“You have cancer” – a tough phrase for anyone to hear. “Your cancer is highly mutated” – a good phrase to hear for anyone with cancer? Despite its ominous sound, that is precisely what new research is showing, giving hope to some cancer patients that immunotherapy treatments may work better for them. Oncology Central is running a Spotlight on tumor mutation burden as a pathway for immuno-oncology to take the leap forward into the next phase of precision medicine.
First, step back and understand what highly mutated cancers are. A genetic mutation from a normal cell to an abnormal one is the root of cancer. The more mutations in a particular cancer, the higher the “tumor mutation burden”, or TMB, will be. This measure varies wildly across cancer types and increases with age. Here is a good primer from the National Academy of Sciences that explains TMB in more depth with accompanying data and graphics, showing how TMB can be an effective biomarker in targeting specific patients for specific treatments.
Targeted therapies began with the 1977 approval of tamoxifen to treat ER-positive breast cancers, and in the 40 plus years since that first approval, have expanded as the oncology research world uncovered more treatment possibilities through genetic and mutational pathways – the birth of precision molecular medicine. Now, there is evidence that increased mutations can actually yield more positive results with new immunotherapy treatments. The question now evolves into how to use that information to deliver more effective therapies to the individual person, and not simply a group of patients with similar characteristics and higher response rates.
Tumor mutation profiling assays exist, and in 2017, Merck’s Keytruda® (pembrolizumab) became the first drug approved for a solid tumor with specific genetics – microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). It was the first step towards more precise medicines; the right medicine for the right person at the right time. THAT concept is one any patient could understand. Separating the genetics from the site of origin was a huge development; for the first time, science could prove something worked across shared biological qualities of the human body, instead of simply across loosely defined groupings.
The use of TMB to selectively pick patients for treatments is still in its infancy. While a giant step forward, it isn’t a complete picture of treatment options. Highly-mutated tumors often fail immunotherapies that statistics indicate would be more responsive than “normal” tumors. Conversely, some patients with low-mutated tumors will respond, even though the odds are against them. This “true negative” could lead oncologists to dismiss a treatment type as an unlikely long shot even though it may actually work. Unfortunately, it may also be used as evidence by payers and regulators to deny access or coverage to someone who stands to gain clinical benefit, simply because too many others with similar tumor burden did not respond to the same treatment.
As a patient, it is confusing to think that being genetically “worse” actually may lead to a better outcome. The average person may struggle understanding the biology of cancer, and the advances in medicine that rely on specific biomarkers, mutations, and genetics. A melanoma patient may be able to tell you their BRAF status, but often has no idea what “BRAF positive” or “BRAF wild type” means, outside of what treatments for which they are eligible. Same for HER2, BRCA, KRAS, and the many other mutations in breast, lung, and other common cancers. We may not know what those really are, we just know it’s usually bad.
Articulating how a targeted treatment responds – or doesn’t respond – to a patient is a delicate subject. How do you tell someone WHAT is wrong with them (cancer), test to determine just HOW wrong it is (mutation burden), and then base a treatment off that “what” and “how”? Can a physician say, “Let’s hope your body has MORE of the ‘wrong’ stuff in it, because that means there is a better chance of a successful treatment outcome”?
Understanding this somewhat-nebulous concept is confusing, stressful, and clinical – and very much patient-unfriendly. This is usually on top of digesting the rest of a cancer diagnosis: “What kind of cancer?” “How do I treat it?” “What is immunotherapy?” “What is a clinical trial?” “Are there side effects?” “HOW LONG DO I HAVE??” and the dozens of other questions that form post-diagnosis. There is no real good way to relate genetic mutation information in lay terms, and clinicians may struggle to satisfy the varied levels of patient understanding regarding deeper knowledge of their disease state. Don’t let that keep you from trying, though, as for every patient who does not understand or doesn’t want to understand their tumor mutations, there is another who is looking for that depth of knowledge of their cancer.
There is still a long way to go in medicine to definitively confirm or remove immunotherapy options based on only one factor, like TMB. It is progress towards a much grander goal, as biotechnology accelerates the endless possibilities of treatment matches, combinations, and sequences. As this march into the next frontier continues at unprecedented rates, remember patients, and their understanding of their own bodies’ complex biologics, deserve to be brought up to speed as well.
T.J. Sharpe is a Stage IV melanoma patient who shares his journey through cancer in the Patient #1 Blog on www.oncology-central.com, www.philly.com/patient1/, www.SkinCancer.net, and on www.NovartisOncology.com. He was diagnosed in August 2012 with melanoma tumors in multiple organs, only 4 weeks after his second child was born. Since then, he has undergone six surgeries and four immunotherapy treatments over two different clinical trials. The initial failures, and subsequent complete response, have been chronicled in his blog posts since December 2012. In addition to writing, he is a keynote speaker and consultant to the biopharma and clinical research industries, bringing an educated patient voice as a true stakeholder in challenging healthcare’s status and making a difference in patients’ lives via his company, Starfish Harbor LLC. A South Jersey native, T.J. lives in Fort Lauderdale, FL, with his wife Jennifer and two young children, Josie and Tommy.