Women with a BRCA1 genetic mutation are at high risk for an aggressive form of breast cancer. But immunotherapies may beat BRCA1 cancer.
In 2013, actress Angelina Jolie revealed she had a double mastectomy — not because she had breast cancer, but because she feared getting the same aggressive type of malignancy her late mom had experienced. Jolie explained in a New York Times editorial tests showed she had inherited a harmful mutation in a gene known as BRCA1, placing her at high risk for a difficult-to-treat form of breast cancer known as triple-negative.
While about 12 percent of women in the U.S. will develop breast cancer during their lifetime, the risk of breast cancer soars to between 55 and 65 percent by age 70 for women like Jolie who have the BRCA1 mutation; the related BRCA2 mutation raises the risk of breast cancer to 45 percent, according to the National Cancer Institute. These genetic forms of cancer are also linked to a higher incidence of ovarian cancer.
Like Jolie, women with either of the BRCA mutations may opt for surgery to have their breasts and ovaries removed to greatly lower the odds of developing cancer. Those who decide against prophylactic mastectomies typically are screened regularly for breast cancer. But while it’s true breast cancer caught early is often highly treatable and even curable, that’s not usually the case with the aggressive type of breast cancer associated with the BRCA1 gene mutation.
However, there’s a potential new treatment on the horizon for this form of breast cancer. A team of Australian scientists think they’ve found a way to spur the immune system of women with BRCA1 cancer to defeat the malignancy.
Here’s why finding a new approach to treating genetic BRCA1 breast cancer is sorely needed.
In other, more common forms of breast cancer, there are often hormone receptors in the breast tumor; estrogen and progesterone latch onto these receptors, spurring on the tumor growth. Cancer cells removed during breast cancer surgery or biopsies are tested to see if a tumor is hormone receptor positive or negative. If positive for estrogen or progesterone receptors, cancer drugs can block the hormones and prevent breast cancer from growing and spreading.
Unfortunately, BRCA1 breast cancers lack hormone receptors, the American Cancer Society explains, and they are more like likely to be triple-negative cancers. The tumors are called triple-negative because they not only don’t have estrogen or progesterone receptors, but they also test negative for a protein called human epidermal growth factor receptor 2 (HER2), which can trigger the growth of cancer cells.
A lack of HER2 may sound like an advantage, but it’s not. Being HER2 negative limits treatment choices. HER2 positive breast cancers are highly treatable using drugs to block the protein. But since women with BRCA1 breast cancer are HER2 negative, HER2 blocking drugs can’t help them.
Bottom line: While chemotherapy and surgery can still be somewhat useful in treating BRCA1 breast cancer, other therapies used to treat breast cancer — hormone blockers and HER2 blockers — simply aren’t effective for triple-negative BRCA1 malignancies. The result is BRCA1 cancers tend to grow and spread faster and more aggressively than most other types of breast malignancies. However, a research team from the Walter and Eliza Hall Institute for Medical Research and the Peter MacCallum Cancer Center in Melbourne, Australia, have discovered a treatment they believe could halt triple-negative breast cancers.
Their study, published in Science Translational Medicine, suggests a combination of two already existing immunotherapy drugs — anti-PD1 and anti-CTLA4 immunotherapies — could harness the immune system of patients with BRCA1 mutation breast cancers to successfully treat their disease.
Some cancer cells have the ability to “switch off” and avoid tumor-destroying immune cells, the researchers explained. But the anti-PD1 and anti-CTLA4 immunotherapies, known as immune checkpoint inhibitors, are capable of over-riding cancer cells’ ability to block critical immune cells, allowing the immune system to attack a malignancy.
“BRCA1-related triple negative breast cancers have some of the most ‘chaotic’ genomes, and we see many immune cells accumulate in and around the tumor,” said researcher Daniel Gray, PhD, a cancer genetics expert. “This suggests that the immune cells can readily detect that something is awry, but they aren’t able to respond properly, because they have been disabled by tumor cells. We showed that a combination of anti-PD1 and anti-CTLA4 therapies restored their ability to attack and kill triple-negative breast tumor cells, and very effectively control tumor growth.”
Although the study by Gray and colleagues was performed in a laboratory model, previous research has shown these immunotherapy drugs are especially effective at treating tumors marked by genetic mutations. In fact, the drugs have been called a “game changer” for some previously difficult to successfully treat melanomas and lung cancers.
The findings have increased interest in testing the combined immunotherapy in women with BRCA1 breast cancers. In fact, scientist Sherene Loi, PhD, head of breast cancer clinical trials research at the Peter MacCallum Cancer Center, announced work is underway to test the treatment in women with BRCA1 breast cancer.
“Our lab-based findings provide compelling evidence to progress to a clinical trial of this combination of immunotherapy drugs, and chemotherapy, in women with BRCA1-related breast cancer,” Loi said. “There is also a rationale to consider the same for BRCA2-related cancers and triple-negative breast cancer more broadly.”
“Importantly, there are already a number of immunotherapy-based clinical trials underway in breast cancer, and these two drugs — anti-PD1 and anti-CTLA4 — are in use for other cancers, so we would hope to begin a trial of this specific combination of immunotherapies in suitable breast cancer patients in the near future.”
March 16, 2020
Christopher Nystuen, MD, MBA