Sex Differences in Gastrointestinal Cancer

Pamela Kunz, MD, understands that workplace equity for health care systems employees and health equity for patients share a goal: improving care.

“If we are going to give everyone an opportunity to achieve their full health potential, we need people who think differently in our hospitals and other care facilities — people who come from different backgrounds, different genders, and different races,” said Kunz, associate professor of medicine (medical oncology) and vice chief of diversity, equity, and inclusion for the Section of Medical Oncology in Yale School of Medicine’s Department of Internal Medicine. “I like to think about solutions. About how I can use a scientific lens to overcome historic knowledge gaps about sex, gender, race, and ethnicity. And advance patient health equity.”

With this year’s Wendy U. and Thomas C. Naratil Pioneer Award and co-funding from Yale Cancer Center, Kunz is achieving that goal. An oncologist, associate professor of medicine at Yale School of Medicine, and director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center, Kunz is conducting one of the first studies to examine sex differences in treating neuroendocrine neoplasms (NENs), a rare form of cancer often found in the gastrointestinal tract.

“There have been very few studies about sex differences in many types of cancers,” Kunz said, noting how much research dating back decades involved exclusively studying males. “I think the assumption has been that there wouldn’t be sex differences, so it wasn’t deemed relevant to look for them. But in many fields, we are seeing how much sex and gender can play a role in how diseases develop and respond to treatment.”

Research has found sex differences in the 12,000 Americans diagnosed with an NEN every year, including where the cancer starts and survival rates. But few studies have been dedicated to examining sex differences in the side effects caused by treating this type of cancer.

The most common chemotherapy and radiation therapy treatments for NENs can produce toxic side effects that contribute to poor quality of life, worse outcomes, and increased costs for both patients and the health care system. These challenges are especially important in chronic cancers such as NENs, particularly if treatments are interrupted or doses reduced.

One small, retrospective study on this subject found that female patients with the disease receiving two multikinase inhibitors, a type of anti-tumor drug, were more likely than men to develop liver toxicity, headaches, fever, nausea and vomiting, hair disorders, skin disorders, and dizziness. Another small study of a combination of two chemotherapy pills for treating NENs showed that female patients had twice the rate of low platelets (cells that help blood clot) and five times the risk of low white blood cells (the cells that fight infection).

While it remains unclear why females have higher rates of these treatment-related toxicities, Dr. Kunz said this difference could stem from how some of these medications are given at fixed doses or doses based on height and weight — measurements that do not account for differences in metabolism and body fat, nor the different systemic effects of female and male sex hormones.

“Any one of these things can affect how females metabolize medications” Kunz said. “And can result in increased side effects.”

In her WHRY pilot project, unlike the earlier smaller sample studies, Dr. Kunz and her team are analyzing a large U.S. database of patient information and four large completed clinical trials to benchmark the extent of sex differences in NEN treatment outcomes and adverse events and to better design future studies that include sex as a key variable.

For example, one of the categories of increased side effects in female patients involves lower counts of red and white blood cells and platelets in bone marrow. If the study confirms an increase in treatment-related toxicities for female patients with NENs, oncologists could administer boosters for these immune system cells, possibly even preventatively. Or, researchers could conduct studies to determine if lowering doses for female patients taking certain medications could reduce negative effects without lowering the medication’s effectiveness at targeting cancer cells.

Importantly, Dr. Kunz also is identifying candidate genes or common gene variations to help determine which patients are at risk for a single toxicity from treatment or a cluster of related toxicities. The overall goal is to optimize treatment selection for all patients to better predict outcomes and mitigate toxicity, perhaps by conducting a genetic test before treatment to tailor the therapy to the patient.

Because patients with NENs typically have chronic, slow growing cancer that spreads to other sites, Dr. Kunz wants to make sure these patients can tolerate treatments that can extend for a decade or more.

“Our number one goal is to improve the lives of patients when they are on long-term treatments,” she said.

Dr. Kunz expressed her appreciation for WHRY’s funding, which, with guidance from WHRY, has led to supplementary funding from a private foundation.

“This is an example of how contributions can multiply,” she said. “By stringing together smaller amounts of money, it can grow into a lot more. Not just additive — it’s synergistic.”

That synergy extends to her team, which includes Dr. Maryam Lustberg, associate professor of medicine (oncology) and director of the Center for Breast Cancer at Yale Cancer Center; Dr. Namrata Vijavergia, assistant chief of gastrointestinal medical oncology at Fox Chase Cancer Center in Philadelphia; and Dr. Stephen T. Sonis, a professor at the Harvard School of Dental Medicine and senior surgeon at the Dana-Farber Cancer Institute. She has also recruited a pair of internal medicine residents, Dr. Wan Ying Tan from Norwalk Hospital and Dr. Caroline Gordon from Yale New Haven Hospital.

“I love teaching and mentoring,” Kunz said. “As I transition from mid-career to someone more senior, I want to inspire the next generation to do research on how sex and gender influence health. And to broaden health equity for everyone.”

Dr. Pamela Kunz earned her MD from Dartmouth Medical School and her BA from Dartmouth College. At Yale School of Medicine, she is an associate professor of medicine in the Division of Oncology and director of the Center for Gastrointestinal Cancers at Yale Cancer Center (YCC) and Smilow Cancer Hospital. She is also the chief for gastrointestinal medical oncology and the vice chief of diversity, equity, and inclusion for the medical oncology section at YCC. Dr. Kunz is an international leader in the treatment and clinical research of patients with neuroendocrine neoplasms and is advancing the field through clinical trials and translational science that are defining the next generation of therapies for patients with this rare diagnosis.