PI3K Inhibitors for ER+ Breast Cancer

Medically Reviewed by Melinda Ratini, MS, DO on April 18, 2024
4 min read

In 2024, an estimated 310,720 women in the United States will be diagnosed with invasive breast cancer -- and about 80% of breast cancers are estrogen-receptor-positive, or ER+ breast cancer, making it the most common breast cancer subtype.

Tumors that are ER+ have multiple estrogen receptors. Hormone therapies are often used to treat ER+ breast cancer. In advanced cases of ER+ breast cancer -- and even in some early stages of the disease -- tumors may be resistant to hormone therapy treatment.

A recent study found that those with metastatic breast cancers that were hormone-receptor-positive (HR+) and human-epidermal-growth-factor-receptor 2-negative (HER2-) did not respond as well to certain chemotherapy medications and had lower survival rates.

New treatments were needed to increase progression-free survival rates (the amount of time breast patients lived without the disease getting worse).

The search for alternative treatments led to the finding that the phosphatidylinositol-3-kinase (PI3K) pathway that controls cell metabolism, growth, division, and survival and allows the cells to function properly, often fails to operate normally in those with breast cancer.

A mutation, or change, in the PIK3CA gene causes the process of cell division and replication to go haywire and is linked to several kinds of cancer, including colon cancer, endometrial cancer, lung cancer, and breast cancer.

The PIK3CA gene also plays a role in hormone-positive breast cancer. In fact, research shows that mutations of this gene are found in up to 40% of estrogen-receptor (ER)-positive breast cancer.

The goal of PI3K inhibitors is to suppress the genes that have gone haywire and to cause the cancer cells to die and tumors to shrink. These drugs have emerged as a promising option for treating advanced breast cancer. The FDA approved the first PI3K inhibitor to treat breast cancer in 2019.

The drugs were designed for postmenopausal women and men with advanced breast cancer whose tumors are hormone-receptor-positive and HER2-negative cancer with the PIK3CA mutation. The oral medication is given with a second drug that blocks the impact of estrogen on cancer cells.

To determine if a PI3K inhibitor is the right treatment for breast cancer, health care providers use an FDA-approved kit to test a blood sample for the PIK3CA gene mutation.

In multiple clinical trials, research showed that the combination of a PI3K inhibitor and hormone-blocking drug was an effective treatment for those with HR-positive, HER2-negative advanced breast cancer with a PIK3CA mutation.

One major finding was that the drug was linked to progression-free survival rates of 11 months, compared with less than 6 months for breast cancer patients with the PIK3CA mutation who did not receive PI3K inhibitors.

The effectiveness of the first PI3K inhibitor led to the development of additional drugs. PI3K inhibitors are often used in combination with other therapies, including endocrine therapy.

PI3K inhibitors were designed for those with a PIK3CA gene mutation. Certain cancers, including colorectal, brain, and gastric cancers, have high rates of mutation in this gene; one of the drugs in this class is also an effective treatment for those with breast cancer.

Mutation in one gene that is part of the PI3K pathway is often found in HR+/HER2– or HER2+ advanced breast cancer tumors; the same mutation is also found in 9% of triple-negative breast cancer tumors.

When the cells on the PI3K pathway are overactive, it can lead to resistance to common breast cancer treatments, including endocrine therapy and chemotherapy. In these cases, PI3K inhibitors can be used as a first-line treatment.

Different PI3K inhibitors target different proteins within the cells in an attempt to shrink tumor cells and kill cancer cells.

The PI3K inhibitors that target fewer cell proteins are linked with fewer side effects. With fewer side effects, patients can take the medication at higher doses for longer, uninterrupted periods.

The more cell proteins the PI3K inhibitors target, the greater the risk of side effects. In some instances, severe side effects have required health care providers to reduce the dosage, recommend a medication holiday (take a break from the drug), or stop prescribing it altogether.

In general, PI3K inhibitors are associated with several common side effects, including nausea and vomiting, decreased appetite, weight loss, mouth sores, hair loss, and kidney, liver, or pancreatic issues. Due to the possibility of rashes with peeling and blistering and other severe skin reactions, PI3K inhibitors may not be recommended for those with a history of reactions.

High blood sugar is another common side effect associated with PI3K inhibitors. Animal studies showed that adopting a ketogenic, or “keto,” diet that is high in fat and low in carbohydrates or taking a common diabetes drug to control insulin was linked with greater reductions in tumor size than taking the PI3K inhibitor alone.

When it comes to breast cancer treatment, learning more about the role a PI3K mutation plays in ER+ breast cancer and how PI3K inhibitors could help is an important part of being an educated patient and feeling in control of your treatment plan.