The breast cancer treatment landscape is changing rapidly. As Hyo Han, MD, Research Director, Department of Breast Oncology at Moffitt Cancer Center, told attendees at the 42nd Annual Miami Breast Cancer Conference (MBCC) last week, “We have made a lot of progress [with] many agents showing improved survival. It’s very exciting. But there’s a lot of work to be done.”

Invasive BC diagnoses are growing, especially among younger patients, increasing the need for more-effective treatment options.

American Cancer Society. Breast Cancer Facts & Figures. 2025.

At the same time, tumor heterogeneity and drug resistance make this especially challenging.

About this exciting new class of drugs

One targeted therapy physicians will likely be seeing more of is the trophoblast cell surface antigen 2 (TROP-2) directed antibody-drug conjugates, such as datopotamab deruxtecan and sacituzumab govitecan.

TROP-2 inhibitors are part of a new class of targeted therapies called antibody-drug conjugates (ADCs), and they are transforming treatment for patients with early stage or advanced breast cancer.

TROP-2 is a cell surface glycoprotein that is typically found at low levels in normal tissues but is significantly overexpressed in a range of solid tumors, including all breast cancer subtypes. It is known to play a key role in tumor development and progression.

Yujun T, Xiaobing F, Huan L, Tiantian L. Advances in Trop-2 targeted antibody-drug conjugates for breast cancer: mechanisms, clinical applications, and future directions. Frontiers in Immunology. October 31, 2024.

When TROP-2 is upregulated, tumors grow, invade, and spread. They also become resistant to chemotherapy. TROP-2 inhibition, however, is associated with delayed growth in TNBC cells and tumors—making it an ideal tumor target.

Unsurprisingly, TROP-2 and other ADCs were a hot topic at this year’s MBCC. Heather McArthur, MD, MPH, Professor of Internal Medicine and Clinical Director of the Breast Cancer Program at UT Southwestern Medical Center, discussed the TROPION-Breast03 trial—a randomised phase III global trial of datopotamab deruxtecan ± durvalumab in patients with TNBC and residual invasive disease at surgical resection after neoadjuvant therapy. 

She said the drug sees a “high response rate… which is very encouraging.”  

How they work

According to authors writing in Therapeutic Advances in Medical Oncology, datopotamab deruxtecan (Dato-DXd) is connected to an antibody (datopotamab) by a stable linker. Datopotamab binds to TROP2 and is brought inside the tumor cell, releasing deruxtecan to kill it.

Bardia A, Pusztai L, Albain K, et al. TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy. Therapeutic Advances in Medical Oncology. 2024;16. doi:10.1177/17588359241248336.

“By delivering DXd directly to cancer cells, Dato-DXd reduces exposure in the rest of the body, reducing the risk of side effects,” the authors write.

ADCs: The way of the future?

ADCs are referred to as “biological missiles,” but they’re still emergent, according to research published last year in Precision Oncology.

Zhou D, Zhai X,, Zhang L, et al. A new TROP2-targeting antibody-drug conjugate shows potent antitumor efficacy in breast and lung cancers. npj Precis. Onc. 8, 94 (2024). doi.org/10.1038/s41698-024-00584-z

“The key requirements for a successful ADC include selection of an appropriate target, antibody, linker, and cytotoxic payloads, all of which affect its druggability characteristics, such as antitumor effects, pharmacokinetics, stability, and cytotoxicity,” the authors write. “Therefore, although the concept of an ADC is clear and straightforward, it is still challenging to develop an ideal ADC with the appropriate combination of antibody, linker, and payload, and as a result, commercially available ADCs are still limited.” On the use of ADCs like datopotamab deruxtecan and sacituzumab govitecan, Dr. McArthur said, “We need to understand mechanisms of resistance, optimal sequencing… but there’s a lot of effort in that space because it’s an area of rapid drug development. We need to understand how best to apply these agents.”