Turning the Tables on Cancer

Cancer immunotherapies are revolutionizing the world of oncology. This exciting new class of medicines retrains the body’s own immune system to fight cancer. Unlike cytotoxic chemotherapy, the immune system is “smart” and can adapt and evolve with the cancer over time – potentially resulting in unprecedented long-term benefit.

However, every individual’s cancer is unique, and not everyone responds equally to the same immunotherapy. The ability to predict who is most likely to respond to an immunotherapy could save crucial time, and offer significant clinical benefit. So how do we do it?

The answer may lie in the cancer’s genome.

“Faulty genomes are the common denominator of all cancers,” explains Vincent Miller, MD, Chief Medical Officer at Foundation Medicine. “Tumors with an especially high number of mutations are more likely to produce new, abnormal proteins called neoantigens. The immune system recognizes these neoantigens as foreign and goes on high alert, initiating a complex series of steps to attack the tumor.”

This multi-step process is called the cancer-immunity cycle, and it’s what our immune systems normally go through to protect our bodies from cancer. But some cancers have evolved ways of evading the immune system by expressing proteins that inactivate certain types of critical immune cells. To prevent this immune system inactivation, some immunotherapies have been designed to block action of these suppressive proteins. For these classes of immunotherapies (which include anti-PD1 and anti-PDL1 antibodies), a growing body of evidence suggests higher levels of neoantigens are associated with improved response rates and longer duration of response.

Determining the presence of and nature of neoantigens in a patient represents enormous challenges, including time, cost and tissue constraints. Additionally, traditional gene-by-gene testing can’t capture the countless variations that may give rise to these new proteins. Instead, we use a powerful approach known as comprehensive genomic profiling (CGP). While genomic tests are akin to a close-up view in a magnifying glass, CGP is a wide-angle lens that provides a snapshot of the entire genomic landscape of a tumor. This global perspective allows us to pick up on problems and opportunities other methods miss.

One particularly promising measurement is tumor mutational burden (TMB), sometimes referred to as total mutational burden or mutational load. TMB is defined as the total number of mutations per coding area of the genome. Tumors that have high TMB are believed to express more neoantigens, and therefore may respond better to immunotherapy. There are many ways cancer cells can end up with high TMB, including exposure to tobacco or UV light. Another way is microsatellite instability (MSI), a condition where problems with DNA repair result in highly variable lengths of repetitive areas of the genome.

MSI and TMB are not new, but previously they could only be assessed separately, using time- and labor-intensive techniques such as immunohistochemistry or PCR and whole exome or whole genome sequencing, respectively. At Foundation Medicine, our goal is to empower doctors and patients with a full range of relevant, actionable genomic information. That’s why we’ve developed a unique solution to assess MSI and TMB simultaneously and with unprecedented accuracy, supported by sophisticated algorithms and rooted in contextual insights from FoundationCORETM, our database of over 80,000 real-world tumor samples. This is something no other next-generation sequencing platform is able to offer.

“Comprehensive genomic profiling with FoundationOne® measures two independent biomarkers that may help identify the patients who will benefit most from certain immunotherapies – information that could improve clinical outcomes and help get important new therapies to market,” says Steven Kafka, PhD, President and COO of Foundation Medicine. “We’re encouraged by the emerging evidence demonstrating the power of this approach across a wide range of tumor types.”

We’re continuing to work with our biopharmaceutical partners to evaluate TMB as a predictive biomarker for specific immunotherapies. Together with the full suite of genomic assays and decision support tools Foundation Medicine offers, these data provide crucial insights that can help doctors match patients with treatments or clinical trials. This is a transformative time for precision medicine in oncology, and with our unique ability to repurpose cancer’s faulty genome to our advantage, we’re excited to help turn the tables on cancer.