A large group of Duke Cancer Institute investigators led by researcher Gayathri Devi, PhD, has been awarded a three-year $1.6 million U.S. Department of Defense Breakthrough Level 2 grant for research directed at investigating the mechanisms underlying inflammatory breast cancer metastasis. Level 2 Breakthrough Awards fund projects that are already supported by preliminary data with the potential to make significant advancements in clinical translation.

“Inflammatory breast cancer research is, in general, rarely funded, so this grant is timely and exciting for our IBC consortium,” said Devi, founder and program director for the Duke Consortium for Inflammatory Breast Cancer — DCI’s home, for the past six years, for inflammatory breast cancer research.

Inflammatory breast cancer (IBC) is a rare and understudied cancer — accounting for only one to 5% of all breast cancer cases. However, it remains one of the deadliest cancers, accounting for 10% of all breast cancer deaths or 4,200 people each year, a dramatic statistic considering the low incidence of IBC cases.

It differs from other types of breast cancer in its symptoms, behavior, treatment and outlook.

First, unlike other breast cancers, IBC patients have a unique and often very painful presentation — the inflamed swollen breast.

“This appearance derives from the cancer cells growing not as solid masses as in other types of breast cancers, but as small highly mobile tumor cell clusters called lymphatic emboli, which invade and block lymph vessels in the skin of the breast,” explained Devi. “It’s usually not detectable by a breast self-exam or by a mammogram and is often misdiagnosed as an infection. Naturally, this causes a delay in treatment.”

Inflammatory breast cancer tends to be more aggressive — growing and spreading much more quickly than more common types of breast cancer. In fact, in one of every three cases it has already spread to distant parts of the body by the time it’s diagnosed.

According to the American Cancer Society, the five-year relative survival rate for a patient with metastatic IBC is only 19% as compared to 56% when it’s local or regional at diagnosis.

Once IBC is diagnosed, treatment can be a challenge. The fact that IBC shares standard molecular features (ER/PR/HER2) with other breast cancers — for which there are already approved drugs on the market — has hindered development of new treatment approaches. Because of the way IBC behaves, these drugs are not as effective and currently there are no approved IBC-specific treatments.

The environment around IBC clusters often contains immune cells, like macrophages and various molecules elaborated by them, that collectively create a stress on the tumor cells called chronic inflammation, which, rather than eliminating the cancer, seemingly drives it to grow more aggressively.

This chronic inflammation may be genetically determined (e.g., some people have gene variants associated with greater production of inflammatory molecules), but it has also been linked in epidemiologic studies to modifiable characteristics like obesity, early age at first pregnancy, and lack of breastfeeding.

“Prior work in the field has not established an explanation for the biologically distinct behavior of this type of breast cancer,” explained Devi, principal investigator on the new DoD-funded project and a recipient of past DoD, National Institutes of Health, and American Cancer Society grants for breast cancer research.

Devi believes she and her team are getting close to an explanation.

The new grant — "Preventing Inflammatory Breast Cancer Metastases by Interrupting Cellular Stress Signaling in Lymphatic Emboli and Circulating Tumor Cell Clusters" — was awarded in October 2020 in the amount of $1,585,200. With pre-clinical and clinical aims, it builds on advanced breast cancer biology research in Devi’s lab (Cell Death Lab) that led to the discovery of a cell-death signaling pathway in IBC cells that links the chronic inflammatory stress of the IBC tumor environment to its aggressive behavior.

“We hypothesize that IBC may be controlled or destroyed by interrupting this inflammation-responsive pathway and eliminating the cells and molecules in their environment that create the chronic inflammation,” said Devi. “This will first require a clearer picture of the various immune cells, their secreted molecules, and components of the inflammation-responsive tumor cell signaling pathway that are associated with more rapid and invasive tumor growth — a challenging and expensive undertaking that’s now possible with this new DoD funding.”

Devi is partnering with Gregory Palmer, PhD (director of the Palmer Lab in the Department of Radiation Oncology); Bruce Klitzman, PhD and David Brown, MD, PhD, in the Department of Surgery; and a host of research trainees (undergraduates, graduate students, surgical residents, and fellows in the Departments of Surgery, Pathology, Medical Physics, the Pratt School of Engineering,Trinity School of Arts and Sciences, and The Fuqua School of Business) to develop innovative IBC preclinical models derived from IBC-patient tumor cells that mimic the tumor emboli and lymphatic microenvironment.

These models will be used to study tumor-lymphatic and macrophage interactions and to test strategies that interrupt cellular stress signaling in lymphatic emboli and circulating tumor cell clusters in combination with macrophage depletion.

The aim is the development of a less toxic treatment regimen compared to standard chemotherapies. One such strategy to be tested is a re-purposing of disulfiram — a drug that’s FDA — approved to manage alcohol abuse — for IBC therapy. Devi has already received a patent for this. (The team is also currently working with the Duke Office of Licensing and Ventures on developing patents for these IBC preclinical models).

Devi’s project co-investigators include GI oncologist Michael Morse, MD (professor in the Department of Medicine, Division of Medical Oncology, who helps with identifying immune biomarkers;); cancer pathologist Shannon McCall, MD (vice chair for Translational Research in the Department of Pathology, director of the Duke BioRepository & Precision Pathology Center shared resource and PI for the National Cancer Institute's Cooperative Human Tissue Network Southern Division); Gregory Palmer, PhD; and biostatician Jesse Troy, PhD (assistant professor in the Department of Biostatistics & Bioinformatics) along with collaborators Sarah Sammons, MD (assistant professor in the Department of Medicine, Division of Medical Oncology) and Susan Dent, MD, FRCPC (associate director of Breast Cancer Clinical Research and co-director of the Duke Cardio-Oncology Program). The group will also work closely with DCI Shared Resources — the Cancer Center Isolation Facility (CCIF), the Transgenic and Knockout Mouse and Optical Molecular Imaging and Analysis.

This DoD project is also expected to include robust collaborations — toward IBC biospecimen collection and analysis — with IBC-International Consortium investigators: pathologist Savitri Krishnamurthy, MD (MD Anderson Cancer Center), Steven Van Laere, PhD and Peter Van Dam, MD (University of Antwerp and Sint Augustinus Hospitals & Clinics, Belgium) and Francois Bertucci, MD, PhD (Institut Paoli Calmettes, Marseille, France).

Nationally recognized breast cancer patient advocate, Patty Spears (with the UNC Lineberger Comprehensive Cancer Center) will partner on this multidisciplinary project by communicating, to the local community, the importance of this scientific research.

“Advocacy is a key feature of large multidisciplinary DoD grants and an incredible opportunity to encourage more cancer-patient advocates in our local community to join our consortium efforts toward IBC awareness and education in North Carolina,” said Devi, noting that the consortium has already established a partnership with the Durham Union Baptist Church’s Cancer Survivor Support Ministry (led by Margie Scott) in annual breast cancer awareness forums.