated genomic profiling can substantially speed drug development. Given the ability to more routinely characterize the genomic alterations in an individual with advanced cancer, an era of precision medicine has indeed arrived.

At some level, each patient is different and certain driver genomic alterations or conditions such as NTRK fusions may occur in well less than 1% of screened patients. Nonetheless, it is essential that we identify and treat such patients with cognate targeted therapies.

Given that the likelihood of a given critical alteration may be 1-2% but that multiple such alterations can exist across a population, a mandate for broad based profiling of all known cancer genes from a single assay and a broad swath of clinical trials is essential. Clinical trial efforts such as LUNG-MAP, TAPUR and NCI-MATCH, all of which employ comprehensive genomic profiling to some degree if not exclusively, and all of which contain multiple therapeutic arms defined by predictive biomarkers increase the likelihood of a matched therapy for any given patient.

What do you think is the future of precision medicine?

Today, we recognize that cancer is driven by many different genomic alterations, and each person’s cancer has a different genomic profile. Genomic testing is important to identify patients that may respond to certain treatments. However, traditional genomic testing (hotspot testing) often tests for a single gene or small number of genes at one time. This can exhaust precious tissue or require additional biopsies if multiple tests are needed.

Comprehensive genomic profiling (CGP) – which tests for hundreds of genes in a single test -- can help physicians make more informed choices by giving them a better picture of a person’s unique cancer. By identifying potentially targetable mutations within a single assay, our assays help ensure that patients receive the optimal treatment as soon as possible. And in some cases, it may identify novel mutations which we can use to relate to treatment response and design better treatment protocols in the future.

This approach is becoming increasingly common in the clinic. For example, professional clinical care guidelines in the US for non-small cell lung cancer recommend molecular testing of certain genomic biomarkers that can help guide treatment with targeted therapy.

I believe CGP is a critical piece of the future of personalized medicine and will help patients, physicians and caregivers navigate the diverse and complex therapeutic landscape of treating cancer.

While CGP is essential to successful deployment of precision medicine other types of assays including gene expression profiling or RNA sequencing, monitoring assays, assays to detect minimal residual disease after definitive treatment and others will almost certainly be needed to allow longitudinal care of patients with cancer in an era of precision medicine.

Will precision oncology become the standard care for patients with advanced cancer in the future?

The discovery of genomic biomarkers has transformed how we treat cancer, and with these advances we believe that personalized medicine can and should be the standard of care in clinical practice. Recognizing the importance of such molecular insights will be critical for implementing comprehensive genomic profiling (CGP) more routinely into clinical care and expanding access.

Recent developments in the cancer treatment landscape also underscore the importance of CGP. The FDA approval of the immunotherapy pembrolizumab for all microsatellite instability (MSI) high tumors was an historic decision and demonstrates the importance of probing for genomic biomarkers to identify patients who may benefit from treatment.

As mentioned previously, our recent US FDA approval of FoundationOne CDx through the Parallel Review program, which included a draft National Coverage Determination, represents an important step in expanding access to precision medicine. Continued advances like this will be important for elevating the role of CGP.

Today Foundation Medicine’s molecular solutions are empowering thousands of oncologists as well as our biopharma partners to help inform treatment and drug development. In addition, we continue to evolve and improve our genomic testing and interpretation of results to make it more straightforward for oncologists and pathologists. Together, this is bringing us one step closer to making CGP a standard of care.

If you had one word to describe precision medicine, what would you say?


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