U.S. Pharmacist

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Hormonal Therapies in Breast and Prostate Cancers

Michael Steinberg, PharmD, BCOP
Assistant Professor of Pharmacy Practice,
Massachusetts College of Pharmacy and Health Sciences,
Worcester, Massachusetts

10/18/2007

US Pharm. 2007;32(10):14-26.

ABSTRACT: In the United States, breast cancer and prostate cancer are the most common types of cancer diagnosed in women and men, respectively. Due to the hormonal sensitivity of these cancers, treatment options include not only traditional chemotherapy, radiation, and surgery but also agents that interfere with hormonal pathways involving either estrogens or androgens. Applicable drugs employ a variety of mechanisms aimed at reducing the hormonal influence on these cancers in an effort to enact a cure or control disease-related symptoms. This article reviews hormonal agents used in the management of breast cancer and prostate cancer and presents clinical data supporting their indications.

In 2007, an estimated 180,510 Americans will be diagnosed with breast cancer, and 40,910 will die of the disease.1 Furthermore, 218,890 men will be diagnosed with prostate cancer, and 27,050 men will die of the malignancy. Breast cancer and prostate cancer are the most common cancer diagnoses in women and men, respectively. Lung cancer is the only malignancy estimated to cause more deaths than either breast or prostate cancer.1 Breast cancer and prostate both involve hormones that mediate the growth of cancer cells. Although treatments such as surgery, radiation, and traditional chemotherapy are used to manage patients in various stages of these diseases, endocrine-based therapies are commonly selected for use in patients with hormone-sensitive disease.2,3 A significant amount of clinical investigation has been performed to determine the most opportune endocrine agent and when to use it  in patients based on disease and patient characteristics. The application of various combinations of agents from different classes has also been studied. This article identifies agents of pharmacologic classes that are used to manage patients via hormonal processes in either breast or prostate cancer and describes their indications and mechanisms of action.

Breast Cancer
Since the early 20th century, different staging systems have been used to assess the extent of disease in patients with breast cancer and other cancers. Although these staging systems are useful in establishing a prognosis and selecting appropriate treatment options based on disease characteristics such as size of the tumor, regional spread to lymph nodes, and presence of distant metastases, they do not consider such factors as hormonal status.4 Evaluation of tumor biopsy specimens is also useful in identifying cellular characteristics; this information can help in the selection of therapeutic agents.

The Role of Estrogen: Estrogen, a major determinant of female characteristics, mediates normal growth of breast and uterine tissue.5 Prior to menopause, estrogen is produced primarily in the ovaries, but also in the adrenal glands and adipose tissue. However, in postmenopausal women, the adrenal glands and adipose tissue become the only sites of estrogen production, as the ovaries lose this function. In premenopausal women, the level of circulating estrogen is controlled by a negative feedback system involving the hypothal­ amus, which secretes gonadotropin-­ releasing hormone (GnRH), that in turn stimulates the anterior pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones stimulate the ovaries to produce estradiol and estrone, which are endogenous forms of estrogen. Circulating estrogen then interacts with target cells containing receptors for the hormone, such as those in breast, uterine, heart, liver, bone, and brain tissue.5

Estrogen is an important factor in breast cancer due to the presence of receptors for estrogen on the surface of breast cancer cells.5 Estrogen not only stimulates normal breast cells but also influences the growth of estrogen receptor–positive (ER+) cancer cells. About 70% to 80% of patients with breast cancer have cancers that are ER+. Interestingly, as a patient's age at the time of diagnosis of breast cancer increases, the likelihood for the breast cancer cells to be ER+ increases. This is important in selecting therapy, as it suggests that younger women may be less likely to respond to hormonal therapy targeted at controlling the effects of estrogen on breast cancer cells than are older women who have passed menopause.5


Selective Estrogen-Receptor Modulators: Since a variety of tissues have receptors for estrogen, this hormone has multiple functions. Selective estrogen-receptor modulators (SERMs) provide antagonistic effects of estrogen on breast cancer cells, but an agonistic effect on normal cells, such as those in the uterus, bone, and heart.5 This results in the maintenance of some of the positive effects of estrogen that are otherwise absent with the use of a pure estrogen antagonist. Three SERMs are currently available in the United States (see Table 1 for FDA-approved indications). Tamoxifen was the first to be approved, in 1997, while toremifene (Fareston) and raloxifene (Evista) are more recent additions. 5-7 Only toremifene and tamoxifen are currently approved by the FDA for the treatment of women with breast cancer.8



Raloxifene has been compared to tamoxifen in its ability to prevent the occurrence of breast cancer in women at risk of the disease.9 The National Surgical Adjuvant Breast and Bowel Project's Study of Tamoxifen and Raloxifene trial involved the monitoring of more than 19,000 postmenopausal women older than 35 years who were judged to have a five-year predicted breast cancer risk of at least 1.66% based on the existence of specific risk factors--such as menarche, age of first live birth, and number of first-degree relatives (i.e., mother or sister) with breast cancer--in each study participant. Study participants received either tamoxifen 20 mg daily or raloxifene 60 mg daily for five years. According to the results, raloxifene was statistically as effective as tamoxifen in reducing the risk of invasive breast cancer; however, there was a significantly higher risk in the occurrence of noninvasive breast cancer in women taking raloxifene than in those taking tamoxifen.9 Currently, the only approved indication for raloxifene is in the treatment and prevention of osteoporosis in postmenopausal women.7

Tamoxifen is considered to be the standard by which other hormonal therapies can be compared.10 This agent has been demonstrated to be effective as monotherapy or in combination with traditional chemotherapy to treat advanced breast cancer and prevent recurrence. It is also effective in prolonging survival as adjuvant therapy in early-stage disease (i.e., stage I orII). Tamoxifen has also been shown to lower the incidence of contralateral breast cancer (i.e., cancer occuring in the breast that was not included in the original diagnosis).10 Toremifene has been shown to be effective in extending disease-free survival and overall survival in peri- and postmenopausal women with ER+ breast cancer.11

Due to the agonist–antagonist activity of SERMs, there are a variety of side effects that patients taking these drugs can experience. On the positive side, several beneficial estrogenic actions are preserved owing to the agonistic characteristics of the agents in this class. Prior to menopause, rates of coronary events in women are much lower than in men due to the cardioprotective effects of estrogen.12 But after menopause, this protection is lost, and increases in LDL cholesterol and total cholesterol, as well as a decline in HDL cholesterol, may occur.12 SERMs may help in the metabolism of cholesterol by reducing levels of LDL cholesterol.5 Although the full effect that SERMs such as tamoxifen may have on managing coronary disease is unknown, the results have thus far been promising.12 Likewise, the estrogenic effects of SERMs have a protective effect on maintaining bone density and reducing the risk of bone fractures due to osteoporosis.5 On the negative side, SERMs can prolong the discomforting symptoms of menopause, such as hot flashes, vaginal bleeding and discharge, weight gain, and fatigue.5 Tamoxifen has also been found to pose a slightly increased risk in the development of endometrial cancer in women because of the stimulatory effects on uterine tissue. SERMs may also contribute to the development of thromboembolic events, such as deep venous thrombosis and pulmonary emboli.5

Luteinizing Hormone–Releasing Hormone Analogs: As mentioned, the ovaries are the major site of estrogen production in premenopausal women. In postmenopausal women, only the adrenal glands and adipose tissue produce estrogen. Therefore, in premenopausal women with breast cancer, surgical removal of the ovaries, through oophorectomy, or chemical suppression of estrogen synthesis in the ovaries results in a postmenopausal state. Chemical suppression can be obtained with the use of luteinizing hormone–releasing hormone (LHRH) analogs, which are also called GnRH agonists.13 When administered under chronic conditions, such as with depot injections, these agents cause the release of LH and FSH. which initially flood the ovaries with the message to synthesize more estrogen. However, chronic exposure to LHRH analogs leads to a down-regulation of GnRH receptors and suppression of gonadotropin (i.e., LH and FSH) secretion. Within three weeks, a reduction in estradiol levels that mimics those seen in a postmenopausal woman is obtained. 5,13,14 Two LHRH analogs are currently available in the U.S., goserelin (Zoladex) and leuprolide (Lupron), but only the former is approved for use in the treatment of breast cancer. As mentioned, to accomplish the constant exposure to LHRH analogs that facilitates suppression of estrogen synthesis in the ovaries, these agents are administered as subcutaneous depot injections given every four weeks or more, depending on the dosage of the injection. 13-15

With regard to the efficacy of LHRH analogs, one meta-analysis examined these agents: (1) as a substitute for chemotherapy; (2) in combination with adjuvant hormonal therapy; and (3) in combination with adjuvant chemotherapy and hormonal therapy.16 Analysis indicated that goserelin 3.6-mg injection given every 28 days for a period of two years to premenopausal women with ER+ breast cancer resulted in a statistically equivalent disease-free survival and overall survival, compared to women who received the CMF (cyclophosphamide, methotrexate, fluoro­ uracil) chemotherapy regimen every 28 days for six cycles. Likewise, goserelin 3.6 mg given every 28 days for at least two years as either monotherapy or in combination with other hormonal therapy, namely tamoxifen 20 mg daily for five years, resulted in statistically equivalent disease-free survival. Finally, the data regarding the concomitant use of goserelin and tamoxifen compared with six cycles of CMF is less convincing due to limited results. The studies that were performed showed that relapse and overall survival may be similar, but short-term follow-up and limited patient recruitment have constrained the ability to make a reasonable conclusion in this third situation.16

Another meta-analysis examined the potential benefits of goserelin alone or in combination with tamoxifen in premenopausal patients with ER+ advanced breast cancers.17 The meta-analysis also included a study that used the LHRH analog buserelin, which is not commercially available in the U.S., and one study that used tamoxifen 30 mg daily. Taking this into account, it was still observed that the combined endocrine treatment (LHRH analog plus tamoxifen) resulted in a statistically significantly greater overall survival over the LHRH analogs used alone. Progression-free survival was also statistically improved in patients receiving the combination treatment.17

The benefits observed with LHRH analogs have made them a consideration for use as second-line therapy in the treatment of breast cancer. The National Comprehensive Cancer Network (NCCN), a respected source for evidence-based cancer treatment algorithms, states that an LHRH analog should be considered for use in premenopausal women who have recurred within at least one year of previous estrogen receptor antagonist therapy, or in combination with an estrogen receptor antagonist in women who have not already received an agent in this pharmacologic class.2 Furthermore, either pre- or postmenopausal women who have benefited from initial hormonal therapy should receive additional endocrine therapy, which may include an LHRH analog, at the time of recurrence.2

Due to the suppression of estrogen synthesis that is accomplished with use of LHRH analogs, symptoms associated with estrogen deprivation that are typically observed in postmenopausal women may occur in patients receiving these agents. These symptoms may include hot flashes, vaginal bleeding, headaches, depression, and vaginal dryness.14 Another important concern in patients taking LHRH analogs after six months is the loss of bone density resulting from the lack of estrogen. The addition of hormone replacement therapy with an estradiol/progestin combination product can allow for a continuation of LHRH analog use beyond six months. This treatment reduces the side effects of low estrogen levels without compromising the anticancer actions of the LHRH analog. But using an estrogen in this situation requires additional investigation and should not be routinely practiced.13,14


Aromatase Inhibitors: Inhibiting the synthesis of estrogen from nonovarian sites is another method to control estrogen activity in breast cancer. The adrenal glands produce androgens that enter the circulation and are converted to estrogen by the enzyme aromatase.5 Aromatase inhibitors prevent this conversion from occurring. These agents are useful only in postmenopausal women or in those women who have had their ovaries removed or suppressed with an LHRH analog, as they are ineffective against estrogen produced in the ovaries.5 Three aromatase inhibitors are currently available in the U.S.: letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin).18-20

The inclusion of aromatase inhibitors among agents to be considered for first-line therapy is due in part to results of the Arimidex, Tamoxifen, Alone or in Combination trial.21 In this study, tamoxifen or anastrozole alone or the two in combination were randomized to more than 9,000 participants as adjuvant therapy to postmenopausal women with localized breast cancer. After five years of treatment, anastrozole was associated with a statistically improved disease-free survival and time to recurrence in all patients regardless of receptor status. Furthermore, among patients with ER+ disease, significant improvement in disease-free survival and time to recurrence was observed in patients receiving anastrozole.21


The Breast International Group 1-98 study compared the use of tamoxifen with that of letrozole as adjuvant endocrine therapy in postmenopausal women with hormone receptor–positive breast cancer. 22 In this study, 8,010 women were randomized to receive either letrozole or tamoxifen for five years; letrozole for two years, followed by tamoxifen for three years; or tamoxifen for two years, followed by letrozole for three years. Women were assessed for disease-free survival and overall survival.22 Disease-free survival was found to be statistically improved in patients receiving letrozole as initial monotherapy, compared to those receiving tamoxifen. Although the overall survival also favored the letrozole group, it was not statistically different from that of patients who received tamoxifen.22

Finally, in the Italian Tamoxifen Anastrozole Trial, 448 postmenopausal women who had already received two to three years of tamoxifen therapy were continued on tamoxifen 20 mg daily or switched to anastrozole 1 mg daily for a total treatment period of five years.23 Patients were evaluated for disease recurrence and incidence of death. A significant benefit with regard to disease recurrence and recurrence-free survival was seen in patients who were switched to anastrozole versus those who remained on tamoxifen.23

Considering this evidence, the NCCN practice guidelines for breast cancer suggest that adjuvant endocrine therapy, in the form of a SERM, be considered for use in hormone receptor–positive women with breast cancer regardless of their menopausal status, age, or human epidermal growth factor receptor type 2 (HER2/neu) status.2 Although a specific first-line agent is not recommended by the NCCN guidelines, tamoxifen is suggested as the agent with the most data to support its use as a first choice. An aromatase inhibitor can also be considered for use in postmenopausal women as first-line therapy, as sequential therapy after two years of tamoxifen, or as extended therapy following 4.5 to six years of tamoxifen. Aromatase inhibitors are contraindicated in premenopausal women.2

Similarly, the American Society of Clinical Oncology (ASCO) technology assessment on the use of aromatase inhibitors as adjuvant therapy also states that these agents should be considered for use in postmenopausal women with hormone receptor–positive breast cancer.24 The ASCO assessment suggests that an aromatase inhibitor can be used as first-line therapy for five years in women who are contraindicated to receive tamoxifen or as second-line therapy in women who have been taking tamoxifen for two to three years or five years. The duration of aromatase inhibitor therapy would depend on how long they had taken tamoxifen.24

Aromatase inhibitors do not act upon estrogen receptors and thus lack many of the positive effects seen in SERMs, such as improved lipid metabolism and maintenance of bone density. Due to the lack of action at estrogen receptors, aromatase inhibitors also lessen the potential for endometrial cancer.9 Although these agents may be less likely to cause symptoms related to endometrial effects, vaginal pain and dryness can still be problematic.5

Estrogen Antagonists: In comparison to SERMs, estrogen antagonists have no agonistic estrogenic activity. Instead, these agents bind to and block estrogen receptors, leading to their degradation.5,25 Fulvestrant (Faslodex) is the only drug with this mechanism of action that is available in the U.S.26,27 Fulvestrant has the ability to reduce the level of progesterone receptors on breast cancers, an outcome that has not been observed with the use of SERMs but may help in the control of breast cancer. 27

Two studies have been conducted to assess the result of using fulvestrant as second-line therapy in postmenopausal women with progressing advanced breast cancer. One trial compared fulvestrant 250 mg administered intramuscularly once a month to anastrozole 1 mg orally daily in patients with locally advanced or metastatic breast cancer that had progressed during previous endocrine therapy.28 A total of 451 patients were randomized and observed for a median of 14.4 months. Nearly all patients (97% in the fulvestrant group and 98% in the anastrozole group) had previously received tamoxifen. The remaining patients had received other available hormonal therapy, so all patients were receiving study treatment as non–first-line therapy. Analysis showed no statistical difference in the time to progression among patients treated with either fulvestrant or anastrozole. With regard to time to treatment failure, again, no statistical difference was observed. Response rates were also not statistically different.28

Another study investigated the activity of fulvestrant 250 mg monthly versus anastrozole 1 mg daily in women with locally advanced or metastatic breast cancer whose disease had progressed on previous endocrine therapy.29 The 400 patients randomized to each treatment were followed for a median of 16.8 months. Ninety-five percent of fulvestrant participants and 96% of anastrozole participants had previously received tamoxifen. There was no significant difference in time to progression, time to treatment failure, or rate of overall response.29

Together these studies show that fulvestrant offers postmenopausal women with advanced breast cancer an option that appears statistically equal to that of an aromatase inhibitor after disease has progressed with tamoxifen therapy.

Side effects that have been observed with the use of fulvestrant include nausea, diarrhea, constipation, vomiting, headache, back pain, hot flashes, and pharyngitis. 26

Prostate Cancer
As is the case in breast cancer, therapeutic modalities for prostate cancer may include surgery, radiation, traditional chemotherapy, and/or hormonal agents; but androgens take the place of estrogen as the target hormone. Surgery may include orchiectomy or prostatectomy.30 Susceptibility of androgen synthesis pathways and androgen receptors to endocrine therapy helps guide the selection of treatment in this disease. Hormonal therapy for prostate cancer involves either androgen ablation with LHRH analogs or blockade of androgen receptors with androgen antagonists (Table 2). 31 These drugs may be helpful in controlling symptoms of disease and prolonging survival, but androgen-independent disease that is resistant to hormonal therapy may develop.30,31 Typically, resistance to hormonal therapy develops after one to two years of treatment.32 The point at which hormone-refractory disease develops may actually be delayed in those patients who begin therapy at an earlier stage in their disease. 32



Luteinizing Hormone–Releasing Hormone Analogs: LHRH analogs have an effect in prostate cancer similar to the one they have in breast cancer; these drugs reduce the production of testosterone, the active androgen in men. Unfortunately, as is the case with breast cancer, endocrine therapy is limited by the lack of androgen-dependent disease in all cases. Although androgen receptors are found on normal prostate tissue, expression in prostate cancers is believed to be affected by posttranslational and epigenetic modifications that may occur with progression of the disease.33 Hormonal therapy is typically used in combination with local therapy, such as prostatectomy. 34 The intended action of hormonal therapies in prostate cancer is to eliminate the presence or activity of testicular androgens to the degree achieved with surgical castration. Typically, clinical outcomes include palliation of disease-related symptoms by slowing disease progression, since a cure with hormonal therapy is unlikely to occur. Hormonal therapy also offers an alternative to orchiectomy, which may be inappropriate for some men due to side effects such as loss of libido, muscle mass, hot flashes, and osteoporosis. Many men also find this procedure psychologically unacceptable. 34

LHRH analogs used in prostate cancer treatment include leuprolide (Lupron, Eligard), histrelin (Vantas), and goserelin (Zoladex).13,15,35,36 Although all of these drugs have the same mechanism of action, a key pharmaceutical difference between them is the frequency of administration based on formulated dosage. Lower dosages, such as the goserelin 3.6-mg product, are given every four weeks; however, the histrelin 50-mg product is manufactured as a subcutaneous implant that is given once every 12 months. 13,36

Practical guidelines on the treatment of prostate cancer, prepared by the NCCN, allude to the difficult decision as to when androgen deprivation therapy should be initiated. According to the guidelines, each case should be considered on an individual basis. Factors that might encourage use of androgen deprivation therapy include advanced disease, rate of rising prostate specific antigen, and ability of patients to tolerate potential side effects of therapy.3 The NCCN guidelines suggest that an LHRH agonist is comparable to surgical castration. The concomitant use of an androgen antagonist for at least the first seven days of LHRH analog use may be helpful in reducing the incidence or severity of symptoms associated with tumor flare that occurs with the increase in testosterone production prior to the therapeutic downregulation of hormone levels.3

Possible side effects of LHRH analog use in men include hot flashes, sexual dysfunction, and decreased quality of erections. 13,15 Additionally, insertion site reactions may occur with the administration of histrelin.36 Long-term androgen deprivation can also lead to increased bone loss, subsequent osteoporosis, and an increased risk of pathologic fractures.32

Androgen Antagonists: The androgen antagonists block testosterone from binding to the androgen receptor and inhibit the subsequent stimulus of cellular activities that include differentiation, secretion, and proliferation. 30,33 Androgen receptor antagonists that are currently available in the U.S. include bicalutamide (Casodex), flutamide (Eulixin), and nilutamide (Nilandron).37-39

The Prostate Cancer Trialists' Collaborative Group has evaluated the use of androgen antagonists in combination with other therapy for prostate cancer that produces what is referred to as total androgen blockade.40 Findings revealed that the addition of a total androgen blockade extended the five-year survival of patients by about 2% to 3%, compared to androgen suppression alone.40 This is a measurable yet small benefit of using androgen antagonists as a component of combination treatment. The ASCO 2007 Update suggests that despite this small benefit, the use of androgen antagonists should be considered because of the limited risk of significant toxicity compared to the use of androgen suppression alone.41

Side effects of androgen antagonist therapy are often associated with the reduction in androgen activity and may include gynecomastia, breast tenderness, and hot flashes.32,37 Hepatic toxicity has also been observed--more so with the use of flutamide and nilutamide versus the use of bicalutamide. 32,37,38

Conclusion
Both breast and prostate cancers represent a large proportion of newly diagnosed cancers and cancer-related deaths that occur in women and men in the U.S. The sensitivity of these cancers to endocrine therapy increases the number of choices practitioners can select from to treat patients. Pharmacologic categories include drugs that block the activity of estrogen or androgens at their respective receptors or drugs that reduce the synthesis of these hormones. Unfortunately, although these therapies have been found to provide benefit, questions about the timing and duration of therapy, as well as its combination with other therapeutic modalities, in various stages of malignancy still exist.

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