Adjuvant Endocrine Treatment For Estrogen Receptor
Makoto Kubo
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University , Japan
Correspondence to:
Keywords: Early breast cancer ER-positive/HER2-negative adjuvant endocrine treatment ovarian function suppression multigene expression assay
Submitted Mar 23, 2020. Accepted for publication May 25, 2020.
doi: 10.21037/cco-20-125
Mtor Inhibitor Plus Steroidal Ai
In the phase III BOLERO-2 trial, exemestane plus everolimus significantly improved mPFS compared to exemestane plus placebo ., Subgroup analysis found that the more lines of treatment patients had received, the more benefits patients obtained from everolimus. However, none of the patients in this trial were previously treated with CDK4/6 inhibitors and there were no trials that directly assessed the efficacy of exemestane plus everolimus in patients post CDK4/6 inhibitors.
A retrospective study conducted in Portland showed that this regimen has the same effects on patients with HR+ ABC regardless of prior CDK4/6 inhibitor use . The study involved 43 patients, 17 who had received prior CDK4/6 inhibitors and 26 who had not. Patient characteristics, including other prior therapies and metastasis sites, were not significantly different. Thus, everolimus plus exemestane may be effective for HR+ ABC regardless of prior CDK4/6 inhibitor use.
Why Is Knowing Hormone Receptor Status Important
Knowing the hormone receptor status of your cancer helps doctors decide how to treat it. If your cancer has one or both of these hormone receptors, hormone therapy drugs can be used to either lower estrogen levels or stop estrogen from acting on breast cancer cells. This kind of treatment is helpful for hormone receptor-positive breast cancers, but it doesnt work on tumors that are hormone receptor-negative .
All invasive breast cancers should be tested for both of these hormone receptors either on the biopsy sample or when the tumor is removed with surgery. About 7 of 10 breast cancers have at least one of these receptors. This percentage is higher in older women than in younger women. DCIS should also be checked for hormone receptors.
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Risk Of Recurrence: Early And Late
Research has shown the HER2-positive early breast cancers are two to five times more likely to recur than HER2-negative tumors. Even very small HER2-positive tumors with negative lymph nodes have a much higher risk of recurrence relative to tumors that are HER2-negative. Treatment with Herceptin can cut this risk by half.
The pattern of breast cancer recurrence may also differ. Small tumors are also more likely to have a metastatic recurrence if they are HER2-positive.
Despite the fact that HER2-positive and estrogen receptor-negative tuors are more likely to recur early on than estrogen receptor-positive and HER2-negative cancers, late recurrences are much less common.
With estrogen receptor positive breast cancers, the cancer is more likely to recur after five years than in the first five years, and the risk of recurrence remains steady each year for at least 20 years following the diagnosis. In contrast, those who have HER2 positive tumors and reach their five-year mark are much more likely to be “in the clear” and remain recurrence free.
How Is This Cancer Treated
Your treatment plan will depend on where the cancer has spread, the extent of the disease, other medical conditions you have, and your age and menopause status. Common therapies include:
- Ovarian suppression For premenopausal women with metastatic breast cancer of this type, hormone therapy almost always begins with ovarian suppression by means of surgery to remove the ovaries or drugs, such as goserelin or leuprolide, that stop the ovaries from producing hormones, says Brufsky. Ovarian suppression lowers hormone levels in the body so the tumor cant get the estrogen it needs to grow.
- Aromatase inhibitors Postmenopausal women and premenopausal women who have undergone removal or suppression of their ovaries are often treated with AIs, such as anastrozole, exemestane, and letrozole. These drugs block the activity of the enzyme aromatase, which the body uses to make estrogen in the adrenal glands and fat tissue. This means less estrogen is available to stimulate the growth of HR-positive breast cancer cells, according to the National Cancer Institute.
- CDK4/6 inhibitors These drugs, which include palbociclib, ribociclib, and abemaciclib, block proteins in the cell known as cyclin-dependent kinases . CDKs regulate cell proliferation and growth and are often elevated in breast cancer, fueling uncontrolled growth of cancer cells. They are typically used in combination with AIs as a first-line treatment for HR-positive/HER-2-negative metastatic breast cancer, Brufsky says.
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Cdk4/6 Inhibitors Plus Immunotherapy
In vitro research has shown that CDK4/6 inhibitors plus an anti-programmed cell death 1 ligand 1 drug is a more effective regimen than either drug alone. Therefore, the phase II PACE trial is a randomized, open-label, multicenter trial assessing the utility of ongoing CDK4/6 inhibitors plus fulvestrant following progression on CDK4/6 inhibitors plus AIs. The patients in this trial were randomized into three groups: group A: fulvestrant monotherapy group B: ongoing CDK4/6 inhibitor palbociclib plus fulvestrant and Group C: anti-PD-L1 drug plus ongoing CDK4/6 inhibitor palbociclib and fulvestrant. We are looking forward to the trial results. The trial will indicate whether it is effective to continue the CDK4/6 inhibitor plus fulvestrant or plus an anti-PD-L1 drug and fulvestrant, among patients who developed resistance on CDK4/6 inhibitors plus AIs.
Her2 Breast Cancer Treatment
Targeted therapy is the hallmark of treatment for HER2-positive cancer. The drug used most often is trastuzumab . Trastuzumab interferes with HER2 production and slows or prevents the cancer cells from growing. It is often administered with the chemotherapy agent emtansine in a combined drug called T-DM1.
Another medication, pertuzumab , is sometimes prescribed with trastuzumab when the cancer has spread to other parts of the body or metastasized. Oncologists also may prescribe an aromatase inhibitor, such as lapatinib or neratinib to lower estrogen levels.
If the cancer is also HR-positive, oncologists often prescribe endocrine therapy after the completion of targeted therapy. Endocrine or hormone therapy helps prevent cancer from returning by suppressing estrogen production. Tamoxifen is a common form of endocrine therapy used primarily in premenopausal women. It belongs to a class of drugs called selective estrogen receptor modulators .
Postmenopausal women have the option instead of taking an aromatase inhibitor , such as anastrozole , exemestane , or letrozole to block estrogen production. Postmenopausal women who have completed a tamoxifen regimen may be encouraged to follow up with an AI for added benefit.
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Breast Cancer Hormone Receptor Status
Breast cancer cells taken out during a biopsy or surgery will be tested to see if they have certain proteins that are estrogen or progesterone receptors. When the hormones estrogen and progesterone attach to these receptors, they stimulate the cancer to grow. Cancers are called hormone receptor-positive or hormone receptor-negative based on whether or not they have these receptors . Knowing the hormone receptor status is important in deciding treatment options. Ask your doctor about your hormone receptor status and what it means for you.
Determining Your Her2 Status
A breast biopsy is used to determine HER2 status. The biopsy can be sent for laboratory testing with an immunohistochemistry test. The fluorescence in situ hybridization test looks for the HER2 gene in breast cancer cells.
The results of an immunohistochemistry test show different levels of HER2 positivity. For example, a tumor may be reported as 0, 1+, 2+, or 3+. Tumors with a higher number may be referred to as having an overexpression of HER2.
According to the American Cancer Society, immunohistochemistry test results should be considered as follows:
| Designation | |
|---|---|
| Equivocal | |
| 3+ | HER2-positive |
The impact of being HER2-positive on breast cancer survival is, of course, a top concern. Unfortunately, statistics can be misleading without considering other aspects of your diagnosis, including cancer stage at diagnosis and whether the tumor is also estrogen and/or progesterone receptor-positive.
With this in mind, you may also be tested for progesterone and estrogen receptors. Triple-negative breast cancers are negative for HER2, estrogen, and progesterone, while triple-positive breast cancers are positive for all three.
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Current Endocrine Treatment Approach For Hr
Targeting the estrogen receptor is one of the most important treatment strategies used to control endocrinesensitive mbca,,. Endocrine treatment strategies include medications that lower estrogen production, modulate signalling through the estrogen receptor, or antagonize and degrade the estrogen receptor itself. Additionally, novel drugs given in combination with endocrine treatment are now available and have also been incorporated into clinical practice. Endocrine therapy might be suitable for patients with hr-positive, her2-negative mbca who have low-burden disease and for those who have experienced a long disease-free interval to enrich for more endocrine-responsive disease,. Patients with rapidly progressive visceral disease or with a risk or evidence of end-organ dysfunction or significant disease-related symptoms should be offered chemotherapy,. The choice of endocrine agent should be based on menopausal status, comorbidities, prior adjuvant therapy, drug availability, patient preference, and drug safety profile,.
What Is Triple Negative Breast Cancer
In addition to being negative for estrogen and progesterone receptors, triple negative breast cancer cells also lack a protein known as HER2. Human epidermal growth factor receptor-2 is a protein that promotes cell growth and HER2 positive breast cancers have a higher than normal presence of these proteins, because of mutations in HER2 gene.
Triple negative cancers account for approximately 15% of breast cancers. Triple negative breast cancer more often occurs in African-American women younger than 40, or women who have an inherited mutation in BRCA1 gene, which normally is a tumor suppressor gene, which suppresses cell growth.
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Hormone Receptor Status And Early Breast Cancer Prognosis
Hormone receptor status is related to the risk of breast cancer recurrence.
Hormone receptor-positive tumors have a slightly lower risk of breast cancer recurrence than hormone receptor-negative tumors in the first 5 years after diagnosis .
After about 5 years, this difference begins to decrease and over time, goes away .
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For a summary of research studies on hormone receptor status and survival, visit the Breast Cancer Research Studies section. |
What Are The Categories Of Breast Cancer
Breast cancers are categorized into the following groups based on the hormone receptor and HER2 status:
- Luminal A: ER and PR positive, and HER2 negative breast cancer
- Luminal B: ER positive, PR negative and HER2 positive breast cancer
- HER2 positive: HR negative and HER2 positive breast cancer
- Triple positive: ER, PR and HER2 positive breast cancer
- Triple negative : HR and HER2 negative breast cancer
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All About Er Positive Her2 Negative Breast Cancer
About one in eight women in the United States will develop breast cancer, according to commonly used statistics.
But other reports indicate that breast cancer rates are on the decline, likely because of improved recognition, prevention, and treatment. One advancement is the ability to identify different breast cancer types based on specific molecules found in tumors. The distinction greatly aids in breast cancer treatment selection and helps doctors predict how aggressive cancers will advance.
A crucial step in the process of beast cancer evaluation is testing tumor tissue removed during a biopsy or surgery to determine if it has estrogen and progesterone receptors molecules that the hormones bind to.
Cancerous cells may have none, one, or both receptors. Breast cancers that have estrogen receptors are called ER-positive . Those with progesterone receptors are referred to as PR-positive .
In addition to hormone receptors, some breast cancers have high levels of a growth-promoting protein called HER2/neu. If a tumor has this property, it is called HER2-positive. HER2 positive cancers are more aggressive than HER2 negative cancer.
Knowing breast cancer type, leads doctors to determining best treatments.
HER2 negative cancers will not respond to treatment with drugs that target HER2, such as trastuzumab and lapatinib .
Overall, estrogen receptor-positive breast cancer is treatable, especially when diagnosed early.
Cdk4/6 Inhibitor + Fulvestrant
The three CDK4/6 inhibitors, palbociclib, abemaciclib, and ribociclib, were evaluated in combination with fulvestrant for the second-line treatment of HR+HER2mBC patients in the PALOMA-3, MONARCH-2, and MONALEESA-3 studies, respectively. Significantly superior PFS was noted with the combination vs. fulvestrant monotherapy in all three studies, including in patients with visceral disease . .
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Grade High Vs Low Or Intermediate
To evaluate racial differences within risk subgroups available in routine clinical practice, we also performed stratified analyses by overall tumor grade in the full study population . Grade is strongly associated with high-risk features and serves as a prognostic and predictive marker in the absence of gene profiling assays . We observed early separation of recurrence curves by race among women with high grade tumors . At 5âyears, Black women with high grade tumors had a recurrence risk of 16.6% , compared with 12.0% among White women. By comparison, Black and White women with low grade tumors had similar 5-year recurrence risk .
Standardized risk of recurrence among hormone receptor-positive/HER2â tumors stratified by race and grade. Pairwise log-rank tests were performed with Bonferroni correction for multiple comparisons. Compared with White women with low or intermediate grade, White women with high grade tumors and Black women with high grade tumors were statistically significantly different. Compared with Black women with low or intermediate grade tumors, Black women with high grade tumors were statistically significantly different . No other pairwise comparisons were statistically significant. Risk was standardized for age and stage.
RFD and 95% confidence intervals for treatment history and health insurance status for Black vs White women
| Treatment history and health insurance status . | White, No. nâ=â202 . |
|---|
Progress In Treating Her2
HER2-positive and triple-negative breast cancer are among the most aggressive forms of breast cancer and traditionally have had lower survival rates than other types of the disease. However, early detection with routine screening has contributed to improved survival for both in recent years. Further, treatment advancesall available at Regional Cancer Care Associates , one of the nations largest networks of cancer specialists with locations in New Jersey, Maryland, and Connecticutalso have helped improve outcomes in HER2-positive cancer. Meanwhile, intensive research and emerging therapeutic strategies are offering new hope for women with triple-negative breast cancer.
Four RCCA medical oncologists recently explained what drives the development of these breast cancers, how they are treated, and how women can play an important and potentially life-saving role in identifying the cancers in their earliest stages, when they can be treated most effectively.
Aileen Chen, MD, a board-certified medical oncologist practicing with RCCA in Freehold and Holmdel, NJ says, Its an exciting time in the fight against breast cancer. Next-generation sequencing technology is detecting genetic mutations that we can treat with targeted therapies in many forms of the disease. This has enhanced our ability to practice personalized medicine by customizing a patients treatment based on her molecular and genetic profiles.
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Study Selection And Characteristics
A total of 5397 RCTs and 3409 RWE studies published between 2011 and 2019 were identified. Of these, 12 RCTs corresponding to 9 unique trials and 12 RWE studies were considered for full-text review. In total, 9 RCTs and 12 RWE studies were identified that fulfilled the inclusion criteria . Finally, 8 RCTs and 4 RWE studies were included for meta-analysis feasibility assessment after screening for the reporting of relevant recurrence outcomes of interest . Two studies provided poor reporting of recurrence data of interest and thus were subsequently excluded from the compilation of recurrence outcomes however, study and patient baseline characteristics information from these studies were compiled .
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram summarizing the process for the identification of the eligible studies.
Abbreviations: PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses RCT = randomized controlled trials RWE = real-world evidence SLR = systematic literature review.
Other Things To Consider
Learning the basics of HR-positive/HER2-negative breast cancer makes it easier for you and your loved ones to understand your options and cope with your diagnosis.
In addition to HR and HER2 status, a number of other things will factor into your choice of treatment:
- Stage at diagnosis. Breast cancer is divided into stages 1 through 4 to indicate tumor size and how far the cancer has spread. Cancer is easier to treat in the early stages, before it has the chance to spread. Stage 4 means the cancer has reached distant tissues or organs. This is also called advanced or metastatic breast cancer.
- Tumor grade. Breast tumors have a tumor score of 1 to 3. Grade 1 means the cells are close to normal in appearance. Grade 2 means theyre more abnormal. Grade 3 means they bear little resemblance to normal breast cells. The higher the grade, the more aggressive the cancer.
- Whether this is a first cancer or a recurrence. If youve previously been treated for breast cancer, youll need a new biopsy and pathology report. This is because your HR and HER2 status may have changed, which will affect the approach to treatment.
As well, your overall health including other medical conditions, your age and whether youre pre- or postmenopausal, and personal preferences will dictate the course of treatment.
Cancer treatment is likely to go more smoothly when you ask questions and communicate openly with your oncology team.
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How Are Breast Tumors Tested For Her2
Either a test called an immunohistochemistry test or fluorescence in situ hybridization test is used to find out if cancer cells have a high level of the HER2 protein.
See Testing Biopsy and Cytology Specimens for Cancer and Understanding Your Pathology Report: Breast Cancerto get more details about these tests.