Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer

  • leading cause of death from cancer in women worldwide.
  • Hormone receptor-positive (ie, estrogen [ER] and/or progesterone [PR] receptor-positive) breast cancers comprise the most common types of breast cancer, accounting for 75 percent of all cases.

OVERVIEW OF TREATMENT OPTIONS

  • selective estrogen receptor modulator (SERM), tamoxifen
  • Aromatase inhibitors, which block the peripheral conversion of androgens to estrogens.
  • Ovarian suppression or ablation, which inhibits endogenous estrogen production from the ovaries, which can be done on a temporary basis (ovarian suppression) or permanently through oophorectomy or radiation therapy to the ovaries (ovarian ablation).

TREATMENT APPROACH

  • For women with estrogen receptor- or progesterone receptor-positive breast cancer, à adjuvant endocrine therapy.
  • the approach is supported by the consistent improvements in rates of recurrence, second breast cancers, and survival that have been observed in clinical trials enrolling patients with hormone receptor-positive tumors of any size.
  • approach to treatment decisions for women with nonmetastatic, hormone receptor-positive breast cancer à  according to menopausal status.
  • Definition of menopause
  • For women with breast cancer who were premenopausal at diagnosis, particularly those treated with adjuvant chemotherapy, amenorrhea is not a reliable indicator of menstrual status.
  • following definitions of menopause
  • women 60 years and older postmenopausal.
  • women less than 60 years postmenopausal if one of the following conditions are met:
  • previously underwent a bilateral oophorectomy.
  • have not had any menstrual periods for 12 months or more in the absence of tamoxifen, chemotherapy, or ovarian suppression, and the serum estradiol is in the postmenopausal range.
  • are amenorrheic on tamoxifen, and follicle-stimulating hormone (FSH) and serum estradiol are in the postmenopausal range.
  • For women who were premenopausal prior to chemotherapy but experience therapy-induced amenorrhea, oophorectomy or serial measurement of FSH and estradiol are needed to ensure postmenopausal status if considering initiation of an aromatase inhibitor (AI).
  • Premenopausal women
  • For women with high-risk breast cancerà ovarian suppression plus exemestane rather than tamoxifen
  • For women with low-risk breast cancerà tamoxifen as single-agent therapy, given better tolerability than ovarian suppression plus either an aromatase inhibitor (AI) or tamoxifen.
  • ovarian suppression plus exemestane rather than tamoxifen as single-agent therapy.
  • the recommendation is based on the results of the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT)
  • An AI is not appropriate as single-agent therapy for women with intact ovarian function.

Postmenopausal women

  • AI rather than tamoxifen.
  • While AIs are associated with improved outcomes compared with tamoxifen, both agents reduce recurrences and new primary breast cancers, and some women may tolerate the risks and toxicities of tamoxifen better than AI.
  • For women who wish to discontinue an AI, it would be reasonable to switch to tamoxifen. The duration of endocrine therapy is discussed below.

OVARIAN SUPPRESSION OR ABLATION

  • For premenopausal women, ovarian function can be permanently suppressed by surgery (oophorectomy) or pelvic radiation (ovarian ablation).
  • Temporary amenorrhea is also possible with the administration of pharmacologic interventions to induce ovarian suppression (OS), such as the gonadotropin-releasing hormone agonists (GnRHa).
  • Ovarian suppression plus tamoxifen or aromatase inhibitors
  • The use of OS with either tamoxifen or aromatase inhibition (AI) provides some benefit over tamoxifen alone, but also is associated with increased toxicity
  • recommendation is based on the results of the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT)
  • Across both trials, toxicities were greater among those receiving OS, with osteoporosis and musculoskeletal side effects being most common among patients receiving exemestane in combination with OS.
  • Taken together, the data suggest a possible modest DFS benefit with the addition of OS to either tamoxifen or AI over tamoxifen alone for patients with hormone receptor-positive breast cancer, but may not justify the added toxicities for most average-risk patients.
  • OTHER FORMS OF ENDOCRINE THERAPY

Tamoxifen

  • selective estrogen receptor modulator (SERM)
  • inhibits the growth of breast cancer cells by competitive antagonism of the estrogen receptor (ER).
  • adjuvant treatment of premenopausal women and for postmenopausal women who are not candidates for an aromatase inhibitor (AI)
  • Dosing — 20 mg pill taken on a daily basis.
  • Side effects — significantly increased risk of thromboembolic disease (ie, deep vein thrombosis and pulmonary emboli)
  • increased the risk of uterine cancer, fatty liver disease, hot flashes, vaginal discharge, sexual dysfunction, menstrual irregularities, and increased risk of diabetes
  • Resistance — A number of factors may contribute to tamoxifen resistance in breast cancer, including
  • Variable expression of ER-alpha and beta isoforms
  • Interference with the binding of coactivators and corepressors
  • Alternative splicing of ER mRNA variants
  • Modulators of ER expression (eg, epidermal growth factor and its receptors such as EGFR1 and EGFR2, also called human epidermal growth factor receptor 2 [HER2])
  • Inherited drug metabolizing CYP2D6 genotypes

Aromatase inhibitors

  • AIs suppress plasma estrogen levels by inhibiting or inactivating aromatase, the enzyme responsible for the peripheral conversion of androgens to estrogens
  • improve outcomes for postmenopausal women with hormone receptor-positive breast cancer compared with tamoxifen.
  • inactive in women with intact ovarian function, including those who experienced therapy-induced amenorrhea. (See ‘Definition of menopause’ above and ‘Reactivation of ovarian function’ below.
  • Dosing — Drugs in this class, with usual dosing, include:
  • Anastrozole (1 mg daily)
  • Letrozole (2.5 mg daily)
  • Exemestane (25 mg daily)

Versus tamoxifen

  • Reduced breast cancer recurrence
  • Lower 10-year breast cancer mortality
  • Comparison between AIs — Evidence suggests similar clinical outcomes and tolerability between the aromatase inhibitors (AIs). As such, anastrozole, exemestane, and letrozole are all appropriate options for those warranting adjuvant treatment with an AI.
  • Side effects —The AIs are associated with musculoskeletal side effects including carpal tunnel syndrome as well as AI-associated musculoskeletal syndrome (AIMSS), characterized by joint pain and stiffness
  • Sexual dysfunction – Because AIs block peripheral estrogen production, women are at an increased risk for vaginal symptoms and sexual dysfunction.
  • Hot flashes
  • Compared with tamoxifen, the AIs are also associated with a higher risk of osteoporosis, fractures, cardiovascular disease, diabetes, and hypercholesterolemia
  • By contrast, they are associated with a lower risk of venous thrombosis and endometrial cancer and a lower risk of fatty liver disease
  • Timing of endocrine therapy —
  • For patients receiving adjuvant chemotherapy, the initiation of endocrine therapy is commonly begun after chemotherapy has completed (ie, sequentially) rather than during chemotherapy (ie, concurrently).
  • For women receiving adjuvant radiation therapy (RT) for breast cancer, initiate endocrine therapy concurrently with RT. Multiple studies show that the timing of endocrine therapy in relation to RT does not impact survival
  • PATIENTS WITH HER2-POSITIVE TUMORS
  • Most patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive early breast cancer are treated with adjuvant chemotherapy plus trastuzumab followed by maintenance trastuzumab to complete one year of treatment

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