Hormonal Therapy: Current Status in the Treatment of Metastatic Breast Cancer

Continuing Medical Education InformationHormonal Therapy: Current Status in the Treatment of Metastatic Breast Cancer

Activity Release Date: October 1, 2007
Activity Expiration Date: October 1, 2008

 

About the Activity
This activity is based on a brief article developed as part of the E-Update Series and posted on the Web. The series is geared to oncologists and addresses new treatments of cancer or modifications thereof.

This activity has been developed and approved under the direction of Beam Institute.

Activity Learning Objectives
After reading this article, participants should be able to: 

Understand the role of hormonal therapy in the treatment of metastatic breast cancer.Identify the mechanisms of action of hormonal agents for treating breast cancer.List types of patients likely to benefit from hormonal therapy.Know when to consider using hormonal agents and the sequence to follow.Summarize the historic and current use of tamoxifen to treat postmenopausal patients with metastatic breast cancer.Classify aromatase inhibitors into first-, second-, and third-generation agents and whether they are nonsteroidal/reversible or steroidal/reversible.List significant findings and understand the implications of key trials using aromatase inhibitors.Understand the role of fulvestrant as an additional treatment option for postmenopausal women with metastatic breast cancer.Know how fulvestrant compared to aromatase inhibitors and to tamoxifen in clinical trials.Identify the modalities used to achieve ovarian ablation and ovarian suppression and the advantages and disadvantages of each.List targeted agents being evaluated in combination with aromatase inhibitors.

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This activity targets physicians in the fields of oncology and hematology.

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Financial Disclosures
Dr. Dang is a consultant and a member of the speakers' bureau and has received research support from Genentech. Dr. Hudis is a member of the speakers' bureau for AstraZeneca and Genentech; he is also a member of the advisory boards of Amgen, Bristol-Myers Squibb, Novartis, Sanofi-Aventis, Pfizer, and Roche. Dr. Hudis has indicated ownership stock in Genomic Health. He has performed research for Kosan Biosciences.

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Introduction

In general, metastatic breast cancer (MBC) is treated systemically using chemotherapy, hormonal therapy, and newer targeted therapies when appropriate. About 75% of breast cancers test positive for estrogen receptors (ER) and progesterone receptors (PR), and estrogen stimulation of these receptors plays an important role in the proliferation of these tumors.¹

For patients with ER/PR-positive breast cancer, hormonal therapy is the preferred treatment if possible. For patients with rapidly progressive tumors or those in visceral crises, chemotherapy may be preferred because of its rapid rate of response, although even in this situation, hormonal therapy may be feasible.

Hormonal therapy is generally attractive because there are a variety of effective options available and the toxicities are generally mild. An important indicator of response is the presence of the ER and PR on the tumors² and their quantitative levels.³ Following the observation by Sir Beatson over a century ago that oophorectomy in premenopausal women induced tumor regression,⁴ hormonal therapy has been extensively used in the treatment of patients with ER/PR-positive breast cancer. The mechanisms of action of hormonal agents include:

• blocking the interaction between estrogen and estrogen receptors with selective estrogen receptor modulators (SERM);
• degrading the estrogen receptors with selective estrogen receptor down-regulators (SERD); and
• inhibiting estrogen production with an aromatase inhibitor (AI) or with surgical, radiation, or chemical ovarian ablation in premenopausal patients.

This E-Update will focus on the hormonal treatment options for MBC.

Tamoxifen

Since the 1970s, tamoxifen, a SERM with partial estrogen antagonist and agonist effects, has been the gold standard in the front-line treatment of postmenopausal patients with MBC. Tamoxifen binds to the ER competitively and causes cells to stay in the G1 phase of the cell cycle, which ultimately results in interrupted cell proliferation and cell death.⁵

The overall response rate with tamoxifen has been reported to be as high as 70%.² Despite the effectiveness of tamoxifen in most patients with ER/PR-positive MBC, these patients eventually experience relapse. The mechanism of resistance is unknown. It may be due to an increase in intratumoral aromatase activity leading to a higher level of estrogen, a disrupted interaction between tamoxifen and the ER, or the estrogen agonist effect of tamoxifen over time.⁶

Tamoxifen is generally well tolerated but has a few side-effects that are worth noting.  These include an increased risk of thromboembolic events (1.9 x)and uterine cancer (2.4 x).^7,8 On the other hand, the estrogen agonistic effect of tamoxifen helps prevent bone demineralization in postmenopausal patients as well as improving their lipid profile.⁹

Following first-line tamoxifen, the second-line drugs were progestins or the first-generation aromatase inhibitor, aminoglutethimide (AG) with corticosteroid support. Over the last several years, new hormonal agents have become available and have now challenged tamoxifen as the gold standard for the treatment of patients with hormone receptor-positive MBC.

Aromatase Inhibitors

Aromatase is an enzyme of the cytochrome P-450 family and is found in tissues in the breast (normal tissues and adenocarcinoma), and in the liver, brain, muscle, and fat.¹⁰ Aromatase converts the adrenal androgen (androstenedione) to estrogen in the peripheral tissues, which is the primary source of estrogen synthesis in postmenopausal women (Figure 1). Because AIs may not overcome ovarian aromatase activity, only patients with nonfunctioning ovaries (postmenopausal) appear to benefit from these drugs at this point in time.

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AIs are classified as first-, second-, and third-generation based on their potency and specificity inhibiting the aromatase enzyme. In addition, AIs are further categorized as nonsteroidal/reversible or steroidal/irreversible. (See Table 1.)

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Nonsteroidal inhibitors bind reversibly to the aromatase enzyme, resulting in a competitive inhibition. Steroidal inhibitors bind irreversibly to the enzyme and cause a permanent inactivation of the aromatase enzyme, and thus new enzymes would have to be synthesized by the peripheral tissues.

The third-generation AIs-anastrozole (Armidex), letrozole (Femara), exemestane (Aromasin)-are the most potent and selective AIs. Unlike the nonspecific first-generation AI, aminoglutethimide (AG [Cytadren]), these third-generation AIs can be used without corticosteroid and can decrease estrogen production by > 95%.¹⁰

Second-Line Therapy
The first set of trials evaluated AIs in patients who had progression of disease on tamoxifen or relapsed within 12 months after stopping adjuvant tamoxifen. Four AIs (anastrozole, letrozole, exemestane, vorozole [R83842]) were compared with megestrol acetate (MA, Megace) and all were superior to MA.^11-17 Letrozole and vorozole were also compared against AG with corticosteroid and were found superior.^18,19

Based on these results, the third-generation AIs, with the exception of vorozole, which was discontinued from clinical development, became standard second-line treatment after tamoxifen failure for postmenopausal patients with ER/PR-positive MBC.

First-Line Therapy
Based on the positive results of AIs in the second-line setting after tamoxifen failure, the third-generation AIs were then compared against tamoxifen as first-line treatment.

Anastrozole vs Tamoxifen
The Tamoxifen and Arimidex Randomized Group Efficacy and Tolerability (TARGET) multicenter trial compared anastrozole with tamoxifen as first-line treatment for patients with ER-positive or PR-positive MBC or with unknown receptor status. The endpoints were time-to-progression (TTP), overall response rate (ORR), and clinical benefit rate (CB). The trial was conducted simultaneously in Europe and North America.

The European TARGET trial, reported by Bonneterre et al,²⁰ enrolled 668 patients. Overall outcomes were the same for anastrozole vs tamoxifen in terms of TTP (8.2 vs 8.3 months, P = not significant [NS]), ORR (32.9% vs 32.6%, P = NS), and CB (56.2% vs 55.5%, P = NS). Both treatments were well tolerated and as expected, patients in the tamoxifen group had more thromboembolic events (7.3% vs 4.8%) and vaginal bleeding (2.4% vs 1.2%).

The North American TARGET trial, reported by Nabholtz et al,²¹ enrolled 353 patients and found that anastrozole was as effective as tamoxifen in terms of ORR (21% vs 17%, P = NS). Anastrozole was superior to tamoxifen in terms of CB (59% vs 46%, P = .0098) and TTP (11.1 vs 5.6 months, P = .005). Again, there were higher incidences of thromboembolic events (8.2% vs 4.1%) and vaginal bleeding (3.8% vs 1.2%) with tamoxifen.²¹

Based on these two reports of results, anastrozole was approved as first-line therapy for MBC. In a combined analysis of these two studies with a median follow-up of 18.2 months, anastrozole was equivalent to tamoxifen in terms of TTP (8.5 vs 7.0 months, P = NS) and ORR (29% vs 27.1%, P = NS).²² In a subset of patients whose tumors were ER-positive or PR-positive, anastrozole was better than tamoxifen, with a TTP of 10.7 months vs 6.4 months (P = .022). (See Table 2.)

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Letrozole vs Tamoxifen
Mouridsen et al have reported the results of the International Letrozole Breast Cancer Group study that compared letrozole with tamoxifen as first-line therapy in patients with ER-positive or PR- positive MBC or with unknown receptor status.²³ The study enrolled 907 patients and found that letrozole was superior to tamoxifen in terms of TTP (9.4 vs 6.0 months, P < .0001), ORR (32% vs 21%, P  = .0002), CB (50% vs 38%, P = .0004), and time to treatment failure (TTF, 9.0 vs 5.7 months, P < .0001). The median overall survival (OS) rates were similar between the two groups (34 vs 30 months, P = NS), but the 1-year OS (83% vs 75%, P = .004) and 2-year OS (62% vs 57%, P = .025) favored letrozole. (See Table 2.) The total duration of therapy (time to chemotherapy) also favored letrozole (16 vs 9 months, P = .005). About 50% of the patients in each arm crossed over. Data from this study led to the approval of letrozole as first-line treatment for MBC.

Exemestane vs Tamoxifen
The European Organization for Research and Treatment of Cancer led a phase III randomized trial comparing exemestane in 382 patients with ER-positive or PR-positive MBC or with unknown receptor status. ²⁴ The results were in favor of exemestane in terms of ORR (43% vs 29%) and progression-free survival (PFS, 10.9 vs 6.7 months, P = .04). (See Table 2.) Although exemestane does not have an official indication as first-line therapy in MBC, this result is encouraging.

Considering Overall Results
Overall, the above mentioned trials show that AIs have supplanted tamoxifen as the gold standard for the treatment of postmenopausal patients with ER-positive or PR-positive MBC in the first-line setting. A meta-analysis of multiple trials (total of 8,504 patients) comparing several AIs with tamoxifen or progestins in MBC has shown a survival benefit with third-generation AIs (anastrozole, letrozole, exemestane, vorozole), but not with the first-generation AI (aminoglutethimide) or second-generation AIs (formestane or fadrozole). The benefit of the third-generation AIs in the first-line setting was identical to their benefit in the second-line and subsequent-line settings.²⁵ Thus, it is clear that third-generation AIs should be used in any line of treatment for postmenopausal patients with ER-positive or PR-positive cancers.

Sequencing Aromatase Inhibitors
Is there a role for sequencing the AIs? Lonning et al reported that the use of a steroidal AI (exemestane) in patients who had progression of disease while on a nonsteroidal AI (anastrozole, letrozole, AG), produced a CB rate of 24.3%.²⁶ Similarly, Bertelli et al showed that patients who progressed on exemestane can derive benefit with anastrozole or letrozole.²⁷

Gradishar et al reported the results of the EFFECT trial, a double-blind, double-dummy phase III study comparing the efficacy and tolerability of fulvestrant (Faslodex) vs exemestane in 693 postmenopausal women with ER/PR-positive MBC who progressed after prior nonsteroidal AI therapy. The primary endpoint was TTP and was the same, 3.7 months, for both drugs. The ORR for fulvestrant was 7.4% vs 6.7% for exemestane (P = .74) and CB rates were 32% vs 31.5% (P = .85). The data are not mature for OS analysis but suggest that sequential use of steroidal and non-steroidal AIs may be feasible. ²⁸ (Fulvestrant is further described later in this E-Update.)

AI With a Biologic Therapy
What about an AI with a biologic therapy? Mackey et al reported the results of the TAnDEM trial, which randomized 208 postmenopausal patients with HER2/neu and hormone-receptor positive disease to anastrozole alone vs anastrozole and weekly trastuzumab (Herceptin).²⁹ The primary endpoint was PFS and secondary endpoints were ORR, CB, TTP, duration of response (DOR), OS, 2-year survival, and safety.

Outcomes were superior with the combination arm in terms of PFS (4.8 vs 2.4 months, P = .0016), ORR (20.3% vs 6.8 %, P = .018), and CB (42.7% vs 27.9%, P = .026). Although there was a trend in OS favoring the combination arm, it was not statistically significant (28.5 vs 23.9 months, P = .325). About 70% of the patients in the anastrozole only group crossed over to receive trastuzumab upon progression of disease, and the OS was the same in this group as in those who received the upfront combination.

Thus, in this population, it is reasonable to either give the combination upfront or start with anastrozole alone and sequence into trastuzumab upon disease progression. There were no unexpected adverse events with the anastrozole and trastuzumab combination, but there were more grade 3/4 adverse events in the combination arm than in the anastrozole alone arm (25% vs 15%). 

Fulvestrant

Fulvestrant (Faslodex) is a new anti-estrogen that downregulates the ER and has no agonistic effect; in essence, it is a “pure anti-estrogen.” Fulvestrant binds to the ER and inhibits the DNA binding, resulting in rapid ER degradation and a significant decrease in PR expression.³⁰

Second-Line and Subsequent-Line Therapy
Two phase III trials compared fulvestrant to anastrozole in postmenopausal women who had progression of disease while on tamoxifen.^31,32 A prospectively planned combined analysis of these two trials showed that fulvestrant was at least as effective as anastrozole in terms of TTP (5.5 vs 4.1 months, P = NS), ORR (19.2% vs 16.5%, P = NS), and median DOR (16.7 vs 13.7 months).³³ Both drugs were well tolerated, and the most common adverse events (AE) in both groups were hot flushes, nausea, pain, headache, and asthenia. Patients taking fulvestrant had fewer joint disorders than those taking anastrozole (P = .0036), and local injection-site reactions occurred in only 1% of patients.

In the EFFECT study, as mentioned earlier, fulvestrant was compared to exemestane in women who had disease progression after nonsteroidal AIs. Outcomes for the two AIs were equal.²⁸ Fulvestrant has received approval in many countries as second-line therapy in the treatment of postmenopausal ER/PR-positive MBC. 

Limited retrospective analyses have shown that patients can achieve a clinical benefit with AIs or progestins as well as with tamoxifen after progression on fulvestrant.^34-35 Thus, fulvestrant may provide an additional treatment option, especially after progression on other endocrine therapies, and may delay the requirement for chemotherapy.

First-Line Therapy
Fulvestrant was then compared to tamoxifen as first-line treatment in a randomized, phase III trial.³⁶ While TTP was the same for both drugs, fulvestrant was inferior to tamoxifen in terms of CB (54.3% vs 62.0%, P = .026), TTF (5.9 vs 7.8 months, P = .026), and OS (36.9 vs 38.7 months, P = .04). In a planned analysis of patients with ER-positive or PR-positive tumors, the outcomes were similar in terms of TTP, ORR, CB, and OS.

Treatments were well tolerated in both groups. The most common AEs in both groups were asthenia, nausea, and bone pain. The incidence of hot flashes was higher in the tamoxifen group (25.7% vs 17.7%, P = .05).

Overall, the inferior result of fulvestrant in the intention-to-treat patient population was surprising since fulvestrant was found to be at least as effective as anastrozole^31-33 and anastrozole was found to be at least as effective²⁰ or better than tamoxifen.²¹ Thus, fulvestrant did not get its approval as first-line hormonal treatment for MBC.

Ovarian Ablation/Ovarian Suppression

In premenopausal patients, the ovaries are the predominant sites of estrogen synthesis. Ovarian ablation (OA) was the original systemic therapy for breast cancer⁴ and can produce responses as high as 80% in women with ER/PR-positive disease.³⁷

The modalities used historically to achieve OA are oophorectomy or ovary irradiation. More recently, surgical and radiation-based OA have largely been replaced by ovarian suppression (OS) by the luteinizing hormone-releasing hormone (LHRH) analogues. These analogues suppress the circulating estrogen level by acting on the hypothalamic-pituitary-ovarian axis. OS results in lower morbidities than OA.

In the late 1970s, tamoxifen was found to be effective in premenopausal patients.³⁸ Thus, for premenopausal women, hormonal options include oophorectomy, ovarian irradiation, LHRH agonist, tamoxifen, or a combination. Which options then are preferred or most effective for premenopausal women?

Oophorectomy, ovarian irradiation, and medical OS have never been formally studied head-to-head in large randomized trials. Limited data from two trials show that LHRH analogues have similar efficacy to surgical OA or ovarian irradiation.^38,39 Taylor et al reported the results of a trial in which premenopausal patients with ER/PR-positive MBC were randomized to goserelin (Zoladex) vs oophorectomy.³⁹ No differences were noted in PFS or OS rates, but the trial was closed early due to poor accrual, so any subtle differences could not be detected.

Boccardo et al reported the data on the second trial, in which premenopausal women with ER/PR-positive or unknown receptor status were randomized to oophorectomy or ovarian irradiation with or without tamoxifen vs goserelin with or without tamoxifen.⁴⁰ In this study the outcomes were statistically similar in all arms, but this trial was also closed early due to low accrual, so any differences will never be seen.

In terms of OA/OS, ovarian irradiation is the least preferred in the United States, due to long-term toxicities of pelvic irradiation. Surgical castration has the advantage of promptly reducing the estrogen level to a postmenopausal range in 100% of the patients. The only truly major downside is the hospitalization required for the procedure.

The advantages of medical ovarian suppression include no requirement for hospitalization and the reversibility of menopause when therapy is discontinued. Disadvantages include the requirement for frequent administration, usually monthly injections. Another disadvantage of the LHRH analogues is the initial surge of gonadotropins and estrogen levels. This surge is believed to cause a “tumor flare” phenomenon, followed by a decline in estrogen levels within 2 to 3 weeks of use.⁴¹ Examples of the LHRH analogues include goserelin, leuprolide, buserelin (Suprefact), and triptorelin (Trelstar Depot). The tolerance of these drugs is good, with the most common AEs being hot flushes and tumor flare reactions.

A meta-analysis found tamoxifen to be as effective as OA as first-line therapy for ER/PR-positive MBC.⁴² Is a combination of an LHRH analogue with tamoxifen better than an LHRH analogue alone? Three randomized studies have compared the combination of an LHRH analogue and tamoxifen (to achieve complete estrogen blockade) with an LHRH analogue alone in premenopausal and perimenopausal women with ER/PR-positive MBC or unknown receptor status.^40,43,44 A meta-analysis of these trials showed superior outcomes with the combination in terms of ORR, PFS, and OS.

The caveats of these trials are that the patient number is small and that there was no crossover to tamoxifen for those on the LHRH analogue alone. Nevertheless, the combination of LHRH analogue and tamoxifen is accepted as a standard hormonal treatment in premenopausal and perimenopausal patients. Studies are now evaluating the utility of an LHRH analogue with an AI.^45-46

Conclusions

Tamoxifen has been the gold standard in the treatment of ER/PR-positive MBC for several decades, but now has been supplanted by the aromatase inhibitors as the gold standard in postmenopausal women. Fulvestrant is yet another available hormonal option for postmenopausal patients. For premenopausal and perimenopausal patients, ovarian suppression with an LHRH analogue and tamoxifen is considered a standard hormonal treatment. In lieu of an LHRH analogue, ovarian ablation via surgery or irradiation is acceptable.

In summary, the following proposed sequence is suggested when considering hormonal agents:

For hormone therapy nave postmenopausal ER/PR-positive patients:

• Nonsteroidal AIs (anastrozole, letrozole) or steroidal AIs (exemestane) should be considered as the first choice. 
• In HER2/neu-positive and ER/PR-positive patients, consider trastuzumab with anastrozole. Sequencing anastrozole into trastuzumab upon disease progression is acceptable.
• Upon progression of disease in patients taking an AI, consider tamoxifen, fulvestrant, or an alternate class of AI (switching from a nonsteroidal to a steroidal AI and vice versa). However, the best hormonal agent in this setting is yet to be defined.
• Progestins can still be offered after progression in patients receiving tamoxifen and AIs.

For postmenopausal patients who received tamoxifen as first-line treatment for MBC or who progressed after tamoxifen as adjuvant therapy:

• Nonsteroidal or steroidal AIs or fulvestrant may be considered as the next option.
• Progestins may be considered after progression in patients taking AIs.

For premenopausal and perimenopausal patients:

• Ovarian suppression with an LHRH analogue with tamoxifen is the standard hormonal option.
• Ovarian ablation via surgery or irradiation in lieu of ovarian suppression is acceptable.

Hormonal agents are certainly the preferred systemic treatments for patients with ER/PR-positive MBC with an indolent course. With the availability of several hormonal agents, the time to systemic cytotoxic therapy can be delayed.

Future Directions

There are still unanswered questions about hormonal therapy in the treatment of metastatic breast cancer. What is the utility of an LHRH analogue and an AI in premenopausal patients? What is the benefit of AIs or tamoxifen after fulvestrant? Only prospective trials can resolve these issues.

In the era of biologic therapies, trastuzumab combined with anastrozole has been found to be superior to anastrozole alone upfront. Bevacizumab (Avastin) is another biologic agent being evaluated with an AI. Traina et al reported that it is feasible to combine bevacizumab, an antiangiogenic agent, with letrozole in postmenopausal patients with hormone receptor-positive metastatic or locally advanced breast cancer.⁴⁸ With an acceptable safety profile from this study, a multicenter phase III trial is opening to evaluate first-line endocrine therapy with or without bevacizumab within the Cancer and Leukemia Group B.

Other targeted agents being evaluated with AIs include the novel antiangiogenic agents sunitinib (Sutent) and sorafenib (Nexavar) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. We look forward to the results of these trials.

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