Antibody-Drug Conjugates in Breast Cancer: Toward a Molecular Perspective in Clinical Practice

“Doctors Roberto Paz-Manrique, Joseph Pinto, and Henry Gómez Moreno from Peru have published a narrative review article in the latest edition of JCO Precision Oncology, related to a new treatment that is revolutionizing the therapeutic landscape in various types of cancer. This time, the text explores the role of antibody-drug conjugates (ADCs) in breast cancer.

Antibody-drug conjugates (ADCs) are a significant advancement in cancer therapy, merging targeted precision with cytotoxicity. The concept, introduced by Paul Ehrlich in the early 1900s, has evolved with advances in bioengineering and cancer biology. ADCs consist of a monoclonal antibody, a linker, and a cytotoxic payload, specifically designed to target antigens on tumor cells while minimizing damage to healthy tissue. They are internalized through endocytosis, releasing the cytotoxic agent within the lysosome, which may also affect adjacent tumor cells, a phenomenon known as the bystander effect.

The development of ADCs has progressed through several generations, each improving upon the previous one. The first generation, exemplified by gemtuzumab ozogamicin, faced challenges such as immunogenicity and low potency. The second generation, which includes trastuzumab emtansine (T-DM1), demonstrated improved efficacy in targeting HER2-positive breast cancer, reducing toxicity compared to traditional chemotherapy. The third generation, represented by trastuzumab deruxtecan (DS-8201), presents enhanced stability and potency, effectively treating HER2-positive breast cancer, even in resistant cases.

ADCs are characterized by their linkers, which can be cleavable or non-cleavable, influencing the release of the cytotoxic payload. Cleavable linkers respond to specific physiological conditions, while non-cleavable linkers remain intact until internalized by the target cells. The mechanism of action involves the internalization of the ADC-antigen complex, leading to the release of the payload and the potential destruction of neighboring cells.

Recent clinical trials have shown promising results for ADCs in various breast cancer scenarios, including triple-negative breast cancer (TNBC) and low HER2 populations. Sacituzumab govitecan and datopotamab deruxtecan are notable ADCs targeting TROP-2, showing improved progression-free survival (PFS) and overall survival (OS) compared to traditional therapies.

Despite their potential, ADCs face challenges such as resistance mechanisms and associated toxicities. Ongoing research aims to optimize the components of ADCs to overcome these barriers. The future of ADCs includes exploring new surface antigens, bispecific antibodies, and masked ADCs for targeted activation, enhancing their role in precision oncology treatment. This review provides a comprehensive overview of the evolution of ADCs in breast cancer therapy, emphasizing their molecular mechanisms and clinical implications.”

written by Roberto Paz-Manrique, M.D.
Surgical Oncologist

Roberto Paz-Manrique is a Surgical Oncologist of Genitourinary Malignancies and a Medical Science Liaison (MSL) for Oncology in Peru and Ecuador at Johnson & Johnson Innovative Medicine Latin America. Previously, he served as a Graduate Research and Teaching Assistant for the “Principles and Practice of Clinical Research” course at Harvard T.H. Chan School of Public Health, and worked as a Medical Prevention Officer at Oncosalud.

Other posts featuring antibody-drug conjugates on OncoDaily:

Paper Alert ! Use of Antibody–Drug Conjugates in the Early Setting of Breast Cancer

The journey of ADCs is a story of perseverance

Zymeworks Announces First Patient Dosed in Phase 1 Clinical Trial Evaluating ZW191

Francisco Esteva: ADCs are making waves in the fight against advanced HER2+ breast cancer