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

Most treatment success stories in breast cancer result from the rational design of therapies. Researchers uncovered the right therapeutic targets—molecular processes that cancer cells need to survive—in the estrogen receptor, which drives the growth of ER-positive tumors, and HER2, whose signaling promotes the progression of HER2-positive tumors. By using drugs that specifically block these pathways, the targets became Achilles’ heels and the therapies ultimately proved fatal for most breast cancer cells. But as triple-negative breast cancer (TNBC) lacks breast cancer’s three major classifications—ER, PR (progesterone receptor), and HER2—therapeutic targets have been much more difficult to find.

Researchers fully understand the urgency of this disease. 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 a less-targeted therapeutic mainstay: chemotherapy. While chemotherapies are highly effective at killing tumor cells and have saved millions of lives, they are also characterized by their 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 can differ widely from patient to patient and 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 chemotherapy—testing different types of chemo drugs, trying new combinations, providing it to early-stage patients before surgery—and response rates did improve.

Recently though—as more sophisticated analytical technologies, exciting discoveries in the broader cancer field, 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, which are DNA repair genes. Two therapies, talazoparib (Talzenna®) and olaparib (Lynparza®), were approved for metastatic, HER2-negative breast cancer in 2017-2018, and recent findings presented at the American Society of Clinical Oncology’s annual meeting in 2021 showed their immense promise 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. But, they show incredible promise and researchers still have much more to learn about them.
  • Antibody-drug conjugates (ADCs): A major challenge in cancer therapy is the possibility of drugs affecting healthy cells. Antibody-drug conjugates (ADCs) aim to address this by helping drugs home in on tumors through cancer-cell specific antibodies. An ADC called sacituzumab govitecan (Trodelvy®)—approved for metastatic TNBC in 2020—has an antibody that attaches to Trop2, which is present in many breast cancers. That antibody is linked to a toxic payload that subsequently kills the cancer cell.

BCRF investigators have been part of many of these advances and are engaged in clinical trials now—and, no doubt, in the future—that 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 the ADC space, the scientific community is eagerly anticipating the presentation of results from DESTINY-Breast04 (assessing T-DxD/Enhertu® in HER2-low breast cancer) along with a follow-up study validating exciting initial results on datopotamab deruxtecan that were presented by BCRF investigator Dr. Ian Krop at the most recent San Antonio Breast Cancer Symposium (SABCS).

In addition, the hunt for targeted therapies continues; the CAPItello-290 trial testing the use of an AKT inhibitor is a pivotal phase III study. 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 has an upcoming clinical study exploring the role of the androgen receptor—a compelling but unproven target in TNBC.

At least 30 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 said at SABCS 2021: “I think we’ve turned the corner, and that’s why I have some excitement about where things are going.”

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