- Email: [email protected]
Fulvestrant: Clinical application of an estrogen receptor downregulator
CLINICAL THERAPEUTICSVVOL. 24, SUPPL. A, 2002
Roundtable Discussion Fulvestrant: Clinical Application of an Estrogen Receptor Downregulator Moderator: Michael Torosian, MD’ Participants: Joyce O’Shaughnessy, MD,z Leroy Monroe Parker, MD,3 and Charles Vogel, MD4 ‘Fox Chase Cancer Center; Philadelphia, Pennsylvania, 2Baylor-Charles A. Sammons Cancer Center; US Oncology, Dallas, Texas, ‘Harvard Medical School and The DanaFarber Cancer Institute, Boston, Massachusetts, and 4Private practice, Plantation, Florida
INTRODUCTION Fulvestrant is the first of a new class of endocrine agents, the estrogen receptor (ER) downregulators. In clinical trials, fulvestrant has been demonstrated to be effective in patients with tamoxifen-resistant advanced breast cancer,’ and approval for use from the US Food and Drug Administration is anticipated in the first quarter of 2002. With the expanding number of options for endocrine therapy for breast cancer, the role and optimal use of fulvestrant with respect to other therapies need to be defined. A roundtable discussion was held via teleconference on November 1, 2001, to discuss the efficacy, mechanism of action, and side effects of fulvestrant and to define the role of fulvestrant with respect to other endocrine agents and the sequence of endocrine therapies for hormonesensitive advanced breast cancer.
0149.2918/02/$19.00
ROLE AND SELECTION OF HORMONAL THERAPIES IN BREAST CANCER Dr. Torosian: Dr. O’Shaughnessy, could you describe the current role of hormonal therapy in patients with advanced breast cancer? Dr. O’Shaughnessy: Many oncologists believe that hormonal therapies are the best treatment option in the appropriately chosen patient-someone who is ER positive [ER+] or progesterone receptor positive [PgR+]. The patient should have somewhat indolent disease that is not in visceral crisis, but it is important to note that she may have visceral disease, including lung or liver metastasis. If she has had a reasonably long disease-free intervalthat is, 22 years from her time of primary diagnosis-there is a greater likelihood that she will respond to hormonal therapy.2
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Patients who fit this profile usually have either an objective response or prolonged stable disease with hormonal therapy. In my opinion, the duration of benefit from hormonal therapy+ither an objective response or prolonged stable diseaseis generally longer than that seen with chemotherapy. This results in better disease control for a longer period. The sideeffect profile also is better with hormonal therapy than with chemotherapy. There is less collateral damage with hormonal therapy because it is targeted therapy against ERs and/or PgRs. If a woman responds to one hormonal therapy, we definitely want to follow with another one. So, in general, the sequential use of hormonal therapies for the appropriately chosen patient represents the best possible therapy we have to offer at this time. Dr. Torosian: What are the currently available classes of endocrine therapies that are used in patients with advanced breast cancer who are ER+‘? Dr. Parker: First, it is important to differentiate between premenopausal and postmenopausal patients. For premenopausal patients, there are 2 principal treatment options-either antiestrogens (ie, tamoxifen) or ovarian ablation (medical or surgical).’ In the postmenopausal group, treatment options include the antiestrogen tamoxifen and the third-generation aromatase inhibitors. The aromatase inhibitors are at least as effective as tamoxifen for firstline therapy for metastatic disease.“,j Tamoxifen works by blocking the ER activation functions. The aromatase inhibitors work by lowering postmenopausal estrogen to barely detectable lev-
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els. Other endocrine therapies, such as the progestational agent megestrol acetate, still have a role in sequential treatment.6 All of these drugs have some degree of toxicity, although far less than that seen with cytotoxic chemotherapy. Because the toxicities associated with a particular hormonal therapy can be problematic for some patients, new treatment options that are equally active with less toxicity are in demand. The treatment of postmenopausal patients has shifted from the original use of estrogen to the current use of aromatase inhibitors, which are among the least toxic drugs used in clinical medicine. Dr. Torosian: How does one choose among the available drugs and methods of hormonal therapy in both premenopausal and postmenopausal patients‘? Dr. Parker: In premenopausal patients with metastatic disease, my preference is to create a postmenopausal state. This can be done either by ovarian ablation or with a luteinizing hormone-releasing hormone [LHRH] agonist. LHRH agonists reduce ovarian estrogen synthesis by disrupting the pituitary-ovarian axis and removing the stimulus that promotes the ovaries to produce estrogen.’ If a patient is responsive to that treatment, the next step would be to add either tamoxifen or an aromatase inhibitor to her therapy to prolong that remission. In the postmenopausal state, aromatase inhibitors can now be used as initial treatment for metastatic disease and they are generally better tolerated than tamoxifen. The type of flare that was common with estrogen and tamoxifen is not seen with aromatase inhibitors. Furthermore, in patients with bony metastases, the aromatase inhibitors are a milder treatment option,
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Dr. O’Shaughnessy: I also use an LHRH agonist such as goserelin or suggest a laparoscopic oophorectomy. A highly effective combination is that of an LHRH agonist or oophorectomy with an aromatase inhibitor, particularly in patients who have received tamoxifen in the past. Likewise for postmenopausal women, the aromatase inhibitors are now the first-line treatment of choice for metastatic breast cancer, even if these patients have been treated previously with adjuvant tamoxifen. In terms of time to disease progression, data suggest that aromatase inhibitors are better than tamoxifen as first-line therapy in patients with ER+/PgR+ breast cancer.4,5 Both drugs had similar response rates, and overall survival was the same, but there was an improved time to disease progression and less toxicity with regard to thromboembolic complications and fewer disease flares with the aromatase inhibitors. These data support the use of aromatase inhibitors as first-line treatment for this patient population. Dr. Vogel: It is important to note that there are no data to support the use of aromatase inhibitors in premenopausal patients. It is difficult to understand how an aromatase inhibitor, which is meant to counteract the very small amounts of estrogens being produced from androgen precursors from the adrenal gland in postmenopausal women, can be used in premenopausal women to counteract the huge surge of estrogens coming from the ovary. In postmenopausal patients, there are 9 hormonal manipulations that can be used; some of them are long forgotten but can be used in selected patients. Because some women have very indolent disease over long periods, hormones can be manipulated for long periods.
If one starts with a nonsteroidal aromatase inhibitor (eg, anastrozole or letrozole), the second option would be an antiestrogen. If there is a long response with an antiestrogen, the next step would be to try antiestrogen withdrawal. The fourth option would be a steroidal aromatase inhibitor. Megestrol acetate would be the fifth option. In patients who have been significantly estrogen deprived through the use of antiestrogens and the aromatase inhibitors, estrogenic therapy would be the sixth option because these patients can actually get a response. The next option would be an androgen such as fluoxymesterone, followed by androgen withdrawal. Finally, there is fulvestrant, the topic of this discussion. Fulvestrant is likely to move further up in this scheme, to option 1, 2, or 3. These are the 9 hormonal manipulations for the postmenopausal woman that I use in my practice for selected patients.
FULVESTRANT: A NEW ESTROGEN RECEPTOR DOWNREGULATOR Dr. Torosian: How does the mechanism of action of fulvestrant differ from that of the other hormonal therapies just described? Dr. Parker: Fulvestrant, a pure antiestrogen, has the ability to inhibit the activating functions of the ER and leads to degradation of the ER from within the cell. Throughout the duration of therapy, the cells lack the ER, the function of which is entirely suppressed. Some experimental studies, in animal tumors and in limited patient samples, have shown that once the drug is withdrawn, the ER returns. The time frame for this reversible effect is rather rapid, over days to weeks.s
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Dr. Torosian: Explain why there is a need for another agent, such as fulvestrant, in this armamentarium of hormonal therapy. Dr. Parker: Major limitations to current hormonal therapy are toxicity and compliance. Fulvestrant has no estrogenic effects on other tissues. This factor is important for women with an intact uterus because there is a concern that estrogenie exposure may cause endometrial cancer in some patients.” The second issue is with compliance. Fulvestrant is the first drug in the United States for postmenopausal patients that is administered once monthly by intramuscular [IM] injection when the patient is seen by the clinician. We will know that our patients are receiving treatment. Dr. O’Shaughnessy: Fulvestrant has potential advantages over currently existing hormonal therapies. Animal models have shown that, over time, tamoxifen can turn into an agonist by recruiting coactivatot-s.‘” This is of particular concern in the adjuvant setting for high-risk women with many positive nodes. Because fulvestrant destroys ERs, there is no ability to recruit those coactivators, which means that it cannot turn into an agonist over prolonged periods of time. This needs to be further monitored in the adjuvant setting. In the metastatic setting, patients with hormonedependent indolent disease may benefit from additional treatment options, as their survival time has improved. Data suggest that the human epidermal growth factor receptor [HER21 signals most effectively as a survival signal in breast cancer cells, when the ER is occupied by a ligand, whether it be estrogen or tamoxifen.” The idea of destroying that ER in this context is intriguing. Fulves-
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trant could represent an advance over tamoxifen in those patients with HER2 overexpressing breast cancer that may be relatively resistant to tamoxifen. Fulvestrant also could play a role in reducing breast cancer risk. In patients with atypical lobular or ductal hyperplasia, or lobular carcinoma in situ, the precancer cells are dependent on estrogen as a survival signal.” After treatment with fulvestrant, the ER in those cells would be destroyed, which may eradicate these dysplastic cells.
FULVESTRANT
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TRIALS
Dr. Torosian: In 2 recent Phase III trials, fulvestrant demonstrated efficacy and safety comparable to those of anastrozole in postmenopausal women with hormoneresistant advanced breast cancer. What is your impression of the evidence to date on fulvestrant as an agent for the treatment of advanced breast cancer‘? Dr. Vogel: Two well-designed randomized trials compared fulvestrant with anastrozole, which has already been shown to be at least as effective as. if not superior to, tamoxifen.‘.” Therefore, this new drug not only has the potential to provide benefit in patients who are resistant to antiestrogens, it also may be superior to any currently available first-line treatment. As for the tolerability of a monthly injection, 1 was initially concerned about 5 mL of volume being injected into a woman’s buttocks. However. fulvestrant has proven antitumor activity and has been well tolerated. It also eliminates any questions about compliance. The major question is where this drug will be positioned. To date, I would strongly consider it as second-line therapy: ulti-
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mately, it could prove to be at least equivalent to whatever is used as our first-line therapy.
who have stopped taking tamoxifen order to achieve a prolonged duration response.
Dr. Parker: In the double-blind North American trial, both anastrozole and fulvestrant were well tolerated, and it was impossible to know which of the 2 agents the patients were receiving.14 I have been particularly impressed with the various reviews of these trials, examining the duration of response. It would appear that fulvestrant has the edge over anastrozole in this regard, which is very enticing. So, certainly in my practice, I am going to use this drug immediately in a number of patients in the early treatment of metastatic disease.
Dr. Torosian: Why was there a difference in duration of response between the double-blind North American trial and the open-label international trial?
Dr. O’Shaughnessy: I agree with that as well. We also participated in the doubleblind study, and there was no way to tell which agent the patient was receiving. This trial provided an objective measure of duration of response and time to disease progression. In terms of duration of response in the North American trial, there was an advantage with fulvestrant over anastrozole (-19 months vs 10 months). Fulvestrant was also well tolerated. The data on duration of response from this double-blind study are rather compelling and favor fulvestrant over anastrozole. Because fulvestrant is not cross-resistant with tamoxifen, it is ideal as first-line treatment of metastatic breast cancer in patients who received adjuvant tamoxifen. Data will soon become available with regard to the effectiveness of fulvestrant following an aromatase inhibitor. That is, what is the efficacy of fulvestrant as third-line therapy? For now, we definitely want to use this drug in patients
in of
Dr. O’Shaughnessy: I can only answer theoretically. In the international trial, patients receiving anastrozole were seen every 3 months, whereas patients receiving fulvestrant were seen each month for their injection. This leads to the possibility that a bias occurred in detecting progressive disease sooner in those receiving fulvestrant because the patients were seen monthly. Dr. Vogel: Another potential bias occurred because 23% of the patients were receptorunknown in the international trial versus 6% in the North American trial. As seen in other clinical trials with targeted therapy, there is the possibility that many of these patients with unknown receptors might have been hormone receptor-negative. This results in an imbalance in the proportion of receptor-negative patients between the international and North American trials, and therefore a potential reduction in observed efficacy. Dr. Torosian: Are there any concerns or potential barriers regarding fulvestrant use? Dr. Parker: In the beginning, there was a reluctance to administer monthly IM injections, but they have proven to be well tolerated. The major problem is that patients have to receive them on a monthly basis. This is not necessary for patients
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who are in a stable remission taking an oral agent such as an aromatase inhibitor.
ting, but as we move into the adjuvant and preventative settings, these issues will be of critical importance.
Dr. O’Shaughnessy: I agree. I think that none of us wants to inconvenience patients. However, the patients are enthusiastic about coming in monthly for a treatment that is giving them a durable remission with few side effects. In the North American trial, we administered two 2.5~mL injections rather than a single 5-n&. injection. There were no complaints with the 2 injections. The pharmacokinetic data also look very good, showing no difference between one 5-mL and two 2.5~mL injections. I am not concerned about the survival data not being mature enough for analysis. There is very good follow-up in terms of time to disease progression in these studies, and .the anastrozole and fulvestrant arms are basically equivalent. Because the aromatase inhibitors play a pivotal role in the estrogen pathway, it will be important to define their antitumor activity in patients who already have been treated with fulvestrant. In addition to examining fulvestrant versus tamoxifen, it will be important to study the effects of fulvestrant on other pathways, such as the tyrosine kinase pathway. It will be of interest to initiate studies that combine the various tyrosine-kinase receptor inhibitors with fulvestrant to see how the different pathways interact. It is also important to assess the longterm effects of fulvestrant therapy. For example, in the case of the selective estrogen receptor modulators, there is proven benefit on the bone and lipid profiles in postmenopausal women. What will happen if fulvestrant has detrimental effects on bone and lipid profiles? It may not be as important in the metastatic disease set-
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Dr. Torosian: What role will fulvestrant play in premenopausal vanced breast cancer?
patients
with ad-
Dr. Vogel: It is an important
research question to discover the role of this drug in premenopausal women. It took 20 to 25 years to determine that tamoxifen was equally effective in premenopausal and postmenopausal women. Studies evaluating the effect of fulvestrant in the premenopausal patient population should be initiated.
CLINICAL APPLICATIONS OF FULVESTRANT Dr. Torosian: Describe the advantages of fulvestrant
as a hormonal
agent.
Dr. Vogel: The side effects of fulvestrant appear to be comparable to those of anastrozole. There may be a slight increase in thromboembolic phenomena, but the differences are so small as perhaps to be insignificant. The tolerability is good, even though it is an injection. There are some gastrointestinal effects and hot flashes. The hot flashes are similar to those seen with anastrozole and tamoxifen. Aside from that, in the side-effect profiles in the controlled randomized trials, the drug appears to be incredibly well tolerated. That, coupled with the long duration of disease control, makes this a very exciting agent.
Dr. Torosian: How should fulvestrant
be used with respect to other therapies-and are there any other roles, or any future
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roles that we can envision or look forward to, for the use of this new agent?
Dr. O’Shaughnessy: The results of the Arimidex and Tamoxifen Alone or in Combination [ATAC] trial of anastrozole versus tamoxifen versus the combination in postmenopausal women with earlystage breast cancer will be available soon.15 This study may show that anastrozole, which has already been demonstrated to have an improved time to disease progression over tamoxifen in first-line metastatic breast cancer treatment, will have similar benefits in the adjuvant setting. Unfortunately, even if this proves to be true, some women treated with anastrozole as adjuvant therapy will still relapse, as with all endocrine therapies. In the study ‘of first-line tamoxifen versus anastrozole for metastatic breast cancer, once patients’ disease progressed, some patients crossed over to receive the other agent as part of their standard care. By combining the objective response rate and prolonged stable disease, the clinical benefit rate was 58% with tamoxifen in patients who had anastrozole as their initial treatment.15 Because fulvestrant is not cross-resistant with tamqxifen, it likely can be used in women whose disease progressed on anastrozole.
Dr. Parker: There will be an explosion of information regarding this new drug, and it will have the potential to replace both tamoxifen and the aromatase inhibitors in all areas of breast cancer care. However, it is too early to draw any conclusions.
Dr. Torosian: What is the potential role of fulvestrant in the treatment with breast cancer?
of patients
Dr. Vogel: For patients who already have been treated with an antiestrogen and an aromatase inhibitor, I would use fulvestrant before megestrol acetate, which would make fulvestrant the third-line therapy. Available data indicate that it could replace anastrozole for second-line use. A broad array of large-scale clinical trials is needed, including rational crossover designs, to determine that this putative benefit, the dowmegulation of the ER, does not actually inhibit the hormonal cascade.
Dr. Torosian: Can anyone describe his or her experiences in the Compassionate Use trial, using an aromatase inhibitor followed by fulvestrant and vice versa? Dr. Vogel: We have 10 patients
in the Compassionate Use trial, and it is far too early to make any comments. I can only tell you that it has been very well tolerated. We haven’t had any complaints from any of the patients regarding tolerability. To date, I have tended to use this in faradvanced disease. Many of these women already have had 6 or 7 hormonal therapies plus cytotoxic chemotherapy; tberefore, seeing responses in even 20% of these women would be exciting. So I am very anxious to see what our Compassionate Use experience will reveal.
CASE STUDY PRESENTATIONS Case No. 1
Dr. Parker: A 78-year-old
widow who had a lumpectomy and axillary lymph node dissection 9 years ago was treated with 4 cycles of doxorubicin and cyclophosphamide in a clinical trial. She was then placed on tamoxifen for 5 years, after which time she stopped treatment.
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Three years later she developed back pain, and a bone scan documented that she had widespread lytic and sclerotic metastases. X-rays confirmed this diagnosis. Computed tomography [CT] scans did not show any visceral disease. The patient began pamidronate therapy. She had a limited income and no prescription plan. To help in this regard, she was restarted on tamoxifen that was provided at no charge. She had not had tamoxifen for the past 3 years. After 4 months of therapy, her cancer demonstrated resistance to the drug. She had ER+ and PgR+ breast cancer that w.as HER%/neu-negative at the outset. What would be this patient’s next treatment option?
Dr. O’Shaughnessy:
This patient is a good candidate for a clinical trial. If a clinical trial is not available, fulvestrant and an aromatase inhibitor would be her major options. Because she does not have a prescription plan, it is probably going to be a bit easier for her to get the monthly injection. It is important to know if patients prefer taking a pill or getting an injection. I would be inclined to recommend fulvestrant at this time, also because of the improvement in duration of response compared with anastrozole.
Dr. Parker: This patient did participate in a clinical trial and did receive fulvestrant. She had stable disease for 42 months, and more recently she has demonstrated an increase in the amount of her bony disease as well as rising tumor markers. She requires pain medication at this point in time, which she had not required to any significant degree for the previous 3 years. There was no evidence of visceral disease. In this situation, what would be your next step?
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Dr. Vogel: I would
use another hormone. The principal choice at this juncture would be an aromatase inhibitor that she hasn’t yet received. The major questions here are, what is her subjective clinical status and what is the clinical objective evidence of disease progression? Even though she has bone-only disease and requires some pain medication, I would still try hormonal manipulation. She had a 42month response to fulvestrant, which is wonderful.
Dr. O’Shaughnessy:
I, too, would use another hormone. This woman had 42 months of stable disease, so she obviously has hormone-dependent disease. Her cancer cells have been deprived of any sort of estrogen stimulation for 42 months. I would withdraw the fulvestrant and see what happens. It would be interesting if her own endogenous estrogen was able to act as a cytostatic or cytotoxic agent after fulvestrant withdrawal. I would wait a couple of months to see if her disease responded. Conversely, her breast cancer might again be stimulated by her endogenous estrogen, in which case an aromatase inhibitor should be beneficial.
Dr. Parker: I think that both your comments are appropriate. In this case, I started her on the chemotherapeutic agent vinorelbine, and her breast cancer has responded. Once we reach a plateau with that treatment, my plan will be to place her on an aromatase inhibitor. Case No. 2
Dr. Parker: A 44-year-old
premenopausal woman came to the emergency department with dyspnea. She had neglected a breast mass and subsequent-
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ly experienced weight loss and anorexia, and she had bilateral pleural effusions. Her hone scan showed no evidence of metastases. CT scans of the chest, abdomen, and pelvis showed only the pleural effusions and no visceral metastases. One of her effusions, the larger one, was drained with a chest tube and sclerosed. A core needle biopsy of her breast mass was performed, and it showed that the breast cancer ER and PgR were both positive. The HER2/neu was 3+ by immunostaining. In the hospital, the patient received tamoxifen and was placed on goserelin, an LHRH agonist. She has responded very nicely, with a decrease in tumor markers, regression of breast mass, and no reaccumulation of pleural effusions. However, after 2 years of this therapy, her tumor markers started rising rapidly. Restaging showed minimal change in her assessable disease. How would you manage this woman who is currently receiving tamoxifen and monthly injections of an LHRH agonist and who is now progressing? Dr. Vogel: Because this patient has progressed after using goserelin and tamoxifen, I would use goserelin and an aromatase inhibitor. Then. the next question is, which aromatase inhibitor? One randomized study that compared tamoxifen and letrozole in patients who were HER2/neu-positive showed that letrozole was superior to tamoxifen.16 However, it is important to remember that this is only a single, small study. At the moment, I would treat the patient with goserelin plus letrozole because we have no data on fulvestrant in premenopausal women, and neither anastrozole nor exemestane has presented any similar efficacy data in HER2/neu-positive tumors.
Dr. O’Shaughnessy: I would agree. Due to the uncertainty regarding the effectiveness of fulvestrant in premenopausal women at this time, I would not combine it with an LHRH agonist. If the woman no longer wanted the goserelin injections, another option would be oophorectomy. Dr. Parker: If you were to remove her ovaries so she was now surgically postmenopausal, would you consider using fulvestrant as opposed to an aromatase inhibitor? Is a major deterrent the fact that she is currently receiving the LHRH agonist? Dr. O’Shaughnessy: Yes, because there may be some fluctuations in her estrogen levels with goserelin. If she had an oophorectomy, I would have no hesitation offering her fulvestrant as an option, due to the longer duration of action. Dr. Parker: These 2 cases bring up some of the kinds of clinical problems that clinicians will be faced with when this exciting new agent becomes available.
REFERENCES Jones SE, Morris CQ, for the 0020 and 002 1 Trial Investigators. Prolonged disease control with Faslodex compared with Arimidex in postmenopausal women with advanced breast cancer progressing on prior endocrine treatment. In: Programs and Abstracts of the 3rd Annual Lynn Sage Breast Cancer Symposium, Poster Session; October 19, 2001; Chicago, Illinois. Abstract 6A.
2. Osborne CK, Yochmowitz MG, Knight WA 3rd, McGuire WL. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancel: 1980; 46( 12 Suppl): 28842888.
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M, Sawka CA, DeBoer G, et al. An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer. Breast Cancer Res Treat. 1997;44: 201-210.
Coregulators determine the direction of transcription by antagonist-occupied steroid receptors. J Steroid Biochem Mol Biol. 1999;69:45-50.
3. Crump
4. Mourisden H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results from a phase III study of the International Letrorole Breast Cancer Group. J Clin Oncol. 2001: 19:2596-2606. 5. Nabholtz JM, Buzdar A, Pollak M, et al, for the Arimidex Study Group. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. J Clin Oncol. 2000;18:3758-3767. 6. Von Roenn JH, Bonomi PD, Gale M, et al. Sequential hormone therapy for advanced breast cancer. Semin Oncol. 1988; 15(2 Suppl 1):3843. 7. Pritchard KL. Current and future directions in medical therapy for breast carcinoma: Endocrine treatment. Cancel: 2000; SS(Suppl 12):3065-3072. 8. Osborne CK, Hobbs K, Clark GM. Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice. Cuncer Rex 1985;45:584-590. 9. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Rex 199 I;.51:38673873. 10. Takimoto GS, Graham JD, Jackson TA, et al. Tamoxifen resistant breast cancer:
Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coattivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998: 95:927-937.
II.
12. Curran M, Wiseman L. Fulvestrant. Drugs. 2001;61:807-8 14. 13. Bonneterre J, Thurlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000; I8:3748-3757. 14. Osborne CK, Zhao H. Fuqua SA. Selective estrogen receptor modulators: Structure, function, and clinical use. J C/in Oucol. 2000; 18:3 172-3 186. 15. Simons WR. Bassi R, Gandhi S. et al. A comparison of quality-adjusted time to disease progression of anastrozole vs tamoxifen as the first-line treatment of postmenopausal patients with advanced breast cancer. Presented at the 24th Annual San Antonio Breast Cancer Symposium; December 10-13, 2001; San Antonio, Texas. Abstract 448. 16. Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB- l- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol. 2001: 19:3808-38 16.
_ Address Cancer
correspondence Center,
to: Joyce
US Oncology,
[email protected]
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O’Shaughnessy, MD, Baylor-Charles A. Sammons 3535 Worth Avenue, Collins-5, Dallas, TX 75246. E-mail:
Roundtable Discussion Fulvestrant: Clinical Application of an Estrogen Receptor Downregulator Moderator: Michael Torosian, MD’ Participants: Joyce O’Shaughnessy, MD,z Leroy Monroe Parker, MD,3 and Charles Vogel, MD4 ‘Fox Chase Cancer Center; Philadelphia, Pennsylvania, 2Baylor-Charles A. Sammons Cancer Center; US Oncology, Dallas, Texas, ‘Harvard Medical School and The DanaFarber Cancer Institute, Boston, Massachusetts, and 4Private practice, Plantation, Florida
INTRODUCTION Fulvestrant is the first of a new class of endocrine agents, the estrogen receptor (ER) downregulators. In clinical trials, fulvestrant has been demonstrated to be effective in patients with tamoxifen-resistant advanced breast cancer,’ and approval for use from the US Food and Drug Administration is anticipated in the first quarter of 2002. With the expanding number of options for endocrine therapy for breast cancer, the role and optimal use of fulvestrant with respect to other therapies need to be defined. A roundtable discussion was held via teleconference on November 1, 2001, to discuss the efficacy, mechanism of action, and side effects of fulvestrant and to define the role of fulvestrant with respect to other endocrine agents and the sequence of endocrine therapies for hormonesensitive advanced breast cancer.
0149.2918/02/$19.00
ROLE AND SELECTION OF HORMONAL THERAPIES IN BREAST CANCER Dr. Torosian: Dr. O’Shaughnessy, could you describe the current role of hormonal therapy in patients with advanced breast cancer? Dr. O’Shaughnessy: Many oncologists believe that hormonal therapies are the best treatment option in the appropriately chosen patient-someone who is ER positive [ER+] or progesterone receptor positive [PgR+]. The patient should have somewhat indolent disease that is not in visceral crisis, but it is important to note that she may have visceral disease, including lung or liver metastasis. If she has had a reasonably long disease-free intervalthat is, 22 years from her time of primary diagnosis-there is a greater likelihood that she will respond to hormonal therapy.2
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Patients who fit this profile usually have either an objective response or prolonged stable disease with hormonal therapy. In my opinion, the duration of benefit from hormonal therapy+ither an objective response or prolonged stable diseaseis generally longer than that seen with chemotherapy. This results in better disease control for a longer period. The sideeffect profile also is better with hormonal therapy than with chemotherapy. There is less collateral damage with hormonal therapy because it is targeted therapy against ERs and/or PgRs. If a woman responds to one hormonal therapy, we definitely want to follow with another one. So, in general, the sequential use of hormonal therapies for the appropriately chosen patient represents the best possible therapy we have to offer at this time. Dr. Torosian: What are the currently available classes of endocrine therapies that are used in patients with advanced breast cancer who are ER+‘? Dr. Parker: First, it is important to differentiate between premenopausal and postmenopausal patients. For premenopausal patients, there are 2 principal treatment options-either antiestrogens (ie, tamoxifen) or ovarian ablation (medical or surgical).’ In the postmenopausal group, treatment options include the antiestrogen tamoxifen and the third-generation aromatase inhibitors. The aromatase inhibitors are at least as effective as tamoxifen for firstline therapy for metastatic disease.“,j Tamoxifen works by blocking the ER activation functions. The aromatase inhibitors work by lowering postmenopausal estrogen to barely detectable lev-
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els. Other endocrine therapies, such as the progestational agent megestrol acetate, still have a role in sequential treatment.6 All of these drugs have some degree of toxicity, although far less than that seen with cytotoxic chemotherapy. Because the toxicities associated with a particular hormonal therapy can be problematic for some patients, new treatment options that are equally active with less toxicity are in demand. The treatment of postmenopausal patients has shifted from the original use of estrogen to the current use of aromatase inhibitors, which are among the least toxic drugs used in clinical medicine. Dr. Torosian: How does one choose among the available drugs and methods of hormonal therapy in both premenopausal and postmenopausal patients‘? Dr. Parker: In premenopausal patients with metastatic disease, my preference is to create a postmenopausal state. This can be done either by ovarian ablation or with a luteinizing hormone-releasing hormone [LHRH] agonist. LHRH agonists reduce ovarian estrogen synthesis by disrupting the pituitary-ovarian axis and removing the stimulus that promotes the ovaries to produce estrogen.’ If a patient is responsive to that treatment, the next step would be to add either tamoxifen or an aromatase inhibitor to her therapy to prolong that remission. In the postmenopausal state, aromatase inhibitors can now be used as initial treatment for metastatic disease and they are generally better tolerated than tamoxifen. The type of flare that was common with estrogen and tamoxifen is not seen with aromatase inhibitors. Furthermore, in patients with bony metastases, the aromatase inhibitors are a milder treatment option,
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DISCUSSION
Dr. O’Shaughnessy: I also use an LHRH agonist such as goserelin or suggest a laparoscopic oophorectomy. A highly effective combination is that of an LHRH agonist or oophorectomy with an aromatase inhibitor, particularly in patients who have received tamoxifen in the past. Likewise for postmenopausal women, the aromatase inhibitors are now the first-line treatment of choice for metastatic breast cancer, even if these patients have been treated previously with adjuvant tamoxifen. In terms of time to disease progression, data suggest that aromatase inhibitors are better than tamoxifen as first-line therapy in patients with ER+/PgR+ breast cancer.4,5 Both drugs had similar response rates, and overall survival was the same, but there was an improved time to disease progression and less toxicity with regard to thromboembolic complications and fewer disease flares with the aromatase inhibitors. These data support the use of aromatase inhibitors as first-line treatment for this patient population. Dr. Vogel: It is important to note that there are no data to support the use of aromatase inhibitors in premenopausal patients. It is difficult to understand how an aromatase inhibitor, which is meant to counteract the very small amounts of estrogens being produced from androgen precursors from the adrenal gland in postmenopausal women, can be used in premenopausal women to counteract the huge surge of estrogens coming from the ovary. In postmenopausal patients, there are 9 hormonal manipulations that can be used; some of them are long forgotten but can be used in selected patients. Because some women have very indolent disease over long periods, hormones can be manipulated for long periods.
If one starts with a nonsteroidal aromatase inhibitor (eg, anastrozole or letrozole), the second option would be an antiestrogen. If there is a long response with an antiestrogen, the next step would be to try antiestrogen withdrawal. The fourth option would be a steroidal aromatase inhibitor. Megestrol acetate would be the fifth option. In patients who have been significantly estrogen deprived through the use of antiestrogens and the aromatase inhibitors, estrogenic therapy would be the sixth option because these patients can actually get a response. The next option would be an androgen such as fluoxymesterone, followed by androgen withdrawal. Finally, there is fulvestrant, the topic of this discussion. Fulvestrant is likely to move further up in this scheme, to option 1, 2, or 3. These are the 9 hormonal manipulations for the postmenopausal woman that I use in my practice for selected patients.
FULVESTRANT: A NEW ESTROGEN RECEPTOR DOWNREGULATOR Dr. Torosian: How does the mechanism of action of fulvestrant differ from that of the other hormonal therapies just described? Dr. Parker: Fulvestrant, a pure antiestrogen, has the ability to inhibit the activating functions of the ER and leads to degradation of the ER from within the cell. Throughout the duration of therapy, the cells lack the ER, the function of which is entirely suppressed. Some experimental studies, in animal tumors and in limited patient samples, have shown that once the drug is withdrawn, the ER returns. The time frame for this reversible effect is rather rapid, over days to weeks.s
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Dr. Torosian: Explain why there is a need for another agent, such as fulvestrant, in this armamentarium of hormonal therapy. Dr. Parker: Major limitations to current hormonal therapy are toxicity and compliance. Fulvestrant has no estrogenic effects on other tissues. This factor is important for women with an intact uterus because there is a concern that estrogenie exposure may cause endometrial cancer in some patients.” The second issue is with compliance. Fulvestrant is the first drug in the United States for postmenopausal patients that is administered once monthly by intramuscular [IM] injection when the patient is seen by the clinician. We will know that our patients are receiving treatment. Dr. O’Shaughnessy: Fulvestrant has potential advantages over currently existing hormonal therapies. Animal models have shown that, over time, tamoxifen can turn into an agonist by recruiting coactivatot-s.‘” This is of particular concern in the adjuvant setting for high-risk women with many positive nodes. Because fulvestrant destroys ERs, there is no ability to recruit those coactivators, which means that it cannot turn into an agonist over prolonged periods of time. This needs to be further monitored in the adjuvant setting. In the metastatic setting, patients with hormonedependent indolent disease may benefit from additional treatment options, as their survival time has improved. Data suggest that the human epidermal growth factor receptor [HER21 signals most effectively as a survival signal in breast cancer cells, when the ER is occupied by a ligand, whether it be estrogen or tamoxifen.” The idea of destroying that ER in this context is intriguing. Fulves-
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trant could represent an advance over tamoxifen in those patients with HER2 overexpressing breast cancer that may be relatively resistant to tamoxifen. Fulvestrant also could play a role in reducing breast cancer risk. In patients with atypical lobular or ductal hyperplasia, or lobular carcinoma in situ, the precancer cells are dependent on estrogen as a survival signal.” After treatment with fulvestrant, the ER in those cells would be destroyed, which may eradicate these dysplastic cells.
FULVESTRANT
CLINICAL
TRIALS
Dr. Torosian: In 2 recent Phase III trials, fulvestrant demonstrated efficacy and safety comparable to those of anastrozole in postmenopausal women with hormoneresistant advanced breast cancer. What is your impression of the evidence to date on fulvestrant as an agent for the treatment of advanced breast cancer‘? Dr. Vogel: Two well-designed randomized trials compared fulvestrant with anastrozole, which has already been shown to be at least as effective as. if not superior to, tamoxifen.‘.” Therefore, this new drug not only has the potential to provide benefit in patients who are resistant to antiestrogens, it also may be superior to any currently available first-line treatment. As for the tolerability of a monthly injection, 1 was initially concerned about 5 mL of volume being injected into a woman’s buttocks. However. fulvestrant has proven antitumor activity and has been well tolerated. It also eliminates any questions about compliance. The major question is where this drug will be positioned. To date, I would strongly consider it as second-line therapy: ulti-
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mately, it could prove to be at least equivalent to whatever is used as our first-line therapy.
who have stopped taking tamoxifen order to achieve a prolonged duration response.
Dr. Parker: In the double-blind North American trial, both anastrozole and fulvestrant were well tolerated, and it was impossible to know which of the 2 agents the patients were receiving.14 I have been particularly impressed with the various reviews of these trials, examining the duration of response. It would appear that fulvestrant has the edge over anastrozole in this regard, which is very enticing. So, certainly in my practice, I am going to use this drug immediately in a number of patients in the early treatment of metastatic disease.
Dr. Torosian: Why was there a difference in duration of response between the double-blind North American trial and the open-label international trial?
Dr. O’Shaughnessy: I agree with that as well. We also participated in the doubleblind study, and there was no way to tell which agent the patient was receiving. This trial provided an objective measure of duration of response and time to disease progression. In terms of duration of response in the North American trial, there was an advantage with fulvestrant over anastrozole (-19 months vs 10 months). Fulvestrant was also well tolerated. The data on duration of response from this double-blind study are rather compelling and favor fulvestrant over anastrozole. Because fulvestrant is not cross-resistant with tamoxifen, it is ideal as first-line treatment of metastatic breast cancer in patients who received adjuvant tamoxifen. Data will soon become available with regard to the effectiveness of fulvestrant following an aromatase inhibitor. That is, what is the efficacy of fulvestrant as third-line therapy? For now, we definitely want to use this drug in patients
in of
Dr. O’Shaughnessy: I can only answer theoretically. In the international trial, patients receiving anastrozole were seen every 3 months, whereas patients receiving fulvestrant were seen each month for their injection. This leads to the possibility that a bias occurred in detecting progressive disease sooner in those receiving fulvestrant because the patients were seen monthly. Dr. Vogel: Another potential bias occurred because 23% of the patients were receptorunknown in the international trial versus 6% in the North American trial. As seen in other clinical trials with targeted therapy, there is the possibility that many of these patients with unknown receptors might have been hormone receptor-negative. This results in an imbalance in the proportion of receptor-negative patients between the international and North American trials, and therefore a potential reduction in observed efficacy. Dr. Torosian: Are there any concerns or potential barriers regarding fulvestrant use? Dr. Parker: In the beginning, there was a reluctance to administer monthly IM injections, but they have proven to be well tolerated. The major problem is that patients have to receive them on a monthly basis. This is not necessary for patients
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who are in a stable remission taking an oral agent such as an aromatase inhibitor.
ting, but as we move into the adjuvant and preventative settings, these issues will be of critical importance.
Dr. O’Shaughnessy: I agree. I think that none of us wants to inconvenience patients. However, the patients are enthusiastic about coming in monthly for a treatment that is giving them a durable remission with few side effects. In the North American trial, we administered two 2.5~mL injections rather than a single 5-n&. injection. There were no complaints with the 2 injections. The pharmacokinetic data also look very good, showing no difference between one 5-mL and two 2.5~mL injections. I am not concerned about the survival data not being mature enough for analysis. There is very good follow-up in terms of time to disease progression in these studies, and .the anastrozole and fulvestrant arms are basically equivalent. Because the aromatase inhibitors play a pivotal role in the estrogen pathway, it will be important to define their antitumor activity in patients who already have been treated with fulvestrant. In addition to examining fulvestrant versus tamoxifen, it will be important to study the effects of fulvestrant on other pathways, such as the tyrosine kinase pathway. It will be of interest to initiate studies that combine the various tyrosine-kinase receptor inhibitors with fulvestrant to see how the different pathways interact. It is also important to assess the longterm effects of fulvestrant therapy. For example, in the case of the selective estrogen receptor modulators, there is proven benefit on the bone and lipid profiles in postmenopausal women. What will happen if fulvestrant has detrimental effects on bone and lipid profiles? It may not be as important in the metastatic disease set-
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Dr. Torosian: What role will fulvestrant play in premenopausal vanced breast cancer?
patients
with ad-
Dr. Vogel: It is an important
research question to discover the role of this drug in premenopausal women. It took 20 to 25 years to determine that tamoxifen was equally effective in premenopausal and postmenopausal women. Studies evaluating the effect of fulvestrant in the premenopausal patient population should be initiated.
CLINICAL APPLICATIONS OF FULVESTRANT Dr. Torosian: Describe the advantages of fulvestrant
as a hormonal
agent.
Dr. Vogel: The side effects of fulvestrant appear to be comparable to those of anastrozole. There may be a slight increase in thromboembolic phenomena, but the differences are so small as perhaps to be insignificant. The tolerability is good, even though it is an injection. There are some gastrointestinal effects and hot flashes. The hot flashes are similar to those seen with anastrozole and tamoxifen. Aside from that, in the side-effect profiles in the controlled randomized trials, the drug appears to be incredibly well tolerated. That, coupled with the long duration of disease control, makes this a very exciting agent.
Dr. Torosian: How should fulvestrant
be used with respect to other therapies-and are there any other roles, or any future
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roles that we can envision or look forward to, for the use of this new agent?
Dr. O’Shaughnessy: The results of the Arimidex and Tamoxifen Alone or in Combination [ATAC] trial of anastrozole versus tamoxifen versus the combination in postmenopausal women with earlystage breast cancer will be available soon.15 This study may show that anastrozole, which has already been demonstrated to have an improved time to disease progression over tamoxifen in first-line metastatic breast cancer treatment, will have similar benefits in the adjuvant setting. Unfortunately, even if this proves to be true, some women treated with anastrozole as adjuvant therapy will still relapse, as with all endocrine therapies. In the study ‘of first-line tamoxifen versus anastrozole for metastatic breast cancer, once patients’ disease progressed, some patients crossed over to receive the other agent as part of their standard care. By combining the objective response rate and prolonged stable disease, the clinical benefit rate was 58% with tamoxifen in patients who had anastrozole as their initial treatment.15 Because fulvestrant is not cross-resistant with tamqxifen, it likely can be used in women whose disease progressed on anastrozole.
Dr. Parker: There will be an explosion of information regarding this new drug, and it will have the potential to replace both tamoxifen and the aromatase inhibitors in all areas of breast cancer care. However, it is too early to draw any conclusions.
Dr. Torosian: What is the potential role of fulvestrant in the treatment with breast cancer?
of patients
Dr. Vogel: For patients who already have been treated with an antiestrogen and an aromatase inhibitor, I would use fulvestrant before megestrol acetate, which would make fulvestrant the third-line therapy. Available data indicate that it could replace anastrozole for second-line use. A broad array of large-scale clinical trials is needed, including rational crossover designs, to determine that this putative benefit, the dowmegulation of the ER, does not actually inhibit the hormonal cascade.
Dr. Torosian: Can anyone describe his or her experiences in the Compassionate Use trial, using an aromatase inhibitor followed by fulvestrant and vice versa? Dr. Vogel: We have 10 patients
in the Compassionate Use trial, and it is far too early to make any comments. I can only tell you that it has been very well tolerated. We haven’t had any complaints from any of the patients regarding tolerability. To date, I have tended to use this in faradvanced disease. Many of these women already have had 6 or 7 hormonal therapies plus cytotoxic chemotherapy; tberefore, seeing responses in even 20% of these women would be exciting. So I am very anxious to see what our Compassionate Use experience will reveal.
CASE STUDY PRESENTATIONS Case No. 1
Dr. Parker: A 78-year-old
widow who had a lumpectomy and axillary lymph node dissection 9 years ago was treated with 4 cycles of doxorubicin and cyclophosphamide in a clinical trial. She was then placed on tamoxifen for 5 years, after which time she stopped treatment.
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Three years later she developed back pain, and a bone scan documented that she had widespread lytic and sclerotic metastases. X-rays confirmed this diagnosis. Computed tomography [CT] scans did not show any visceral disease. The patient began pamidronate therapy. She had a limited income and no prescription plan. To help in this regard, she was restarted on tamoxifen that was provided at no charge. She had not had tamoxifen for the past 3 years. After 4 months of therapy, her cancer demonstrated resistance to the drug. She had ER+ and PgR+ breast cancer that w.as HER%/neu-negative at the outset. What would be this patient’s next treatment option?
Dr. O’Shaughnessy:
This patient is a good candidate for a clinical trial. If a clinical trial is not available, fulvestrant and an aromatase inhibitor would be her major options. Because she does not have a prescription plan, it is probably going to be a bit easier for her to get the monthly injection. It is important to know if patients prefer taking a pill or getting an injection. I would be inclined to recommend fulvestrant at this time, also because of the improvement in duration of response compared with anastrozole.
Dr. Parker: This patient did participate in a clinical trial and did receive fulvestrant. She had stable disease for 42 months, and more recently she has demonstrated an increase in the amount of her bony disease as well as rising tumor markers. She requires pain medication at this point in time, which she had not required to any significant degree for the previous 3 years. There was no evidence of visceral disease. In this situation, what would be your next step?
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Dr. Vogel: I would
use another hormone. The principal choice at this juncture would be an aromatase inhibitor that she hasn’t yet received. The major questions here are, what is her subjective clinical status and what is the clinical objective evidence of disease progression? Even though she has bone-only disease and requires some pain medication, I would still try hormonal manipulation. She had a 42month response to fulvestrant, which is wonderful.
Dr. O’Shaughnessy:
I, too, would use another hormone. This woman had 42 months of stable disease, so she obviously has hormone-dependent disease. Her cancer cells have been deprived of any sort of estrogen stimulation for 42 months. I would withdraw the fulvestrant and see what happens. It would be interesting if her own endogenous estrogen was able to act as a cytostatic or cytotoxic agent after fulvestrant withdrawal. I would wait a couple of months to see if her disease responded. Conversely, her breast cancer might again be stimulated by her endogenous estrogen, in which case an aromatase inhibitor should be beneficial.
Dr. Parker: I think that both your comments are appropriate. In this case, I started her on the chemotherapeutic agent vinorelbine, and her breast cancer has responded. Once we reach a plateau with that treatment, my plan will be to place her on an aromatase inhibitor. Case No. 2
Dr. Parker: A 44-year-old
premenopausal woman came to the emergency department with dyspnea. She had neglected a breast mass and subsequent-
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DISCUSSION
ly experienced weight loss and anorexia, and she had bilateral pleural effusions. Her hone scan showed no evidence of metastases. CT scans of the chest, abdomen, and pelvis showed only the pleural effusions and no visceral metastases. One of her effusions, the larger one, was drained with a chest tube and sclerosed. A core needle biopsy of her breast mass was performed, and it showed that the breast cancer ER and PgR were both positive. The HER2/neu was 3+ by immunostaining. In the hospital, the patient received tamoxifen and was placed on goserelin, an LHRH agonist. She has responded very nicely, with a decrease in tumor markers, regression of breast mass, and no reaccumulation of pleural effusions. However, after 2 years of this therapy, her tumor markers started rising rapidly. Restaging showed minimal change in her assessable disease. How would you manage this woman who is currently receiving tamoxifen and monthly injections of an LHRH agonist and who is now progressing? Dr. Vogel: Because this patient has progressed after using goserelin and tamoxifen, I would use goserelin and an aromatase inhibitor. Then. the next question is, which aromatase inhibitor? One randomized study that compared tamoxifen and letrozole in patients who were HER2/neu-positive showed that letrozole was superior to tamoxifen.16 However, it is important to remember that this is only a single, small study. At the moment, I would treat the patient with goserelin plus letrozole because we have no data on fulvestrant in premenopausal women, and neither anastrozole nor exemestane has presented any similar efficacy data in HER2/neu-positive tumors.
Dr. O’Shaughnessy: I would agree. Due to the uncertainty regarding the effectiveness of fulvestrant in premenopausal women at this time, I would not combine it with an LHRH agonist. If the woman no longer wanted the goserelin injections, another option would be oophorectomy. Dr. Parker: If you were to remove her ovaries so she was now surgically postmenopausal, would you consider using fulvestrant as opposed to an aromatase inhibitor? Is a major deterrent the fact that she is currently receiving the LHRH agonist? Dr. O’Shaughnessy: Yes, because there may be some fluctuations in her estrogen levels with goserelin. If she had an oophorectomy, I would have no hesitation offering her fulvestrant as an option, due to the longer duration of action. Dr. Parker: These 2 cases bring up some of the kinds of clinical problems that clinicians will be faced with when this exciting new agent becomes available.
REFERENCES Jones SE, Morris CQ, for the 0020 and 002 1 Trial Investigators. Prolonged disease control with Faslodex compared with Arimidex in postmenopausal women with advanced breast cancer progressing on prior endocrine treatment. In: Programs and Abstracts of the 3rd Annual Lynn Sage Breast Cancer Symposium, Poster Session; October 19, 2001; Chicago, Illinois. Abstract 6A.
2. Osborne CK, Yochmowitz MG, Knight WA 3rd, McGuire WL. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancel: 1980; 46( 12 Suppl): 28842888.
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M, Sawka CA, DeBoer G, et al. An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer. Breast Cancer Res Treat. 1997;44: 201-210.
Coregulators determine the direction of transcription by antagonist-occupied steroid receptors. J Steroid Biochem Mol Biol. 1999;69:45-50.
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4. Mourisden H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results from a phase III study of the International Letrorole Breast Cancer Group. J Clin Oncol. 2001: 19:2596-2606. 5. Nabholtz JM, Buzdar A, Pollak M, et al, for the Arimidex Study Group. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. J Clin Oncol. 2000;18:3758-3767. 6. Von Roenn JH, Bonomi PD, Gale M, et al. Sequential hormone therapy for advanced breast cancer. Semin Oncol. 1988; 15(2 Suppl 1):3843. 7. Pritchard KL. Current and future directions in medical therapy for breast carcinoma: Endocrine treatment. Cancel: 2000; SS(Suppl 12):3065-3072. 8. Osborne CK, Hobbs K, Clark GM. Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice. Cuncer Rex 1985;45:584-590. 9. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Rex 199 I;.51:38673873. 10. Takimoto GS, Graham JD, Jackson TA, et al. Tamoxifen resistant breast cancer:
Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coattivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998: 95:927-937.
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12. Curran M, Wiseman L. Fulvestrant. Drugs. 2001;61:807-8 14. 13. Bonneterre J, Thurlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000; I8:3748-3757. 14. Osborne CK, Zhao H. Fuqua SA. Selective estrogen receptor modulators: Structure, function, and clinical use. J C/in Oucol. 2000; 18:3 172-3 186. 15. Simons WR. Bassi R, Gandhi S. et al. A comparison of quality-adjusted time to disease progression of anastrozole vs tamoxifen as the first-line treatment of postmenopausal patients with advanced breast cancer. Presented at the 24th Annual San Antonio Breast Cancer Symposium; December 10-13, 2001; San Antonio, Texas. Abstract 448. 16. Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB- l- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol. 2001: 19:3808-38 16.
_ Address Cancer
correspondence Center,
to: Joyce
US Oncology,
[email protected]
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O’Shaughnessy, MD, Baylor-Charles A. Sammons 3535 Worth Avenue, Collins-5, Dallas, TX 75246. E-mail: