Endocrine – Hormone Therapy for Early Stage Breast Cancer

NATALEE clinical trial results support the addition of CDK inhibitor drugs to standard endocrine therapy in early stage hormone receptor (HR) positive breast cancers including those with node negative disease.

Charles H. Weaver, MD
20–30 minutes
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Estrogen is an essential female hormone that is produced by the ovaries and adrenal glands. It serves many critical functions in the body, including developing the female sex organs in puberty, preparing the breasts and uterus for pregnancy in adulthood, and maintaining cardiovascular and bone health. Without estrogen, the female body is unable to sustain pregnancy and is susceptible to heart disease and osteoporosis.

Estrogen can also cause some cancers to grow. The breasts, uterus and other female organs are composed of cells that contain estrogen receptors. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer’s growth. Cancer cells that have estrogen receptors are referred to as estrogen receptor-positive (ER+ positive) cancers.The growth of ER+positive breast cancer cells can be prevented or slowed by reducing the exposure to estrogen. This is the goal of endocrine (hormonal) therapy for breast cancer.

A reduction in estrogen levels however, can also result in side effects because estrogen is necessary for important body functions, such as bone growth and cardiovascular health. Lower estrogen levels lead to decreased bone density and heart disease. Tamoxifen was the first anti-estrogen drug but it has largely been replace by aromatase inhibitors (AI) and Faslodex (fulvestrant), alone or combined with cyclin-dependent kinases (CDK) inhibitors because they are better at delaying cancer progression and prolonging survival in women who can benefit from anti-estrogen therapy.

How Does Endocrine Therapy Work?

In premenopausal women, the ovaries are the major source of estrogen. After menopause, when ovarian hormone production drops dramatically, some estrogen continues to be produced in tissues outside of the ovaries. In this process, androgens produced by the adrenal glands are converted into estrogen. An enzyme called aromatase is required for this conversion.1 The goal of hormonal therapy is to decrease the effect of estrogen on cancer cells. Reducing the effects of estrogen can be accomplished in the following ways:

  • by removing the ovaries, which produce the majority of estrogen in premenopausal women
  • by blocking the conversion of androgens to estrogens by inhibiting the aromatase enzyme, or
  • by blocking the estrogen receptors so that estrogen cannot bind and stimulate growth-related activity in breast and other cells.

Currently, the types (classes) of anti-estrogen drugs that are approved for the treatment of patients with breast cancer are called:

  • Aromatase inhibitors
  • Selective estrogen receptor modulators (SERMs)
  • Estrogen receptor antagonists

These three classes of drugs work by decreasing estrogen’s effects on the body, but they do so through different mechanisms.

Aromatase Inhibitors: 

Aromatase inhibitors (AI) block the conversion of androgens to estrogen, and reduce estrogen levels in postmenopausal women. Currently, three anti-aromatase drugs2-4 are approved for the treatment of postmenopausal women with breast cancer:

Femara, and Arimidex are non-steroidal aromatase inhibitors that bind reversibly to aromatase. Aromasin is a steroidal aromatase inhibitor that binds permanently to aromatase.

Selective Estrogen Receptor Modulators (SERM): 

SERMs block estrogen receptors within breast cells, thereby reducing estrogen-stimulated growth. Currently, tamoxifen is the most common SERM used for the hormonal treatment of breast cancer. However, tamoxifen is associated with side effects, including an increased risk of uterine cancer.

Estrogen Receptor Antagonist: Like SERMs, estrogen receptor antagonists work by preventing estrogen from stimulating the growth of estrogen receptor-positive cells. Faslodex® the first estrogen receptor antagonist, binds to and degrades estrogen receptors so that estrogen is no longer able to bind to the receptors and stimulate cellular growth.

CDK Inhibitors

Combination Therapy: A major hallmark of cancer cells is their ability to multiply rapidly. Precision cancer medicines known as cyclin-dependent kinases (CDK) inhibitors interfere with this process by blocking the activity of enzymes known as CDKs, particularly CDK 4 and CDK 6, that help to regulate cell division. Combining a CDK inhibitor with another anti-estrogen drug delays the time to cancer progression and prolongs survival.5 CDK inhibitors can be added to AI’s for the treatment of HR+, HER2- early stage and metastatic breast cancer in combination with an anti-estrogen drug. 

CDK Inhibitors in depth…

Endocrine Therapy Treatment of Early-stage Breast Cancer

The use of endocrine therapy appears to benefit all women with hormone receptor-positive early-stage breast cancer. The primary benefit is a reduction in the risk of cancer recurrence. For premenopausal women hormone therapy is typically used for a period of five to ten years. Suppression of ovarian hormone production can be achieved through surgical removal of the ovaries, radiation to the ovaries, or drugs such as leutenizing hormone releasing hormone (LHRH) agonists.

For women not wanting to have the ovaries surgically removed medicines may be used to stop the ovaries from functioning temporarily. Zoladex (chemical (goserelin) and Lupron (leuprolide) can be given as injections once a month for several months or every few months. When the medicines are stopped the ovaries usually begin functioning again.13

The Breast Cancer Index (BCI) can be used to predict if ovarian function suppression in premenopausal patients with early-stage HR-positive breast cancer is beneficial according to an analysis of data from the SOFT trial.41,42

For postmenopausal women, use of an aromatase inhibitor appears to produce better outcomes than tamoxifen. When considering how best to use aromatase inhibitors in the treatment of postmenopausal breast cancer, researchers have considered several possibilities:

  • Aromatase inhibitors could be used for extended hormonal therapy, after a woman has completed tamoxifen treatment.14
  • Women could be switched to aromatase inhibitors after a brief (two to three year) period of tamoxifen therapy.15
  • Aromatase inhibitors could be used in place of tamoxifen as initial hormone therapy.16,17

While it’s still uncertain which of these approaches is best, each of them appears to produce better outcomes than use of tamoxifen alone.The benefits of hormonal therapy for women with estrogen receptor-positive breast cancer also apply to women with ductal carcinoma in situ (DCIS). Ductal carcinoma in situ (DCIS) is the earliest possible clinical diagnosis of breast cancer and is frequently diagnosed with screening mammography.18

CDK Inhibitors in Early Stage Breast Cancer

Cyclin-dependent kinase (CDK) inhibitors are a relatively new class of oral drugs and appear to be very well tolerated with minimal side effects. Both Verzenio and Kisqali (ribociclib) combined with traditional endocrine therapy delay the risk of cancer recurrence among patients with hormone receptor–positive/HER2-negative early breast cancer compared with endocrine therapy alone.

MonarchE Trail in High Risk HR + Early Breast Cancer

The monarchE clinical trial was designed to determine if the combination of the CDK inhibitor Verzenio with standard hormone therapy could improve outcomes in high risk early stage breast cancer. The trial enrolled 5,637 patients with HR+, HER2- node-positive, high risk early stage breast cancer to treatment with Verzenio twice daily plus standard adjuvant endocrine therapy or standard adjuvant endocrine therapy alone. Verzino was administered for 2 years following completion of primary therapy that must have included surgery. High-risk disease was characterized by 4 or more positive axillary lymph nodes, or 1 to 3 positive lymph nodes in the setting of a tumor of at least 5 cm, grade 3 or centrally confirmed Ki-67 expression of at least 20% in untreated breast tissue.

The 4-year survival without disease recurrence was 86% for patients receiving Verzenio compared to 79% for treatment with standard endocrine therapy alone.28,39 Verzenio was the first CDK4/6 inhibitor to show a significant improvement when combined with endocrine therapy in patients with hormone receptor positive ESBC.The results of the monarchE study stands in contrast to two other studies of adjuvant CDK4/6 inhibitors plus in HR+/HER2- breast cancer. Neither the PALLAS or PENELOPE-B clinical trials found any benefit when adjuvant Ibrance (palbociclib) was added to standard endocrine therapy.29-32  There are several factors that could explain the different results between these trials. Verzenio is a more potent inhibitor of CDK4 and CDK6 than ibrance.31 Moreover, verzenio is dosed continuously versus a 21-day on, 7-day off schedule for ibrance. The continuous dosing of might provide an advantage in the form of constant cell cycle inhibition. Longer follow-up is needed to determine if verzenio will have sustained long term benefits.32

Natalee Clinical Trial in HR+ HER2- Early Breast Cancer

A lower dose of Kisqali than used in previous trials in order to improve tolerability in treatment adherence was used in the NATALEE clinical trial which compared Kisqali combined with an AI to an AI alone in women with hormone receptor (HR)–positive, HER2-negative early-stage breast cancer. 

According to study results published in the March 2024 New England Journal of Medicine adding Kisqali to standard hormone therapy improves distant disease-free survival and recurrence-free survival in women with stage 2 or 3 HR-positive, HER2-negative early breast cancer. Adding Kisqali to the standard hormone therapy resulted in a relative reduction in the recurrence rate by as much as 25%.

Stage II or III HR-positive HER2 negative breast cancer are typically treated with surgery and radiation and in some cases chemotherapy, followed by endocrine therapy for up to 10 years to help reduce their risk of recurrence. Despite this treatment the risk of recurrence with stage 2 disease, is 27% to 37%, and 46% to 57% for stage 3 disease.

The NATALEE clinical trial enrolled 5101 patients with stage 2 or 3 HR positive, HER2 negative early breast cancer and participants were treated with endocrine therapy consisting of a non-steroidal aromatase inhibitor with or without Kisqali. At the three-year mark, the invasive disease-free survival rates were 90.4% for the combination arm, compared to 87.1% for women who were treated with the aromatase inhibitor alone. Patients on the combination had a 91.7% recurrence-free survival compared to 88.6% for endocrine therapy alone. A trial update released at ASCO 2024 further demonstrated that the combination benefited all patients including the lowest risk patients with no cancer involving their lymph nodes.  

The side effects were similar in both groups, with the most common issues being neutropenia, arthralgia and liver-related events.44,45

How Long Should You Take Hormone Therapy?

The American Society of Clinical Oncology updated their guidelines for the use of adjuvant endocrine therapy for women with hormone receptor-positive breast cancer extending the duration of tamoxifen treatment beyond the five-year standard. Specifically, women in two large studies who used tamoxifen for a total of 10 years experienced “modest gains in survival” compared with those who used tamoxifen for five years. As well, women treated for 10 years had a lower risk of recurrence and of developing cancer in the other (previously unaffected) breast. 

Aromatase inhibitors have been shown to provide a somewhat higher disease-free survival rate than tamoxifen. A number of randomized trials have compared 5 years with 10 years and In general, these trials have shown no additional benefit from further endocrine therapy in the lymph node–negative population. The results in lymph node–positive patients have been mixed, with one trial showing some benefit and the other trials showing little or no benefit. 

The GIM4 clinical trial studied the role of extended therapy with Femara (letrozole) after 2-3 years of tamoxifen for postmenopausal women with early stage breast cancer.36  A total of 2,056 patients were treated with either 2 to 3 years of Femara for a total of 5 years of treatment or 5 years of Femara for a total of 7 to 8 years of treatment. Twelve years from treatment initiation 62% of women treated for 5 years survived cancer free compared to 67% of those treated for 7-8 years. The 12-year overall survival was 84% for 5 years and 88% for 7-8 years of treatment. Two other trials have reported no benefit for 10 years compared to 7-8 years and are consistent with GIM4, suggesting that 7-8 years of endocrine may be the optimal duration of extended adjuvant therapy.37,38

As always, patients are encouraged to discuss all treatment options with their physician in order to make the best decision for optimal care.

Can Genomic Assays Help with Treatment Decision Making?

Genomic testing looks at a cancer cells DNA. Genomic testing can provide information to better understand an individuals cancer and how best to manage it – which drugs might or might not work. For example, if someone has a mutation in the estrogen receptor (ER) gene ESR1, aromatase inhibitors probably will not work. Emerging evidence also suggests that patients with the PIK3CA mutation are more likely to respond to the phosphoinositide 3-kinase inhibitor Piqray (alpelisib). Individuals being treated with hormone therapy for breast cancer should discuss the role of blood based genomic monitoring to detect resistant mutations and early cancer progression. 

ctDNA and Minimal Residual Disease Monitoring

Cancer is caused by genetic mutations, and these mutations can be detected by measuring circulating tumor DNA, or ctDNA, in the blood. Detection of ctDNA allows for personalized cancer surveillance based on an individual’s unique set of cancer mutations. As many as 30% of early-stage breast cancers recur and recurrence surveillance currently relies on imaging techniques like computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). These imaging tools are limited in their ability to detect MRD – ctDNA can be detected in the blood long before it appears on a CT or MRI scan and has the potential to change how breast cancer is managed.

How is ctDNA used for the management of early-stage cancers?

Across all stages of surgically removed cancer, detection of ctDNA following surgery is a strong predictor of cancer recurrence.

The Breast Cancer Index

The Breast Cancer Index test analyzes the activity of 11 genes to help predict the recurrence risk of early-stage, hormone-receptor-positive breast cancer 5 to 10 years after diagnosis. The test can help women and their doctors decide if extending hormonal therapy from 5 to 10 years would be beneficial. The Breast Cancer Index reports two results40:

  • How likely the cancer is to come back 5 to 10 years after diagnosis.
  • Is a woman likely to benefit from taking hormonal therapy for a total of 10 years.

Many women experience side effects from endocrine therapy and want to know if extending treatment from 5 to 10 years is worth tolerating the side effects. The Breast Cancer Index test which is performed on preserved tissue that was removed during the original biopsy or surgery returns two results:

  • Prognostic result estimates how likely the cancer is to come back 5 to 10 years after diagnosis (late recurrence). The result is given as a percentage. So a prognostic result of 2.5% means that you have a 2.5% risk of the cancer coming back 5 to 10 years after diagnosis.
  • Predictive result is reported as “yes” or “no.” A yes result means you’re likely to benefit from 5 more years of hormonal therapy. A no result means you’re not likely to benefit from 5 more years of hormonal therapy. 

Can Hormonal Therapy Reduce the Risk of Developing Breast Cancer?

Drugs that block the effects of estrogen have been shown to reduce the risk of breast cancer in women at high risk of the disease. Two drugs that have been approved for breast cancer risk reduction in certain groups of women are tamoxifen and Evista® (raloxifene). Tamoxifen is approved for breast cancer risk reduction in women who are at high risk of the disease (including high-risk premenopausal women). Evista – originally approved for the prevention and treatment of osteoporosis — is approved for breast cancer risk reduction in postmenopausal women with osteoporosis or postmenopausal women at high risk of breast cancer.

To directly compare Evista to tamoxifen in the prevention of breast cancer in high-risk women, researchers conducted a clinical trial known to as the STAR trial (The NSABP Study of Tamoxifen and Raloxifene [STAR] P-2 Trial).24 The study found that Evista is as effective as tamoxifen in reducing the risk of invasive breast cancer in high-risk postmenopausal women, but may be less effective in reducing the risk of noninvasive breast cancers such as ductal carcinoma in situ (DCIS). Evista carried a lower risk of blood clots and cataracts than tamoxifen, but is not without side effects. Evista has been found to increase the risk of blood clots and fatal strokes in women with coronary heart disease or at risk for coronary heart disease.25

Are There Other Benefits Associated with Hormonal Therapy?

Hormonal treatment may offer additional benefits beyond the treatment of cancer. Although tamoxifen acts against the effects of estrogen in breast tissue, it acts like estrogen in certain other body systems. Tamoxifen may help to lower blood cholesterol and reduce the rate of bone loss (osteoporosis). Two clinical studies have reported that women treated with tamoxifen had a lower risk of cardiac disease than women not treated with tamoxifen.26 In addition, Evista®, another selective estrogen receptor modulator (SERM), is FDA-approved for the prevention and treatment of osteoporosis and appears to reduce the risk of breast cancer.27

What Are the Side Effects of Endocrine Therapy?

Endocrine therapy is associated with some side effects similar to symptoms of menopause, which include hot flashes, irregular menstrual periods and vaginal discharge or bleeding. Not all women will experience these symptoms. Bone loss or osteopenia is a significant complication of endocrine therapy that can be prevented with bisphosphonate drugs.

Tamoxifen: More serious side effects can also occur as a result of long-term use of tamoxifen. There is a small increase in the number of blood clots in individuals taking tamoxifen. Individuals taking tamoxifen have a slightly increased risk of developing cataracts. In addition, tamoxifen appears to increase a woman’s risk of developing uterine cancer by about 2-3 times that of the general population.5-9 This risk of uterine cancer is similar to that for women taking postmenopausal estrogen replacement therapy. Since the majority of uterine cancers can be detected at an early stage when they are highly curable, the overall benefit of anti-estrogen treatment in breast cancer patients probably outweighs the risk of uterine cancer. All women who have a uterus and are receiving anti-estrogen therapy should undergo regular gynecologic examinations. The most common side effects caused by tamoxifen are

  • Hot flashes
  • Vaginal dryness
  • Discharge or Irritation
  • Decreased interest in sex.

These side effects are not usually serious, but they can be bothersome. Other side effects that are rare but are more dangerous include:

  • Overgrowth of the lining of the uterus (endometrial hyperplasia).
  • Cancer of the lining of the uterus (Endometrial cancer).
  • An increased risk of blood clots (in the legs (deep vein thrombosis and the lungs (pulmonary embolism).
  • A small increased chance of stroke.
  • Ovarian cysts
  • An increased risk of eye cataracts – Five or more years of tamoxifen use increases cataract risk and at higher doses and for longer periods of time, may lead to retinopathy. Breast cancer patients should have a baseline eye exam within the first year of treatment including an examination of the macula and testing of central and color vision.

Aromatase inhibitors: Possible side effects of AIs include joint pain and decreased bone density. In fact, as many as half of women on AI therapy experience joint pain, and 20% become non-compliant with their AI therapy because of side effects. The origin of AI-associated joint pain is unclear. There are no effective supportive care therapies to mitigate AI-associated joint pain and premature discontinuation of AI therapy may adversely affect breast cancer outcomes. Overall two-thirds of the women with AI-associated joint pain appear to have resolution or improvement of their symptoms once AI therapy was discontinued. For women whose joint pain is significantly affecting quality of life, it is important to discuss quality of life factors, side effects and benefits of staying on therapy with their physician in order to make an informed treatment decision.10,11

In a study known as the Intergroup Exemestane Study, postmenopausal women who had received two-to-three years of tamoxifen were assigned either to continue on tamoxifen or to switch to the aromatase inhibitor Aromasin. Women who switched to Aromasin had improved survival, but also experienced a minor loss of bone mineral density in the lumbar spine.12 Women who are treated with aromatase inhibitors may wish to talk with their doctor about bone health.

Sexual Function: Both Tamoxifen and aromatase inhibitors can have a negative impact on sexual functioning and diminish sexual enjoyment Sexual dysfunction should be addressed early and proactively in patients undergoing endocrine therapy.33

Connect With Others for Support and information

Cancer Connect was the first social network created for people with cancer. Founded by oncologists to support breast cancer patients and their caregivers, over 40 million individuals have accessed Cancer Connect programs since 1997. Cancer Connect is used by leading cancer centers like Dana Farber, Roswell Park and The James at Ohio State to support their patients. Join the conversation, ask questions, share your experience, and learn how the best cancer centers are treating breast cancer from others. Share your experience, ask a question, or start a conversation by posting on Cancer Connect.

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