Rare Cancers and the Role of Biomarker Testing In Addressing Their Challenges

September 30, 2020, marks the 2nd annual Rare Cancer Day. It was created by the Rare Cancer Coalition under the auspices of the National Organization for Rare Disorders (NORD). This coalition of 27 rare cancer-specific organizations works to bring attention to the issues people living with rare cancers face such as late diagnosis and misdiagnosis, as well as broader issues such as lack of research interest and drug development. This year’s theme focuses on the role that biomarker testing can play in addressing diagnostic challenges as well as in developing and accessing targeted therapies.

What are rare cancers?

Rare cancers are tumors or blood cancers that occur in a small proportion of the general population. The definition of how small this proportion is varies. The National Cancer Institute (NCI) defines rare cancers as those that are newly diagnosed in fewer than 15 per 100,000 people per year. The International Rare Cancer Initiative (IRCI) defines them as cancers that are newly diagnosed in fewer than six per 100,000 people per year. These cancers can differ widely from each other and may occur in various organs. Collectively rare cancers account for 22% of cancer diagnoses globally with 198 cancers counted amongst them. This large group of cancer patients face significant diagnostic and therapeutic challenges because their individual cancers place them in very small patient populations.

SOURCE: Cancer Council

What are the challenges for patients with rare cancers?

Clinical research into rare cancers

As a result of small patient numbers, rare cancers tend to receive less attention from researchers. This is because the scientific convention and, often, regulatory authorities require that a drug’s effectiveness be proven via clinical trials conducted in a large number of patients. Compared to more common cancers, there are far fewer clinical trials for rare cancers. Trial design for rare cancers is often difficult and costly. In addition, these trials take longer because it is harder of find an adequate number of patients. Clinical research adds to a critical body of knowledge about rare cancers and enhances clinical practice. Low prevalence rates mean that clinicians do not often see these rare cancers. As a result, they may not clinically suspect rare cancers when the patient presents with unfamiliar signs and symptoms. This can delay definitive diagnosis as well as treatment. Lack of clinical information, such as treatment protocols or society guidelines may further delay care after patients have been diagnosed.

Drug development for rare cancers

The high cost of developing investigational new drugs for rare cancers has led to pharmaceutical companies shying away from this sub-group of cancer drug development. This type of drug development is not commercially viable because of the small number of patients. In response, regulatory authorities have made efforts to incentivize companies to investigate and develop drugs for rare cancers. This is done through initiatives such as the FDA’s Orphan Drug Designation Program. An “orphan drug” is one that is developed for “orphan diseases”. These are rare diseases that have not been of interest to pharmaceutical companies because drug development does not have clear not financial benefit. Governments, acting in the public interest, give developers of orphan drugs financial incentives such as faster pathways to marketing approval or longer periods of exclusivity. While it is the case that this approach has yielded results, much more is needed to help the many patients with rare cancers who remain without any treatment options.

Misdiagnosis of rare cancers

Traditionally cancers have been definitively diagnosed by obtaining a tissue sample of adequate quality and then examining it under a microscope. This is known as histopathological examination and is performed by pathologists — physicians who specialize in examining tissues from the body to make definitive diagnoses. They are trained to identify cancers by examining the cells in the tissue sample as well as looking at how the cells are arranged within it. Lack of experience with rare cancers sets up a situation where pathologists may fail to make the correct diagnosis. While histopathological examination can also have limitations when diagnosing common cancers, it still remains the gold standard diagnostic technique for many cancers. However, techniques are now being developed that do not rely on the human eye and do not necessarily require a tissue sample of a particular size and quality. These techniques rely on testing for biomarkers specific to the tumor’s cells that are obtained directly from the tumor or from another source such as blood. As is often the case with an emerging field, the terms and definitions used to refer to these new biomarker testing techniques are evolving. Before looking at impact of this emerging field on rare cancers, it is important to give some context and clarity to the terminology used to describe it.

Patient advocacy groups are calling for the term ‘biomarker testing’ to be adopted.

What is biomarker testing and how is it used in precision medicine?

To understand biomarker testing and the role it can potentially play in addressing the challenges of rare cancers it is useful to first briefly discuss the concept of precision medicine.

The Precision Medicine Initiative uses the following definition:

“Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.”

Within the context of cancer in general this means using diagnostic techniques that identify characteristics (e.g. gene mutations) that are specific to individual cancer. This focus on specific characteristics is then carried over into developing treatments that specifically target individual cancer’s characteristics, potentially resulting in greater effectiveness and fewer side effects. The term “personalized medicine” is sometimes used to refer to this approach but it is less favored. Reason being that it may create the incorrect impression that the approach is focused on the individual person as opposed to the person’s individual cancer.

There is also some variability around terms used to describe diagnostic techniques that are used in precision medicine. The existence of multiple terms has led to confusion among patients and these potentially pivotal diagnostic techniques are underutilized. A multi-stakeholder initiative called the Consistent Testing Terminology Working Group recently developed recommendations regarding the terms used to describe testing in precision medicine. Clinicians, pathologists, drug developers, and patient advocacy groups contributed to the working group’s deliberations and white paper which noted:

“‘Biomarker testing’ was selected as the preferred term for tests that identify characteristics, targetable findings or other test results originating from malignant tissue.”

The definition above includes:

• Targets that are genomic i.e. molecules or proteins produced as a direct result of mutations or alterations in the patient’s genes.
• Targets that are non-genomic i.e. tumor-specific molecules or proteins that are produced as a result of the tumor but are not as a direct result of a gene mutation or alteration.

Terms such as “genomic testing”, “molecular profiling”, “tumor profiling” and “tumor sequencing” are currently used interchangeably to describe testing within the context of precision medicine. With its use becoming increasingly relevant in rare cancers the need for consensus around terminology is even more apparent and patient advocacy groups including the Cholangiocarcinoma Foundation are calling for the term ‘biomarker testing’ to be adopted to describe:

“Tests that identify characteristics, targetable findings, or other test results originating from malignant tissue or blood.”

How biomarker testing addresses the challenges of rare cancers

Biomarker testing has emerged as a very useful tool in screening at-risk individuals while also providing earlier, more precise diagnoses in patients who have already developed rare cancers. As the use of biomarker testing becomes the standard care in a variety tumors its use is increasingly widespread. More and more genomic information about cancers is becoming available and collected (along with clinical data) in knowledge networks such as NIH’s Genomic Data Commons. The data collected is shared among researchers around the world making more research into rare cancers possible. Alongside these public databases, bioscience companies are also investing more in the potential of biomarker testing with improvements in technology further contributing to improvement is research.

The molecular basis of different cancers is becoming better understood, and biomarker testing is more widely available. Subtypes of cancer in the same organ (e.g. breast) are now known to occur because of different gene mutations producing tumor-specific molecular alterations. These tumors in the same organ are molecularly distinct with differences in prognosis and treatment strategies. On the other hand, cancers occurring in different organs may have the exact same or similar molecular targets. Identifying these shared molecular targets, using biomarker testing, is a good foundation for faster and more efficient development of targeted therapies for rare cancers. In some instances clinical trials, using a new trial design known as “basket trials”, are investigating single drugs in multiple cancers on the basis of a shared molecular target. Biomarker testing provides the information that makes these inferences possible and is increasingly opening doors to participation in clinical trials.

Helping patients with rare cancers in their search for treatment options

myTomorrows’ end-to-end platform uses the valuable information provided by biomarker testing to the full benefit of patients. Our search process is guided by patient-specific medical information. By including biomarker testing results whenever they are available we aim to provide patients with information about treatment options (clinical trials and expanded access programs) that is highly relevant and actionable. This information is provided free of charge and compiled impartially in a personalized listing called the Treatment Search Report. To facilitate access to these options, we work together with a number of industry partners. As part of efforts to facilitate access to treatment, pharmaceutical companies are now partnering with bioscience companies that offer biomarker testing to patients. This highlights the importance of biomarker testing in today’s drug development paradigm. It has the potential to increase participation in clinical trials and lead to the development of much-needed therapies. The growing understanding of the molecular basis of cancer, therapies targeted at tumor-specific molecules, and more efficient trial designs are all contributing to addressing the challenges of rare cancers. Biomarker testing is emerging as, and expected to remain, the cornerstone of these efforts.

Read our rare cancer patient story here.

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