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Evidence-based Breast Cancer Treatment Guidance - The State of the Art
Compiled by: Constantine Kaniklidis, medical researcher,
Member, European Association for Cancer Research (EACR)
[ Breast Cancer Watch is a member of the Evidencewatch portal of evidence-based medicine sites ]


Breast Cancer Watch is a unique service providing the latest best evidence-based guidance on state-of-the-art breast cancer therapies, annotated with critical commentaries, and clinical practice recommendations. Critical appraisal and systematic review is undertaken aggressively with major updates monthly, and at least weekly revisions for high-impact findings. The series addresses two problems: (1) the lack of any timely single-source evidence-based systematic review of breast cancer treatment research findings for both healthcare professionals and informed patients, and (2) the rapid aging of breast cancer guidelines issued on less timely schedules (e.g., NCCN, ASCO and other guidelines).      [updated: 11/01/07]



Fulvestrant (Faslodex) Endocrine Therapy

Position in Endocrine Therapy

New Findings on Fulvestrant

  • Fulvestrant Field Notes: What the Experts Say
    In addition, Dr. William Gradishar in a recent interview cites indirect data suggesting that the sequence of a nonsteroidal aromatase inhibitor (anastrozole (Arimidex) and letrozole (Femara)) to fulvestrant may benefit 25% to 30% percent of patients (Patterns of Care in Medical Oncology (2005): Endocrine Therapy for Metastatic Disease). And Dr. Gabriel N Hortobagyi in the same interview notes that not only is fulvestrant is financially favorable over and equi-efficacious with aromatase inhibitors, but also that trials of fulvestrant underestimate the efficacy of this agent, given that the dosing schedule used was probably too low (as witness that by the time steady state was reached, many patients were off study); he states his own clinical practice of administering loading doses of 500 mg of fulvestrant followed by 500 mg two weeks later and then 250 mg monthly, and believes that given such more optimal dosing, fulvestrant is likely to be superior to aromatase inhibitors.

    Dr. Adam M Brufsky (same interview, above) cites his own clinical practice of using fulvestrant not only as third-line, but also use it first line treatment particularly in women who can’t afford an aromatase inhibitor. And Dr. Gerson Locker noted that although studies have shown no significant difference between anastrozole and fulvestrant, differences occur in subset analyses: (1) the duration of response seemed to be longer in patients who responded to fulvestrant, and (2) patients who had visceral disease seemed to respond better than those who did not, concluding that the takeaway message is that fulvestrant and AIs are equally efficacious, but there may be subsets of patients in whom use of fulvestrant might be preferable, particularly those for whom compliance may be an issue or those with visceral disease, and that third-line aromatase inhibitors are efficacious after fulvestrant and vice versa so that switching is flexible.

    Dr. Stephen E Jones (same interview, above) observes that evidence exists that a proportion of women have a longer response to fulvestrant than to anastrozole when given right after tamoxifen. His own clinical practice prefers fulvestrant to an aromatase inhibitor after tamoxifen because approximately 20 percent of patients have long responses with it in this setting. Dr Jones adds an intriguing observation, namely that we are just beginning to see patients who have been treated with two or three years of adjuvant anastrozole and then relapsed, and there are multiple options including fulvestrant, exemestane and even tamoxifen (if the patient is tamoxifen-naive), still a useful drug in this context.

    And in another interview (Breast Cancer Update (2005): Clinical experience with fulvestrant), Dr. Charles L Vogel noted that fulvestrant is a very good drug with minimal toxicity, and not much buttock pain even with a five-cc injection, and with less degree of joint discomfort that seen with the aromatase inhibitors, so that it is certainly a viable alternative to aromatase inhibitors in patients who have disease progression on tamoxifen. The pain of the intramuscular site injection can be effectively mitigates either by Emla Cream (lidocaine 2.5% and prilocaine 2.5%) by patch applied one-hour before injection, or somewhat more effectively, by vapocoolant (Fluori-Methane) which unlike Emla Cream is immediate in onset of action and relatively inexpensive (Mawhorter et al., J Travel Med (2004): Topical vapocoolant quickly and effectively reduces vaccine-associated pain: results of a randomized, single-blinded, placebo-controlled study).

    [added] Dual Endocrine (Concurrent AI + Fulvestrant)
    In discussing the case of a patient who relapsed while receiving adjuvant anastrozole, John Robertson at the University of Nottingham proposed: "Another option would be to continue the anastrozole and start fulvestrant. The basis for that is preclinical data that were published in The Journal of Biological Chemistry by DR Martin (Martin 2003). If you grow cells in estrogen-deprived media, they become more sensitive to low levels of estrogen. People assume that perhaps, in patients who’ve been treated with an aromatase inhibitor over a long period of time, this is what happens. It’s one of the potential mechanisms of resistance to aromatase inhibitors. If you take cells that have been estrogen deprived for a long time and administer increasing doses of fulvestrant, then you can inhibit cell growth. The hypothesis is that when you have relapse on an aromatase inhibitor and the tumor becomes sensitive to these very low levels of estradiol, if you simply use fulvestrant and stop the aromatase inhibitor, then you increase estradiol again, which might compete with fulvestrant. Therefore, perhaps it may be better to keep the estradiol level low and bring in fulvestrant" (Breast Cancer Update (2006): V. 5, Issue 6: Conversations with Oncology Investigators - Bridging the Gap between Research and Patient Care). The foundational preclinical research was done by Lesley-Ann Martin at Royal Marsden Hospital and her coresearchers (Martin et al., J Biol Chem (2003): Enhanced Estrogen Receptor (ER) , ERBB2, and MAPK Signal Transduction Pathways Operate during the Adaptation of MCF-7 Cells to Long Term Estrogen Deprivation) who found that fulvestrant (aka, ICI 182780) might be more effective in the treatment of breast cancers that acquire resistance to estrogen deprivation rather than in de novo hormone responsive disease, given the super-sensitivity of tumor cells to the effects of estrogen during long term estrogen deprivation (LTED), requiring ER for both proliferation and ER-directed transcription. The strategy of adding fulvestrant to existing aromatase inhibitor therapy - was also espoused by Ian Smith of Royal Marsden Hospital when queried on the optimal sequencing of endocrine (hormonal) agents: "I would be inclined to use fulvestrant with estrogen deprivation. In other words, I would continue an aromatase inhibitor because I can’t see any reason why it would be worse than fulvestrant alone" (Breast Cancer Update (2006): V. 5, Issue 6: Conversations with Oncology Investigators - Bridging the Gap between Research and Patient Care).

    Note that these field experiences not only argue for superior efficacy of dual endocrine therapy per se, but also motivate such therapy by virtue of addressing the potentially clinically adverse upswing in estrogen levels following discontinuation of the estrogen deprivation induced by an aromatase inhibitor (AI), given that tumor cells grown in such estrogen deprived environments are highly sensitized to even very low levels of estrogen and so may compromise subsequent fulvestrant monotherapy unless the aromatase inhibitory activity is continued concurrently with fulvestrant to manage the induced increased estradiol levels (see also the supporting research of the SAKK trial (Perey et al., Ann Oncol (2006): Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00)).

    This viewpoint is also that of the Fox Chase team of Eric Ariazi and colleagues in their evaluation of antihormonal resistance using endocrine-resistant xenografts in mice, noting that fulvestrant plus estradiol in Phase II antihormone-resistant tumors reversed the estradiol-induced inhibition and instead resulted in growth stimulation, a scenario that arises clinically in the context fulvestrant deployment after the termination of aromatase inhibitor therapy (Ariazi et al., J Steroid Biochem Mol Biol (2006): Emerging principles for the development of resistance to antihormonal therapy: Implications for the clinical utility of fulvestrant).

Fulvestrant: Breast Cancer Watch Summary

  • A selective estrogen receptor downregulator (SERD)
  • A pure antiestrogen (no agonist activity on endometrium, lipids, bone)
  • Monthly intramuscular injection
  • At least as effective as tamoxifen and aromatase inhibitors
  • Active in tamoxifen-resistant patients
  • High tolerability, minimal toxicity
  • Lower incidence of joint/bone disorders
  • Time from onset of response to disease progression significantly greater than anastrozole
  • Non-statistically significant but trend / umerical increase in overall survival over anastrozole
  • Possibly longer duration of response than AIs
  • Patients with visceral disease are more fulvestrant-responsive
  • No androgenic side-effects (viralization, weight gain, alopecia, hypertrichosis, hoarseness) unlike steroidal AI exemestane (Aromasin)
  • Switchable from, or to, tamoxifen and AIs
  • More affordable than AIs

Breast Cancer Watch notes in agreement with other investigators, that on these findings, fulvestrant is unjustifiably underutilized.
 

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Copyright © 2006. Constantine Kaniklidis