Tumor Mutation Burden May Identify Those at Risk for Depression

An increased tumor mutation burden (TMB) may be a factor in determining which patients with lung cancer are at higher risk for depression, according to study findings presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.

“Something that's biological could be used to identify which patients may be at risk for depression or have depression,” Dr. Daniel McFarland, from the Department of Psychiatry and Behavioral Sciences at Memorial Sloan Kettering, said in an interview with CURE. “That's a key piece, knowing that we as oncologists are not always able to identify those patients who are suffering with depression. Getting a little bit of help along the way, and looking at the biology, which is something we're looking at anyway, could be very beneficial.”

Depression and inflammation are two factors typically associated with lung cancer. Meanwhile, TMB — a marker of how many mutations are in a person's cancer, McFarland explained – is used to predict which patients will respond best to immunotherapy, because it relies on tumor immunogenicity (a form of inflammation).

“What TMB is basically taking advantage of is our bodies' innate immune system that responds to cancer as a foreign thing. It up-regulates inflammation, and then actually fights against the cancer, which is what immunotherapy does. At the same time, there's a lot of data to say that inflammation is predictive of developing depression,” he added.

Therefore, McFarland and colleagues evaluated 96 patients with either non-small cell lung cancer and small cell lung cancer for depression severity to determine whether higher TMB was associated with increased depression as well as various forms of inflammation.

“The idea behind this study was because you have TMB as an up-regulator of inflammation around cancer, does that inflammation, which is also associated with depression, lead to depression in this scenario of people who have cancer?” McFarland said.

TMB appeared to be higher among patients who were treated with chemotherapy (12%) and immunotherapy (14.4%), compared with targeted therapy (4.8%).

The average number of mutations was 10.8, while 24% of patients met screening criteria for depression.

The researchers found that TMB was associated with depression severity and increased inflammation using neutrophil to lymphocyte ratio. However, a multivariate model — which basically weeds out all of the other factors that are involved, like demographics, age, gender, type of lung cancer, and treatment type, explained McFarland – showed that TMB and inflammation determined by C-reactive protein predicted depression severity.

“What was interesting was that overall, if you had a high TMB, it predicted depression in both univariate and multivariate analyses,” he added.

The researchers concluded that the exact mechanism of inflammation and depression should be further evaluated and that the results also warrant replication.

“We looked at an interaction, thinking that if TMB causes depression, it's probably through inflammation. However, we didn't actually find an interaction,” McFarland said. “That could be because the sample was too small…It could be because there are other mechanisms involved, and there are other hidden variables, for example.”

“One idea would be that people who are smokers have higher levels of TMB, and people who are smokers also have higher levels of depression,” he added. “So those kinds of questions need to be worked out.”

Ultimately, if researchers can confirm these findings, physicians can identify those at risk for depression or alter their treatment to prevent it. “Basically if the association with inflammation seems to be what's driving this association, there are specific treatments that can actually look at lessening the inflammation or treating the downstream effects of having the inflammation, and basically treat the depression,” McFarland said. “That's important because patients who have cancer and depression have worsened quality of life and may actually have lower survival rates. It's important to address those psychosocial issues like depression.”