Overcoming Endocrine Resistance in Metastatic Breast Cancer with Targeted Therapy

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• Endocrine Resistance Mechanism
• Estrogen Receptor Mutation Discovery
• Clinical Impact of Resistance
• New Generation Inhibitors
• Treatment Future and Quality of Life
• Full Transcript

Endocrine Resistance Mechanism in Hormone Receptor-Positive Breast Cancer

Over 75% of breast cancers express estrogen or progesterone receptors. Endocrine therapy is the cornerstone treatment for these hormone receptor-positive tumors. However, a significant clinical challenge is intrinsic and acquired resistance to these therapies. Dr. Ido Wolf, MD, explains that all patients with metastatic breast cancer receiving hormone therapy will eventually develop resistance. This resistance represents a major escape mechanism for tumors, allowing cancer progression despite treatment.

Estrogen Receptor Mutation Discovery and Significance

A pivotal discovery in 2013 identified a key mechanism behind endocrine resistance. Dr. Ido Wolf, MD, notes that his laboratory, along with two others, discovered a specific mutation in the estrogen receptor. This mutation is functionally special because it confers complete resistance to all forms of endocrine cancer therapy. Breast cancer cells expressing this mutated protein can proliferate independently, even in the complete absence of estrogen. Dr. Anton Titov, MD, highlights the importance of this finding for understanding the fundamental cause of treatment failure.

Clinical Impact of Endocrine Resistance

The estrogen receptor mutation is not merely a marker of resistance; it also alters tumor biology. Dr. Ido Wolf, MD, states that this mutation is responsible for resistance in approximately 30 to 40% of all breast cancer patients. Furthermore, the mutation drives a more aggressive cancer phenotype. Patients who develop resistance often experience rapid disease progression with a higher burden of metastases. This explains the clinical observation of sudden, aggressive spread in some women after their cancer becomes resistant to hormonal treatment.

Development of New Generation Receptor Inhibitors

The identification of this mutation has directly fueled the development of novel therapeutic agents. Dr. Ido Wolf, MD, confirms that several companies are now working on specific inhibitors designed to target the mutated estrogen receptor. Current breast cancer medications cannot effectively bind to and inhibit this altered receptor. The new generation of drugs is being engineered to overcome this limitation. Dr. Anton Titov, MD, inquires if these new medications could restore tumor sensitivity, potentially avoiding a switch to chemotherapy.

Future of Treatment and Patient Quality of Life

These advancements are poised to transform the treatment paradigm for metastatic breast cancer. Dr. Ido Wolf, MD, clarifies that these new inhibitors will not be effective for triple-negative breast cancer, as those tumors lack the estrogen receptor target. However, for hormone receptor-positive disease, these drugs represent a monumental step forward. The goal is to provide another line of effective endocrine therapy instead of immediately resorting to chemotherapy. Dr. Ido Wolf, MD, emphasizes that this strategy will not only prolong life but will also dramatically improve a patient's quality of life by offering a better-tolerated treatment option.

Full Transcript

Hormone therapy against breast cancer is often limited by cancer drug resistance. A leading oncologist and precision medicine expert discusses new methods to overcome drug resistance in breast cancer.

Dr. Anton Titov, MD: Let's talk about breast cancer. Over 75% of breast cancers express estrogen and/or progesterone receptors. Endocrine cancer therapies are used to treat such breast cancers. Unfortunately, not every patient with breast cancer is responsive to those treatments. We also see that there is a molecular escape of tumors from the influence of endocrine cancer therapy.

You study endocrine cancer therapy. How can it help to treat people, especially patients with metastatic breast cancer?

Dr. Ido Wolf, MD: All women with breast cancer express the hormone receptors, estrogen receptor or progesterone receptor. Patients who have metastatic breast cancer receive hormone therapy. We know that with time all such breast cancer patients will develop resistance to cancer therapy.

The question is, why? Until a few years ago, no one knew what was the major mechanism of resistance for breast cancers. In 2013, our lab simultaneously with two other labs in the world discovered a new mutation in the estrogen receptor. This mutation is very special. It confers endocrine resistance.

That means that breast cancer cells that express these mutated proteins can live even without estrogen around them. These breast cancer cells are resistant to all endocrine cancer therapy. That was a major discovery.

We now know that about 30 to 40% of all breast cancer patients develop endocrine cancer therapy resistance. They develop resistance due to this specific mechanism. This is important because the first step in treating someone with cancer is knowing the cause of cancer.

Identification of that specific mutation has opened new avenues for breast cancer treatment. Now there are several companies working on specific inhibitors of that receptor. It always takes time from the time you find a mutation to the time cancer treatment goes to the clinic. But the discovery of it was of major importance.

We also know now that the mutation is important not just in mediating resistance. It also makes the breast cancer tumor much more aggressive. This explains why women who develop endocrine resistance suddenly have cancer that is much more aggressive.

Breast cancer spreads with more metastases that develop rapidly. Because that mutation makes the cancer cells grow much faster in many places in the body.

Dr. Anton Titov, MD: Medications could be developed addressing or targeting that mutation. Would they restore the sensitivity of tumors to cancer endocrine therapy? Would they help with the therapy be directed at those tumors that have the mutation, without the need of endocrine therapy?

Dr. Ido Wolf, MD: There are now new cancer medications developed that can inhibit the mutated estrogen receptor. Breast cancer medications in use now cannot bind that endocrine receptor. The new generation of breast cancer medications will be able to bind mutated estrogen receptor and inhibit cancer.

Dr. Anton Titov, MD: That would be also effective in a so-called triple negative breast cancer?

Dr. Ido Wolf, MD: Probably not, because these medications will target only ER, the estrogen receptor. Triple negative breast cancers do not express the estrogen receptor at all. For these breast cancers we need a whole new array of medications.

But clearly that will advance our ability to treat the tumors that express the estrogen or progesterone receptors. We should be able to find another endocrine cancer therapy instead of switching to breast cancer chemotherapy.

It will not only prolong life. It will improve significantly quality of life. It is going to be much easier for women to take hormonal therapy of new generation than to switch to chemotherapy.