Is There a Future for Immunotherapy in Breast Cancer?

Lately, immunotherapy—treatment that helps the body’s own immune system fight cancer—has made frequent appearances in news headlines. Indeed, researchers have reported remarkable clinical trial results for a new class of drugs known as ‘immune checkpoint blockade drugs‘ in the treatment of metastatic melanoma, lung, and kidney cancers. Approvals from the U.S. Food and Drug Administration (FDA) for the drugs Keytruda and Opdivo for melanoma and lung cancer have quickly followed. However, it may be that immunotherapies won’t work for all cancers, but only for those considered to be ‘immunogenic’; that is, cancers that trigger activation of the immune system. Researchers are studying different types of breast cancer to determine whether they are immunogenic, and what that might mean for their prognosis and treatments.

When pathologists examine a biopsy of a tumor, they sometimes notices an accumulation of certain immune system cells within the tumor or in the surrounding normal tissue (stroma). The presence of these cells, called ‘tumor-infiltrating lymphocytes’ (TILs), is a rough indication that the tumor has attracted the attention of the immune system, resulting in migration and accumulation of TILs. TILs may signal that immunotherapies could be used to further activate the immune system to destroy the tumor.

In a large study completed 5 years ago, more than 1,000 breast tumor biopsies were analyzed for TILs prior to neoadjuvant (before surgery) chemotherapy with anthracycline and taxane drugs. Patients with high TIL levels had better responses to chemotherapy: 40% of patients with high TIL levels responded, versus only 5% of patients with low TIL levels.

These findings were confirmed by another study, in which researchers analyzed the ‘immune signature’ of breast cancers. They examined whether immune system genes were ‘switched on’ (expressed) in tumors, indicating the presence of TILs. Patients whose tumors had an activated immune signature (higher expression of genes associated with immune function) had better responses to neoadjuvant therapy; the results held true for all breast cancer subtypes.

More focused studies have examined the significance of TILs and immune signatures in different subtypes of breast cancer. Triple-negative breast cancers (TNBCs) have shown a particularly strong correlation between the presence of TILs in tumor stroma and disease-free survival, as well as overall survival. Similar observations have been made for HER2-positive cancers. To quote just one of several studies, the percentage of patients who responded to neoadjuvant therapy was 59.9% for those with “immune-rich tumors” and 33.8% for patients with “immune-poor” tumors.

A recent study also showed that an activated immune signature predicts a better response to Herceptin in women receiving it as an adjuvant (after surgery) therapy for HER2-positive cancer. Since Herceptin works by tagging onto tumor cells and eliciting their destruction by immune cells, these results are perhaps not entirely surprising.

The correlation between immune signatures in TNBC and HER2-positive breast cancer and responses to chemotherapy and Herceptin, respectively, could become a valuable tool in choosing the most relevant treatments for each patient. But could immune signatures also help predict responses to immunotherapies?

It is probably too early to predict whether breast cancers may be responsive to the immune checkpoint blocker drugs that have shown unprecedented success in melanoma (Keytruda and Opdivo, now FDA-approved) and lung cancer (Opdivo, FDA-approved for squamous lung cancer). So far, only one report has described preliminary data on the efficacy of Keytruda in TNBC. At the San Antonio Breast Cancer Symposium last year, researchers reported that Keytruda produced responses in 5 of 32 patients, including 1 patient who had no more signs of her tumor after treatment; 7 patients had their disease stabilized. This is encouraging; however, as observed in other cancers treated with so-called PD-1 blocker drugs, there is a need for a way to identify which patients are most likely to respond. Nevertheless, clinical trials of immunotherapy drugs in metastatic breast cancer are ongoing, including at least five with Keytruda and two with Opdivo.

What about patients whose tumors are unlikely to respond to immune checkpoint blockers? Patients whose tumors have low TILs or low-activity immune signatures? It would be highly desirable to find treatments that enhance response to immunotherapies for these patients.

Three oncologists recently suggested that the immunogenicity of breast cancers could be enhanced by using radiation therapy before giving immunotherapy drugs. Animal testing has shown that applying local radiation to just one of several metastatic tumors can activate the immune system. By killing some tumor cells and ‘spilling’ their proteins for presentation to immune cells, radiation may activate the immune system to recognize and attack tumor cells in other parts of the body. This attractive hypothesis is already being explored in clinical trials.

A clinical trial in Australia (NCT02303366) will soon begin recruiting breast cancer patients with bone metastases to test whether localized radiotherapy may boost responses to Keytruda. And, a trial in Philadelphia (NCT02303990) will recruit patients with several types of cancer, including breast cancers, to examine if hypofractionated radiation therapy followed by Keytruda is effective.

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