Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy.
TL;DR: Fulvestrant has recently gained US Food and Drug Administration approval for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy and these new hormonal treatments expand the choice of endocrine therapy for women with advanced breast cancer.
Abstract: Since its introduction more than 30 years ago, tamoxifen has been the most widely used endocrine therapy for the treatment of women with advanced breast cancer. More recently, a number of alternative endocrine treatments have been developed, including several selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and, most recently, fulvestrant ('Faslodex'). Fulvestrant is an estrogen receptor (ER) antagonist, which, unlike the SERMs, has no known agonist (estrogenic) effect and downregulates the ER protein. Tamoxifen is effective and well tolerated, although the non-steroidal AIs, anastrozole and letrozole, are more effective treatments for advanced disease than tamoxifen. Fulvestrant has recently gained US Food and Drug Administration approval for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. In two global phase III clinical trials fulvestrant was at least as effective and as equally well tolerated as anastrozole for the treatment of postmenopausal women with advanced and metastatic breast cancer. In a retrospective analysis of the combined data from these trials, mean duration of response was significantly greater for fulvestrant compared with anastrozole. These new hormonal treatments expand the choice of endocrine therapy for women with advanced breast cancer and offer new options for sequencing and combining treatments.
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Dissertation•
01 Jun 2012
TL;DR: The findings in this study suggest that a transcriptional complex of SRC1/ERα/HMGB2 regulate the transcriptional activity of BCAS3 in endocrine resistant breast cancer.
Abstract: The high mobility group box 2 protein (HMGB2) is an abundant chromatin remodelling
protein with an affinity for unusual DNA structures. It induces architectural
modifications to DNA structure, thereby allowing easier access for transcriptional
machinery to promoters of interest. Immunohistochemical staining of our patient tissue
microarray revealed that patients who are positive for HMGB2 in their primary tumour
have a reduced risk of breast cancer recurrence. This favourable outcome could be due
to the interaction between the estrogen receptor α (ERα) and HMGB2, as ERα positive
tumours promote the formation of a luminal type tumour, which are less aggressive in
general. HMGB2 was identified as a steroid receptor coactivator 1 (SRC1) binding
partner in an endocrine resistant cell model, but not the endocrine sensitive model. In
contrast to HMGB2, SRC1 has previously been associated with a reduced disease free
survival. It is possible that the role of HMGB2 changes as the tumour develops
resistance to an endocrine therapy. This study demonstrates that HMGB2 increases the
interaction between ERα and SRC1 in an endocrine resistance breast cancer cell line.
We have shown that HMGB2 binds to the estrogen regulated breast cancer amplified
sequence 3 (BCAS3) promoter in an endocrine resistant cell line. Furthermore, estrogen
and tamoxifen treatment increase this level of binding. HMGB2 has also been shown to
regulate protein expression of BCAS3 in endocrine resistance. A knock-down study of
HMGB2 resulted in a decreased expression of BCAS3. Conversely, over-expressing
HMGB2 resulted in increase in BCAS3 protein expression. The findings in this study
suggest that a transcriptional complex of SRC1/ERα/HMGB2 regulate the
transcriptional activity of BCAS3 in endocrine resistant breast cancer.
2 citations
Dissertation•
01 Jan 2011
TL;DR: While the mechanism underlying residual growth warrants future investigation, targeting ER alone may not be the best treatment regimen and a combination of targets may be required as the optimum strategy to treat ER+ breast cancer.
Abstract: Greater concentrations of fulvestrant are being employed within the clinic due to increased oestrogen receptor (ER) down-regulation and greater clinical benefit in ER+ breast cancer. However, complete ER down-regulation has not been achieved. The importance of residual ER is unknown and could allow cells to survive initial anti-hormone impact and progression to hormone insensitivity. This project aims to go further than current clinical therapy, using the MCF-7 cell model to target and assess the importance of residual ER. Cells were treated with fulvestrant aiming to achieve maximal ER down-regulation. The effect of any residual ER on signalling and growth was subsequently assessed. An alternative model for ER loss, ER siRNA, was employed to see whether this had a greater anti-ER effect. Finally, fulvestrant and ER siRNA were employed in combination to assess whether these agents work synergistically to give greater ER down-regulation and increased anti- tumour effect. With fulvestrant at 10"7M, ER levels were markedly reduced, although residual ER was observed that remained with increasing drug concentrations. There was significant reduction of ER signalling, proliferation and growth, but the inhibition was incomplete. When ER siRNA was assessed, similar results were obtained, with comparable and incomplete ER loss, residual signalling and growth. Following combination treatment of fulvestrant and ER siRNA, residual ER was almost undetectable, though this did not correspond to greater loss of ER signalling or growth when compared to either agent alone. While this work showed greater ER loss than previously recorded by targeting both protein and mRNA together, no greater anti-tumour activity was observed. Thus, while the mechanism underlying residual growth warrants future investigation (along with longer exposure), targeting ER alone, no matter how successfully, may not be the best treatment regimen and a combination of targets may be required as the optimum strategy to treat ER+ breast cancer.
2 citations
TL;DR: In this review, the latest information on three major classes of therapeutic intervention, including estrogen deprivation through aromatase inhibition or ovarian ablation or suppression; and sex steroid therapies, are summarized, with an emphasis on evidence-based approaches to management.
2 citations
01 Jan 2010
2 citations
Cites background from "Fulvestrant ('Faslodex')--a new tre..."
...…breast cancer disease whose cancer had progressed on OH-Tam (TTP: 5.5 months for fulvestrant and 5.1 months for anastrozole); however, there was no statistically significant difference in the overall clinical benefit between the two drugs (Howell, Robertson et al. 2002; Morris and Wakeling 2002)....
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01 Nov 2014
TL;DR: Hormonal lecba is a modality of lecebne modality založene na ctyřech principech, a metoda that is individuallyizovane, individualizovana, and individualizative as mentioned in this paper.
Abstract: Hormonalni lecba je nejstarsi a nejbezpecnějsi klinicky ověřena lecebna metoda použivana ve vsech stadiich karcinomu prsu. Je to lecba
cilena, individualizovana. Do klinicke praxe byly postupně zařazeny lecebne modality založene na ctyřech principech, a to metoda
ablativni, kompeticni, inhibicni a aditivni. Jde o preferovanou lecbu u hormonalně dependentnich karcinomů prsu vcetně visceralniho
postiženi pokud neni vysoke riziko nebo důkaz hormonalni rezistence nebo je nutne rychle dosahnout lecebnou odpověď. V clanku
je uvedena soucasna doporucovana kaskada hormonalni lecby se zakladnimi studiemi, z nichž doporuceni vychazi, nežadouci ucinky
a možnosti překonani hormonalni rezistence diky novým lekům, přichazejicim do klinicke praxe.
References
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TL;DR: The FACT-G meets or exceeds all requirements for use in oncology clinical trials, including ease of administration, brevity, reliability, validity, and responsiveness to clinical change.
Abstract: PURPOSEWe developed and validated a brief, yet sensitive, 33-item general cancer quality-of-life (QL) measure for evaluating patients receiving cancer treatment, called the Functional Assessment of Cancer Therapy (FACT) scale.METHODS AND RESULTSThe five-phase validation process involved 854 patients with cancer and 15 oncology specialists. The initial pool of 370 overlapping items for breast, lung, and colorectal cancer was generated by open-ended interview with patients experienced with the symptoms of cancer and oncology professionals. Using preselected criteria, items were reduced to a 38-item general version. Factor and scaling analyses of these 38 items on 545 patients with mixed cancer diagnoses resulted in the 28-item FACT-general (FACT-G, version 2). In addition to a total score, this version produces subscale scores for physical, functional, social, and emotional well-being, as well as satisfaction with the treatment relationship. Coefficients of reliability and validity were uniformly high. The ...
5,232 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...The Functional Assessment of Cancer Therapy – Breast (FACT-B) questionnaire (Cella et al. 1993) is a sensitive measure for evaluating physical, functional, social and emotional well-being of the patient....
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TL;DR: Anastrozole is an effective and well tolerated endocrine option for the treatment of postmenopausal patients with hormone-sensitive early breast cancer and longer follow-up is required before a final benefit:risk assessment can be made.
1,905 citations
Journal Article•
TL;DR: The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.
Abstract: Previous studies from this laboratory have described a series of 7 alpha-alkylamide analogues of estradiol with pure antiestrogenic activity, exemplified by ICI 164,384. A new compound, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10 )- triene-3,17 beta-diol (ICI 182,780) has now been identified which has significantly increased antiestrogenic potency and retains pure estrogen antagonist activity. The antiuterotrophic potency of ICI 182,780 in the immature rat was more than 10-fold greater than that of ICI 164,384 (50% effective doses of 0.06 and 0.9 mg/kg, respectively). This order of magnitude increase of in vivo potency was also reflected, in part, by intrinsic activity at the estrogen receptor. The relative binding affinities of ICI 182,780 and ICI 164,384 were 0.89 and 0.19, respectively, compared with that of estradiol (1.0). Similarly, the in vitro growth-inhibitory potency of ICI 182,780 exceeded that of ICI 164,384 in MCF-7 human breast cancer cells, where 50% inhibitory concentrations of 0.29 and 1.3 nM, respectively, were recorded. ICI 182,780 was a more effective inhibitor of MCF-7 growth than 4'-hydroxytamoxifen, producing an 80% reduction of cell number under conditions where 4'-hydroxytamoxifen achieved a maximum of 50% inhibition. This increased efficacy was reflected by a greater reduction of the proportion of cells engaged in DNA synthesis in ICI 182,780-treated cell cultures compared with tamoxifen-treated cells. Sustained antiestrogenic effects, following a single parenteral dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, antitumor activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in nude mice. A single injection of ICI 182,780 provided antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks. The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.
1,158 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...In pigtailed monkeys, sustained antiestrogenic effects were apparent following a single parenteral dose of fulvestrant (Wakeling et al. 1991)....
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...Like tamoxifen, fulvestrant competitively binds to the ER but with a much greater affinity than tamoxifen – approximately 89% that of estradiol, compared with 2.5% for tamoxifen (Wakeling & Bowler 1987, Wakeling et al. 1991)....
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...Further observations from this study showed that the oral antiuterotropic activity of fulvestrant was one order of magnitude less than its parenteral potency (Wakeling et al. 1991)....
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...Similar reductions of tumor growth were seen in the Br10 human tumor model (Wakeling et al. 1991)....
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TL;DR: Risk of endometrial cancer increases following tamoxifen therapy for invasive breast cancer; however, net benefit greatly outweighs risk, and tamoxIFen treatment for breast cancer should continue.
Abstract: BACKGROUND Tamoxifen is advantageous in treating all stages of breast cancer. However, studies have suggested that incidence and severity of endometrial cancer increase in women treated with tamoxifen. PURPOSE We compared rates of endometrial and other cancers in tamoxifen- and non-tamoxifen-treated patients and described the pathologic characteristics of the endometrial cancers. METHODS Data were analyzed on 2843 patients with node-negative, estrogen receptor-positive, invasive breast cancer randomly assigned to placebo or tamoxifen (20 mg/d) and on 1220 tamoxifen-treated patients registered in NSABP B-14 subsequent to randomization. Average time on study is 8 years for randomly assigned patients and 5 years for registered patients. RESULTS The incidence rates of liver, gastrointestinal, urinary tract, and nonuterine genital tumors were not increased by tamoxifen treatment. Twenty-five endometrial cancers were originally reported, one of which was reclassified after subsequent review. Two cases occurred in the placebo group in patients whose medical status subsequent to random assignment had required tamoxifen treatment. Twenty-three occurred in the tamoxifen groups. Twenty-one of the 24 originally reported endometrial cancers were FIGO stage 1; 18 of 23 gradable cases were of good to moderate histologic grade. Four tamoxifen-treated women died of uterine cancer. The average annual hazard rate of endometrial cancer as a first event within the first 5 years of follow-up in the randomized, tamoxifen-treated group was 1.2/1000 patient-years; the cumulative hazard rate was 6.3/1000. Findings for the registered, tamoxifen-treated group were similar. Including all originally reported endometrial cancers, the annual hazard rate through all follow-up was 0.2/1000 in the placebo group and 1.6/1000 in the randomized, tamoxifen-treated group; the relative risk of endometrial cancer for the latter versus the former group was 7.5. Again for the latter group, using population-based rates of endometrial cancer from SEER data and information from another NSABP (B-06) trial, relative risks were 2.2 and 2.3, respectively. The 5-year cumulative hazard rate for disease-free survival in the randomized tamoxifen group was 38% less than that in the placebo group. Some data in this paper were provided by an investigator who submitted fraudulent data to the NSABP [see the "News" section]; therefore, the reader must read the entire text including Table 10 and the Editor's notes. In brief, data on 182 of the 2843 randomly assigned patients and 37 of the 1220 registered patients were provided by the investigator in question. After review, 24 of the 182 records showed falsification, all involving characteristics of patients prior to random assignment. Of the 37 registered-patient records, 8 showed falsification. CONCLUSIONS Risk of endometrial cancer increases following tamoxifen therapy for invasive breast cancer; however, net benefit greatly outweighs risk. Endometrial cancers occurring after tamoxifen therapy do not appear to be of a different type with a worse prognosis than are such tumors in non-tamoxifen-treated patients. IMPLICATIONS Tamoxifen treatment for breast cancer should continue. In addition, the relative risk of endometrial cancer observed in B-14 tamoxifen-treated patients is consistent with the twofold relative risk used in the initial risk-benefit computation for the NSABP breast cancer prevention trial.
1,149 citations
TL;DR: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate, and its results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.
Abstract: PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor– and/or progesterone receptor–positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median,...
997 citations
"Fulvestrant ('Faslodex')--a new tre..." refers background in this paper
...Both the third-generation, non-steroidal AIs, anastrozole (‘Arimidex’) and letrozole, have efficacy advantages over tamoxifen in postmenopausal patients as first-line therapy (Bonneterre et al. 2000, Nabholtz et al. 2000, Mouridsen et al. 2001)....
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