Comprehensive Genomic Profiling as the Driver of Change in Rarer Cancers

Precision medicine has helped revolutionize the way we diagnose and treat cancer. The unprecedented volume of data that tumor mutation testing, particularly comprehensive genomic profiling (CGP), delivers has helped to transform our knowledge of cancer genetics and continues to challenge our fundamental understanding of what it means to have a certain cancer type … and how to treat it.

The transformation occurring in how we name or categorize a cancer has broader implications beyond our approach to treatment; it is a transformation that touches every facet of the oncology landscape – from our research methodology, to the way we counsel patients about prognosis or risk to other family members, the method and frequency of follow-up visits to monitor disease progression and treatment response.

There is one area of oncology in particular where this shift to molecular classification is even more significant, and that is in the rarest forms of cancer. But how is CGP helping to overcome some of the barriers that have prevented progress in this area in the past?

Finding the needle in a haystack

One of the greatest obstacles to overcome in rarer cancers has been how to accurately make uncommon diagnoses for patients with these conditions in the first place. When a patient originally presents with a tumor, we tend to first consider common diagnoses that would explain the constellation of clinical findings and the appearance of the abnormal cells under the microscope. Rarer diagnoses are usually considered when the more common ones are ruled out (diagnosis of exclusion) or when an expert recognizes features that are classic for a rare tumor (i.e. recognizing a black and white striped horse as a zebra). It’s a simple fact that you don’t tend to find something if you’re not looking for it, or recognize something you have never encountered before. And for rarer cancers, this presents a problem that can ultimately lead to missed or delayed diagnosis, and poorer outcomes.

Clear cell sarcoma is an example of a rare soft tissue tumor that can present in young adults. This tumor has features under the microscope that look like the much more common skin malignancy, cutaneous melanoma, and can be misdiagnosed. The prognosis and treatment of clear cell sarcoma is very different from melanoma. A particular fusion between the EWSR1 and ATF1 genes is seen in clear cell sarcoma but not in melanoma, and thus, identification of this genomic event by tumor profiling supports accurate initial diagnosis and assists in correcting misdiagnosis for these patients.

Through tumor testing, we are also starting to recognize special, rarer subtypes of more common cancers, such as ROS1-mutated non-small cell lung cancer (NSCLC). ROS1 fusions occur in only 1-2% of NSCLCs¹ and usually in patients who don’t have the more common driver mutations that are frequently tested for using hot spot or single gene panels. Additionally, ROS1-mutated lung cancers often occur in patients with fewer lung cancer risk factors, develop in the outer parts of the lungs, where there are often no recognizable symptoms in the early stages, and can grow and spread quickly. It is not surprising then that this rare form of lung cancer is most often diagnosed at an advanced stage and the delayed diagnosis reduces the outcomes of treatment even further for this group of patients.

We need to rethink the concept of diagnosis and include genomic testing results as part of the process. Saying a patient has non-small cell lung cancer, for example, is insufficient today, as diagnosis should include the genomic findings, such as ROS1-mutated, in addition to the site of tumor origin (lung) and the microscopic, histologic pattern (non-small cell carcinoma) in order to be complete and informative for patient care. Making comprehensive genomic testing standard as part of diagnosis would provide oncologists with all relevant information upfront and minimizes the risk of misdiagnosing rare cancers and also “missing” the rare but highly significant molecular subtypes of a common cancer type.

Mutation not location – the significance of a pan-tumor approach for rare cancers

Improving identification and categorization of rarer cancers also gives us a much stronger foundation for research and accelerates the development of new treatments that can benefit patients. One barrier to progress in many rare diseases is the difficulty of conducting feasible clinical trials to test efficacy of different treatments. Even with high levels of participation by patients with rare tumors, it can take a long time or ultimately prove impossible to adequately power a clinical trial for a single rare diagnosis. This means that the development of new treatments for rarer cancers is, at best, an incredibly slow process.

We’re seeing more organizations design clinical trials based on the presence of a certain mutation, regardless of where it appears in the body, meaning that small groups of patients all sharing the same mutation across different types of cancer can be pooled in order to identify enough patients to adequately run a trial. One example was a trial testing a drug developed for melanoma in non-melanoma tumors with a BRAF mutation—it revealed promising results in a rare type of ovarian tumor much earlier than a traditional clinical trial plan. This pan-tumor approach to evaluating targeted therapies is reigniting research across the spectrum of rarer cancers, broadening drug indications and approvals and accelerating much needed progress. And we are only just beginning to see the impact of this approach.

NTRK fusions, for example, are rare gene mutations that are responsible for certain rare types of salivary gland and sarcomas, and are also a cause of a subset of lung and thyroid cancers. As with other rare mutations, these fusions are generally not what an oncologist might be “looking” for and wouldn’t be identified through more limited testing approaches. Tumors with NTRK fusions may not respond well to the typical regimens chemotherapy or radiotherapy used for the general diagnosis.

Two drugs specifically targeting the effects of the abnormal NTRK fusion protein have transformed outcomes for patients with these NTRK fusion mutations. These treatments have demonstrated incredible response rates of up to 75% in adults² and up to 94% in children³ across a range of solid tumor types—and for many patients, these responses are sustained for a year or more. In contrast, patients with similar appearing tumors but without the NTRK fusion do NOT show similar clinical benefit and only experience physical and economic side effects of the treatment, reinforcing the importance of specificity (avoidance of false positive results) in tumor genomic testing.

The growing threat to progress in rare cancers

Progress towards improved patient outcomes is dependent on high quality, comprehensive molecular results integrated with other components of the patient’s diagnostic work up, not just in rare cancers but across oncology. Our ability to identify patients with rare mutations drives interest and research into novel therapeutics, allows us to better understand frequency of mutations across tumor types, enables sufficient participation in clinical trials and is pivotal to ultimately matching each of them to their best treatment plan. Unfortunately, only about 25% of patients today are receiving comprehensive genomic testing⁴ at any point during their cancer journey.

Until we get to a place where CGP is standard practice for all patients, we will never be able to realize the full potential of precision medicine for all cancer patients, and especially those with rarer cancers. Today we have the tools, ability and the opportunity to transform our perception of rarer cancers and change outcomes for these patients now and in the future.