Rethinking HER2 in Breast Cancer: Dr. Jasmin Hundal on Antibody-Drug Conjugates

Excluding skin cancers, breast cancer is the most commonly diagnosed cancer in women in the United States, with approximately 1 in 8 women developing the disease in their lifetime (National Breast Cancer Foundation, 2026). While survival rates are higher when breast cancer is diagnosed at an earlier stage, women diagnosed with stages III and IV face a worse prognosis.

For me, progress in breast cancer treatment is also personal. My maternal grandmother was diagnosed with breast cancer more than 20 years ago. Her cancer was detected and treated early, and she remains a survivor today. Her experience has shaped my interest in how advances in cancer treatment can improve outcomes for patients facing this disease.

Among these advances are antibody-drug conjugates, or ADCs, which link an antibody that recognizes a specific target on cancer cells to a cytotoxic drug (Curtis, 2026). To better understand the evolving role of ADCs, I spoke with Dr. Jasmin Hundal, a recent graduate of the hematology-oncology fellowship at Cleveland Clinic. We discussed how these therapies work, why HER2 expression is becoming an increasingly nuanced part of treatment selection, and what questions remain as ADCs move into additional treatment settings.

Traditional Treatments and Where ADCs Come In

Breast cancer develops through genetic changes that can disrupt the regulation of cell growth and division, allowing abnormal cells to proliferate uncontrollably and potentially form tumors. Most cells express membrane proteins or cell-surface receptors to regulate processes like division and growth through cell-to-cell communication, and tumor cells are no exception. Some of these proteins, including HER2 and TROP2, act as targets for certain breast cancer therapies.

Traditionally, breast cancer therapies have included systemic treatments– like chemotherapy, which targets rapidly dividing cells, including some healthy ones– and local treatments, such as surgery. Hormone receptor status now guides endocrine therapies, while proteins such as HER2 help determine patient eligibility for targeted treatments. With ADCs, the targeting ability of monoclonal antibodies is combined with cytotoxic drugs, available in one therapy.

In my conversation with Dr. Hundal, I gained a better understanding of how this combination therapy works and what makes it unique. When asked to describe ADCs, she put it simply, “[it’s] a targeted delivery system. It combines the recognition capability of an antibody with [the] cancer killing power of chemotherapy” (Hundal, 1:36). In order to do so, there are three distinct components of an ADC: the antibody, the linker, and the payload. The antibody, according to Dr. Hundal, is the targeting piece that recognizes cell-surface antigens such as HER2 and TROP2. The linker connects the antibody and the payload and influences the release of the payload, while the payload is the drug component that damages the cancer cell. The payload is usually a chemotherapy agent, such as a topoisomerase I inhibitor or a microtubule inhibitor, capable of disrupting essential processes needed for cancer cell survival and division (Hundal, 3:35). However, current ADCs are not toxicity-free, says Dr. Hundal.

ADC Impact on Tumor Classification

Traditionally, breast cancers have been classified as either HER2-positive or HER2-negative, depending on HER2 protein overexpression or gene amplification. With the development of ADCs, Dr. Hundal explained that her “thinking therefore has kind of shifted from simply asking, ‘Is it HER2-positive?’ to asking, ‘What is the exact HER2 score, on which specimen, and at what point in the disease course?’” (Hundal, 6:45). This is because certain ADCs have shown activity in tumors with lower levels of HER2 expression, expanding treatment possibilities beyond traditional HER2-positive disease. While HER2-positive remains a distinct category, subtle differences in expression levels require close collaboration with pathologists, as these findings can influence a patient’s eligibility for a HER2-directed ADC therapy (Hundal, 5:12).

The bystander effect further explains how certain ADCs can affect tumor cells with lower levels of HER2 expression. Some tumors are heterogeneous, meaning their cells can express varying levels of HER2. Let’s think about it this way. Imagine an HER2-directed ADC is delivered to a patient with a heterogeneous tumor. The antibody successfully binds to a HER2-expressing cell, allowing the ADC to deliver and release its payload. A neighboring cell may express much lower levels of HER2, yet both cells can be damaged as the released payload crosses cell membranes (Hundal, 7:28). Ultimately, the bystander effect, along with the activity of certain ADCs with low HER2 expression, highlights how these therapies are expanding treatment possibilities beyond the traditional binary framework of HER2-positive and HER2-negative.

What ADCs Can Do for the Future of Breast Cancer Treatment

As ADCs expand into additional breast cancer treatment settings, their clinical impact extends beyond the development of new drugs. They are also changing how clinicians interpret biomarkers, assess treatment eligibility, and approach therapeutic sequencing.

My conversation with Dr. Hundal highlighted an important shift: HER2 expression is no longer just a positive-or-negative consideration for every treatment decision. The degree of expression, the specimen tested, and the timing of testing are all important data when assessing treatment eligibility (Hundal, 6:45).

Yet important questions remain about toxicity, resistance, and which patients are most likely to benefit. We’ll continue to explore these challenges and what they mean for the future of ADC treatment in breast cancer.