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 these pathways and the cancers’ growth, these drugs served as Achilles’ heels and ultimately proved fatal 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 been without viable targeted therapies because it lacks three major factors used to classify 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 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 throughout the body.

Over the years, as molecular sequencing and analysis technologies advanced, scientists doggedly probed TNBC for new therapeutic targets. What they learned is that this catchall subtype of breast cancer is actually a group of diseases that can differ widely from patient to patient and can adapt to resist therapies. This makes targets even harder to pin down, and a few trials assessing targeted therapies failed in the 2010s. But all the while, researchers continued refining  existing therapies—testing different types of chemo drugs, trying new combinations, treating early-stage patients before surgery—and 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 an 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 leveraging the immune system to eradicate tumors. Checkpoint inhibitors, which are designed to activate immune cells, were practice changing for TNBC when combined with chemotherapy. The first FDA approval for immunotherapy in metastatic TNBC arrived in 2019, and subsequent approvals continue to expand options for metastatic patients—depending on the presence of an important immune marker called PD-L1 in their tumors—and early-stage patients. At this point, these drugs are effective only in a subset of patients and can burden them with life-long complications, including autoimmune disorders. However, they do have 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.

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.

The immunotherapy field continues to expand as researchers test novel combination therapies and seek new biomarkers to help predict patient benefit.

In 2022, the scientific community eagerly anticipated results from DESTINY-Breast04 which tested the ADC trastuzumab-durextecan (T-DXd/Enhertu®) in HER2-low breast cancer. The trial results were practice changing, demonstrating that an additional 55 percent of patients with breast cancer could benefit from T-DXd, including some TNBCs that actually express low HER2 levels. Other ADCs are moving into clinical trials. For example, BCRF investigator Dr. Ian Krop and his colleagues are testing the ADC datopotamab deruxtecan in patients with previously untreated, locally recurrent, inoperable, or metastatic TNBC who are not candidates for anti-PDL1 therapy. Thus far, this ADC shows great promise in these patients.

And the hunt for additional targeted therapies continues. Most recently, results from the pivotal CAPItello-290 trial led the FDA to approve capivasertib (Truqap®), the first-in-class AKT inhibitor for treating hormone receptor–positive/HER2-negative breast cancer. Further testing will be needed to assess its efficacy in TNBC.

Researchers also hope to expand the use of PARP inhibitors to patients who lack inherited BRCA mutations but have tumors that are similarly susceptible to DNA damage. And BCRF’s own Drug Research Collaborative is supporting a clinical study exploring the role of the androgen receptor—a compelling but unproven target in TNBC.

About 25 percent of BCRF’s portfolio 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.”