Hormone Refractory Breast Cancer

Hormone refractory breast cancer, also called endocrine-resistant breast cancer, occurs when breast cancer cells that were once controlled by hormone therapy develop the ability to grow without responding to these treatments.

Table of contents

• What is hormone refractory breast cancer?
• How resistance develops
• Types of endocrine resistance
• Impact on treatment and outcomes
• Treatment options for endocrine-resistant disease
• Monitoring and retesting

What is hormone refractory breast cancer?

Hormone refractory breast cancer refers to estrogen receptor-positive (ER-positive) breast cancer that no longer responds to hormone therapy. Approximately 70% of all breast tumors are ER-positive, meaning they have proteins called hormone receptors on their surface that bind to the hormones estrogen and progesterone^[1][2]. When these hormones attach to the receptors, they signal the cancer cells to grow and divide.

Hormone therapy, also called endocrine therapy, is designed to block the body’s ability to produce hormones or to interfere with how hormones affect breast cancer cells. This treatment slows or stops the growth of hormone-sensitive tumors^[1]. Different types of hormone therapy work in various ways: some block estrogen receptors on cancer cells, like the drug tamoxifen, while others reduce estrogen levels in the body, such as aromatase inhibitors^[2].

Despite the effectiveness of hormone therapy, some tumors develop the ability to grow independently of hormone signals. When this happens, the cancer is described as hormone refractory or endocrine-resistant^[2][6].

How resistance develops

Over time and with exposure to treatments, breast cancer cells can evolve and adapt, finding ways to grow that do not rely on the estrogen receptor. The cancer cells become more dysregulated and develop alternative pathways for cell growth^[8].

Several molecular mechanisms of endocrine resistance have been identified. These include alterations in the ESR1 gene, which codes for the estrogen receptor, and changes in the PIK3CA/mTOR pathway, which is involved in cell growth and survival^[2][10]. When breast cancer progresses, the tumor may upregulate different cell signaling pathways inside the cancer cell that do not depend on estrogen^[22].

The mechanisms of endocrine resistance are manifold and complex, which presents a major challenge in treating this condition^[2]. Understanding these molecular changes is crucial for developing new treatment strategies.

Types of endocrine resistance

Endocrine resistance is classified into two main types based on when it develops.

Primary endocrine resistance is defined as a relapse within 2 years of adjuvant endocrine treatment, or disease progression during the first 6 months of first-line endocrine therapy for advanced or metastatic breast cancer^[2][10]. This means the cancer never responded well to hormone therapy from the start.

Secondary resistance, also called acquired resistance, is defined in early breast cancer as a relapse that occurs after at least 2 years of endocrine therapy^[2][10]. This occurs when a cancer that initially responded to hormone therapy eventually stops responding. Up to 30% of women with primary breast cancer taking tamoxifen can become resistant, and the majority of women with hormone receptor-positive secondary breast cancer will develop resistance over time^[8].

Impact on treatment and outcomes

The development of hormone resistance significantly impacts treatment options and patient outcomes. When breast cancer is diagnosed at an early stage, five-year relative survival rates are very high, ranging from 90% to close to 100%. However, an estimated 20% to 40% of people diagnosed with early-stage estrogen receptor-positive breast cancer will develop metastatic disease^[18].

For those with metastatic hormone receptor-positive breast cancer, research suggests that the five-year relative survival rate is about 35%^[18]. Once cancer has progressed on initial hormone therapies, subsequent treatments often provide only modest improvements in survival and can cause significant side effects^[13].

Research shows that not taking hormone therapy as prescribed—including taking less medication than prescribed, skipping doses, stopping early, or never starting—can put patients at greater risk for breast cancer recurrence, metastatic spread, or cancer-related death^[15]. Studies have found that postmenopausal women who stopped hormone therapy early were 35% to 56% more likely to have a recurrence than those who completed treatment, while premenopausal women who stopped early were nearly twice as likely to experience recurrence^[15].

Treatment options for endocrine-resistant disease

When hormone therapy ceases to be effective, several treatment strategies may be considered. Overcoming primary or acquired resistance to endocrine treatment remains a major challenge, but new approaches have been developed^[2].

For patients with endocrine-resistant metastatic breast cancer, treatment goals shift from trying to eradicate the cancer to controlling the disease and preventing it from spreading^[18]. Healthcare providers often try to maximize the use of endocrine therapy or targeted therapies for as long as possible because they are generally less toxic than chemotherapy^[22].

Combination therapies have shown promise in overcoming resistance. CDK4/6 inhibitors, mTOR inhibitors, and PI3K inhibitors have been shown to improve the efficacy of endocrine treatment when used in combination^[2][10]. The standard of care for those newly diagnosed with hormone receptor-positive metastatic breast cancer usually includes an aromatase inhibitor along with one of three approved CDK4/6 inhibitors^[18].

Antibody-drug conjugates (ADCs) represent a novel approach for overcoming challenges of resistance and toxicity. These treatments preferentially target chemotherapy to malignant cells, resulting in greater efficacy often with more manageable side effects. Important randomized phase III trials of ADCs such as sacituzumab govitecan and trastuzumab deruxtecan have shown significant improvements in outcomes for patients with hormone receptor-positive, HER2-negative metastatic breast cancer^[13].

If a breast cancer that came back during or after treatment with hormone therapy, patients may be offered a different type of hormone therapy in combination with other treatments^[16]. The choice of treatment depends on what therapies have already been used and how the cancer has changed.

Monitoring and retesting

When breast cancer returns or spreads, the hormone receptor status can change. For example, if the first tumor was treated with hormone therapies, a cancer that has returned may become resistant to that therapy. In other cases, a tumor may undergo changes or mutations to gain or lose hormone receptor presence that it didn’t have before^[4][19].

Because of these potential changes, doctors may recommend retesting the cancer’s biomarkers if it comes back or progresses. This is particularly important when the cancer isn’t progressing as normally expected, as the pattern may indicate that the cancer’s biology has changed^[22].

Patients can track changes in their symptoms and share these with their healthcare team. Documenting symptoms may help determine whether current treatment is effective and may help indicate if treatment is not working. While most changes in symptoms won’t signify resistance, sharing concerns with doctors ensures that any signs of hormone therapy resistance will be noticed early^[8].