A Path With Less Pain

Genetic Clues Show Which Breast Cancer Patients Are Prone to Post-Treatment Agony

By Kim Krieger

woman chooses between two marked paths

Sickness and pain go together. We think of them as a matched pair, a married couple. Pain signals sickness, sickness causes pain. But this is not always the case. Especially in early stage cancer, often there is no pain — until the patient is treated.

UConn Health researchers have discovered genetic clues that could eventually reveal which people might be vulnerable to post-treatment pain, they reported in the June issue of Biological Research for Nursing.

“We’ll hear women say ‘If I knew the pain would be this bad, I’d have rather died of breast cancer,’” says Erin Young, a UConn Health pain geneticist. Young and her research partners wondered: Can we really call such treatment a “cure”? It would be better if we could know in advance which patients might suffer from which treatments.

Young worked with data collected as part of a broader study involving nurse-scientist and director of UConn’s Center for Advancement in Managing Pain Angela Starkweather, neuroscientist Kyle Baumbauer, and colleagues at the University of Florida and Kyung Hee University in Seoul, South Korea. Young’s analysis found that common variants in two genes contribute to certain symptoms during and after chemotherapy treatment for breast cancer. The results could one day help patients, and their nurses and doctors, make informed treatment decisions and prepare for — or avoid — damage to patients’ quality of life.

The researchers looked at the genetics of 51 women with early-stage breast cancer who had no previous chemotherapy and no history of depression. The women rated their well-being both before and after treatment for cancer, reporting on their pain, anxiety, depression, fatigue, and sleep quality. Young and her colleagues then looked for connections between genes and symptoms.

Can we really call treatment a “cure”? It would be better if we could know in advance with patients might suffer from which treatments.

They looked at three genes in particular: NTRK1, NTRK2, and COMT. These genes are already associated with pain from other research. NTRK1 is connected to rapid-eye-movement sleep (dream sleep), and a specific variant is linked to pain insensitivity. NTRK2 is associated with the nervous system’s role in pain, fatigue, anxiety, and depression. And some common versions of COMT are linked to risks of developing certain painful conditions. The researchers also chose these genes because the variants associated with pain, fatigue, and other symptoms are fairly common, making it possible to get meaningful results from a sample size of just 51 people.

After the analysis, a couple results jumped out at them. Two of the genes, COMT and NTRK2, had significant correlations with pain, anxiety, fatigue, and sleep disturbance. The other gene didn’t.

“I always like having a yes/no answer — if we get some nos, then we know the analysis wasn’t just confirming what we wanted to see,” says Young.

Such a quick look at a small sample of cancer patients can’t give all the answers as to who is going to develop postoperative and post-chemotherapy pain. But what they did find is very suggestive. Some of the gene variants were associated with symptoms before surgery. For example, women with two copies of the A variant of COMT reported more anxiety than other women did. COMT was also linked with pain, both during and after cancer treatment: women with one variant of COMT reported more pain, while women with a different variant reported less.

Fatigue also seems to have a genetic component. Women with one copy of the T variant of NTRK2 reported more posttreatment fatigue than others, and women with two copies reported much more.

Surprisingly, the genes linked to various symptoms worked independently, and didn’t work together to increase overall pain and discomfort. In other words, they weren’t synergistic; they didn’t make each other worse.

The gene variants predicted pain and fatigue above and beyond any differences explained by treatment effects.

The genes’ effects were also independent of the type of treatment the women received; the 51 women followed a number of different types of treatments: different surgeries, different chemotherapies. The gene variants predicted pain and fatigue above and beyond any differences explained by treatment effects. Other experiments by other researchers have shown the COMT variants are connected to the development of skeletal muscle pain.

“So it’s not just our study but the entire literature that suggests COMT could be playing a role in how sensitive you are to many different types of pain,” says Young.

“We are focusing on how we can identify women who are at risk of experiencing persistent pain and fatigue, as these symptoms have the highest impact on reducing quality of life after treatment,” says Starkweather. “It’s a great example of how we can make progress toward the goal of personalized health care. The next piece of the puzzle is to identify the most effective symptom-management interventions based on the patient’s preferences and genetic information.”

Young, Starkweather, and their colleagues say further research, ideally looking at a person’s whole genome, is needed to refine the connections between genetic profiles and the risk of pain. With that knowledge, patients could work together with their care team to develop individualized symptom-management plans. Properly prepared patients would feel more control and less suffering. And perhaps the cure would no longer hurt worse than the disease.

Lab Notes – Summer 2016

Researchers Reveal a Secret of Sepsis

human cell rendering

Severe bacterial infections can push the human body into sepsis, a life-threatening cascade of inflammation and cell death that can be difficult to cure. In the May 19 issue of Cell, immunologist Vijay Rathinam and colleagues at UConn Health proposed an explanation for how bacteria trigger such a dangerous reaction: The human cells aren’t really being invaded. They just think they are, at least when sepsis is caused by gram-negative bacteria. Gram-negative bacteria secrete vesicles of lipopolysaccharides (LPS) that can get inside human cells and set off alarms. When the cell detects the LPS, it thinks a bacterium has slipped past its defenses and self-destructs, spilling inflammatory cytokines that prompt the bacteria to emit more LPS, setting off a vicious cycle.

Nanoparticles: guided missiles for drug delivery

Powerful drugs such as chemotherapy and steroids can be devastatingly effective against their intended targets — but they have a tendency to devastate other, healthy body systems as well. UConn chemist Jessica Rouge is working to make these medications more discriminating in their action by bundling them into guided nanoparticles. Her lab is developing aptamers, molecules that bind to a specific target proteins or cell receptors, that can be attached to the nanoparticles to guide them straight to damaged or diseased cells. This approach could help cancer patients avoid the worst side effects of chemotherapy. It could also be useful for asthmatics who need steroidal anti-inflammatory drugs. With this strategy, the drugs could be sent straight to the lungs, side-stepping side effects completely.

Walnuts May Improve Your Colon Health

a walnut in its shell

Eating walnuts may change gut bacteria in a way that suppresses colon cancer. A team of researchers from UConn Health and The Jackson Laboratory for Genomic Medicine found that mice that ate 7-10.5 percent of their total calories as walnuts (about an ounce per day for humans) developed fewer colon cancers. Walnuts are packed with compounds known to be important nutritionally, but it may be as a whole food that they pack the most significant anti-cancer punch against colon cancer, the third most common cancer in the world. The research, supported in part by the California Walnut Commission and the American Institute for Cancer Research, was published May 23 in the journal Cancer Prevention Research. UConn Health Center for Molecular Medicine cancer researcher Dan Rosenberg and colleagues are now working on a long-term study in humans.

Congestive Heart Failure plus Type 2 Diabetes Worse Than We Knew

Diabetes blood Sugar monitor and test strip

Data from more than 5,300 patients with Type 2 diabetes has shown that these patients face a one-in-four chance of dying within 18 months of being hospitalized for congestive heart failure, according to the global EXAMINE study, led by UConn Health professor of medicine Dr. William B. White. Patients with Type 2 diabetes have two to three times the heart disease risk of the general population. White hopes the results inspire patients and doctors to focus more on preventing cardiovascular disease. The findings were presented June 11 at the American Diabetes Association’s (ADA) annual meeting in New Orleans and published online in the ADA journal Diabetes Care.