How Research is Turning the Tide on Triple-Negative Breast Cancer

In honor of TNBC Day on March 3, BCRF reflects on hopeful recent gains against this form of the disease

Most therapeutic success stories in breast cancer are because of the rational design of therapies. Researchers were able to uncover the right therapeutic target in estrogen receptor (ER)–positive tumors, which largely depend on estrogen, and HER2-positive tumors, which depend on HER2 signaling. By blocking certain pathways and the cancers’ growth, these drugs ultimately proved effective for most breast cancer cells. But for triple-negative breast cancer (TNBC), therapeutic targets—molecular processes that cancer cells need to survive—have been much more difficult to find.

Researchers fully understand the urgency of this disease, which has historically been without viable targeted therapies because it’s defined by the fact that it lacks three major factors used to classify and more effectively treat breast cancer: ER, PR (progesterone receptor), and HER2. Inherently, TNBC is more aggressive, tends to be diagnosed at an earlier age than other breast cancers, and is overrepresented among Black patients and BRCA mutation carriers. But if we take a step back to look at progress in the field over the years, there are new reasons to feel hopeful.

Until recently, the 10 to 15 percent of breast cancer patients diagnosed with TNBC were restricted to less-targeted therapeutic mainstays: chemotherapy and radiation. While these therapies are highly effective at killing tumor cells and have saved millions of lives, they may also have toxic side effects as they can affect some healthy cells in the body.

Over the years, as molecular sequencing and analysis technologies advanced, scientists doggedly probed TNBC for new therapeutic targets. This catchall subtype of breast cancer can differ widely from patient to patient and can adapt to resist therapies, making targets even harder to pin down, and a few trials assessing targeted therapies failed in the 2010s. But all the while, researchers continued studying TNBC, identifying and defining drivers of the disease, and refining existing therapies—testing different types of chemo drugs, trying new combinations, treating early-stage patients before surgery. Because of that work, response rates did improve.

As more sophisticated analytical technologies, exciting discoveries in the broader cancer field, identification of targets for specific TNBC subsets, and new drugs emerged, the limited toolbox of options for treating TNBC has expanded to a small but growing arsenal of options. Among them:

• PARP inhibitors: People with TNBC who have inherited mutations in a BRCA gene (approximately 15 percent of patients) may be treated with PARP inhibitors. These drugs inflict catastrophic DNA damage on cancer cells that lack functional BRCA1 or BRCA2 DNA repair genes. Two therapies, talazoparib (Talzenna®) and olaparib (Lynparza®), were approved for metastatic, HER2-negative breast cancer in 2017-2018 and are effective in patients with early-stage (pre-surgical) TNBC as well.
• Immunotherapy: Over the last decade, many researchers shifted their focus from targeting cancer cells to activating the immune system to eradicate tumors. The combination of pembrolizumab (Keytruda®)—a type of immunotherapy called a checkpoint inhibitor—with chemotherapy was practice-changing for patients with TNBC tumors that express PD-L1, an important immune marker. First approved for metastatic TNBC, Keytruda is now being used in high-risk early-stage TNBC as well. Immunotherapy holds incredible promise and there is still much more to learn.
• Antibody-drug conjugates (ADCs): A major challenge in cancer therapy is the fact that lifesaving drugs can impact healthy cells. Game-changing antibody-drug conjugates (ADCs) aim to address this by delivering drugs directly to tumors through cancer-cell specific antibodies. ADCs are engineered to contain a target-specific antibody linked to a toxic drug payload. Once the antibody recognizes and binds to its target, the payload is released. This technology was used to create an ADC called sacituzumab govitecan (Trodelvy®) that was approved for metastatic TNBC in 2020. This ADC contains an antibody that attaches to Trop2, a protein present on many breast cancer cells. More recently, the FDA expanded approval of another ADC called trastuzumab durextecan (Enhertu®) to include patients with low and ultralow levels of HER2. Some patients whose tumors are classified as TNBC may actually have low and ultralow levels of HER2 and could benefit from this treatment. 

BCRF investigators have been integral to many of these advancements and their engagement in clinical trials now—and, no doubt, in the future—will keep propelling TNBC research forward. About 25 percent of BCRF-funded projects touches on TNBC, and we’re supporting studies exploring immunology, metastasis, new drug combinations, and other pressing challenges. We will keep working to unpack this complex disease.

There is still so much more to learn, but as BCRF investigator Dr. Lisa Carey has said: “I think we’ve turned the corner, and that’s why I have some excitement about where things are going.”