NEW YORK – Researchers at the University of Southampton have identified a biomarker that they believe could help guide anti-HER2 treatment decisions for HER2-positive breast cancer patients, particularly those who are overweight or obese.
The research, which was published Tuesday in Nature Scientific Reports, showed that a specific formation of macrophages in the body fat tissue in and around the breast, called "crown-like structures" can influence patients' response to treatment with Genentech's Herceptin (trastuzumab).
"It's generally accepted that there's an association between the prevalence of crown-line structures in adiposity and obesity," said Charles Birts, a lecturer in antibody therapeutics at the University of Southampton and one of the lead authors of the Scientific Reports paper. "But [data on] what their role was and how they could influence response to therapy was contradictory."
Prior research had produced a range of findings on the association between body fat — called adipose tissue — and breast cancer prognosis and treatment response. But Birts and his team wanted to clarify exactly how these crown-like structures' location in the breast tissue and molecular markers influenced breast cancer metastases and treatment response.
To conduct the study, Birts and colleagues analyzed a cohort of 188 patients who had been diagnosed with HER2-positive invasive breast cancer between 1982 and 2012 at the University Hospital Southampton National Health Service Foundation Trust.
Importantly, because of the date range of these samples, a decent percentage of patients analyzed in the study had predated the routine use of Herceptin for HER2-overexpressing breast cancer. This allowed the researchers to assess the biomarker's prognostic significance independent of Herceptin.
"In a way, it's quite a fortuitous cohort," Birts said. "That's what allowed us to compare those patients who had been treated with it and those who hadn't."
The researchers analyzed the phenotype of these crown-like structures, as well. What they ultimately found through a combination of immunohistochemistry tests and microscopic analysis, was that the crown-like structures were more frequently located at the border between the breast cancer tumor and the body fat tissue when patients' body mass index (BMI) was at least 25.
The macrophages that made up these structures were more often CD16-positive and CD32B-positive in these overweight patients, and these surface markers — particularly the CD32B-positivity — were associated with a shorter disease-free survival time and poorer response to Herceptin among overweight patients. To rule out the possibility that other health risks associated with high BMI were driving the shorter disease-free survival time and Herceptin response, Birts and researchers performed a multivariable analysis. Here, they found that the presence of CD32B-positive crown-like structures located near the border of the fat tissue and the breast cancer tumor were themselves an independent prognostic factor for metastatic breast cancer.
With the caveat that more research is needed to confirm exactly how this specific type of crown-like structure plays into tumor metastases and treatment response, Birts spoke to the potential mechanism at play.
"Adiposity in patients with high BMI is known to induce tissue inflammation … which has the effect of increasing adipokine expression and cytokine expression, recruiting immune cells into that environment," he explained. "We then think that could cause metabolic dysfunction in those immune cells such as in the macrophages we see in those areas of high adiposity."
In overweight patients, he continued, the tissue inflammation and immune cells' metabolic dysfunction in the area surrounding tumor cells can prevent the immune cells from effectively clearing the cancer cells. Instead, the cells support tumor growth.
In patients without a high BMI, in contrast, "you don't have this underlying level of inflammation, so you don't get this metabolic dysregulation of the immune cells in that area, and they are able to work more effectively with their cancer-clearing roles."
Birts underscored that the presence of these crown-like structures in this tumor-border area with the particular CD32B-positive phenotype correlated better with disease-free survival time and response to therapy than did BMI on its own.
Among HER2-positive patients treated with adjuvant Herceptin who had at least one crown-like structure located at the tumor-adipose border that was CD32B-positive, the metastases-free survival time was significantly shorter, the researchers found.
"What really surprised us was how striking the effect of having these CD32B-positive border crown-like structures was on the response to therapy," Birts said. "It was to the point where, after we performed the analysis, it looked like those patients who had those … structures just hadn't received trastuzumab therapy. It looked like these border crown-like structures had effectively negated any therapeutic benefit in those patients."
Potential biomarker utility
Going forward, Birts and colleagues said, it could be possible to evaluate the tissue surrounding patients' breast cancer tumors and determine, accordingly, whether they might benefit from more intensive therapy than Herceptin alone, or vice versa.
Theoretically, "if this was introduced into the clinic tomorrow, what would happen is that a patient would go in and get a biopsy from their tumor, and we'd then perform immunohistochemistry staining on that biopsy for … the macrophage marker," he explained. "Then, it would be a matter of having a pathologist look at those stained biopsies under a microscope and look for those CD32B-positive crown-like structures upon the border where the adipose meets the tumor."
Based on these findings, for patients who have many of these crown-like structures and a BMI over 25, oncologists might begin with a more intensive therapeutic strategy, which Birts said could possibly involve combination treatment or a HER2-directed antibody drug conjugate such as Genentech's Kadcyla (trastuzumab-emtansine) or Daiichi Sankyo/AstraZeneca's Enhertu (trastuzumab deruxtecan).
It might be possible to detect some of these structures using imaging approaches, too, Birts added, though his team has yet to evaluate this. If this were possible, it could potentially eliminate the invasive biopsy element of testing for the biomarker, since patients who didn't have border crown-like structures wouldn't need CD32B testing.
All of these hypotheticals will need additional research before they can be applied by oncologists to guide treatment strategies for patients. According to Birts, some of these next-step studies are already in the works, though.
Later this year, he and his team are hoping to publish a paper on the activity of antibody therapy in combination with metabolic inhibitors in these patients, and in the longer term, they hope to validate these findings prospectively in patients who are actually treated according to these biomarkers.
As they work to validate the biomarkers, Birts said that he and his team are working to better detail the molecular mechanisms underlying these findings. "By better understanding what these mechanisms are, we will hopefully be able to target them better."
In looking at the importance of this research with a wider lens, Birts reflected that there is a pressing need to conduct these studies in obese patients with cancer, given the rising rates of obesity, particularly in the US, UK, and Western world. While many studies have hammered home the fact that high BMI is associated with poorer outcomes on the whole, few have identified the aspects of obesity, on a "basic science" level, that play into poorer prognoses and impact therapy response, and then further considered how to mitigate these factors.
"We're lucky we have had the funding … to allow us to do this work," he said. "But this area needs a lot more critical investment from funders, especially as it becomes much more important in the clinic."