Kornelia Polyak, MD, PhD
Professor of Medicine, Dana-Farber and Harvard Medical School
Co-leader, Harvard Cancer Consortium Cancer Cell Biology Program
Why do some early breast cancers spread while others remain harmless? For nearly three decades, Kornelia Polyak, MD, PhD, a breast cancer researcher at Dana-Farber Cancer Institute, has worked to answer that question. Her efforts have produced discoveries that are reshaping scientists’ understanding of how breast cancer develops and creating new opportunities to predict risk, guide treatment decisions, and potentially prevent the disease before it begins.
The latest advances from Polyak’s laboratory include the identification of a specific immune-cell population associated with the progression of ductal carcinoma in situ (DCIS), an early non-invasive form of breast cancer. This finding may help clinicians distinguish which cases are likely to become dangerous and which are not. Her team is also developing a first-of-its-kind preventive vaccine that, in preclinical studies, stopped breast tumors from forming. Together, these discoveries are opening new possibilities for both precision risk assessment and cancer prevention.
Following the Biology of Progression
Polyak’s search for answers began with DCIS. Sometimes called stage 0 breast cancer, DCIS is an abnormal growth of cells confined to the milk ducts that has not spread into surrounding breast tissue. While many cases never become life-threatening, clinicians have long struggled to determine which patients require treatment and which can be safely monitored.
Researchers initially believed the answer would be found within the cancer cells themselves. The prevailing theory was that additional genetic mutations drove the transition from DCIS to invasive cancer. But when Polyak and her colleagues compared DCIS with invasive breast cancers, they found surprisingly few differences.
“We discovered that the genes mutated in breast cancer are already mutated in DCIS,” she explains.
The finding prompted a shift in focus. Rather than searching for additional genetic changes within cancer cells, Polyak and her colleagues began looking more closely at the environment surrounding them.
The answer appeared to lie in the tumor microenvironment—the community of immune cells, connective tissue, blood vessels, and other normal cells that surround a tumor. Studies from Polyak’s laboratory showed that dramatic changes occur in this environment as breast cancer progresses, even when the cancer cells themselves show few differences. The team found alterations in the myoepithelial layer, a protective layer of cells that surrounds breast ducts, as well as changes in the surrounding supportive tissue known as the stroma. These findings helped demonstrate that the environment around a tumor plays a critical role in shaping how breast cancer develops and progresses.
While many cases never become life-threatening, clinicians have long struggled to determine which patients require treatment and which can be safely monitored.
I want to cure people, but I would like even more to prevent cancer from developing in the first place.
Kornelia Polyak, MD, PhD
Recent work from Polyak and collaborators has helped address that challenge. In a 2022 Cancer Cell study, researchers identified molecular features associated with clinical outcomes in DCIS, providing important insights into which cases may be more likely to progress.
As technologies advanced, Polyak’s lab continued to challenge conventional assumptions. Her team became a leader in studying intratumor heterogeneity—the presence of multiple distinct populations of cancer cells within a single tumor. Rather than acting as a uniform mass, tumors often contain diverse groups of cells that interact with one another and respond differently to treatment. In influential studies that helped shape the field, the researchers showed that this diversity can actively contribute to tumor growth and treatment resistance, helping explain why some therapies succeed while others fail.
The Immune System Comes into Focus
As her research evolved, Polyak’s attention also increasingly turned to the role of the immune system in cancer. Her work suggested that cancer development is shaped not only by what happens within a tumor, but also by the condition of the person in whom that tumor develops.
“Everything interacts in your body,” Polyak says. “The preexisting condition of the host determines your cancer risk and whether you get progressive cancer or not.”
This broader perspective ultimately led to one of the lab’s most promising recent discoveries.
Using single-cell analysis, a technology that allows researchers to examine individual cells one at a time, Polyak’s team identified a specific type of immune cell known as a regulatory T cell, or Treg. Under normal circumstances, Tregs help prevent the immune system from attacking healthy tissues. However, the researchers found a subset of these cells, called “cycling Tregs,” that appears to suppress the body’s ability to recognize and eliminate developing cancer cells during the transition from DCIS to invasive disease. This finding was recently published in Cancer Cell.
“These cycling Tregs seem to be predicting progression,” Polyak points out. “They’re really important for establishing immune suppression.”
For the hundreds of thousands of women diagnosed with DCIS each year, the implications could be significant. If validated in additional studies, the findings could help clinicians distinguish which patients are most likely to develop aggressive disease and which may be able to avoid unnecessary treatment. The research also suggests a potential new therapeutic strategy: targeting these immune cells to strengthen the body’s natural anti-cancer response.
From Understanding Cancer to Preventing It
The same focus on the immune system is now driving Polyak’s efforts to prevent breast cancer altogether.
Her laboratory is developing a preventive vaccine designed to stop cancer before it forms. The vaccine targets proteins, known as antigens, that are found primarily in breast tissue. By training the immune system to recognize and eliminate abnormal breast cells before they become cancerous, the approach prevented tumor formation in preclinical models.
“I want to cure people, but I would like even more to prevent cancer from developing in the first place,” Polyak stresses.
For women at especially high risk of breast cancer, including those with inherited cancer-predisposing mutations, such an approach could one day offer an alternative to preventive surgeries such as prophylactic mastectomy, which removes healthy breast tissue to reduce cancer risk.
Beyond prevention, Polyak’s team continues to apply these insights to challenging forms of breast cancer, uncovering new biological vulnerabilities that could lead to more effective treatments.
Looking Ahead
Achieving these advances has required sustained investment from both public and private partners. Polyak’s research has been supported by the National Institutes of Health, the Breast Cancer Research Foundation, Susan G. Komen, the Ludwig Center at Harvard, the V Foundation, the Sidney Kimmel Foundation, Breast Cancer Alliance, Metavivor, Avon Foundation, DOD, Harvard-MIT Bridge grant, National Foundation for Cancer Research, American Cancer Society, Cancer Prevention Initiative, Mark Foundation, and the American Society of Clinical Oncology. Their support has enabled the long-term research needed to uncover the biological mechanisms that drive breast cancer progression.
Many of these efforts are strengthened by collaborations across Dana-Farber and the broader Harvard research community, including work with colleagues such as Nancy Lin, MD, founder and director of the Metastatic Breast Cancer Program and the Program for Patients with Breast Cancer Brain Metastases at Dana-Farber, and Matthew Vander Heiden, MD, PhD, Director of the Koch Institute for Integrative Cancer Research at MIT, to translate discoveries in breast cancer biology into new opportunities for patients.
Polyak’s current focus is on moving these discoveries toward the clinic. She and her colleagues are working to generate the data needed to validate their findings, launch clinical studies, and determine how new approaches to risk prediction and prevention can be incorporated into patient care. The ultimate aim is to ensure that discoveries made in the laboratory will lead to meaningful benefits for the women who need them most.
Team Members: Kornelia Polyak, MD, PhD, Nancy Lin, MD, Matthew Vander Heiden, MD, PhD
Team Members
Nancy U. Lin, MD
Associate Chief, Division of Breast Oncology, Dana-Farber
Founder and Director, Metastatic Breast Cancer Program and the Program for Patients with Breast Cancer Brain Metastases
Professor of Medicine, Harvard Medical School,
Matthew Vander Heiden, MD, PhD
Director, Koch Institute for Integrative Cancer Research
Lester Wolfe (1919) Professor of Molecular Biology, MIT
