Chemotherapy is a trusted breast cancer treatment, but standard chemotherapy kills all cells that divide quickly, including healthy ones. While chemotherapy is effective, it also brings patients a variety of unwanted side effects, including hair loss, fatigue and a weakened immune system. Today, antibody-drug conjugates (ADCs) are emerging as an alternative to conventional chemotherapy for treatment of breast cancer, but what exactly are ADCs, and what do they mean for patients?
Researchers have been seeking a more specific way to target and kill cancer cells without harming nearby healthy cells. This search for a “magic bullet” goes back as far as 100 years, when German scientist and Nobel laureate Paul Ehrlich was looking for a therapeutic agent that would specifically target infected cells with minimal harm to the rest of the body.
This led to the creation of an experimental treatment called ADCs in the 1980s, which was approved by the FDA in 2000 as a stand-alone treatment for individuals with acute myeloid leukemia. By design, ADCs act like a guided missile, delivering small doses of a powerful chemotherapy drug directly into cancer cells, while sparing the healthy cells around them. But how exactly do ADCs work?
Antibody-Drug Conjugates 101
ADCs are made of three different parts: an antibody that is directed to a specific target on a cancer cell, a tumor killing drug (chemotherapy), or “payload,” and a linker that connects them together. When an ADC encounters a cancer cell, its antibody first binds to the targeted receptor on the surface of the cell. It then releases a chemotherapy drug directly into the cell, which causes cell death.
Antibodies have the power to target cancer cells specifically, but cannot kill them on their own, while conventional chemotherapy targets both healthy and unhealthy cells, which causes unwanted side effects. ADCs provide an option that is the best of both worlds – the ability to target cancer cells specifically and administer a potent dose of chemotherapy directly to them. With ADCs, patients also experience less adverse side effects than with standard chemotherapy.
ADCs in Action
ADCs have already revolutionized the treatment of breast cancer, especially metastatic breast cancer (MBC). Trastuzumab deruxtecan (Enhertu), is a HER2-targeting ADC first approved for HER2-positive MBC in 2019. It has recently shown success in treating breast cancers with low levels of HER2 (called HER2-low) a feat not yet accomplished with traditional HER2-targeted therapies. This expanded the use of this ADC to treat the estimated 55% of people with MBC that are HER2-low.
ADCs are also providing options to people with triple negative breast cancer (TNBC) whose treatment options have historically been limited to chemotherapy, surgery and radiation. Sacituzumab govitecan (Trodelvy), a TROP-2-targeting ADC, was the first FDA-approved ADC for metastatic TNBC in 2020.
As the timeline below shows, ADCs have been around for several decades, and more recently approved by the FDA. Today, researchers continue to investigate how ADCs can help even more patients in the future.
ADCs may also be a key weapon in targeting heterogenous tumors, or tumors made up of a diverse variety of cancer cells, which are difficult to treat. Researchers discovered they can treat biologically diverse tumors by combining multiple treatments into one ADC payload. This is an exciting development that could mean longer lasting effects for patients and less treatment resistance.
Through the Eyes of a Patient
ADCs, like all drugs, do present some challenges for patients. ADCs are given intravenously, so they do not have the convenience of a pill like some other treatments. Also, some patients might encounter financial barriers with out-of-pocket costs for ADCs, including premiums for insurance coverage.
Despite their targeted nature, some ADCs do have adverse side effects, but fewer than traditional chemotherapy. These include peripheral neuropathy, infections, anemia, fatigue, diarrhea, nausea, vomiting and liver enzyme abnormalities. Some HER2-targeted ADCs have also been associated with interstitial lung disease, which causes scarring of the lungs and difficulty breathing. These side effects are often related to the intensity and dosage of chemotherapy given. To ensure ADCs are safe and effective for patients, oncologists may adjust the prescribed dose or temporarily pause treatment.
Today, most patients see ADCs as an exciting possibility for improved survival and quality of life. As researchers continue to refine how ADCs work, they’re also focused on personalizing treatment, or giving the right drug to the right person to minimize side effects and maximize outcomes.
“It’s very important that when patients look for the next drug, that there is something there waiting for them,” says Komen Advocate in Science Thelma Brown. “And that’s what patients see as the promise of these ADCs. It represents more options, and it represents hope.”
Learn even more about how ADCs work here: https://youtu.be/i4Iovjnd-Lk
