Shelley Hwang, MD, MPH is talking to a patient whose back is turned to the camera
Shelley Hwang, MD, MPH

Newly Developed Gene Classifier Identifies Risk of Breast Pre-Cancer Progression

A team of researchers mapping a molecular atlas for ductal carcinoma in situ (DCIS) has made a major advance toward distinguishing whether the early pre-cancers in the breast will develop into invasive cancers or remain stable.

Analyzing samples from patients who had undergone surgery to remove areas of DCIS, the team identified 812 genes associated with cancer progression. Using this gene classifier, they were then able to predict the risk of cancer cells recurring or progressing.

The study, which published this week in the journal Cancer Cell, was led by E. Shelley Hwang, M.D., of the Duke Cancer Institute, and Rob West, M.D., Ph.D., of the Stanford University Medical Center. Their work is part of the Human Tumor Atlas Network under the Moonshot Initiative funded by the National Cancer Institute.

“There has been a long-standing debate over whether DCIS is cancer or a high-risk condition,” Hwang said. “In the absence of a way to make that determination, we currently treat everyone with surgery, radiation, or both.

“DCIS is diagnosed in more than 50,000 women a year, and about a third of those women have a mastectomy, so we are increasingly concerned that we might be overtreating many women,” Hwang said. “We need to understand the biology of DCIS better, and that’s what our research has been designed to do.”

Hwang, West and colleagues analyzed 774 DCIS samples from 542 patients who were a median of 7.4 years post-treatment. They identified 812 genes associated with recurrence within five years from treatment.

The gene classifier was able to predict both recurrence and invasive progression of cancer, with progression appearing to be dependent on a process that requires interactions between invasive DCIS cells and the unique features of the tumor environment.

Hwang said most of the DCIS cancers analyzed in the study were identified to be at low risk for cancer progression or recurrence – a factor that underscores the need to have an accurate predictive model that can be used during clinical visits to guide care.

“We’ve made great progress in our understanding of DCIS, and this work gives us a real path forward to being able to personalize care by scaling treatments to the risk of cancer progression,” Hwang said. “The real goal is diminishing treatment-related harms without compromising outcomes, and we are excited to be getting closer to achieving this for our patients with DCIS.”

In addition to Hwang and West, study authors include co-principal investigator Carlo Maley, Ph.D., of Arizona State School of Life Sciences, and Graham Colditz, Ph.D., of Washington University at St. Louis, for the Breast Pre-Cancer Atlas Center, as well as collaborators from 12 other institutions as part of the Translational Breast Cancer Consortium.

The study is part of the Human Tumor Atlas Network Consortium of the National Cancer Institute, which is part of the National Institutes of Health (R01 CA185138-01, U2C CA-17-035, UO1 CA214183, R01CA193694). Other funding support was from the Department of Defense (BC132057); The Breast Cancer Research Foundation (19-074, 19-028, 18-006); PRECISION CRUK Grand Challenge (AEI RYC2019- 026576-I); “la Caixa” Foundation (LCF/PR/PR17/51120011); the Lundbeck Foundation (R288-2018-35); the Danish Cancer Society (R229-A13616); and Susan G. Komen.

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Many of these families are refugees — from at least seven different countries in Africa, Asia, and the Middle East — who speak Farsi, French, Swahili, Arabic, and other languages. They are building new lives in North Carolina, in a culture and language that is new to many of them. As is the case with many similar communities, their healthcare needs often go unmet. The investigators believe that, compared to traditional methods, mixed-method research is an improved way to establish a community partnership, highlight gaps in the community’s knowledge and risk perception, and pave the way for successful future health interventions. According to co-PI Nosayaba (Nosa) Osazuwa-Peters, BDS, MPH, PhD, an associate professor in the Department of Head and Neck Surgery & Communication Sciences, Project CHECKERS takes an important step in improving community engagement. “Traditional research is very systematic, very top-down. The researchers have knowledge and decide what they believe the community needs. But these outside scientific experts do not know the values, the culture, the knowledge, or the risks inherent in that community,” he explained. For example, traditional surveys restrict participants to answering either yes or no; for many people, that binary does not tell a complete story. “Project CHECKERS will help us understand the lived experiences of people in these communities,” added Osazuwa-Peters. “We’ll learn about context, and we’ll learn to ask questions that allow community members to express themselves. We’ll get responses we would never get based on yes or no.” Building a Partnership Project CHECKERS kicked off this fall with focus groups and interviews with community members facilitated by Laura Fish, PhD, MPH, assistant professor in Family Medicine and Community Health, Duke University School of Medicine, and program director for the Behavioral Health and Survey Research Core (a DCI shared resource). An advisory board will provide feedback from both clinical and community perspectives. Lessons learned from these conversations will help the team develop a knowledge and risk factor survey that will be administered during two head and neck cancer screening events with the community in 2024. The CHECKERS team will also recruit providers outside the department to participate in these events to address other health concerns in the community such as primary care, mental health, and women’s health. 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