The pharmacology of the estrogens and androgens is described in detail in Chapters 44 and 45. These agents are of value in certain cancers, most notably those of the prostate and breast, because these organs are dependent on hormones for their growth, function, and morphological integrity.
Hormone Therapy of Breast Cancer
Historically, high doses of estrogen have been recognized as effective treatment of breast cancer. More recent studies have suggested lower doses of estrogen can be effective in the management of endocrine-resistant disease (Ellis et al., 2009). The growth inhibitory effect of estrogens may be related to their ability to induce apoptosis in endocrine-resistant breast cancer (Jordan, 2015; Song and Santen, 2003). However, interruption of estrogen-induced signaling with antiestrogens such as tamoxifen and drugs that reduce estrogen production such as AIs and GnRH analogues have been found to be more effective and better tolerated. These drugs have largely replaced estrogens or androgens for the treatment of breast cancer.
The presence of the ER and PR in breast cancer tissue identifies the subset of hormone-receptor-positive (HR+) patients with a more than 60% likelihood of responding to hormonal therapy. The response rate to antiestrogen treatment is somewhat lower in the subset of patients with tumors that are ER+ or PR+ but also positive for human epidermal growth factor receptor HER2/neu amplification. In contrast, ER-negative and PR-negative carcinomas do not respond to hormonal therapy. In patients with metastatic cancer, responses to hormonal therapy may not be apparent clinically or by imaging for 8–12 weeks. The medication typically should be continued until the disease progresses or unwanted toxicities develop.
Antiestrogen approaches for the therapy of HR+ breast cancer include the use of SERMs, SERDs, and AIs (Table 68–1).
Table 68–1Antiestrogen Therapy in Er+ Breast Cancer |Favorite Table|Download (.pdf) Table 68–1Antiestrogen Therapy in Er+ Breast Cancer
|DRUG (DAILY STANDARD DOSE) ||THERAPEUTIC APPROACH IN DISEASE SETTING |
|CHEMOPREVENTION ||ADJUVANT THERAPY ||METASTATIC DISEASE |
|PREMENOPAUSE ||POSTMENOPAUSE ||PREMENOPAUSE ||POSTMENOPAUSE ||PREMENOPAUSE ||POSTMENOPAUSE |
|Tamoxifen (20 mg PO) ||Yes (5 y) ||Yes (5 y) ||Yes (5–10 y) ||Yes (before AI for 2–5 y) ||Yes ||Yes |
|Raloxifene (60 mg PO) ||X ||Yes (5 y) ||X ||X ||X ||X |
|Fulvestrant (500 mg IM day 1, day 15, day 29, then once per month) ||X ||X ||X ||X ||X ||Yes |
|Anastrozole (1 mg PO) ||X ||Yes (5 y) ||X ||Yes (5–10 years) (up front or after Tam) ||X ||Yes |
|Letrozole (2.5 mg PO) ||X || ||X ||Yes (5–10 years) (up front or after Tam) ||X ||Yes |
|Exemestane (25 mg PO) ||X ||Yes (5 y) ||X ||Yes (5–10 years) (up front or after Tam) ||X ||Yes |
Drugs That Target the Estrogen Receptor
Selective Estrogen Receptor Modulators
The SERMs bind to the ER and exert either estrogenic or antiestrogenic effects, depending on the specific organ (Chapter 44). Tamoxifen is the most widely studied antiestrogenic drug used in the treatment of breast cancer. Tamoxifen also exerts estrogenic agonist effects on nonbreast tissues, which influences the overall therapeutic index of the drug. Therefore, several novel antiestrogen compounds that offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen have been developed. These novel antiestrogens can be divided into tamoxifen analogues (e.g., toremifene, droloxifene, idoxifene); “fixed-ring” compounds (e.g., raloxifene, bazedoxifene, lasofoxifene, arzoxifene, miproxifene, levormeloxifene); and the SERDs (e.g., fulvestrant), the latter also termed “pure antiestrogens” (Howell et al., 2004; McDonnell and Wardell, 2010).
Tamoxifen. Tamoxifen was developed as an oral contraceptive but instead was found to induce ovulation and to have antiproliferative effects on estrogen-dependent breast cancer cell lines (Jordan, 2006). Tamoxifen is prescribed for the adjuvant therapy of early-stage breast cancer (Early Breast Cancer Trialists’ Collaborative Group, 2011) and for the therapy of advanced breast cancer (Burstein et al., 2010). Tamoxifen and other SERMs such as raloxifene are also used for the prevention of breast cancer in high-risk patients such as those with a strong family history or prior nonmalignant breast pathology (Visvanathan et al., 2013). The uses, pharmacology, and mechanism of action of raloxifene are discussed in Chapter 44.
Mechanism of Action. Tamoxifen is a competitive inhibitor of estrogens (e.g., 17β-estradiol), binding to the ER, and antagonizes estrogen-induced proliferation of human breast cancer. There are two subtypes of ERs: ERα and ERβ, which have different tissue distributions and can either homo- or heterodimerize. Binding of estrogen and SERMs to the estrogen-binding sites of the ERs initiates a change in conformation of the ER, dissociation of the ER from heat-shock proteins, and ER dimerization. Dimerization facilitates the binding of the ER to specific DNA EREs in the vicinity of estrogen-regulated genes. Coregulator proteins interact with the liganded receptor to act as corepressors or coactivators of gene expression (Chapter 44). Elegant studies of the crystal structure of ERα bound to different ligands indicate that, when an ER agonist is bound to the ligand-binding domain of the ER, helix 12 enables recruitment of coactivators. Conversely, with an estrogen antagonist such as 4-hydroxytamoxifen bound to the ER, helix 12 is displaced, the binding of coactivators is disrupted, and subsequent estrogen-induced gene transcription is inhibited (Nettles and Greene, 2005). Differences in tissue distribution of the ER subtypes and the function and relative amounts of different transcriptional coregulator proteins likely explains the antagonist response to tamoxifen in ER+ breast cancer and partial agonist activities in noncancerous tissues. Organs displaying agonist effects of tamoxifen include the uterine endometrium (endometrial hypertrophy, vaginal bleeding, and endometrial cancer); the coagulation system (thromboembolism); bone metabolism (increase in bone mineral density, which can slow development of osteoporosis); and liver (tamoxifen lowers total serum cholesterol, low-density lipoprotein cholesterol, and lipoproteins and raises apolipoprotein A-I levels).
ADME. Tamoxifen is readily absorbed following oral administration, with peak concentrations measurable after 3–7 h and steady-state levels reached at 4–6 weeks. Metabolism of tamoxifen is complex and principally involves CYPs 3A4/5, and 2D6 in the formation of N-desmethyl tamoxifen and CYP2D6 to form 4-hydroxytamoxifen, a more potent metabolite (Figure 68–1). Both metabolites can be further converted to 4-hydroxy-N-desmethyltamoxifen (endoxifen), which retains high affinity for the ER. The parent drug has a terminal t1/2 of 7 days. After enterohepatic circulation, glucuronides and other metabolites are excreted in the stool; excretion in the urine is minimal. Polymorphisms in CYP2D6 that reduce its activity lead to lower plasma levels of the potent metabolites 4-OH tamoxifen and endoxifen, but whether this leads to inferior efficacy of tamoxifen treatment and higher risks of disease relapse is unclear (Hertz and Rae, 2016). While drugs that inhibit CYP2D6 activity, such as antidepressants, have been postulated to minimize tamoxifen activity in breast cancer, more recent studies do not suggest a clinically significant impact (Haque et al., 2016).
Therapeutic Uses. Tamoxifen is given orally once per day. Tamoxifen is used for the treatment of women with ER+ metastatic breast cancer or following primary excision of an ER+ tumor as an adjuvant treatment to prevent recurrence and extend overall survival. For the adjuvant treatment of premenopausal women, tamoxifen is given for at least 5 years (Table 68–1). Tamoxifen may also be used for postmenopausal women, but AIs are preferred as they are associated with further reductions in the risk of recurrence (Early Breast Cancer Trialists’ Collaborative Group, 2015). Recent studies indicated that patients with breast cancer derive modest additional benefit, in terms of disease-free survival, overall survival, and decrease in contralateral breast cancer risk, if tamoxifen is taken for up to 10 years or AIs are continued for 5–10 years after completion of 5 years of tamoxifen (Davies et al., 2013; Goss et al., 2016). Of note, while taken for a finite time, Tamoxifen has been shown to have persisting long-term benefits (Ekholm et al., 2016). Tamoxifen may be taken as sole adjuvant therapy or after adjuvant chemotherapy (Table 68–1). Alternative or additional antiestrogen strategies in the adjuvant treatment of premenopausal women with ER+ breast cancer include oophorectomy or suppression of ovarian function with GnRH analogues (Table 68–2) typically given in combination with either tamoxifen or an AI. These combinations used in premenopausal women further reduce estrogen stimulation of breast cancer and result in lower rates of disease recurrence in very young women and in patients receiving chemotherapy (Francis et al., 2015). Some studies suggested improved response rates with these combinations in patients with metastatic disease. Tamoxifen also has shown effectiveness (a 40%–50% reduction in tumor incidence) in preventing breast cancer in women at increased risk (Fisher et al., 1998). In the preventive setting, tamoxifen reduces only ER+ tumors, not ER-negative tumors, and does not affect overall mortality.
Toxicity. The common adverse reactions to tamoxifen include vasomotor symptoms (hot flashes), atrophy of the lining of the vagina, menstrual irregularities, vaginal bleeding and discharge, and pruritus vulvae and occur with increasing severity in postmenopausal women. Because of partial agonist activity, tamoxifen also increases the incidence of endometrial cancer by 2- to 3-fold, particularly in postmenopausal women who receive tamoxifen for more than 2 years. Tamoxifen slightly increases the risk of thromboembolic events, which increase with the age of a patient and also in the perioperative period. Hence, it often is advisable to temporarily halt tamoxifen prior to elective surgery. Tamoxifen can cause retinal deposits, decreased visual acuity, and cataracts, although these changes are uncommon.
Endocrine Resistance. Initial or acquired resistance to endocrine therapies (tamoxifen or AIs) frequently occurs (Moy and Goss, 2006). Multiple mechanisms contribute to endocrine resistance in breast cancer (Clarke et al., 2015); these mechanisms include loss of ER expression, changes in coregulator expression, and hormone-independent activation of the ER by stress kinase or growth factor–activated cellular kinase pathways. In particular, cross talk between the ER and the HER2/neu pathway has been implicated in tamoxifen resistance. In a significant portion of metastatic breast cancers, estrogen-deprivation therapy can lead to selection of cancer cells expressing an ER with mutations that allow hormone-independent activation. Acquired ER mutations also contribute to endocrine-resistant breast cancer growth (Jeselsohn et al., 2015).
Tamoxifen and its metabolites.
Toremifene. Toremifene is a triphenylethylene derivative of tamoxifen and has a similar pharmacological profile, clinical efficacy, and safety (Howell et al., 2004). Toremifene is used occasionally in the metastatic setting for the treatment of breast cancer in women with tumors that are ER+ or of unknown receptor status. In rare cases, toremifene can cause heart rhythm problems through prolongation of the QT interval.
Selective Estrogen Receptor Downregulators
The SERDS, also termed pure antiestrogens, include fulvestrant and a number of agents in experimental trials. SERDs, unlike SERMs, are devoid of any estrogen agonist activity.
Fulvestrant. Fulvestrant is currently the only FDA-approved SERD, either as a single agent or in combination with palbociclib, a CDK4/6 inhibitor (Chapter 67), for postmenopausal women with HR+ metastatic breast cancer that has progressed on antiestrogen therapy.
Mechanism of Action. Fulvestrant is a steroidal antiestrogen that binds to the ER with an affinity more than 100 times that of tamoxifen. The drug not only inhibits the binding of estrogen but also alters the receptor structure such that the receptor is targeted for proteasomal degradation; fulvestrant also may inhibit receptor dimerization. Unlike tamoxifen, which stabilizes or even increases ER expression, fulvestrant reduces the number of ER molecules in cells; as a consequence of this ER downregulation, the drug abolishes ER-mediated transcription of estrogen-dependent genes.
ADME. Fulvestrant is given intramuscularly with initial biweekly loading doses in the first month followed by once monthly injections thereafter. Using this dosing regimen, steady-state levels are achieved within the first month (Robertson et al., 2014) (Table 68–1). Peak plasma concentrations are reached about 7 days after intramuscular administration of fulvestrant and the plasma t1/2 is about 40 days. There is rapid distribution and extensive protein binding of this highly lipophilic drug. Various pathways, similar to those of steroid metabolism (oxidation, aromatic hydroxylation, and conjugation), metabolize fulvestrant. CYP3A4 appears to be the major CYP isoenzyme involved in the metabolism of fulvestrant. The putative metabolites possess no estrogenic activity, and only the 17-keto compound demonstrates a level of antiestrogenic activity (~22% that of fulvestrant). Less than 1% of the parent drug is excreted intact in the urine.
Therapeutic Uses. Fulvestrant is used in postmenopausal women as antiestrogen therapy of HR+ metastatic breast cancer after progression on first-line antiestrogen therapy such as tamoxifen or an AI. Fulvestrant is at least as effective in this setting as the third-generation AI anastrozole. Recently, the addition of a CDK4/6 inhibitor (Chapter 67) to fulvestrant treatment has been shown to prolong disease-free survival (Turner et al., 2015).
Toxicity and Adverse Effects. Fulvestrant generally is well tolerated, the most common adverse effects being nausea, asthenia, pain, hot flashes, arthralgias, and headache. The risk of injection site reactions, seen in almost 10% patients, is reduced by giving the injection slowly.
Drugs That Decrease Estrogen Levels
Aromatase converts androgens to estrogens (e.g., androstenedione to estrone). AIs (Figure 68–2) block this enzymatic activity, thereby reducing estrogen production (Figure 67–3). AIs are now considered the standard of care for adjuvant treatment of postmenopausal women with ER+ breast cancer, either as initial therapy or after tamoxifen. (Dowsett et al., 2010). AIs are also approved in the initial treatment of metastatic HR+ breast cancer, often in combination with CDK4/6 inhibitors, and for disease that has progressed following tamoxifen treatment in postmenopausal women.
Aromatase and its inhibitors. Aromatase trihydroxylates the methyl group at C19, eliminating it as formate and aromatizing the A ring of the androgen substrate. Type 1 AIs are steroidal analogues of androstenedione that bind covalently and irreversibly to the steroid substrate site on the enzyme and are known as aromatase inactivators. Type 2 inhibitors are nonsteroidal, bind reversibly to the heme group of the enzyme, and produce reversible inhibition.
Aromatase (CYP19A1) is responsible for the conversion of adrenal androgens and gonadal androstenedione and testosterone to the estrogens estrone (E1) and estradiol (E2), respectively (Figure 68–3; reactions catalyzed by aromatase are noted by a green A beside the reaction arrow). In postmenopausal women, this conversion occurs in nonovarian tissues (fat, liver, muscle, brain, breast, and breast tumors) and is the primary source of circulating estrogens. In premenopausal women, estrogen is primarily produced in the ovaries. AIs increase gonadotropin production in premenopausal women, which reduces their ability to inhibit ovarian estrogen production. As a result, AIs are not effective in premenopausal women without additional ovarian suppression (e.g., with GnRH analogues; see the next section and Table 68–2). In postmenopausal women, AIs suppress most peripheral aromatase activity, leading to profound estrogen deprivation. AIs are classified as first, second, or third generation. In addition, they are further classified as type 1 (steroidal) or type 2 (nonsteroidal) AI according to their structure and mechanism of action (Figure 68–2). Type 1 inhibitors are steroidal analogues of androstenedione that bind covalently and irreversibly to the same site on the aromatase molecule. Thus, they commonly are known as aromatase inactivators. Type 2 inhibitors are nonsteroidal and bind reversibly to the heme group of the enzyme, producing reversible inhibition.
Third-Generation Aromatase Inhibitors. First- and second-generation (e.g., aminoglutethimide, formestane) AIs are no longer used for breast cancer treatment because of their side effects. Third-generation inhibitors include the type 1 steroidal agent exemestane and the type 2 nonsteroidal imidazoles anastrozole and letrozole; they are approved for use in postmenopausal women (Brodie and Njar, 2000). Third-generation AIs are used as part of the treatment of early-stage and advanced breast cancer in postmenopausal women and for chemoprevention (Table 68–1). The type 1 and 2 AIs have similar clinical efficacy and toxicity profiles (Goss et al., 2013), and these are summarized for AIs using anastrozole as a prototype. For letrozole and exemestane, additional drug-specific information is given.
Anastrozole. Anastrozole is a potent and selective triazole AI. Anastrozole, like letrozole, binds competitively and specifically to the heme of the CYP19. Daily administration of AIs reduces total body androgen aromatization by more than 95% after 1 month of treatment. AIs also reduce aromatization within large ER+ breast tumors.
ADME. Anastrozole is absorbed rapidly after oral administration. Steady state is attained after 7 days of repeated dosing. Anastrozole is metabolized by N-dealkylation, hydroxylation, and glucuronidation. The main metabolite of anastrozole is a triazole. Less than 10% of the drug is excreted as the unmetabolized parent compound. The principal excretory pathway is via the liver and biliary tract. The elimination t1/2 is about 50 h. The pharmacokinetics of anastrozole, which can be affected by drug interactions via the CYP system, are not altered by coadministration of tamoxifen or cimetidine.
Therapeutic Uses. AIs are approved for up-front adjuvant hormonal therapy for 5–10 years or following prior tamoxifen in postmenopausal women with early-stage breast cancer and as treatment of advanced and metastatic breast cancer. In early-stage breast cancer, anastrozole is significantly more effective than tamoxifen in delaying time to tumor recurrence and decreasing the odds of a primary contralateral tumor. In advanced breast cancer, postmenopausal women with disease progression while taking tamoxifen showed a significant survival advantage with anastrozole versus megestrol acetate (see Progestins, next section). Additionally, in women with ER+ or PR+ metastatic breast cancer, anastrozole was significantly better than tamoxifen in median time to disease progression. AIs are used in premenopausal women combined with ovarian suppression, as adjuvant treatment of breast cancer in premenopausal women less than 35 years of age, and in women requiring chemotherapy, where AI use is associated with significant reduction in risk of recurrence.
Adverse Effects and Toxicity. Most adverse effects are related to estrogen depletion. In postmenopausal women, compared to tamoxifen, anastrozole has been associated with a lower incidence of hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, ischemic cerebrovascular events, venous thromboembolic events, and deep venous thrombosis, including pulmonary embolism. Anastrozole is associated with a higher incidence of symptomatic arthralgias, vaginal dryness, and sexual dysfunction than tamoxifen. In addition, the estrogen depletion caused by AIs results in loss of bone mineral density. Compared with tamoxifen, treatment with anastrozole results in significantly lower bone mineral density in the lumbar spine and total hip and has been associated with increased fracture risk. Bisphosphonates (Chapter 48) prevent AI-induced loss of bone mineral density in postmenopausal women.
Letrozole. The clinical uses and side-effect profile of the type 2 AI letrozole are similar to that detailed in the previous section for anastrozole (Table 68–1). Letrozole-specific information is as follows:
ADME. Letrozole is rapidly absorbed after oral administration, with a bioavailability of 99.9%. Steady-state plasma concentrations of letrozole are reached after 2–6 weeks of treatment. Following metabolism by CYP2A6 and CYP3A4, letrozole is eliminated as an inactive metabolite mainly via the kidneys and has a t1/2 of about 41 h.
Therapeutic Uses. The clinical indications for use of letrozole in breast cancer treatment are the same as for anastrozole (Table 68–1). In addition, improved progression-free survival is observed when HR+ advanced stage breast cancer is treated with letrozole in combination with a CDK4/6 inhibitor (Chapter 67) (Finn et al., 2015; Hortobagyi et al., 2016).
Exemestane. Exemestane is a more potent, orally administered analogue of the natural aromatase substrate androstenedione and lowers estrogen levels more effectively than does its predecessor, formestane. Exemestane irreversibly inactivates aromatase and is a “suicide substrate” type 1 inhibitor of aromatase. The clinical uses and side-effect profile of exemestane are similar to that detailed in the section for the AI anastrozole. Exemestane-specific information is as follows:
ADME. Orally administered exemestane is rapidly absorbed from the GI tract; its absorption is increased by 40% after a high-fat meal. Exemestane has a terminal t1/2 of about 24 h. It is extensively metabolized in the liver, ultimately to inactive metabolites. One metabolite, 17-hydroxyexemestane, has weak androgenic activity that may contribute to antitumor activity. Although active metabolites are excreted in the urine, no dosage adjustments are recommended in patients with renal dysfunction.
Therapeutic Uses. The clinical indications for use of exemestane in breast cancer treatment are the same as for anastrozole (Table 68–1). In addition, the use of the mTOR inhibitor everolimus (Chapter 67) with exemestane has been approved for treatment of advanced-stage breast cancer that has progressed on nonsteroidal type 2 AIs (Yardley et al., 2013).
Synthetic GnRH analogues (e.g., triptorelin, goserelin, leuprolide; Table 68–2) have greater receptor affinity and reduced susceptibility to enzymatic degradation than the naturally occurring decapeptide GnRH molecule and are 100-fold more potent GnRH agonists than the native decapeptide. They are used in the adjuvant treatment of breast cancer or metastatic disease for women who have functioning ovaries; typically, they are used in combination with either tamoxifen or AIs. Continuous administration of GnRH agonists downregulates GnRH receptors in the pituitary gland. This suppresses the release of the gonadotropins FSH and LH from the pituitary and prevents follicular maturation in the ovary. Serum estrogen levels are reduced to those seen in postmenopausal women or in women after oophorectomy.
Table 68–2Structures of GnRH and Decapeptide GnRH Analogues |Favorite Table|Download (.pdf) Table 68–2Structures of GnRH and Decapeptide GnRH Analogues
|AMINO ACID RESIDUE ||1 ||2 ||3 ||4 ||5 ||6 ||7 ||8 ||9 ||10 ||DOSAGE FORM |
|GnRH ||PyroGlu ||His ||Trp ||Ser ||Tyr ||Gly ||Leu ||Arg ||Pro ||Gly-NH2 || |
|Leuprolide ||________________________________________ ||D-Leu ||__________________ ||Pro-NHEt || ||IM, SC, depot |
|Buserelin* ||________________________________________ ||D-Ser(tBu) ||__________________ ||Pro-NHEt || ||SC, IN |
|Nafarelin ||________________________________________ ||D-Nal ||_____________________________ ||Gly-NH2 ||IN |
|Deslorelin* ||________________________________________ ||D-Trp ||__________________ ||Pro-NHEt || ||SC, IM, depot |
|Histrelin ||________________________________________ ||D-His (ImBzl) ||__________________ ||Pro-NHEt || ||SC, depot |
|Triptorelin ||________________________________________ ||D-Trp ||_____________________________ ||Gly-NH2 ||IM, depot |
|Goserelin ||________________________________________ ||D-Ser(tBu) ||_____________________________ ||AzGly-NH2 ||SC implant |
|Cetrorelix ||Ac-D-Nal ||D-Cpa ||D-Pal ||______________ ||D-Cit ||_____________________________ ||D-Ala-NH2 ||SC |
|Ganirelix* ||Ac-D-Nal ||D-Cpa ||D-Pal ||______________ ||D-hArg(Et)2 ||_____ ||D-hArg(Et)2 ||_______ ||D-Ala-NH2 ||SC |
|Abarelix ||Ac-D-Nal ||D-Cpa ||D-Pal ||_____ ||Tyr(N-Me) ||D-Asn ||_____ ||Lys(iPr) ||_______ ||D-Ala-NH2 ||SC depot |
|Degarelix ||Ac-D-Nal ||D-Cpa ||D-Pal ||_____ ||4Aph HO ||4Aph (Cbm) ||_____ ||I lys ||_______ ||D-Ala-NH2 ||SC |
ADME. GnRH agonists are administered as an injection once a month or every 3 or 6 months. There is in an initial rise in LH and FSH levels, but after 14–21 days of therapy, a sustained decrease in serum LH and estrogen is observed.
Therapeutic Uses. In the adjuvant setting, recent studies have demonstrated a benefit for GnRH agonists when given in conjunction with either AIs or tamoxifen in very young or higher-risk premenopausal women (Regan et al., 2016). In addition, these drugs can be given with tamoxifen, AIs, or fulvestrant in premenopausal women with metastatic breast cancer.
Toxicity. Side effects are generally related to hypoestrogenism (i.e., hot flashes, vaginal dryness, decreased libido, osteoporosis, amenorrhea, and dyspareunia). The side effects of GnRH agonists are potentially reversible on cessation of therapy. AI use in premenopausal women combined with ovarian suppression with GnRH analogues increases menopausal symptoms and sexual dysfunction and thus benefits and risks must be carefully considered (Burstein et al., 2016).
Drugs That Target the Progesterone Receptor
Progestational agents (see Chapter 44 for details) are mainly used as secondary agents in hormonal therapy for metastatic hormone-dependent breast cancer and are also used in the management of endometrial carcinoma previously treated by surgery and radiotherapy. Progesterone binds to the PR present in target issues, such as breast and the endometrium (Chapter 44). Activation of the PR by progestins in the endometrium is antiproliferative.
Medroxyprogesterone acetate is available for oral administration; an alternative oral progestational agent is megestrol acetate. Beneficial effects have been observed in one-third of patients with endometrial cancer. The response of breast cancer to megestrol is predicted by both the presence of HRs (ER and PR) and the evidence of response to a prior hormonal treatment. The effect of progestin therapy in breast cancer appears to be dose dependent, with some patients demonstrating second responses following dose escalation of megestrol. Clinical use of progestins in breast cancer has been largely superseded by the advent of tamoxifen and AIs. An additional use of progestins is to stimulate appetite and restore a sense of well-being in cachectic patients with advanced stages of cancer and AIDS.
Hormone Therapy of Prostate Cancer
Androgens stimulate the growth of normal and cancerous prostate cells. The critical role of androgens for prostate cancer growth was established in 1941 and led to the awarding of a Nobel Prize in 1966 to Dr. Charles Huggins. These findings established androgen deprivation therapy (ADT) as the mainstay of treatment for patients with advanced prostate cancer. ADT is also given in conjunction with radiation therapy or following surgery for some men with regionally localized intermediate- to high-risk disease. In patients with metastasis, ADT is typically the standard first-line treatment. ADT is accomplished via surgical castration (bilateral orchiectomy) or medical castration (using GnRH agonists or antagonists). Other hormone therapy approaches that are used as second-line treatment include antiandrogens, estrogens, and inhibitors of steroidogenesis. In the advanced setting, ADT is not a curative treatment but does prolong survival. ADT alleviates cancer-related symptoms and provides important quality-of-life benefits, including reduction of bone pain and reduction of rates of pathological fracture, spinal cord compression, and ureteral obstruction.
Disease progression despite ADT signifies the development of castration-resistant prostate cancer (CRPC). In CRPC, the AR can be overexpressed or mutated and can be activated by weak adrenal androgens or from androgens produced locally in tumors. Therefore, antiandrogens (competitive antagonists of androgens at the AR), inhibitors of steroidogenesis, or estrogens are frequently employed as second-line hormone therapies and are associated with improvements in symptoms and quality of life and with prolongation in survival (Ritch and Cookson, 2016). Antiandrogens are typically administered concurrently with GnRH analogues or in men who have undergone orchiectomy. When patients become refractory to further hormonal therapies, their disease is considered androgen independent.
Common side effects of androgen deprivation include vasomotor instability, loss of libido, impotence, gynecomastia, fatigue, anemia, weight gain, decreased insulin sensitivity, altered lipid profiles, osteoporosis and fractures, and loss of muscle mass. ADT is associated with a slight but significant increased risk of diabetes and coronary heart disease. Skeletal-related events due to ADT may be mitigated by bisphosphonate therapy (see Chapter 48). Antiandrogens, when compared with GnRH agonists, cause more gynecomastia, mastodynia, and hepatotoxicity but less vasomotor flashing and loss of bone mineral density. Estrogens cause a hypercoagulable state and increase cardiovascular mortality in patients with prostate cancer and are no longer standard treatment options.
Androgen Deprivation Therapy
GnRH Agonists and Antagonists
The most common form of ADT involves chemical suppression of the pituitary gland with GnRH agonists (see previous section). GnRH agonists in common use for prostate cancer include leuprolide, goserelin, triptorelin, histrelin, and nafarelin (Table 68–2). Long-acting preparations are available in doses that are approved for 3-, 4-, and 6-month administrations.
The GnRH agonists bind to GnRH receptors on pituitary gonadotropin-producing cells, causing an initial release of both LH and FSH and a subsequent increase in testosterone production from testicular Leydig cells. After 1 week of therapy, GnRH receptors are downregulated on the gonadotropin-producing cells, causing a decline in the pituitary response. The fall in serum LH leads to a decrease in testosterone production to castrate levels within 3–4 weeks of the first treatment. Subsequent treatments maintain testosterone at castrate levels.
ADT is given in patients with localized intermediate- to high-risk prostate cancer in conjunction with radiation therapy or in some cases following surgery. In patients with metastasis, ADT is typically the standard first-line treatment either alone or in combination with chemotherapy. In patients with CRPC, ADT is used in conjunction with antiandrogens. This combination therapy is referred to as combined androgen blockade. The theoretical advantage is that the GnRH agonist will deplete testicular androgens, while the antiandrogen component competes at the receptor with residual androgens made by the adrenal glands. Combined androgen blockade provides maximal relief of androgen stimulation. Several trials suggested a benefit in 5-year survival, but toxicity and costs associated are higher than with ADT alone.
Toxicity. During the transient rise in LH, the resultant testosterone surge may induce acute stimulation of prostate cancer growth and a “flare” of symptoms from metastatic deposits. Patients may experience an increase in bone pain, spinal cord compression, or obstructive bladder symptoms lasting for 2–3 weeks. The flare phenomenon can be effectively counteracted with concurrent administration of 2–4 weeks of oral antiandrogen therapy, which may inhibit the action of the increased serum testosterone levels. Besides avoidance of the initial flare, GnRH antagonist therapy offers no apparent advantage compared with GnRH agonists. The early GnRH antagonists cetrorelix and abarelix (no longer marketed), although effective, are now rarely used for prostate cancer because of the risk for severe systemic allergic reactions. A newer GnRH antagonist, degarelix, is not associated with systemic allergic reactions and is approved for prostate cancer in the U.S.
Drugs That Target the Androgen Receptor
Antiandrogens bind to ARs and competitively inhibit the binding of testosterone and dihydrotestosterone, thereby preventing AR nuclear translocation and inhibiting transcription of downstream androgen-responsive genes. Unlike castration, antiandrogen therapy by itself does not decrease LH production; therefore, testosterone levels are normal or increased. Men treated with antiandrogen maintain some degree of potency and libido and do not have the same spectrum of side effects seen with castration. However, antiandrogen therapy is typically given in combination with ADT. Antiandrogens are classified as steroidal, including cyproterone or nonsteroidal, including enzalutamide, flutamide, bicalutamide, and nilutamide.
Enzalutamide. Enzalutamide is the most recently FDA-approved second-generation antiandrogen. It prolongs survival in patients with metastatic CRPC when given to chemotherapy naïve patients or after docetaxel therapy (Beer et al., 2014; Scher et al., 2012). Enzalutamide is a synthetic nonsteroidal antiandrogen that has 5- to 8-fold higher binding affinity for the AR compared to bicalutamide (Tran et al., 2009). Similar to other antiandrogens, enzalumatide prevents binding of androgens to the AR and reduces binding of AR to DNA and to AR coactivator proteins (see Chapter 45). Enzalutamide can also prevent translocation of AR into the cell nucleus and induces cell apoptosis.
ADME. Enzalutamide has improved efficacy and potency compared to older antiandrogens. Enzalutamide is given orally once daily with a t1/2 of approximately 6 days. Steady-state levels are achieved in 28 days. CYP2C8 is primarily responsible for the formation of the active metabolite N-desmethyl enzalutamide.
Toxicity. Similar to other antiandrogens, enzalutamide has negative effects on sexual function. Other notable side effects include gynecomastia, breast pain, fatigue, diarrhea, headache, and hot flashes. Enzalutamide crosses the blood-brain barrier, and seizures occur infrequently in approximately 1% of patients. Resistance to AR inhibitors develops frequently through mechanisms such as gene rearrangement, mutation, and acquired AR splice variants (Li et al., 2013). Studies are ongoing with newer AR-blocking agents that may overcome resistance to current antiandrogen therapies (Moilanen et al., 2015; Smith et al., 2016).
Bicalutamide. The agent bicalutamide is given once daily in conjunction with a GnRH agonist. Bicalutamide has a t1/2 of 5–6 days. Bicalutamide undergoes glucuronidation to inactive metabolites, and the parent compound and metabolites are eliminated in bile and urine. The t1/2 of bicalutamide is increased in severe hepatic insufficiency and is unchanged in renal insufficiency. Bicalutamide is well tolerated at higher doses and has reduced toxicity and improved tolerability and pharmacokinetic profiles relative to flutamide and nilutamide. Daily bicalutamide is significantly inferior compared with surgical or medical castration and should not be used as monotherapy of prostate cancer.
Nilutamide. Nilutamide is given orally once daily. It has an elimination t1/2 of 45 h and is metabolized to five products that are all excreted in the urine. Common side effects include mild nausea, alcohol intolerance (5%–20%), and diminished ocular adaptation to darkness (25%–40%); rarely, interstitial pneumonitis occurs.
Flutamide. Flutamide is given orally three times per day. It has a t1/2 of 5 h; its major metabolite, hydroxyflutamide, is biologically active. Common side effects include diarrhea, breast tenderness, and nipple tenderness. Less commonly, nausea, vomiting, and hepatotoxicity occur. Rare reports of fatal hepatotoxicity have been observed. It is used infrequently as it has the least-favorable toxicity profile of the antiandrogens.
Drugs That Inhibit Androgen Synthesis
In the castrate state, AR signaling, despite low steroid levels, supports continued prostate cancer growth. AR signaling may occur due to androgens produced from nongonadal sources, AR gene mutations, or AR gene amplification. Nongonadal sources of androgens include the adrenal glands and the prostate cancer cells themselves (see Figure 68–3). Androstenedione, produced by the adrenal glands, is converted to testosterone in peripheral tissues and tumors. Intratumoral de novo androgen synthesis also may provide sufficient androgen for AR-driven cell proliferation. Thus, inhibitors of androgen synthesis may be useful as secondary therapy in reducing AR signaling.
Steroid synthesis pathways. The shaded area contains the pathways used by the adrenal glands and gonads and clinically used agents that inhibit the pathways. Enzymes are labeled in green, inhibitors in red. Pertaining to this figure only, A, aromatase; 3β, 3β-hydroxysteroid dehydrogenase; 5αR, 5α-reductase; 11β, 11β-hydroxylase; 17, 20, C-17, 20-lyase (also CYP17); 17α, 17α-hydroxylase (CYP17); 17βR, 17β-reductase; 18, aldosterone synthase; 21, 21-hydroxylase.
Ketoconazole. Ketoconazole is an antifungal agent that also inhibits both testicular and adrenal steroidogenesis by blocking CYP 11A and primarily CYP17 (17α-hydroxylase). Ketoconazole is administered off label as secondary hormone therapy to reduce adrenal androgen synthesis in CRPC. Diarrhea and hepatic enzyme elevations limit its use as initial hormone therapy; consequent poor patient compliance reduces its efficacy. Oral ketoconazole is coadministered with hydrocortisone to compensate for inhibition of adrenal steroidogenesis. Ketoconazole has limited use in practice due to its toxicity.
Abiraterone. Abiraterone is used with prednisone for the treatment of CRPC in patients who are chemotherapy naïve or in those who have received previous docetaxel. In both settings, it prolongs survival (de Bono et al., 2011; Ryan et al., 2015).
Mechanism of Action. Abiraterone is an irreversible inhibitor of 17α-hydroxylase and C-17,20-lyase (CYP17A1) activity in testicular, adrenal and prostatic cancer tissue (Figure 68–3). Abiraterone inhibition of CYP17A1 reduces the conversion of pregnenelone and progesterone to their 17α-hydroxy derivatives and reduces the synthesis of DHEA and androstenedione. Thus, circulating levels of testosterone drop to almost-undetectable levels after abiraterone administration. Abiraterone also has some activity as an AR antagonist and inhibitor of other steroid synthetic enzymes and CYP450s. Overall, abiraterone has greater potency and selectivity than ketoconazole.
ADME. Abiraterone is the active metabolite of abiraterone acetate. With continuous administration, abiraterone increases ACTH levels, resulting in mineralocorticoid excess. Oral abiraterone acetate is administered with prednisone to counteract adrenal suppression. Abiraterone should be taken on an empty stomach. Abiraterone Cmax and AUC are both increased more than 10-fold when a single dose of abiraterone acetate is administered after food compared to a fasted state.
Toxicity. Side effects include hepatotoxicity, joint swelling, hypokalemia, vasomotor symptoms, diarrhea, cough, hypertension, arrhythmia, urinary frequency, dyspepsia, and upper respiratory tract infection. Resistance to abiraterone, similar to enzalutamide, can occur through selection of tumor cells expressing constitutively active AR splice variants (Antonarakis et al., 2014).
High estrogen levels can reduce testosterone to castrate levels in 1–2 weeks via negative feedback on the hypothalamic-pituitary axis. Estrogen also may compete with androgens for steroid HRs and may thereby exert a cytotoxic effect on prostate cancer cells. Although estrogens reduce bone loss and are as effective as orchiectomy for metastatic prostate cancer, they are no longer used clinically because of their risk for serious and potentially fatal side effects (e.g., myocardial infarctions, strokes, pulmonary emboli) as well as impotence and lethargy.
Paul Calabresi, Bruce Chabner, Beverly Moy, Richard J. Lee, and Matthew Smith contributed to this chapter in recent editions of this book. We have retained some of their text in the current edition.