(TURKISH JOURNAL) – Dr. Zuhal Eraslan – Breast cancer remains one of the leading causes of cancer-related death among women worldwide. In 2022, breast cancer was the most frequently diagnosed malignancy among women in 157 of 185 countries. That same year, about 670,000 people worldwide lost their lives to the disease, highlighting its devastating impact. Among its subtypes, estrogen receptor (ER)-positive / human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common, accounting for 60–75% of cases. While these tumors often respond to endocrine therapy, many patients eventually relapse or develop resistance, particularly in metastatic disease.
Before we go further, let’s briefly explain what ER-positive / HER2-negative breast
cancer is and why it can be so challenging to treat. Think of each cancer cell as a
factory powered by two energy lines: the estrogen line, controlled by the ER, and the
HER2 line. In ER-positive / HER2-negative tumors, the HER2 line is off, but the
estrogen line runs unchecked, continuously fueling growth and survival. Over time,the
machinery malfunctions, regulatory controls fail, and the factory becomes malignant.
Uncontrolled cell division leads to tumor progression and spread.
Endocrine therapy, including aromatase inhibitors, selective estrogen receptor
modulators (SERMs), and selective estrogen receptor degraders (SERDs), aims to cut
this estrogen-driven power line. Aromatase inhibitors block estrogen production, while receptor-targeting drugs block or degrade ER. Yet tumors can acquire ESR1 mutations, which make ER active even without estrogen. The power line becomes self-sustaining, and traditional therapies lose effectiveness.
This challenge inspired the development of Vepdegestrant (ARV-471), a next-
generation oral ER degrader that works differently from anything used before. Using
PROTAC technology, Vepdegestrant tags ER for destruction inside the cell, dismantling
the receptor completely rather than merely blocking it. In other words, it doesn’t just
switch off the machine; it removes the malfunctioning part entirely, preventing the
cancer cell from restarting its growth engine.
The VERITAC-2 Phase III trial has placed Vepdegestrant at the forefront of breast
cancer research. This study compares oral Vepdegestrant with standard fulvestrant in
patients with advanced ER-positive / HER2-negative breast cancer who have
progressed after prior endocrine therapy plus CDK4/6 inhibitors. Interim results from
2025 showed that patients with ESR1-mutant tumors experienced nearly double the
time without disease progression compared to fulvestrant. In the broader patient
population, the benefit was smaller but still encouraging. Importantly, the drug was
generally well tolerated, with relatively few severe side effects.
These findings are significant: Vepdegestrant is the first PROTAC degrader to
demonstrate efficacy in a late-stage breast cancer trial, representing a potential
paradigm shift in the treatment of endocrine therapy–resistant ER-positive / HER2-
negative disease. By directly removing the receptor that drives malignant growth,
Vepdegestrant offers a strategy to overcome one of the most common mechanisms of
resistance in breast cancer.
Beyond its clinical impact, Vepdegestrant exemplifies the power of mechanism-driven
drug design, showing how a deep understanding of cancer biology can translate into
therapies that target the root cause of disease rather than just its symptoms. As
research continues and more data emerge, PROTAC-based ER degraders may
redefine the standard of care for patients with resistant ER-positive / HER2-negative
breast cancer, providing new hope where traditional endocrine therapy has limitations.
References
- Cristofanilli M, et al. Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in
Advanced Breast Cancer. New England Journal of Medicine. 2025. Available at:
https://www.nejm.org/doi/full/10.1056/NEJMoa2505725 - World Health Organization. Breast Cancer. World Health Organization, 14 August , Available at: https://www.who.int/news-room/fact-sheets/detail/breast-
cancer
