Approximately 65-70% of BC tumors express estrogen and/or progesterone receptors.
Breast cancers that are positive for estrogen receptor (ER) and negative for HER2 are the most common subset of breast cancers, accounting for 65% of cases among women less than 50 years of age and 75% among women older woman.
The prognosis of early stage disease is excellent and death rates for advanced disease have been falling over time.
Estrogen binding to ER stimulates receptor regulated transcription, which promotes tumor cell growth and proliferation.
Estrogen is the main driver of cancer cell proliferation in HR (hormone receptor) positive breast cancer.
Upon binding with estrogen, the estrogen receptor access both a direct transcription factor and a regulator of other transcription factors to drive cell proliferation.
The ER drives tumor growth and progression, so that the first line therapy for postmenopausal patients with ER positive tumors is aimed at blocking the activity of the ER, by means of endocrine therapy.
The basis for hormone treatment for ER positive tumors is to deplete estrogen production, interrupt ER signaling, degrade ER, or alter ER regulated signaling or proliferation pathways.
Treatment advances have come from targeting estrogen receptor signaling, which has evolved over time from the use of selective ER modulators, to aromatase inhibitors, and selective estrogen receptor degraders.
Aromatase inhibitors inhibit estrogen production, and include anastrozole, letrozole, and exemestane.
ER modulators inhibit the activity of the ER and include selective ER modulators (SERMs) and selective ER degraders (SERDs).
SERDs find directly to the ER, and instead of activating, the ER, signaling pathway, they cause degradation of the ER.
Presently combinations of endocrine treatments with molecular agents have improved outcomes and include the use of CDK 4/6 inhibitors.
An AI can be effectively combined with a second agent inhibiting the activity of CDK4/6 and these combinations are preferred first line therapies for postmenopausal patients with ER positive/HER2 negative metastatic breast cancer.
CDK 4/6 inhibitors include abemaciclib, palbociclib, and and ribociclib.
A number of chemotherapy regimens are active in the management of hormone receptor positive breast cancer.
Incidence rates of HR positive breast cancer are increasing likely due to increased prevalence of excess body weight and declining fertility rates.
In the treatment of naIve state, advanced HR positive breast cancers that are sensitive to estrogen blockade either aromatase inhibitors for postmenopausal women or a aromatase inhibitor plus ovarian suppression for pre-menopausal women.
Very low ER expression with immunohistochemistry staining of only 1-10% of tumor cells, is found in 2-3% of hormone receptor positive cancers can confer sensitivity to endocrine treatment
1% of breast cancers are classified as ER negative but PR positive and these tumors are associated with intermediate outcomes between those for ER positive cases and those for ER negative.
Estrogen receptor positive breast cancer is a heterogeneous entity, ranging from tumors that are highly estrogen driven and relatively resistant to chemotherapy to highly proliferative diseases that are more likely to respond to cytotoxic agents.
ER positive breast cancers vary in quantitative levels of ER, progesterone receptor (PR) expression, tumor grade, degree of proliferation as measured by Ki-67, patterns of gene expression, and the type and frequency of genomics alterations.
Correlations exist: low-grade, well differentiated tumors have high ER and PR expression and lower rates of proliferation.
Generally, intermediate and high-grade tumors have lower levels of ER, and they lack PR expression, with higher rates of cell proliferation.
Most ER positive breast cancers are of the ductal subtype, but 15% are lobular.
Lobular breast cancers are associated with the loss of cell-adhesion protein E-Cadherin resulting in loss of cell cohesion.
Lobular breast cancers appear as single file pattern tumor growth.
Less common breast cancer subtypes such as cribriform and tubular carcinomas are characterized by strong ER expression, are low grade and associated with excellent prognosis.
ER positive breast cancers with genomic luminal A have lower risk signatures and tend to be strongly ER positive and PR positive with a lower grade, less proliferation, and associated better prognosis.
Small luminal A tumors in the absence of nodal involvement of the lowest risk of recurrence.
Luminal B high risk signatures correlate with lower expression of ER, PR, or both, a higher grade, and greater proliferation with a higher risk of recurrence.
Hormone receptors are the primary transcription factors driving oncogenesis in hormone receptor + BC.
Guidelines recommend endocrine therapy as the first line treatment for patients with advanced breast cancer, reserving chemotherapy for patients with visceral crisis.
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.
ER signaling can be targeted by antagonizing estrogen binding to ER by Tamoxifen, blocking estrogen biosynthesis by aromatase inhibitors and luteinizing hormone releasing hormone (LHRH) agonists, and down regulating ER by fulvestrant.
Majority of patients relapse after treatment with anti-estrogen therapy.
Resistance to endocrine therapy is an inevitable development, and may be acquired or primary.
Acquired resistance is defined as disease progression beyond two years of edge of an endocrine therapy or after at least six months of endocrine therapy in the setting of advanced breast cancer.
Primary resistance is defined as a disease progression within two years of age of an endocrine therapy or after less than six months of endocrine therapy in the advanced setting.
In acquired resistance, genomics mutations or alterations develop going to therapy selection pressures that favor continued cancer so proliferation despite the loss of primary estrogen signaling.
Hormone receptor (HR) positive tumors have molecular and clinical heterogeneity.
HR+ tumors commonly associated with late recurrences.
The incremental change in the anatomical stage and biologic risk factors such as grade, proliferation, ER expression, and genomics signatures increase the risk of recurrence.
Primary resistance, affects a smaller pool of patients, mutations or genomic alterations are present in the untreated breast cancer.
The same prognostic factors above for metastatic recurrence also predict local and regional recurrence after surgery and radiation therapy.
Recurrence rate for ER positive cancers are relatively constant over many years, and tumors may recur over a long arc of time: at least half of recurrences arise five years after diagnosis and events be 10 years are not uncommon.
Risks for early recurrence, in the first five years after diagnosis, and for late recurrence, more than five years after diagnosis, are largely the same: higher nodal and tumor stage, higher grade, and adverse genomic assays.
Breast cancers in pre-menopausal women younger than 40 years of age tend to have lower levels of ER, higher tumor grade, and adverse genomic features, as compared with breast cancers in an older postmenopausal women.
These features, along with a higher stage diagnosis, and the persistence of ovarian function, largely the account for the effects of age on prognosis.
Hereditary breast cancer genes account for 8-10% of ER positive breast cancers: such genes include CHEK2 ,1%, and genes associated with homologous recombination deficiency such as BRCA1, 2%, BRCA 2, 2%, ATM 0.5-1%, and PALB, 0.5 to 1%.
Hereditary breast cancer prevalence in ER positive breast cancer is highest among younger than 40-year-old women, approximately 15%, and declines progressively with increasing age to approximately 10% among women 40 to 60 years of age, and approximately 5% among those over the age of 70 years.
BRCA1 mutations are disproportionately associated with cancers lacking ER and HER 2, most breast cancers arising in BRCA2, PALB2, CHEK2, and ATM mutation carries are ER positive, mirroring the distribution of sporadic cases.
HR+ have an annual recurrence rate following adjuvant anti-estrogen therapy 1%-4% depending on extent of initial disease.
The risk of late recurrence in hormone receptor positive breast cancer has a significantly higher annualized risk of recurrence after five years, compared with patients with hormone receptor negative breast cancer.
In estrogen receptor positive/HER 2-negative Postmenopausal early breast cancer, PIK3CA Mutations are associated with reduced risk of late distant recurrence, whereas amplification’s of 8P11 and BRCA to mutations were associated with increased risk of late distant recurrence.
Majority of breast cancer deaths occur in the setting of an initial hormone receptor positive disease.
Standard treatment of hormone receptor positive metastatic BC varies according to HER2 status: for patients with HER2 negative disease first line strategies with aromatase inhibitors, according to menopausal status, tamoxifen, and ovarian function suppression.
Initial treatment may include chemotherapy, with or without a targeted agent , dependent on the aggressiveness or extent of the disease.
Several trials have demonstrated the benefit of extended adjuvant endocrine therapy after the initial five years in some sets of patients with hormone receptor positive breast cancer.
In second line treatment treatment with non- steroidal aromatase inhibitor exemestane with or without everolimus, plus fulvestrant.
See endocrine therapy for breast cancer.
