What is the optimal sequencing of endocrine therapy in the metastatic setting and what is the role of fulvestrant?

OVERVIEW: Patients with estrogen receptor-positive cancers often experience treatment responses to a number of hormonal therapies, and the optimal sequence of agents has changed as new endocrine interventions have been evaluated. In premenopausal women, tamoxifen and ovarian ablation/suppression seem to be equivalent alternatives as first-line therapy, and some evidence supports the use of the combination. In postmenopausal women, third generation aromatase inhibitors have emerged as a viable alternative to tamoxifen, and are often given as first-line therapy. Recent clinical trial data comparing the estrogen receptor downregulator, fulvestrant, suggests at least equal efficacy as second-line therapy after tamoxifen compared to anastrozole. Fulvestrant is administered as an intramuscular injection, and the integration of this unique endocrine intervention into the algorithm for management of postmenopausal patients will be a key issue in coming weeks when this agent becomes available in a nonprotocol setting.

What first-line endocrine therapy would you recommend for the following patients with ER-positive, HER2-negative metastatic breast cancer?

		TAMOXIFEN	ANASTROZOLE	LETROZOLE	OVARIAN ABLATION	NONE
	Asymptomatic 43-year-old woman with bone metastases who received no adjuvant therapy	60%	15%	20%	5%	-
	Asymptomatic 63-year-old woman with bone metastases who received no adjuvant therapy	35%	30%	35%	-	-
	Asymptomatic 63-year-old woman with liver and lung metastases who received no adjuvant therapy	25%	25%	35%	-	15%
	Very ill 63-year-old woman with liver and lung metastases who received no adjuvant therapy	15%	20%	25%	-	40%
	Asymptomatic 78-year-old woman with bone metastases who received no adjuvant therapy	35%	30%	35%	-	-

NCCN GUIDELINES FOR FIRST-LINE HORMONAL THERAPY OF METASTATIC BREAST DISEASE

The non-steroidal aromatase inhibitors are superior to tamoxifen as first-line treatment in metastatic disease. In the current NCCN guideline, the use of aromatase inhibitors has been moved forward to a first-line option for postmenopausal women with hormone-responsive breast cancer. Tamoxifen also remains a first-line option. Because we have such a preponderance of data using tamoxifen in this setting, the panel did not want to remove it. The non-steroidal aromatase inhibitors – anastrozole and letrozole – are considered equivalent according to the guidelines. Although I have no criticism of practitioners who prefer letrozole, I tend to use anastrozole. It was the first of the selective aromatase inhibitors available. It’s one that I became very comfortable with. I personally use anastrozole almost exclusively in my practice.

The steroidal aromatase inhibitor, exemestane, is not included in the guidelines as a first-line hormonal agent, because we don’t have good comparative data yet available from large randomized studies.

—Robert W Carlson, MD

AROMATASE INHIBITORS AS FIRST-LINE THERAPY

Aromatase inhibitors are far better than tamoxifen, not only in terms of antitumor activity, but also the safety profile, because of the risk of thromboembolic complications with tamoxifen and the agonist effect on the endometrium. Even though there were few such events in the first-line metastatic trials, the risk of vaginal bleeding was almost 50% lower with anastrozole compared to tamoxifen. From the individual patient point of view, postmenopausal bleeding starts a domino effect. An ultrasound is required, the gynecologist becomes involved, and the patient may end up having an endometrial biopsy or D&C. And then you find out that this was the effect of tamoxifen. Whereas, if that can be avoided with a drug with better antitumor activity - controlling the disease for a longer period of time — you have a better overall therapeutic index.

—Aman Buzdar, MD

SECOND-LINE TRIALS FOR METASTATIC DISEASE: FULVESTRANT VERSUS ANASTROZOLE

The European trial and the American trial are a little bit different in their design and results. The American trial — which I think had a better design — was double-blinded. Patients assigned to anastrozole received placebo injections. Because the patients in both groups came to the clinic once a month, there was consistency with regard to the patient being seen.

The European trial was not double-blinded. The patients on anastrozole were seen every three months, while the patients on fulvestrant were seen every month. This design has the potential to have some bias in terms of identifying when the patient progresses. Patients in the fulvestrant group of the European trial were seen more often. Conceivably progression would be identified a little earlier than in the anastrozole group.

Having said that, the results show similar response rates between the two drugs, but in the American trial the response duration is about twice as long for fulvestrant compared to anastrozole. Aromatase inhibitors are very good agents. In one of these new trials, fulvestrant is at least as good as anastrozole. In the other trial, we see an advantage at least in one important parameter.

—C Kent Osborne, MD

Fulvestrant was at least equal to treatment with a third-generation aromatase inhibitor, currently our best endocrine therapy for postmenopausal patients. There were also some hints that fulvestrant might be a bit better, mainly in the North American trial. The overall rates of objective response and clinical benefit were slightly higher for fulvestrant, though not statistically significant. The duration of response in the American trial was significantly better for fulvestrant. It was of a magnitude that is clinically and humanly worthwhile in the metastatic setting. These results suggest that fulvestrant also might give an extra boost as adjuvant therapy, which will be tested in clinical trials.

—Richard Elledge, MD

OTHER EFFECTS OF FULVESTRANT

This is a completely new class of antiestrogen. It differs from tamoxifen and other SERMs in that it increases degradation of the estrogen receptor, resulting in dramatic reductions in this protein. It also shuts down both AF1 and AF2 transcription functions, and it appears not to have any estrogenic activity. This agent may be one of the most important new developments in endocrine therapy. The lack of estrogen agonistic properties would clearly be beneficial in terms of the endometrium. Thus far from available studies, fulvestrant seems to have a neutral effect on bone and lipids. We still need more information about its effect on those systems. Fulvestrant doesn’t seem to cause hot flashes, probably because it is not thought to cross the blood-brain barrier. It is given as a monthly intramuscular injection, which is well-tolerated. Patients with metastatic disease don’t have a problem coming for the injection, because it provides more contact with the oncology nurse. In the adjuvant setting, if fulvestrant proves to be more efficacious, an injection once a month will not be a deterrent to patients receiving this agent.

We have identified a new endocrine therapy option for postmenopausal breast cancer patients, and it is exciting to now have a second antiestrogen, which is clinically active in patients who are tamoxifen-resistant. This is the first time we’ve ever seen an antiestrogen produce clinically significant response rates in a randomized trial in tamoxifen-resistant patients. That is really quite a significant event, and I think that these studies will change the concept of antiestrogen therapy in the same way the anastrozole-m e g e s t rol studies changed concepts of endocrine thera py for breast cancer.

—John F Robertson, MD, FRCS

EFFECTS IN PREMENOPAUSAL PATIENTS

There’s been some reservation about the use of fulvestrant in premenopausal women, because the large randomized trials were in postmenopausal patients. In Trial 19 in premenopausal women about to undergo hysterectomy for fibroids, there was no increase in side effects compared to placebo. It was very well-tolerated. A number of biologic endpoints were measured and were unchanged. Unlike tamoxifen, estrogen levels did not significantly increase when fulvestrant was given to premenopausal patients, and there’s no biologic reason to think that it wouldn’t be effective in these women. We used to think that tamoxifen wouldn’t be effective in premenopausal patients, but the Overview demonstrated that tamoxifen has efficacy in premenopausal women that’s not measurably different than in postmenopausal patients.

—Richard Elledge, MD

INTRAMUSCULAR INJECTION

Coming in every month and getting the injection is not a big problem. It’s a 5 cc injection, which for some reason terrorized everybody in the beginning, and initially we actually gave it in split doses. But in fact, you can give a 5 cc or 2.5 cc dose twice and neither of them cause much in the way of local problems at all. It’s very well-tolerated. In the trials, we could not tell which were fulvestrant injections and which we re the placebo injections. If this drug is move d into the adjuvant setting, that could be more of an issue, but in the metastatic setting it doesn’t seem to be an issue for our patients at all. We’ve had some experience in the adjuvant setting using another injectable over a five-year period, and actually once you get the mechanisms in place to deliver the injection, it doesn’t seem to be a big issue.

— Kathleen Pritchard, MD

FULVESTRANT IN PREMENOPAUSAL WOMEN

There is no reason to believe that fulvestrant would not be effective in premenopausal women. Although we do not yet have long-term disease-oriented clinical trials, the agent appears to have acceptable toxicity in short-term trials in premenopausal women. I would, however, be cautious about considering this agent in premenopausal populations outside the confines of a clinical trial.

In pre-clinical studies, fulvestrant has limited effects on bone marrow density and serum lipids. The data in humans is quite early, and those questions will have to be addressed by clinical trials. Certainly, these issues are especially important if fulvestrant is moved into the adjuvant setting, because women in this setting are long-term survivors in whom bone and cardiovascular events are of substantial concern.

—Robert W Carlson, MD

SEQUENCE OF FULVESTRANT

The role of fulvestrant is going to be interesting, because right now this agent would be used after aromatase inhibitors, but there are studies available showing perhaps equal efficacy and, in some studies, even more efficacy than aromatase inhibitors for management of metastatic breast cancer. The different route of administration for fulvestrant is a good thing for some patients, because they won’t have to remember to take a tablet on a daily basis. On the other hand, they will have to come to the clinic once a month to receive an intramuscular injection.

—Edith Perez, MD

TRIALS 20/21: PHASE III RANDOMIZED STUDY OF ICI 182780 (FULVESTRANT) VERSUS ANASTROZOLE IN POSTMENOPAUSAL WOMEN WITH ADVANCED BREAST CANCER CLOSED PROTOCOL

A third arm in Trial 21, fulvestrant 125 mg, was closed after planned analysis demonstrated that pre-defined efficacy criteria were not met at that dose *Only the North American trial (21) had placebo controls.

TRIALS 20 AND 21: STUDY DESIGN DIFFERENCES

Reproduced with permission from a presentation by Robert W Carlson, M D.

TRIALS 20 AND 21: CLINICAL ENDPOINTS

Reproduced with permission from a presentation by Robert W Carlson, M D.

NCCTG-N0032: PHASE II STUDY OF FULVESTRANT (ICI 182780) IN WOMEN WITH METASTATIC BREAST CANCER WHO HAVE FAILED AROMATASE INHIBITOR THERAPY OPEN PROTOCOL

PROJECTED ACCRUAL: 41-94 patients within 10 months

Patients are followed every 3 months for 5 years or until disease progression. After disease progression , patients are followed every 3 months for 2 years and then every 6 months for 3 years.

STUDY CONTACT James N Ingle, Chair, 507-284-8432 North Central Cancer Treatment Group

MODE OF ACTION

MODE OF ACTION OF ESTRADIOL (E) E binds with high affinity to the estrogen receptor (ER) to form an E-ER complex. The E-ER complex pairs with another E-ER complex (dimerizes) and localizes in the cell nucleus. The two transcription activation functions of ER, called AF1 and AF2, are both active. The E-ER dimer binds to estrogen-sensitive genes at the estrogen response element (ERE). The dimer activates transcription of the estrogen-sensitive gene. (AF1 and AF2 interact with coactivators to stimulate the transcription enzyme RNA polymerase II [RNA POLII].

MODE OF ACTION OF TAMOXIFEN (T) T binds to ER with low affinity compared with E. The T-ER complex dimerizes and localizes in the cell nucleus, and AF1 (but not AF2) is active. The T-ER dimer binds to the gene DNA at the ERE. Transcription of the estrogen-sensitive gene is lessened because AF2 is inactive and coactivator binding is likewise attenuated. AF1 activity results in the partial agonist activity of T.

MODE OF ACTION OF FULVESTRANT (F) F binds to ER with affinity similar to E. F triggers rapid degradation of ER. The F-ER complex results in reduced rate of dimerization and nuclear localization. There is reduced binding of F-ER to ERE on the gene resulting in blocked transcription

Reproduced with permission. H owell A et al. Cancer 2000;89:817-825.

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