Hormonal therapy for breast cancer is utilized for treatment of early stage and recurrent/metastatic disease.
Approximately 75% of BC tumors express estrogen and/or progesterone receptors.
Goals of therapy include symptom palliation and prolongation of survival.
Common adverse effects associated with ET include hot flashes, vaginal dryness, joint pain, and osteoporosis risk.
Both ER and PR are targets of anti-estrogen therapy, and are predictors of response to such therapy.
Estrogen stimulation of ER causes recruitment to specific sites across the genome via specific epigenetic events restricting recruitment to a subset of potential sites.
Adjuvant endocrine therapy is standard treatment for hormone receptor-positive early-stage breast cancer.
Multiple studies show that patients treated with adjuvant tamoxifen for early breast cancer showed a almost 50% reduction in the risk of recurrence during the first five years of follow-up, the period of active therapy.
Recommendations as of 2014 for adjuvant hormonal therapy: for women who are premenopausal at diagnosis of breast cancer or are going through menopause when they are diagnosed should receive adjuvant tamoxifen treatment, and after completing 5 years, women can continue tamoxifen for an additional 5 years of treatment, will be switched to an aromatase inhibitor for 5 years if they have gone through menopause:For women who are postmenopausal at diagnosis the options for adjuvant hormonal therapy include 1 tamoxifen for 10 years, 2, an aromatase inhibitor for 5 years, 3, tamoxifen for 5 years followed by an aromatase inhibitor for up to 5 years or 4, tamoxifen for 2-3 years followed by aromatase inhibitor for 5 years.
Aromatase inhibitor therapy results in a greater reduction in risk of recurrence of five years of tamoxifen, such that most postmenopausal women should consider aromatase inhibitor treatment either as initial therapy or after 2-3 years of tamoxifen.
The patients with stage I or IIA cancers the numerical advantage of aromatase inhibitor-based treatment over tamoxifen is modest, at 3% reduction in recurrence in a 2% reduction in mortality at 10 years.
Aromatase Inhibitors are of more value in the treatment of higher risk cancers based on stage or biologic features and treatment of lobular cancers.
aromatase inhibitors is standard of care for post menopausal patients with early stage estrogen receptorpositive, ERBB2 negative breast cancer.
Extending the duration of treatment from 5-10 years with either tamoxifen or aromatase inhibitors reduces the risk of recurrence, as compared with just five years of treatment.
In the above studies after tamoxifen was discontinued a carryover benefit during years 5 to 9 of an additional 32% reduction in risk of recurrence, and thereafter tamoxifen and control patients had parallel recurrence free survival curves.
Patients with increase risk of late recurrence because of noted status or adverse biologic features probably have greater benefit from extended therapy.
aTTom (Adjuvant Tamoxifen: Longer Against Shorter) trial found 10 years of tamoxifen significantly reduced the risk of recurrence from 32% to 28% in 10 years or more after the diagnosis of estrogen receptor positive early breast cancer.
It is estimated that only 3-5% of patients benefit from 10 vs 5 years of endocrine therapy.
In post menopausal patients with breast cancer who received 2 to 3 years of tamoxifen extended treatment with five years of Letrozole resulted in significant improvement in disease-free survival compared with standard 2 to 3 years of letrozole: sequential endocrine therapy with tamoxifen for 2 to 3 years followed by letrozole for five years should be considered as an optimal standard endocrine treatment for early post menopausal patients with hormone receptor positive breast cancer.
There was a 13% absolute difference in recurrence at 15 years in the tamoxifen adjuvant studies.
Aromatase is a cytochrome P450 enzyme involved in the synthesis of estrogen and aromatase in inhibitors function as anti-estrogen by decreasing the biosynthesis of estrogen from androgens, the primary estrogen biosynthesis pathway in postmenopausal women.
Aromatase Inhibitors suppress residual estrogen level by more than 90% in postmenopausal women.
Aromatase inhibitors are contraindicated in pre-menopausal women who are not undergoing ovarian suppression, because compensatory physiological responses induce ovarian estrogen production.
Extented endocrine trials show that for every 600 women treated with extended adjuvant endocrine therapy 12-16 tumor recurrences will be prevented, but at the cost of 5 endometrial cancers and 2 pulmonary emboli, 13 cases of of osteoporosis, 4 bone fractures and 1 thromboembolism.
Extending aromatase inhibitor treatment from 5 to 10 years improves disease free survival in postmenopausal women with early breast cancer (MA.17 trial)
Ovarian steroid hormones, estrogen and progesterone respectively, control ductal growth and alveolar development in the normal mammary gland.
Response to endocrine management is related to the functional status of these receptors and not just their expression.
50-75% of patients with ER positive breast cancer will respond to first-line endocrine therapy, whereas 25% of those beyond the first line will respond.
In the normal maturing mammary gland epidermal growth factor or may the proliferative effect of progesterone and estrogen to induce side ductal branching and lobular-alveolar development.
Epidermal growth factor receptor (EGFR) family is expressed in normal and malignant breast epithelial cells, and over expression in breast cancer for predicts for a poor outcome.
EGFR promotes tumor progression, invasion, angiogenesis, and metastases, along with resistance to treatment by blocking apoptosis in breast cancer ( Nakamura Y et al).
Endocrine resistance develops in nearly all patients who are treated with endocrine based therapies in the metastatic setting.
ESR1 mutations occur commonly in women with acquired hormonal resistance-somewhere between 30 and 50% of patients with acquired in the resistance have this mutation.
Cross talk between EGFR and hormone receptors contributes to tumor behavior and response to hormonal therapy.
Estrogen receptor exists in two forms: ER-? and ER-?.
ER are required for normal breast development and dramatic increases are noted in premalignant lesions.
ER functions as a nuclear transcription factor and estrogen action in the nucleus is termed nuclear initiated spheroid signaling (NISS).
Estrogen receptors play a key role in normal breast development and in progression of breast cancer.
Endocrine therapy is the most important component in treating the majority of women who are hormonal receptor positive with advanced breast cancer.
Endocrine therapy is the favorite approach over chemotherapy in postmenopausal hormone receptor positive advanced breast cancer patients because of its clinical activity and favorable safety profile.
Women with stage IV or recurrent disease characterized by HR positive, HER2 negative tumors with no visceral involvement are treated with endocrine therapy alone or endocrine therapy in combination with target agents.
Women who progress after a year from the end of adjuvant endocrine based therapy and those who present with de novo stage IV metastatic breast cancer are eligible for first line endocrine therapies.
Endocrine therapy for postmenopausal hormone receptor positive advanced breast cancer patients with no visceral involvement is most appropriate when there is slow disease progression and low tumor burden, especially bone only metastases, and no impending visceral crisis.
Many pre-and post menopausal women with HR positive disease can benefit from sequential use of endocrine therapy at disease progression.
In controlled studies comparing chemotherapy versus endocrine therapy in postmenopausal hormone receptor positive advanced breast cancer patients chemotherapy has an increase response rate but no difference in overall survival.
The standard of care involves sequencing endocrine agents until intolerance, resistance develops or the development of a visceral crisis that necessittates transition to chemotherapy.
SERM’s ( Serum estrogen receptor modulators) tamoxifen and toremifene are cytostatic agents that competitively bind to ER in tumor cells and breast tissue, producing receptor dimerization and nuclear complex that decreases DNA synthesis and inhibits estrogenic effects.
Downstream effects of the binding of SERMs are tissue specific.
SERMs are orally administered, generally well tolerated and protective for bone mineral density.
The incidence of any thromboembolic events in women with early breast cancer receiving adjuvant tamoxifen is approximally 3-4%.
Aromatase inhibitors and anti-estrogens form the two major groups of endocrine therapy in current use.
Aromatase inhibitors reduce circulating estrogen levels by preventing the conversion of androstenedione intake estrogen in peripheral tissues.
Anti-estrogens, ER antagonists, are classified into selective ER modulators (SERMs) typified by tamoxifen, and selective ER down regulators (SERDs) exemplified by fulvestrant.
Fulvestrant blocks estrogen sensitive gene transcription, resulting in no known agonist activity.
SERDs are pure ER antagonists exhibiting exclusively anti-estrogen effects by which they block and down regulate ER activity, accelerate degradation of the estrogen receptor, and inhibit proliferation of the estrogen-dependent breast tumor cells.
Tamoxifen and estrogen deprivation therapies, such as aromatase inhibitors and ovarian suppression effective treatments for patients with early stage estrogen receptor positive breast cancer.
Aromatase inhibitors are contraindicated in women with residual ovarian function and therefore guidelines recommend tamoxifen for premenopausal women who are ER positive and require adjuvant endocrine therapy.
Premenopausal women with ER+ or PR+ BC endocrine treatment include ER antagonist tamoxifen and luteinising hormone releasing hormone (LHRH) agonists such as goserelin, which offer potential for reversible ovarian ablation.
Goserelin has equivalent efficacy in treatment of premenopausal BC with equivalent disease free survival to CMF in patients with ER positive disease.
Combination of tamoxifen plus goserelin improves progression free survival compared with goserelin alone.
Tamoxifen alone or with ovarian function suppression are standard treatments for premenopusal women with ER+ disease.
The absolute reduction in risk of recurrence with aromatase inhibitors compared with tamoxifen in the adjuvant setting is modest, typically amounting to less than 5%.
The use of aromatase inhibitors consistently improves disease free survival in the adjuvant setting when compared to tamoxifen.
In postmenopausal women of the use of adjuvant aromatase inhibitors either as the primary therapy or after 2-3 years of tamoxifen have yielded equivalent outcomes in prospective studies.
The progestin megestrol acetate acts presumably by downregulating and/ or inhibiting the synthesis of estrogen receptors, a having a direct on breast cancer cells.
Megestrol is a 4th line treatment option and is generally used after disease progression on aromatase inhibitors, SERMS, and selective estrogen receptor down regulators.
Semi synthetic progestin megestrol has therapeutic effects for post menopausal women with metastatic breast cancer.
Proposed mechanisms of action in breast cancer include interaction with steroid receptors, reduced cellular estrogen uptake, and growth factor interactions, as well as suppression of the adrenal steroid production and ovarian secretion of androgens.
Megestrol for treatment of ER positive metastatic breast cancer is useful for a second or third line hormonal treatment option for patients who have relapsed on SERM and AI agents.
The duration of adjuvant aromatase inhibitor therapy should not exceed five years.
Of the patients who relapse after adjuvant hormonal treatment up to 50%with ER+ disease who develop metastatic disease do not respond to first line endocrine therapy and the remainder will eventually acquire resistance.
Increasing evidence exists that aberrant signaling through the phosphatidylinositol 3-kinase (PIK3A)-mamillion target of rapamycin (mTTOR) signaling pathway plays a critical role in endocrine resistance.
Approximately 50% of estrogen receptor positive primary breast cancers show abnormal intrinsic activation of the PI3K-mTOR a pathway, and many patients with advanced for metastatic breast cancer develop acquired upregulation of the PI3K-mTOR signaling.
Inhibition of mTOR can overcome endocrine resistance as clinical trials demonstrate a substantial benefit of adding the mTOR inhibitor everolimus endocrine agents especially in the endocrine resistant breast cancer.
Tamoxifen as a second line treatment after failure of an aromatase inhibitor and progression of metastatic breast cancer suggest clinical benefit in almost 50% of patients, but less than 10% have a objective response.
ER mediated signaling can remain functional after the development of hormonal resistance.
Estrogen positive-progesterone negative subtype has an outcome is bad or worse than triple negative breast cancer.
There is a discontinuation rate of approximately 7-10% per year for tamoxifen and aromatase inhibitors.
Studies indicate that only 40-60% of patients with breast cancer finish recommended courses of adjuvants hormonal therapy despite higher recurrence rates and worse survival with treatment of less than five years duration.
In general, treatment decisions are made for patients with hormone receptor positive metastatic breast cancer based on the HER 2 status: patients with HER 2positive disease often receive chemotherapy plus HER2 targeted therapy, while some patients will receive an aromatase inhibitor alone or in combination with anti-HER2 therapy.
Patients with hormone receptor positive, and HER2 negative disease, the most commonly utilized treatment is hormonal therapy.
Hormonal therapy for breast cancer is utilized for treatment of early stage and recurrent/metastatic disease.
Ovarian steroid hormones, estrogen and progesterone respectively, control ductal growth and alveolar development in the normal mammary gland.
Response to endocrine management is related to the functional status of these receptors and not just their expression.
In the normal maturing mammary gland epidermal growth factor or may the proliferative effect of progesterone and estrogen to induce side ductal branching and lobular-alveolar development.
Epithelial growth factor receptor (EGFR) family is expressed in normal and malignant breast epithelial cells, and over expression in breast cancer for predicts for a poor outcome.
EGFR promotes tumor progression, invasion, angiogenesis, and metastases, along with resistance to treatment by blocking apoptosis in breast cancer ( Nakamura Y et al).
Cross talk between EGFR and hormone receptors contributes to tumor behavior and response to hormonal therapy.
Estrogen receptor exists in two forms: ER-? and ER-?.
ER-? Is required for normal breast development and dramatic increases are noted in premalignant lesions.
ER functions as a nuclear transcription factor and estrogen action in the nucleus is termed nuclear initiated spheroid signaling (NISS).
Estrogen receptors play a key role in normal breast development and in progression of breast cancer.
Aromatase inhibitors and anti-estrogens form the two major groups of endocrine therapy in current use.
Aromatase inhibitors reduce circulating estrogen levels by preventing the conversion of androstenedione intake estrogen in peripheral tissues.
Anti-estrogens, ER antagonists, are classified into selective ER modulators (SERMs) typified by tamoxifen, and selective ER down regulators (SERDs) exemplified by fulvestrant.
Tamoxifen and estrogen deprivation therapies, such as aromatase inhibitors and ovarian suppression effective treatments for patients with early stage estrogen receptor positive breast cancer.
The absolute reduction in risk of recurrence with aromatase inhibitors compared with tamoxifen in the adjuvant setting is modest, typically amounting to less than 5%.
The use of aromatase inhibitors consistently improves disease free survival in the adjuvant setting when compared to tamoxifen.
In postmenopausal women of the use of adjuvant aromatase inhibitors either as the primary therapy or after 2-3 years of tamoxifen have yielded equivalent outcomes in prospective studies.
The duration of adjuvant aromatase inhibitor therapy should not exceed five years.
Of the patients who relapse after adjuvant hormonal treatment up to 50% with ER+ disease who develop metastatic disease do not respond to first line endocrine therapy and the remainder will eventually acquire resistance.
ER mediated signaling can remain functional after the development of hormonal resistance.
Estrogen positive-progesterone negative subtype has an outcome is bad or worse than triple negative breast cancer.
There is a discontinuation rate of approximately 7-10% per year for tamoxifen and aromatase inhibitors.
Studies indicate that only 40-60% of patients with breast cancer finish recommended courses of adjuvants hormonal therapy despite higher recurrence rates and worse survival with treatment of less than five years duration.
In general, treatment decisions are made for patients with hormone receptor positive metastatic breast cancer based on the HER 2 status: patients with HER 2 positive disease often receive chemotherapy plus HER2 targeted therapy, while some patients will receive an aromatase inhibitor alone or in combination with anti-HER2 therapy.
Patients with hormone receptor positive, and HER2 negative disease, the most commonly utilized treatment is hormonal therapy.
In a phase 3 trial Breast Cancer Trials of Oral Everolimus ( BOLERO-2) 724 postmenopausal patients with metastatic breast cancer hormonally receptive positive and with progressive disease while receiving aromatase inhibitors anastrozole or letrozole, treated with exemestane plus everolimus resulted in a median progressive free survival of 7.4 months, compared with 3.2 months among those treated with exemestane plus placebo
BOLERO-2 trial of women with advanced hormone resistant estrogen receptor positive breast cancer treated with everolimus and the aromatase inhibitor exemestane found at increased progression free survival from a median of 2.8 months with exemestane alone to 6.9 months for the combination with a 64% reduction in risk of progression or death.
In most instances with hormone receptor positive disease and HER 2 negative disease chemotherapy is withheld until it becomes clinically necessary.
Tamoxifen is a selective estrogen receptor modulator (SERM) that binds to the estrogen receptor and selectively inhibits breast cancer cell transcriptional activity, while activating the receptor in other tissues such as bone and endometrium.
Choosing one hormonal agent over another for postmenopausal hormone receptor positive patients with advanced breast cancer depends on a number of factors including comorbidities, prior endocrine therapy, prior tolerance to specific agents and/or patient or physician preference.
The response rate for patients with ER positive and HER2 negative metastatic disease with antiestrogens such as tamoxifen or aromatase inhibitors ranges from 21-33%.
Aromatase inhibitors in meta-analyses of patients with advanced breast cancer have a survival advantage compared with alternative endocrine therapies.
No significant differences in survival have been observed between different third generation aromatase inhibitors in the treatment of advanced home only positive breast cancer.
In studies comparing fulvestrant at 500 mg with anastrozole 1 mg as first-line endocrine therapy for postmenopausal women with hormonally receptor positive advanced breast cancer reveal the median time to progression 23.4 months for fulvestrant versus 13.1 months for anastrozole, consistent with a 34% reduction in risk of progression: Overall survival data is presently not available.
Postmenopausal women can receive aromatase inhibitors or tamoxifen, and in a second line setting fulvestrant.
In a randomized study of newly diagnosed hormonally receptor positive patients with advanced breast cancer to a single drug and anastrozole compared to a anastrozole plus for fulvestrant revealed a median progression free survival of 13.5 months for this single agent versus 15 months for the combination and a media no role survival of 41.3 months for the single drug and 47.7 months for the combination of drugs: the combination of an Anastrozole and fulvestrant should be considered a new standard in the first-line treatment of metastatic HR positive breast cancer in postmenopausal women.
(Mehta RS et al).
SOFT trial a 3 arm clinical trial Of more than 3000 women premenopausal at breast cancer diagnosis randomly assigned to receive 5 years of the tamoxifen alone, tamoxifen plus ovarian function suppression, or exmestane plus ovarian function suppression: At 67 months patients treated with exemestane plus ovarian function suppression and those treated with tamoxifen plus ovarian function suppression or less likely to experience disease recurrence in those who received tamoxifen alone.
Ovarian function suppression refers to the use of monthly injections of the GnRH agonist, surgical removal of both ovaries, or radiation therapy to the ovaries.
For patients with hormone receptor positive disease and HER2 negative disease who fail hormonal therapy behave similar to those who have triple negative disease.
In most instances with hormone receptor positive disease and HER 2 negative disease chemotherapy is withheld until it becomes clinically necessary.
Postmenopausal women can receive aromatase inhibitors or tamoxifen, and in a second line setting fulvestrant.
For patients with hormone receptor positive disease and HER2 negative disease who fail hormonal therapy behave similar to those who have triple negative disease.
Mechanism for endocrine resistance is an aberrant signaling process through the phosphatidyllinositol 3-kinase (PI3k)-Akt – mammalian target of rapamycin (mTOR) signaling pathway.
Palbociclib approved for the treatment of women with metastatic breast cancer.
Trade name Ibrance.
Inhibits cyclin-dependent kinases (CKDs) 4 and 6, which are involved in promoting the growth of cancer cells.
The drug is intended for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer who have not yet received an endocrine-based therapy.
It is intended for use in combination with letrozole.
Evaluated in a Phase II clinical trial of 165 postmenopausal women with ER-positive, HER2-negative metastatic breast cancer who had not received previous treatment for advanced disease: Patients received Ibrance in combination with letrozole or letrozole alone. Those receiving the Ibrance combination lived 20.2 months without disease progression, while patients receiving letrozole alone lived 10.2 months without disease progressing.
The combination of letrozole and Palbociclib doubled the median progression-free survival.
The most common side effects are: neutropenia, leukopenia, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis.
It is recommended that treatment begin with a 125 milligram dose for 21 days, followed by seven days without treatment.
It is advised to monitor complete blood count prior to start of therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated.
PALOMA-2 palbociclib Plus letrozole are well tolerated.
PALOMA-3 A randomized study of palbociclib plus fulvestrant compared to fulvestrant alone revealing a progressive free survival in patients with advanced breast cancer ER positive with a median progressive survival of 9.2 months in women assigned combination and 3.8 months for women receiving fulvestrant alone.
In the above study both pre-and postmenopausal women derive benefit from the combination therapy.
In the above study both pre-and postmenopausal women derive benefit from the combination therapy.
Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone receptor positive, HER2 negative advanced breast cancer.
Abemaciclib Plus fulvestrant improves overall survival in hormone receptor positive/HER2 negative advanced breast cancer: at 47.7 months to follow up the median overall survival with the combination of drugs was 46.7 months compared with 37.3 months for a placebo plus fulvestrant.
In the MONARCH 2 trial abemaciclib plus fulvestrant resulted in a significant improvement in the median overall survival of 9.4 months for patients with hormonally receptor positive HER2 negative advanced breast cancer in patients who progressed after endocrine therapy regardless of menopausal status.
Early breast cancer is treated with curative intent; hormone positive, HER2 negative early breast cancer is treated with surgery with without radiotherapy or chemotherapy, followed by adjuvant endocrine therapy 5 to 10 years.
Adjjuvant endocrine therapy improves outcomes with recurrence in 27 to 37% of patients with stage Ii disease and 46 to 57% of patients with stage III disease occurring up to 20 years after diagnosis.
High dose estrogen and androgens can also be used doe endocrine resistant therapy of postmenopausal women with ER positive metastatic breast cancer.
Ki-67 score is at week two after preoperative endocrine therapy categorizes prognosis: at two weeks KI 67 positivity below 10% cut off, at five years had a recurrence rate of less than 10%, while those with a cut off greater than 10% at two weeks, had a five-year risk of recurrence greater than 20%.
In the POETIC study above, those who’s Ki 67 score was less than 10% at baseline and week two had a five-year recurrence rate less than 5%.
Standard first line treatment recently it has become aromatase inhibitors in combination with a CDK 4/6 inhibitor.