Over the last decade, scientists have come to realize there is no one breast cancer. It’s actually a collection of molecularly unique diseases, making the challenge of complete responses for patients even more daunting. Fortunately, the identification of the various, distinct molecular subtypes has led to several important breakthrough therapies that have greatly improved survival.
One of these subtypes, HER-2, is a protein naturally expressed at times in the breast during ductal growth, becoming abnormally expressed in about 20 percent of breast cancers. HER-2 was a particularly aggressive and often fatal subtype of breast cancer — until scientists designed a targeted therapeutic antibody against this molecule known as trastuzumab (Herceptin).
When given with chemotherapy, this antibody reduced recurrences of patients with HER-2 positive breast cancer. Combining it with a second antibody, pertuzumab, as well as chemotherapy, further increases complete responses.
Having all disease disappear from the breast and lymph nodes prior to surgery encourages a better prognosis for these patients. Yet despite the use of these HER-2 targeted antibodies, some patients become resistant and can experience a recurrence of HER-2 positive breast cancer.
Biology is pointing towards the immune system to help control and eliminate these tumors. Interestingly, recent studies suggest that having a strong immune response against HER-2 also influences how a patient responds to therapy. The presence of an immune response in the breast cancer area is key.
Other researchers have suggested that a loss of a specific anti-HER-2 CD4 immune cell in the blood occurs during breast cancer growth. Measuring this response and how it changes with therapy can predict a patient’s response to chemotherapy, trastuzumab and pertuzumab — and may predict those at risk to recur.
So the logical question is what can be done to restore this immune response? Several new vaccine approaches to restoring this immune response are on the horizon. A multicenter study, in collaboration between immunologists and oncologists at the Moffitt Cancer Center and the University of Washington, has initiated a clinical trial aimed at restoring this immune response to prevent recurrence.
The immune response is now acknowledged to play a much larger role in breast cancer than originally thought. New therapies that prevent the immune response from turning itself off are showing promise in another subtype of breast cancer called basal or triple negative breast cancer. These antibodies essentially take the brakes off the immune response, causing it to go into “hyper mode.” If these patients have T lymphocytes in the breast tumor, they can be reactivated using a class of molecules called checkpoint inhibitors.
Patients with triple negative breast cancer have already experienced complete disappearance of widely metastatic breast cancer. While this currently works in only small percentages of patients, it is anticipated that these molecules — combined with chemotherapy, radiation therapy or other immune therapies — will lead to greater numbers of responses, and thus more women cured of this aggressive subtype of breast cancer.
The most common forms of breast cancer, Luminal A and Luminal B, express the receptor for estrogen and are commonly known as estrogen receptor (ER-positive) tumors. For years women have been treated with antiestrogens that, like trastuzumab, decrease the risk of breast cancer returning.
Unfortunately for some, even years later these ER-positive tumors can recur.
However, there is growing excitement in the battle for these women: a new, targeted class of drugs called Palbociclib that interferes with the cell replication machinery. These medications inhibit the cell from signaling to replicate, and particularly when combined with anti-estrogens, have had significant positive effects in women with metastatic ER-positive breast cancer. New versions of these medications are now actively being tested, and it is hoped that when used in earlier stages of disease in high-risk women, will decrease the incidence of later recurrences.
Luminal A and Luminal B breast tumors are also impacted by the immune response. While these breast cancers have less frequent accumulation of lymphocytes present compared to HER-2 positive and triple negative breast cancer, this does not mean the immune response is any less impactful.
In fact, infiltration of tumors with anti-tumor lymphocytes during chemotherapy, along with elimination of inhibitory lymphocytes that shut off the anti-breast cancer response, may be critical to making chemotherapy effective.
Combinations of immune manipulations with vaccines and anti-estrogen therapies are also beginning to be recognized as potent breast cancer-fighting combinations.
The definition and better understanding of breast cancer subtypes is allowing scientists to design more specific — and less toxic — targeted molecules to combat breast cancer. But these new agents may require crossing paths with the immune response to truly bring new hope for effective cures to breast cancer patients.
Dr. Brian Czerniecki, MD, PhD, chair and senior member of the Department of Breast Oncology at Moffitt Cancer Center.
The views expressed by contributors are their own and not the views of The Hill.
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