A 57-year-old woman comes to the office due to left breast pain associated with fatigue, nausea, and unexplained weight loss. She is referred for mammography, which reveals a 3-cm dominant mass in the left breast. Biopsy confirms the mass to be adenocarcinoma, and subsequent studies find that the tumor is estrogen receptor-positive and human epidermal growth factor receptor 2- (HER2) negative. The patient experienced menopause at age 52, and her past medical history is otherwise unremarkable. Anastrozole treatment is initiated and leads to a substantial decrease in the size of the primary tumor. Which of the following is the best explanation for the therapeutic effect of this agent?

Question

A 57-year-old woman comes to the office due to left breast pain associated with fatigue, nausea, and unexplained weight loss.  She is referred for mammography, which reveals a 3-cm dominant mass in the left breast.  Biopsy confirms the mass to be adenocarcinoma, and subsequent studies find that the tumor is estrogen receptor-positive and human epidermal growth factor receptor 2- (HER2) negative.  The patient experienced menopause at age 52, and her past medical history is otherwise unremarkable.  Anastrozole treatment is initiated and leads to a substantial decrease in the size of the primary tumor.  Which of the following is the best explanation for the therapeutic effect of this agent?

Quizplus · Accepted Answer

11ec160b_3ba9_fd0c_9249_0b4bb0c37842_MD0001_00 Estrogens are synthesized primarily by the aromatization of androgens. Aromatase belongs to the P450 superfamily and is highly expressed in ovarian tissue (in which expression is gonadotropin dependent). Aromatase is also expressed in the adrenal cortex, subcutaneous fat, and breast. In the postmenopausal state, follicular atresia leads to reduced numbers of granulosa cells and decreased ovarian estrogen synthesis. However, the ovaries and adrenal glands continue to produce androgens in significant quantities, and extraovarian aromatase maintains a low level of estrogen in the peripheral circulation. Estrogen is the main hormone driving the growth and development of estrogen receptor (ER)-positive malignant breast tumors. Aromatase inhibitors (eg, anastrozole, letrozole, exemestane) reduce the synthesis of estrogen from androgens, suppressing estrogen levels in postmenopausal women and slowing progression of ER-positive tumors. They are less effective as monotherapy in premenopausal women, as ovarian aromatase is upregulated substantially in response to gonadotropins. (Choice B) Although inhibition of androgen synthesis could theoretically decrease estrogen synthesis, most androgen synthesis inhibitors (eg, ketoconazole) are nonspecific and suppress other pathways of steroidogenesis (eg, cortisol, mineralocorticoid). (Choice C) Pulsatile stimulation of the pituitary by gonadotropin-releasing hormone (GnRH) increases secretion of LH and FSH. However, continuous GnRH stimulation by long-acting GnRH analogs (eg, goserelin) suppresses LH and FSH release, decreasing production of estrogens in the ovarian follicle. These agents are useful for ovarian suppression in premenopausal women with ER-positive breast cancer. (Choice D) Tamoxifen acts as either an antagonist or a partial agonist of the estrogen receptor, depending on the tissue. In breast tissue, tamoxifen antagonizes the estrogen receptor and can be used as adjuvant therapy for ER-positive breast cancer. (Choice E) Many breast cancers overexpress epidermal growth factor receptor 2 (HER2). Trastuzumab is a monoclonal antibody against HER2 that is used in patients with HER2-positive tumors. It inhibits MAPK and PI3K/Akt signaling pathways, increases degradation of HER2, and facilitates antibody-mediated destruction of tumor cells. Educational objective: Estrogen is the main hormone responsible for the growth and development of estrogen receptor (ER)-positive breast tumors. Aromatase inhibitors (eg, anastrozole, letrozole, exemestane) decrease the synthesis of estrogen from androgens, suppressing estrogen levels and slowing progression of ER-positive tumors. __________ References: Aromatase inhibitors in breast cancer. (http://www.ncbi.nlm.nih.gov/pubmed/19577386)

A 57-Year-Old Woman Comes to the Office Due to Left