A tumor that inhibits the immune system. That seems to be going on in some women with breast cancer as well as a mutation in the BRCA-1 or -2 gene, according to research by Dr. Quirine Manson at UMC Utrecht. "It seems that these patients may possibly benefit from immunotherapy. So far, that has been available mainly for patients with metastatic lung or skin cancer." Breast cancer is the most common form of cancer in women. In the Netherlands, more than 15,000 people are diagnosed with the disease every year. Despite a sharp decline in mortality from breast cancer, more than 3,000 women still die from it each year. Treatment for the disease can include hormone, drug and or chemotherapy, surgery and radiation.

Hereditary predisposition

Of the women who develop breast cancer, about 5 to 10 percent have an inherited predisposition for it. They have a change (mutation) in the DNA of the BRCA-1 or BRCA-2 gene. Women with this mutation have a 60 to 80 percent risk of developing breast cancer at some point in their lives. For women without the BRCA-1 or -2 mutation, that risk is about 15 percent. Breast cancer can also occur in men. If they have the BRCA-1 or-2 mutation, the risk of developing this disease is 3 to 7 percent.

Insensitive

In a portion of patients with breast cancer, hormone therapy or treatment with trastuzumab falls off as a form of treatment. The reason is that the type of tumor they have is insensitive to it. This is also called triple-negative breast cancer. This occurs in 15 percent of patients with breast cancer without and in 60 percent of these patients with a BRCA mutation. "It is possible that immunotherapy could provide a solution for these women in the future," Dr. Manson says. In the laboratory, among other things, she examined immune responses in tissue from "normal" breast tumors and breast tumors from patients with a BRCA mutation. On June 25, she received her doctorate on her research.

Good and long lasting

Immunotherapy in cancer aims to support the patient's own immune system in such a way that it recognizes and destroys cancer cells. To date, immunotherapy is mainly used for metastatic lung cancer and metastatic skin cancer (melanomas). Dr. Manson: "We know that immunotherapy has good and long-lasting results when patients do respond to it. There are also fewer side effects than with chemotherapy, for example." Researchers are studying whether immunotherapy can also be effective in treating other cancers, such as triple-negative breast cancer, which is not sensitive to hormone therapy.

Brake off

Laboratory research by Dr. Manson shows that in some patients with breast cancer and a mutation in the BRCA-1 or -2 gene, the immune system is strongly inhibited by the tumor. This is how it works: the protein PD-1 regulates the immune response. When it binds to the molecule PD-L1, the immune response is inhibited. Normally, this is how the body protects itself from autoimmune reactions, where the immune system needlessly goes wild. A useful function, in other words. But in breast cancer patients with a BRCA-1 or -2 mutation, PD-1 and PD-L1 become active more often than in breast cancer patients without this mutation and, coupled with each other, inhibit the immune system more strongly. "Immunotherapy prevents PD-1 and PD-L1 from binding to each other," Quirine explains. "By thus taking the brake off the immune system, it gains more clout against tumor cells." Precisely because patients with breast cancer and a BRCA-1 or -2 mutation have a higher risk of breast cancer ánd in 60 percent hormone therapy fails, they may be good candidates for immunotherapy, according to Dr. Manson. Her findings prompt additional clinical research into this.

Nobel Prize

The 2018 Nobel Prize in Medicine went to James P. Allison and Tasuku Honjo. They discovered how the brake function of the immune system works and succeeded in uncoupling the brake from immune cells. That discovery laid the foundation for immunotherapy in cancer. This is not the first time a cancer treatment has received the Nobel Prize. In 1988, for example, the prize went to Gertrude Elion and George Hitchings for developing drugs for chemotherapy. Still, according to the Nobel committee, the subject is as relevant as ever. "Worldwide, millions still die of cancer every year, so new treatments remain desperately needed.