However, I see no reason to believe that nab paclitaxel will prove inferior to those drugs with more data. I believe nab paclitaxel will compare favorably, if not prove to be superior.

When you examine clinical trials that have evaluated docetaxel or paclitaxel in similar patient populations with metastatic disease, the indirect evidence shows the activity of nab paclitaxel to be comparable to docetaxel. These agents may have similar antitumor effects, so one should consider other factors, including toxicities, patient convenience and cost.

If nab paclitaxel can offer the same antitumor effect as docetaxel and paclitaxel along with advantages in terms of lack of premedication and shorter infusion time, whether or not it would become the preferred agent is an important question. When you think of busy office practices, the throughput of patients and convenience to patients are important. An upside to nab paclitaxel clearly is the shorter infusion time and the lack of need for premedication.

As for the higher acquisition cost of nab paclitaxel, economic analyses suggest that some of the downstream expenses related to administering paclitaxel or docetaxel — specifically the costs of premedications and antibiotics or growth factors to manage the neutropenias or cytopenias — result in a net savings with the use of nab paclitaxel.

Although we need more information, I believe we shouldn’t necessarily be put off by the up-front cost; we should take into account the whole package of managing the patient’s treatment.

Breast Cancer Update 2006 (8)

DR LIVINGSTON: Let’s assume nab paclitaxel and paclitaxel are equivalent. Should we, therefore, simply substitute nab paclitaxel for paclitaxel? We have a fair amount of data, both from preclinical systems and from clinical trials, to suggest that the drug is superior to paclitaxel, independent of its ability to prevent allergic reactions.

A reputable randomized study was published in the Journal of Clinical Oncology that compared nab paclitaxel to paclitaxel on an every three-week schedule for women with metastatic breast cancer. That study shows a magnitude of difference in terms of response rate and time to progression, which is fairly similar to the magnitude of difference that was demonstrated in ECOG-E2100 between paclitaxel alone and paclitaxel with bevacizumab.

However, the paclitaxel with bevacizumab trial was accepted with great enthusiasm — legitimately — and presented in a fairly frenzied special oral session at ASCO, while the trial involving nab paclitaxel versus paclitaxel was basically disregarded.

A plausible hypothesis is that nab paclitaxel, in conjunction with other treatment, could produce a higher pathologic complete response rate than standard paclitaxel. This question is worth answering and may be answered more expeditiously in the setting of neoadjuvant therapy, where the pathologic complete response endpoint can be obtained quickly, rather than in an adjuvant trial setting, where it will require many years to obtain an answer.

In my own practice, I’m prescribing patients paclitaxel because of the cost differential. If cost were not an issue, I would stop administering paclitaxel today and substitute it with nab paclitaxel.

Interview, September 2006

DR GRALOW: SWOG-S0226 is a randomized, first-line metastatic study in which all patients receive an aromatase inhibitor, and half of them will receive fulvestrant concurrently.

The group that is randomly assigned to receive the aromatase inhibitor alone is asked to switch to fulvestrant at the time of progression, although we know we can’t force their next-line therapy.

So it’s a question of an up-front aromatase inhibitor with a selective estrogen receptor downregulator (SERD), fulvestrant, versus an aromatase inhibitor followed by the SERD. We’re hoping that we’ll obtain complete estrogen blockade by using this regimen.

We know that in the ATAC trial, the anastrozole/tamoxifen combination arm did not appear to be any better than tamoxifen alone and certainly wasn’t going to be the superior arm.

Tamoxifen can have some proestrogenic properties in an otherwise depleted estrogen state. Fulvestrant shouldn’t have these. It’s a pure antiestrogen and thus is an interesting concept that is different from considering an aromatase inhibitor with or without tamoxifen. Certainly, preclinical data suggest that this could work. It makes sense, and we have high hopes that it could be better.

Breast Cancer Update CME Meeting June 2005

DR OSBORNE: In the clinical setting, I believe it is a good idea for patients who are progressing on an aromatase inhibitor to continue with an aromatase inhibitor and add fulvestrant, but we have no data. I have done this with a few patients based on two preclinical studies that have evaluated this: my own and Angela Brody’s.

Fulvestrant seems to work much better when there’s no estrogen around. Even though postmenopausal women have lower estrogen levels in the blood, their tumors don’t necessarily have lower estrogen levels, and fulvestrant seems to be more effective when estrogen is low.

In patients progressing on tamoxifen, tamoxifen binds the estrogen receptors and may actually stimulate growth of the tumor — it certainly is no longer inhibiting it. Treating these patients with an aromatase inhibitor will be ineffective until all the tamoxifen is gone, which takes a couple of months. Fulvestrant, on the other hand, competes with tamoxifen for binding, thus the response may be quicker with fulvestrant than with an aromatase inhibitor in that setting.

Breast Cancer Update 2005 (9)

DR CHARLES L VOGEL: Fulvestrant is a very good drug that has minimal toxicity. We don’t even encounter much in the way of buttock pain with a five-cc injection. We’re also not seeing the degree of joint discomfort that we see with the aromatase inhibitors.

In terms of efficacy, fulvestrant seems to be equivalent to anastrozole. Based on data published this year in Cancer, there seems to be no difference in overall survival in the randomized trials of anastrozole versus fulvestrant. Fulvestrant is a good drug and a viable alternative to aromatase inhibitors in patients who have disease progression on tamoxifen.

We do have to contend with the randomized trial of fulvestrant versus tamoxifen, where we expected a strongly beneficial effect for fulvestrant over tamoxifen, which was not forthcoming. There were some subsets where fulvestrant appeared to be better, but the overall results were about the same.

Breast Cancer Update 2005 (4)

DR GRADISHAR: An important issue is whether fulvestrant at 250 milligrams is optimal, even though that’s the approved dose. Some of the data, including preclinical data generated by Kent Osborne and others, suggest that this dose is on the low end of the curve where you might expect the optimal response rate.

Although we may be able to increase the dose, administering 250 milligrams in each buttock, doing that too frequently becomes prohibitive, and patients may not tolerate it.

Some strategies have evaluated quickly increasing serum levels of fulvestrant, and those strategies have included administering loading doses of 500 milligrams and then, within two weeks, administering another 250 milligrams and then proceeding to the monthly schedule.

Those strategies are based on mathematical modeling that have shown an ability to achieve steady-state levels much quicker and, consequently, achieve a biologically relevant dose of drug circulating in a given patient much faster.

Breast Cancer Update 2005 (4)

DR OSBORNE: We expected fulvestrant to be superior to tamoxifen, but in the first-line setting it proved to be similar, not better. That’s peculiar because second-line trials show fulvestrant to be equal to or better than aromatase inhibitors, and aromatase inhibitors have been shown to be superior to tamoxifen. It may be that we’re not dosing fulvestrant correctly. We know from the randomized trial that half of the currently recommended dose is insufficient, and we know it takes three to six treatments to achieve steady state blood levels with fulvestrant, so perhaps a higher dose or a loading dose (or both) is required. These options are being investigated.

Breast Cancer Update 2004 (3)

DR JOHN F R ROBERTSON: Fulvestrant at 250 milligrams is an effective dose, as demonstrated by the clinical trials. It is as effective as anastrozole as second-line therapy and equivalent to tamoxifen as first-line therapy in postmenopausal women.

In premenopausal women, data suggest that 250 milligrams of fulvestrant is not effective at down-regulating the estrogen receptor. This raises questions about whether a 250-mg dose of fulvestrant leads to complete down-regulation of the estrogen receptor in postmenopausal women. Could a higher dose of fulvestrant achieve more?

Two strategies exist to increase the dose of fulvestrant. The first is a loading dose sequence. The second is the administration of a higher dose of fulvestrant. For example, instead of administering one 5-mL injection every month in one buttock, one might administer one 5-mL injection in each buttock, for a total of 500 milligrams. Future studies are needed to determine the dose-response curve for fulvestrant.

Breast Cancer Update 2004 (9)

DR GABRIEL N HORTOBAGYI: I believe the trials of fulvestrant underestimate the efficacy of this agent. The dosing schedule used was probably too low because by the time steady state was reached, many patients were off study, presumably because of progression.

In my group, we administer loading doses of 500 milligrams of fulvestrant, followed by 500 milligrams two weeks later and then 250 milligrams monthly.

The pharmacokinetics of fulvestrant suggest a loading dose would be beneficial, so it concerns me that the comparison of fulvestrant to anastrozole in a tamoxifen-resistant population might not have revealed the true efficacy of fulvestrant. It showed fulvestrant to be at least as effective as anastrozole, but I expected it to be superior. We may need to repeat some of these studies with a more appropriate dosing schedule.

Breast Cancer Update 2003 (6)

DR O’SHAUGHNESSY: I am a little disquieted by the fact that it can take three to five months to reach a steady state with fulvestrant.

A patient with rapidly progressing disease may not benefit from fulvestrant, but fortunately most women with hormone-responsive breast cancer have relatively indolent disease. I’m interested in the clinical trial in which they are loading fulvestrant at 500 milligrams every two weeks for a couple of doses and then reducing it to 250 milligrams monthly. That makes sense to me.

Breast Cancer Update 2005 (8)

DR VALERO: At MD Anderson, we use a loading dose of fulvestrant. We administer 500 milligrams on day one, 250 milligrams on day 15 and day 29 and then monthly.

Many of the key investigators in the early development of the drug believe it is important to attain steady state, but we have no randomized data for the loading approach. Currently, it is FDA approved at 250 milligrams monthly and is reimbursed by Medicare at that dose.

With all of those caveats, I believe — and I don’t know if this is my bias — the loading approach is reasonable. However, although we think that may be the best dosing schedule, we won’t know unless we do a pharmacokinetic study to show that the doses are equally effective.

Breast Cancer Update 2006 (7)

DR CARLSON: I believe a loading dose of fulvestrant should generally be used in clinical practice, and I continue to see an increase in the number of patients treated with fulvestrant. That’s reasonable, and experience has confirmed the tolerability of the drug and the efficacy of the therapy. My expectation is we’ll see nothing but increased use of fulvestrant.

In terms of use for the premenopausal woman, I believe that in the metastatic setting, we will see increasing numbers of patients treated with fulvestrant after they are put in a menopausal state. In part this is because I believe the truly limited number of endocrine agents we have available for the treatment of premenopausal breast cancer means that, functionally, after a premenopausal woman has been treated with tamoxifen, you’re obligated to make her postmenopausal.

Once she’s postmenopausal, the whole spectrum of endocrine agents, which are effective in the postmenopausal woman, become available.

Because my expectation is that the women will be on hormone therapy for some length of time, I often send those women to the gynecologic oncologist for a laparoscopic oophorectomy.

Dodwell D, Vergote I. A comparison of fulvestrant and the third-generation aromatase inhibitors in the second-line treatment of postmenopausal women with advanced breast cancer. Cancer Treat Rev 2005;31(4):274-82.

Fulvestrant is the first antioestrogen to demonstrate efficacy in tamoxifen-resistant disease, highlighting the difference in mode of action between fulvestrant and the SERMs (which show only limited efficacy in this setting). In phase III studies, fulvestrant was at least as effective as anastrozole in terms of clinical efficacy and was well tolerated.

Furthermore, fulvestrant is associated with significantly fewer joint disorders (arthralgia, arthrosis and arthritis) compared with anastrozole. Indirect comparisons suggest that fulvestrant also offers comparable efficacy to letrozole and exemestane, and may have some tolerability benefits over these agents in the second-line treatment of postmenopausal women with advanced breast cancer.

Breast Cancer Update 2006 (3)

DR GRADISHAR: The SoFEA trial is evaluating the use of endocrine therapy in the metastatic disease setting, comparing exemestane as a single agent to fulvestrant to the combination of anastrozole and fulvestrant. The combined therapy arm may be the most interesting one.

The rationale behind it is not only removing the ligand for the receptor — which is what the aromatase inhibitor would do by decreasing the amount of circulating estrogen — but also eradicating the actual target, which is the receptor. Answering whether absolute removal of those two targets will result in a better outcome is one of the goals of the study.

Breast Cancer Update 2006 (3)

DR ROBERTSON: In cell culture, when MCF7 cells are depleted of estradiol, they become extremely sensitive to low levels of estrogen. The cell line can be inhibited if fulvestrant is then titrated into that long-term estrogen-deprived cell line.

The rationale behind the SoFEA study is that the development of resistance to aromatase inhibitors may result from an increased sensitivity of breast cancer cells to very low levels of estradiol.

Fulvestrant competes with estradiol for the estrogen receptor on a one-toone basis, so that upon progression while on the aromatase inhibitor, the addition of fulvestrant to the aromatase inhibitor might result in a better blocking effect. I hope the SoFEA trial will show that improvement occurs from the combination of fulvestrant and an aromatase inhibitor.

This will be an interesting study, not only because it will tell us what to do in second- or third-line therapy but because it will also tell us about mechanisms of action and whether they are important in breast cancer.

Stephen R Johnston et al. Life following aromatase inhibitors — Where now for endocrine sequencing? Breast Cancer Res Treat 2005;93(Suppl 1):19-25.

Fulvestrant (‘Faslodex’) is a new ER antagonist with no agonist effects that binds, blocks and degrades the ER. Due to its unique mode of action and lack of cross-resistance with existing treatments, fulvestrant is an effective therapeutic agent for use in sequential endocrine regimens. Fulvestrant has established efficacy in tamoxifen-resistant disease and there is a growing body of evidence demonstrating its efficacy in patients with AI-resistant disease.

In preclinical models, MCF-7 cells undergoing LTED are refractory to tamoxifen but sensitive to fulvestrant, suggesting fulvestrant is a more appropriate choice following AI resistance.

The steroidal AI, exemestane is also an option in nonsteroidal AI-resistant disease. Clinical trials are underway to compare fulvestrant with exemestane as an appropriate therapy following the onset of AI resistance.

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