Uncovering Hidden Complexity of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) has long been considered one of the most aggressive and least understood forms of breast cancer. Defined by the absence of three key markers—estrogen receptor, progesterone receptor, and HER2 overexpression—TNBC represents a heterogeneous group of tumors that, until now, have largely been treated the same way.Researchers at the Duke Cancer Institute, led by Maggie DiNome, MD, surgical oncologist with the DCI breast oncology program, are working to change that.While TNBC tumors are classified as HER2-negative, many exhibit low levels of HER2 expression. Recent Duke studies reveal that this distinction is clinically significant.The analysis of a large national database showed that TNBC tumors with HER2-low expression respond less effectively to chemotherapy compared to those with no HER2 expression at all. This finding prompted deeper investigation into the molecular differences between these subtypes.The team discovered that HER2-low TNBC tumors exhibit an immune-evasive profile. These tumors and their surrounding microenvironment show reduced immune cell presence and hypermethylation of genes critical for immune recognition. This matters because the current standard of care for early-stage TNBC includes chemotherapy combined with immunotherapy yet over a third of patients do not respond to this combination therapy.“HER2-low tumors create an environment in and around the tumor that evades the immune system better than HER2-zero tumors,” DiNome said.Preliminary multicenter data suggest that patients with HER2-low tumors have a lower pathologic complete response rate to chemo-immunotherapy compared to those with HER2-zero. These findings could transform how clinicians approach TNBC treatment.“Not all patients respond to immunotherapy, and immunotherapies are not without pretty significant risk” DiNome said. “If we can define the patient set that might not respond, we can save them from the morbidity of that treatment.”This research also opens the door to new strategies, such as combining immunotherapy with antibody-drug conjugates like trastuzumab deruxtecan, which has shown promise in HER2-low tumors.The DCI team is pursuing grant funding to explore mechanisms driving immune evasion and to test synergistic therapies that could improve outcomes for HER2-low patients. They are also investigating the role of epigenetic regulation and external factors, such as comorbidities, stress, and lifestyle, in shaping the immune environment.

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