A study by researchers at the University of Southampton discovered that “crown-like structures” (CLSs) associated with the fat cells in HER2+ breast tumors could hinder the response of some patients to therapy. The results showed that CLSs were more commonly found at the adipose-tumor border (B-CLS) in HER2+ breast cancer, and also linked the presence of multiple B-CLS structures with faster time to metastasis in overweight or obese patients treated using the monoclonal antibody trastuzumab, when compared with treated patients who weren’t overweight. The team, led by Stephen Beers, PhD, Ramsey Cutress FRCS, PhD, and Charles Birts, PhD, suggests the study findings could help lead to improved personalized treatments for patients with HER2+ breast cancer.
Beers and colleagues reported on their study in Scientific Reports, in a paper titled, “Prognostic significance of crown-like structures to trastuzumab 1 response in patients with primary invasive HER2+ breast carcinoma.”
Adipose (fat) tissue is an important component of the healthy human breast, but high body mass index (BMI) is associated with increased risk of developing breast cancer, the authors wrote. Overweight cancer patients also have worse survival rates than those with a healthy body weight. “There is consequently significant interest in understanding the dynamic endocrine and immunological activity of the breast and how high BMI impacts these systems and ultimately influences pathology,” they noted.
In patients with a high BMI, increased body fat surrounding the breast can cause inflammatory macrophage immune cells to gather in the breast fat tissue. These macrophages can then form crown-like structures by surrounding the fat cells. This creates an inflammatory environment in the breast, which can lead to the onset and growth of tumors. How these crown-like structures go on to affect breast cancer progression and respond to therapy is largely unknown. “The prognostic significance of CLS and consequently of white adipose tissue inflammation in patients with HER2+ primary breast cancer is largely unknown.”
The research team assessed samples from 69 trastuzumab-naïve and 117 adjuvant trastuzumab-treated HER2+ breast cancer patients to investigate the link between high BMI and the formation of crown-like structures, and the subsequent effect of these on how patients responded to therapy with trastuzumab. As far as the investigators were aware, no studies had previously assessed directly how the spatial proximity of breast CLS to the adipose/tumor border might impact prognosis and response to therapy. “To our knowledge, this is the first study that reports the role of CLS on therapeutic responses in patients with HER2+ breast cancer,” they further noted.
The results showed that patients who were overweight or obese had significantly more crown-like structures in their fat tissue surrounding the tumor, and that this was associated with a faster time to metastatic disease, an indication of how well the patients have responded to therapy.
They went on to identify a potential molecular biomarker, called CD32B, on the surface of the macrophages in the crown-like structures. When the marker was present in overweight and obese patients, their response to trastuzumab therapy was poorer. “Subgroup analysis showed that the presence of CD32B+ B-CLS was associated with worse disease-free survival in trastuzumab-treated patients with BMI ≥25 kg/m2,” the investigators wrote. “Multivariable analysis revealed that the presence of CD32B+ B-CLS is an independent prognostic factor for metastatic disease.”
Beers, a professor of immunology and immunotherapy at the University of Southampton said, “These findings will be of interest to clinicians and researchers involved in breast cancer treatment as they could potentially be used to develop personalized treatment in patients with HER2 positive overexpressed breast cancer. For example, doctors would know that patients with a high BMI and the marker on their crown-like structures are likely to have a poor response to trastuzumab therapy. They may therefore benefit from more intensive anti-HER2 therapy earlier in their treatment. On the other hand, this study highlights how effective trastuzumab treatment is in patients that do not have the marker. So these patients could benefit from a lower dose of anti-HER2 therapy which may minimize the side effects they experience. Further studies with more patients will be needed to help confirm these initial findings.”
In conclusion, the authors noted, “… we provide evidence which indicates that the presence of B-CLS correlates with clinical outcomes and therapeutic responses in patients with HER2-overexpressed breast cancer. Also, CD32B positivity of B-CLS may represent a predictive biomarker which could potentially be used to optimize the stratification and personalization of treatment in HER2-overexpressed breast cancer patients.”
The research team is now looking at ways to change the behavior of these crown-like structures to improve responses to breast cancer therapy.