What if breast cancer stops responding to hormone therapy?

Breast cancers can be divided into several subtypes based on characteristics about the cancer, such as the substances the cancer cells are using to fuel growth. These substances are referred to as biomarkers. There are three main biomarkers used to categorize breast cancers:

• Estrogen receptors (ER), which attract and attach estrogen hormones, which cancer cells can use to fuel growth.
• Progesterone receptors (PR), which attract and attach progesterone hormones, another type of hormone that cancer cells can use to fuel growth.
• Human Epidermal Growth Factor Receptor 2 (HER2), a protein that promotes cell growth and division, which is found in much larger than normal amounts on some cancer cells.

Cancer cells that have PR or ER or both are hormone receptor-positive (HR-positive). Cancer cells that have higher than normal amounts of HER2 are HER2-positive, and cancers that lack high amounts of HER2 are HER2-negative.

The most common subtype of breast cancer is HR-positive/HER2-negative.

Breast cancer is considered advanced when it has spread beyond the breast. This includes locally advanced breast cancer, where the cancer has invaded nearby tissues and/or lymph nodes. It also includes metastatic breast cancer, where the cancer has spread to distant sites in the body. These cancers cannot be fully removed with surgery and require treatments that act on cancer cells throughout the body.

Initial therapy for advanced HR+/HER2- breast cancer

One way to think about cancer treatment is in terms of first-line therapy and second-line therapy. First-line therapy refers to the initial treatment.

The main first-line treatment for advanced HR-positive/HER2-negative breast cancer is endocrine therapy (also called hormone therapy). Some endocrine therapies lower the amount of estrogen produced by the body. Others block cancer cells from using estrogen. This reduces the amount of estrogen available to cancer cells, slowing or stopping their growth.

Endocrine therapy is typically combined with a targeted therapy called a CDK 4/6 inhibitor. This is a drug that blocks specific proteins (cyclin-dependent kinases) to prevent cancer cells from dividing.

What if HR+ breast cancer stops responding to hormone therapy?

Roughly half of advanced or metastatic HR-positive/HER2-negative breast cancers do not respond or stop responding to endocrine therapy. There are multiple factors that can contribute to drug resistance—cancer cells can become less dependent on estrogen, can change from HR-positive to HR-negative over time, and gene mutations can provide signals for cells to grow even without estrogen.

Second-line therapy is a treatment that is used if the cancer does not respond to initial treatment, stops responding to treatment, or progresses after treatment.

Second line therapies for advanced HR+/HER2- breast cancer can include:

• Targeted therapy, drugs that target additional biomarkers found on or inside cancer cells (apart from ER, PR, or HER2), such as mutated estrogen receptors or altered cell signaling proteins that drive the growth of cancer. Targeted therapy is used alongside endocrine therapy and can help improve the response to endocrine therapy.
• Antibody drug conjugates, which are chemotherapy drugs that can bind directly to cancer cells.
• Additional endocrine therapy combined with a CDK 4/6 drug.
• Standard chemotherapy, which may be used if other options are not effective or if the cancer is causing pain, difficulty breathing, or other symptoms that need to be addressed quickly.

The choice of what therapies to use will depend on several factors, including the results of molecular profiling, a type of biomarker testing that uses blood samples or tumor tissue biopsies to look for acquired genetic mutations that can be driving cancer growth.