Olivia Lara wants a promising cancer treatment to help every patient

The NC TraCS K12 scholar is studying how obesity and stress may affect endometrial cancer and immunotherapy drugs.

Endometrial cancer is the most common gynecologic cancer in the US, and both incidence and mortality are rising. But recently, endometrial cancer care has seen the promising rise of immunotherapy treatments.

These drugs recruit the patient's own immune system to attack the cancer. Normally, our immune system attacks and clears away foreign objects like viruses and abnormal cells. Many cancer cells send a signal to the immune system that shuts this process down—so immunotherapy drugs help shut down that signal, which allows the immune system to recognize and destroy the cancer cells.

These drugs have been shown to improve survival among patients with endometrial cancer. The trouble is, cancer can still often be unpredictable and hard to control.

"I'll see two patients with the same endometrial cancer—same stage, same type of cancer—and they can have very different outcomes just based on how they respond to treatment," says Olivia Lara, a gynecologic oncologist at UNC Health and a member of the Cancer Therapeutics Research Program at UNC Lineberger Comprehensive Cancer Center. "They can receive the same treatment, and one person may go into remission for years, while another may experience a recurrence and face a much more difficult course."

Dr. Lara is now working on research that could help clinicians and scientists understand why different patients with endometrial cancer, even those getting the same treatment, can end up on such different trajectories. This work is part of a K12 research project through the North Carolina Translational and Clinical Sciences (NC TraCS) Institute.

Her project is investigating the complex relationship between cancer, the immune system, obesity, and chronic stress—all factors that could play a role in explaining how a patient's cancer progresses and how well that patient responds to immunotherapy drugs.

"Not knowing why two patients will experience such different outcomes, and not knowing how to better help them, is what drives me to do the research," Dr. Lara says.

Dr. Lara grew up in Texas in a large Mexican-American family, where her grandmother was the matriarch and central figure. Seeing the central role women played in her family helped spark her interest in women's health and ultimately becoming an OB/GYN.

She got her undergraduate degree from Texas A&M, and then did her medical school and residency at the University of Texas, where she developed an interest in oncology and ultimately pursued gynecologic oncology. Before coming to UNC, Dr. Lara completed fellowships at New York University and Texas's MD Anderson Cancer Center, where she found her passion for research. "Day to day, you see your patients in clinic, but through research, you just impact so many more people," she says.

Dr. Lara's current work builds off a robust body of existing research looking at how obesity, stress, and the immune system affect cancer treatments and prognoses. Her primary mentor is UNC gynecologic oncologist Victoria Bae-Jump, director of the UNC Lineberger Endometrial Cancer Center of Excellence, whose research examines how obesity, metabolism and other biological factors influence endometrial cancer development and outcomes.

People who are obese have a higher risk of both being diagnosed with endometrial cancer and dying from endometrial cancer—and Dr. Bae-Jump and her colleagues have found that obesity is associated with more aggressive endometrial tumor growth in mouse models. In a recent study, they also found that weight loss through dietary interventions reversed many of these obesity-related changes and slowed tumor growth in a mouse model of endometrial cancer.

Researchers are still trying to understand how obesity might affect immunotherapy treatments for cancer. On one hand, some research has found that obesity was correlated with better survival among some patients with cancer undergoing immunotherapy. On the other hand, obesity and associated chronic inflammation have also been linked with long-term immune dysfunction—and Dr. Lara, Dr. Bae-Jump, and their colleagues found that obesity was correlated with shorter progression-free survival among patients with advanced or recurrent endometrial cancer treated with pembrolizumab, an immunotherapy drug commonly given to patients with endometrial cancer. This suggests that obesity related factors may influence how patients respond to immunotherapy, although further research is needed to understand why.

Similarly, chronic psychological stress has also been linked with inflammation and immune issues. One way to quantify the impact of stress on the body is through "allostatic load," a combined measurement that includes factors such as blood pressure and various hormone levels. Researchers have found some associations between high allostatic load (meaning high stress) and a higher risk of dying from cancer. Earlier this year, Dr. Lara and her colleagues published a study that found that high allostatic load was associated with lower survival among patients with endometrial cancer, specifically.

Dr. Lara's K project with NC TraCS will start to put all these puzzle pieces together. She says the mentorship in the K12 program is "amazing," and she appreciates how the program is multidisciplinary, so she gets to learn from and alongside other participants studying a wide variety of research topics. After her residency, she worked in a translational lab with a lot of team science and always wanted that kind of experience again.

"It helps my curiosity, as a clinician," Dr. Lara says.

"I'll see two patients with the same endometrial cancer—and they can have very different outcomes just based on how they respond to treatment."

As part of the project, Dr. Lara is prospectively following patients with endometrial cancer who are receiving immunotherapy through a trial funded by the Cancer Health Disparities Specialized Program of Research Excellence (SPORE) in Endometrial Cancer. Her team is collecting tumor samples, bloodwork, microbiome samples, and detailed clinical data before and during treatment. With this information, they can study how the tumor, immune system, and patient-level factors such as obesity and chronic stress change over time and relate to treatment response.

For example, by analyzing how active each patient's immune system is, Dr. Lara can see how immune system activation may affect a patient's response to immunotherapy drugs. She'll work to identify biomarkers that are unique to patients with high allostatic load, which can help her understand how stress levels may impact immunotherapy. Tumor sequencing will also allow Dr. Lara and her colleagues to see how much each person's cancer may be expressing various genes.

A major component of the trial is studying the microbiome, or the community of microbes that naturally live in and around our bodies, and its potential relationship with immunotherapy response. She's taking samples from the microbiome in the digestive system, which has been linked to immune system function, and from the tumor microbiome to understand whether differences in microbial communities are associated with patients' immune systems and response to treatment.

This trial will also be available to patients receiving care at the UNC Health Raleigh Cancer Center, expanding access to the study beyond UNC's main campus in Chapel Hill. This helps to potentially reach patients from a broader geographic area—and Dr. Lara says physicians at Rex have been excited to bring this science to their community.

If Dr. Lara discovers that stress or obesity seems to affect patient outcomes, and why, that could help guide treatment plans and the conversations clinicians have with their patients. Because ultimately, the goal is to make sure that all patients with endometrial cancer are getting the best care they possibly can—and seeing the same good results from promising treatments.

"We need to understand why some patients respond so well to treatment while others don't; if we can understand what drives those differences, we can find better ways to tailor treatment for each patient," Dr. Lara says. "We have a duty to our patients to figure this out."