The landscape of breast cancer care has changed dramatically in a decade, thanks in part to the use of antibody-drug conjugates (ADCs). The medications act as scouts, seeking out and targeting cancer cells like a missile-destroying system. ADCs are resulting in better responses, fewer side effects and improved progression-free survival for some types of breast cancer.

“Think of ADCs like a Trojan horse,” says Lauren Carcas, M.D., a breast and gynecologic medical oncologist with Baptist Health Miami Cancer Institute. “It’s a very toxic payload being delivered to the cancer cell itself. It releases within the cell, which is more toxic than what we can deliver outside of the cell. And then it can permeate the cell membrane and kill surrounding cancer cells.”

Dr. Carcas spoke about antibody-drug conjugate therapy in breast cancer at the Institute’s recent Women’s Cancer Symposium. Experts from the Institute and leading cancer centers in the U.S. and abroad discussed the latest advances at the educational program, which featured multidisciplinary strategies for managing complex challenges in women’s cancer care.

While traditional chemotherapy, a longtime standard for the treatment of breast cancer, attacks all of the body’s rapidly-dividing cells, ADCs are different. They first identify the cancer cell target and attach to it. Then, once pulled into the cell, they release their toxic chemotherapy drug. ADCs are considered a targeted cancer treatment.

ADCs were first used for some blood cancers in the early 2000s. In 2013, they were approved for solid tumors and physicians began to use them to treat HER2-positive breast cancers, or those that have an overexpression of the HER2 protein that can prompt cancer to grow and spread more quickly. Just 15 to 20 percent of breast cancers are HER2-positive, according to the American Cancer Society.

With up to 80 percent of breast cancers being classified as HER2-negative, doctors were still searching for better treatments for the majority of breast cancer patients. Thanks to clinical trials and continued research that Dr. Carcas and other Institute physicians have led and participated in, there are now a growing number of ADCs on the market — including those for HER2-negative tumors.

“As physicians, we want to know how our patients are going to respond. How quickly will they respond? How well will they respond?” Dr. Carcas says. “Participation in clinical trials is very important because that is how we move the field forward. But first and foremost is safety.”

Today, there are more than 100 new ADCs in clinical trials. Among the landmark trials that Dr. Carcas discussed were:

• The DESTINY-Breast04 trial, which was the first to show that the ADC trastuzumab deruxtecan had clinical benefits in HER2-low metastatic breast cancer patients.
• The DESTINY-Breast06 study, which also revealed improved progression-free survival in HER2-low and HER2-ultralow patients.
• The TROPiCS-02 trial, studying the effectiveness of sacituzumab govitecan in patients with limited treatment options for HR+ and HER2- metastatic breast cancer, showing a progression-free survival benefit over chemotherapy.
• The TROPION-Breast01 study, looking at the experimental drug datopotamab deruxtecan for inoperable or metastatic HR+, HER2-negative breast cancer. “This study is continuing and while we have progression-free data that is positive, the overall survival data is not yet mature,” Dr. Carcas says.

Two ADC trials currently underway at Miami Cancer Institute are:

• ATEMPT 2.0: Adjuvant T-DM1 Vs TH - Studying how newly diagnosed HER2+ breast cancer responds to one of two different ADC combination drugs as a treatment after surgery. Site PI Reshma Mahtani, O.
• A Phase III Study of Dato-DXd With or Without Durvalumab Compared With Investigator's Choice of Chemotherapy in Combination With Pembrolizumab in Patients With PD-L1 Positive Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer – Comparing the use of Dato-DXd with durvalumab with the standard of care chemotherapy and pembrolizumab to see if Dato-DXd allows patients to live longer without their breast cancer worsening, or simply to live longer. Site PI Lauren Carcas, M.D.

Each ADC is slightly different and has a unique safety profile, she said. Side effects may include diarrhea, nausea, neutropenia and lung problems such as pneumonitis, but one complication that doctors must watch for is ocular toxicities. “Some of the drugs have a higher risk of this than others, but we have to monitor for toxicities closely. Patients can develop dry eye, keratitis, conjunctivitis and microcyst-like epithelial changes. Typically, this is reversible with an ADC dose delay, reduction or discontinuation.”

Physicians are also studying the sequencing of ADCs to better understand which drugs to try first and how to follow them with other ADCs if resistance develops. “We are also opening a study here that is looking for biomarkers as a predictor for who will and won’t respond to a specific ADC,” Dr. Carcas said. “The SERIES trial, which is an investigator-initiated trial is hoping to reveal how we can best sequence these ADCs and see if we can discover a specific biomarkers to predict response and resistance.”

Overall, Dr. Carcas is optimistic that as research progresses, ADCs will continue to offer a lasting response, not just for specific breast cancer types, but for other cancers as well.