How Might Duffy-Null Status Shape Breast Cancer Outcomes and Trial Access?

Disparities in cancer outcomes stem from both social determinants, such as access to care and insurance, and biological determinants that may be inherited along ancestral lines. One such determinant, the Duffy-null blood type, is common among people of West and Central African ancestry and has been linked to lower neutrophil counts, which can affect clinical trial eligibility, as well as to differences in cancer outcomes.

At the Big Ten Cancer Research Consortium (Big Ten CRC) Summit, CancerNetwork® spoke with Jan Kitajewski, PhD, director of the University of Illinois Cancer Center and head of the Department of Physiology and Biophysics at the University of Illinois Chicago. He discussed:

• how his cancer center approaches biological and social determinants of cancer outcomes;
• what Duffy-null status is and why it may matter in triple-negative breast cancer;
• the implications for neutropenia and trial eligibility;
• a new mouse model his laboratory developed to study these questions.

CancerNetwork: A major focus of your work addresses health equity and the biological underpinnings of cancer disparities. How are you combining tumor and population science to identify drivers that disproportionately affect underserved patients?

Kitajewski: Patients experience differing challenges. They could be challenges based on their genome and family history, like inheriting a BRCA mutation, or challenges such as access to nutrition, exposure to crime, or lack of insurance. The first category is biological determinants; the last is social determinants. Our ultimate goal at the University of Illinois Cancer Center, and at the cancer centers in the Big Ten CRC, is to understand that collective group of determinants so we can provide the best care.

At our cancer center, we treat many underinsured and uninsured patients, as well as patients who are exposed to high levels of violence and live in regions of Cook County that are below the poverty line. We have tailored our therapeutic, diagnostic, and preventive approaches to the specific problems these patients face.

What is the Duffy allele, and why might it matter for patients with cancer?

Many African Americans can trace their ancestry back to West and Central Africa. Many centuries ago in that region, there was a protein on red blood cells that allowed the the malarial parasite [Plasmodium vivax] to infect them; it is a deadly parasite and a deadly disease. At some point, a mutation arose that downregulates this receptor, which we call ACKR1, or atypical chemokine receptor 1. It is a nonfunctioning G protein–coupled receptor [GPCR] expressed only on red blood cells and on the endothelial cells of blood vessels.

If you have lost expression on red blood cells, you are relatively healthy. Some of your circulating proteins are altered, but you are resistant to the form of malaria that is endemic in West and Central Africa. This is referred to as carrying the Duffy[-null] allele; it is a blood type, because you have reduced or absent expression of ACKR1 on red blood cells.

That could have been the end of the story. However, when we look at Duffy allele carriers and their tumor trajectories, we find that in some cancers, such as triple-negative breast cancer, outcomes are worse. Epidemiologic data suggest that this may be a risk factor for more aggressive breast cancer, although we do not know this for sure. The risk is much lower than with a BRCA mutation, which substantially elevates your risk of developing breast cancer; in this case, the concern is that outcomes may be worse than they should be.

How might Duffy-null status affect treatment decisions and clinical trial eligibility?

We do not yet know how to tailor medications based on whether someone carries the Duffy allele. Duffy allele carriers typically have lower neutrophil levels, which is referred to as neutropenia, and that might exclude them from some clinical trials, perhaps appropriately, perhaps not.

What is your laboratory doing to understand the biological consequences of the Duffy allele?

In addition to studying the human data, we have developed a mouse model in which we selectively remove the ACKR1 protein from red blood cells but not from endothelial cells. We are finding that it replicates some of the changes in neutrophil levels and in circulating proteins like cytokines.

By crossing that mouse with a mouse that develops aggressive triple-negative breast cancer, or by implanting a tumor into the mammary gland and following its growth, we can now do very precise, controlled studies of how a tumor grows in a Duffy allele carrier. This is a case in which we have identified a novel biological determinant, passed along an ancestral lineage, that is affecting cancer, but before developing this mouse model, we were unable to understand its consequences. So stay tuned for what we learn about how these tumors grow and spread.

We are already adapting the model to test different agents, their efficacy against tumors, and how they might affect neutrophil levels. In other words, we can use this mouse model to calibrate existing chemotherapeutic agents that may not have been offered to people with lower neutrophil levels. Our goal is to identify situations in which those agents should be used, and to make those judgments with more precision.