Biomedical Engineering Reference
In-Depth Information
5.4
ER/PgR Targeted Therapy for Breast Cancer
Determination of ER/PgR status is mandatory for all newly diagnosed
invasive breast cancer, and on metastatic lesions if they influence
the treatment decisions.
28
Immunohistochemistry (IHC) assays are
recommended for use in testing ER/PgR contents. American Society
of Clinical Oncology/College of American Pathologists Guideline
recommends that tumors are defined as ER/PgR positive if there
are at least 1% positive tumor nuclei by IHC.
29,30
Endocrine therapy
should be given to patients with ER-positive and/or PgR-positive
invasive breast cancer regardless of age, lymph node status, or
whether or not adjuvant chemotherapy is to be administered.
Currently, major ER-targeted endocrine pharmacological
therapies are with the use of SERMs, aromatase inhibitors (AIs), and
selective ER down-regulators (SERDs). SERMs such as tamoxifen
directly bind to ER and block estrogen from binding to its receptors
and alter the molecular conformation of the receptor. This results
in preferential recruitment of the corepressor proteins rather than
the coactivator complex and, therefore, inhibits estrogen-stimulated
tumor growth.
31
AIs reduce the production of estrogen by blocking
the aromatization of androstenedione and testosterone—estrogen
precursors in peripheral tissues.
32
SERDs that bind to ER with high
affinity are pure steroidal antiestrogen with no agonist effects,
leading to both down-regulation and degradation of the receptor.
33-
35
The FDA-approved ER/PgR-targeted drugs for the treatment of
breast cancer are listed in Table 5.1.
Selection for appropriate endocrine therapy depends on the
disease state (early versus recurrent or metastatic) and patient
endocrine status (premenopausal versus postmenopausal). In
premenopausal women, most estrogen is produced in the ovaries
in response to pituitary-derived luteinizing and follicle-stimulating
hormones. In postmenopausal women, estrogen is produced mainly
in peripheral tissues by aromatase conversion of rostenedione and
testosterone produced in the adrenal gland. Inhibition of peripheral
conversion of estrogen precursors to estrogen in premenopausal
patients may lead to a reduced feedback of estrogen to the
hypothalamus and pituitary axis and, consequently, stimulation
of ovarian estrogen production.
Because of this concern, use of
AIs should be avoided in premenopausal patients with functional
ovaries.
36
