Fulvestrant+chemo synergy

[Rich66]

Ann Oncol. 2009 Oct 29. [Epub ahead of print]

Activity of fulvestrant in HER2-overexpressing advanced breast cancer.

FULL TEXT

Robertson JF, Steger GG, Neven P, Barni S, Gieseking F, Nolè F, Pritchard KI, O'Malley FP, Simon SD, Kaufman B, Petruzelka L.
Professorial Unit of Surgery, Division of Breast Surgery, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression increases the aggressiveness of breast cancer cells resulting in poorer prognosis. Patients with HER2-positive disease are less responsive to endocrine therapies. Trastuzumab monotherapy results in objective responses in only approximately 15% of patients. Fulvestrant retains activity in cells overexpressing HER2 that are resistant to other endocrine treatments. This retrospective study evaluated response to fulvestrant treatment among HER2-positive patients with advanced breast cancer (ABC). PATIENTS AND METHODS: Clinical experience data from 10 treatment centres were pooled. Postmenopausal patients with predominantly hormone receptor-positive and HER2-positive disease were included. Clinical benefit (CB) was defined as the proportion of patients achieving a response to treatment (partial or complete) or stable disease lasting >/=6 months. RESULTS: Data for 102 patients were analysed. Fulvestrant resulted in an overall CB rate of 42% (43/101) in HER2-positive patients and 40% (25/63) in patients with visceral disease. Median duration of treatment was 14.5 months (range 6-44 months). Fulvestrant showed activity up to the fourth line of endocrine therapy and up to the seventh line of overall therapy. CONCLUSIONS: Results indicate that fulvestrant may be a suitable treatment option in extensively pre-treated patients with HER2-positive, hormone receptor-positive ABC. Further exploration of its use in this patient population is warranted.
PMID: 19875750

(NOTE: The above study used the original low dose (250mg/monthly dose..might do better at newer 500mg recommendation)




Breast Cancer Res Treat. 2009 Nov;118(2):377-83. Epub 2009 Jun 24.
Predicting benefit from fulvestrant in pretreated metastatic breast cancer patients.

Freedman O, Amir E, Dranitsaris G, Napolskikh J, Kumar R, Fralick M, Chia S, Petrella T, Dent S, Tonkin K, Ahmad I, Rayson D, Clemons M.
Division of Medical Oncology, Princess Margaret Hospital, Suite 5-205, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
Fulvestrant use in pretreated metastatic breast cancer patients is associated with variable response rates. This study aimed to characterize these responses and to develop a prediction model to identify those patients who could potentially derive the most clinical benefit. A nationwide review of patients enrolled in a Canadian compassionate use program from 1999 to 2006 was performed. Prior therapy with tamoxifen, steroidal, and nonsteroidal aromatase inhibitors was mandatory. The dependent variable in the analysis was the proportion of patients requiring chemotherapy at 3 months following the start of fulvestrant. General Linear Mixed modeling was used to identify factors significantly associated with this dependent variable and to subsequently develop the prediction model. Three hundred and five women received at least one dose of fulvestrant; 207 went on to receive chemotherapy (68%). Median duration of fulvestrant treatment was 4.1 months (range 0.8-63.1). Factors predictive of being chemotherapy free at 3 months included older age, no prior adjuvant hormonal therapy, and the absence of lung or brain metastases at the start of therapy. A receiver operating characteristic (ROC) curve analysis had an area under the curve of 0.70 (95% CI 0.60-0.80). This model was able to identify risk information that could be helpful in assessing which patients would most likely benefit from fulvestrant as an intervention with the objective being a delay in chemotherapy.

PMID: 19551499 [PubMed - indexed for MEDLINE]




Text:
http://www.cinj.org/documents/PRAACR...hfield0309.pdf
Contact: Michele Fisher
Media Relations Specialist 732/235-9872
fisherm2@umdnj.edu

Researchers Find Way to Maximize Treatment for Estrogen Receptive Positive Breast Cancer

Study from The Cancer Institute of New Jersey Presented at 100^{th Annual AACR Meeting}

^{New Brunswick, N.J., April 20, 2009 – Researchers from The Cancer Institute of New Jersey (CINJ) are converging on Denver for the 100th Annual Meeting of the American Association for Cancer Research (AACR) to share their findings on a combined treatment targeting breast cancer that is stimulated by the hormone estrogen (estrogen receptive positive). They are joining other top investigators from around the globe for the event, which is highlighting interdisciplinary approaches to cancer research. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.
Among the abstracts being presented is one focusing on how the FDA-approved therapy fulvestrant can influence the effects of chemotherapy drugs on breast cancer cells. Fulvestrant is commonly used in postmenopausal women to treat estrogen receptive positive breast cancer that has spread to other parts of the body.
Breast cancers that respond to female hormones, such as estrogen, generate specific proteins that help tumor cells survive and grow. One such protein, HDM2, is known to be present in higher levels in many cancers including breast. These higher protein levels are strongly correlated with the presence of the estrogen receptor on breast cancer cells, which can affect how well chemotherapy works. Targeting the receptor is a common treatment for breast cancer.
Lead author Adriana V. Jager, PhD, a postdoctoral fellow at CINJ, and her colleagues focused on adding fulvestrant to the traditional chemotherapy agents doxorubicin, etoposide and paclitaxel, as fulvestrant is known to degrade the estrogen receptor and result in less stimulation of tumor cell growth. They found that in two estrogen receptor positive breast cancer cell lines, fulvestrant decreased HDM2 levels and enhanced the sensitivity of these cells to chemotherapy. This enhancement was better than either fulvestrant or chemotherapy alone.
According to the American Cancer Society, 183,000 cases of breast cancer were diagnosed nationwide last year, with 6,300 new cases in New Jersey alone. With such statistics, the team is hopeful that this laboratory-based research can be expanded to a clinical trial with patients in order to further explore improved outcomes.
The author team also includes William N. Hait, MD, PhD, Johnson and Johnson/Centocor; Deborah Toppmeyer, MD, CINJ; Bruce G. Haffty, MD, CINJ; Kim Hirshfield, MD, PhD, CINJ; and Jin-Ming Yang, PhD, Penn State.
The work represented by CINJ members is among the 6,000 abstracts being presented at the gathering, which is featuring more than 17,000 researchers, healthcare professionals, and patient advocates. The goal of the annual AACR event is to provide a forum in which the latest in cutting-edge laboratory, clinical and translational research can be shared.
About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center, and is dedicated to improving the prevention, detection, treatment and care of patients with cancer. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. The Cancer Institute of New Jersey is a center of excellence of UMDNJ-Robert Wood Johnson Medical School. To support CINJ, please call the Cancer Institute of New Jersey Foundation at 1-888-333-CINJ.
The Cancer Institute of New Jersey Network is comprised of hospitals throughout the state and provides a mechanism to rapidly disseminate important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Memorial Hospital, Carol G. Simon Cancer Center at Overlook Hospital, Jersey Shore University Medical Center. Affiliate Hospitals: Bayshore Community Hospital, CentraState Healthcare System, Cooper University Hospital*, JFK Medical Center, Raritan Bay Medical Center, Robert Wood Johnson University Hospital at Hamilton (CINJ at Hamilton), Saint Peter’s University Hospital, Somerset Medical Center, Southern Ocean County Hospital, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate
###}




Cancer Res. 2007 Jun 1;67(11):5337-44.
Estrogen receptor alpha mediates breast cancer cell resistance to paclitaxel through inhibition of apoptotic cell death.

Sui M, Huang Y, Park BH, Davidson NE, Fan W.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Estrogen receptors (ER) are expressed in approximately 65% of human breast cancer. Cumulative data from clinical trials and retrospective analyses suggest that some chemotherapeutic agents may be less effective in patients with ER-positive (ER+) tumors than those with ER-negative (ER-) tumors. Paclitaxel is an active agent used in breast cancer chemotherapy. To investigate the possible influence of ER on the therapeutic efficacy of paclitaxel and its underlying mechanism, we established several isogenic ER+ cell lines by stable transfection of ERalpha expression vectors into ER- breast cancer BCap37 cells. We showed that 17-beta estradiol significantly reduces the overall cytotoxicity of paclitaxel in BCap37-expressing ERalpha but has no influence on the ER- parental cells. Further analyses indicate that expression of ERalpha in BCap37 cells mainly interferes with paclitaxel-induced apoptotic cell death, without affecting paclitaxel-induced microtubule bundling and mitotic arrest. Moreover, we found that the addition of ICI 182,780 (Fulvestrant), a selective ER down-regulator, could completely reverse the resistance of ER+ BCap37 cells to paclitaxel. These findings showed that ERalpha-mediated breast tumor cell resistance to paclitaxel was through selective inhibition of paclitaxel-induced tumor cell apoptosis. Additionally, the combination of ICI 182,780 also sensitizes MCF-7 and T47D cell lines to the treatment of paclitaxel, which further confirmed the correlation between ERalpha and drug resistance in ER+ tumor cells. The results obtained from this study provide useful information for understanding ER-mediated resistance to paclitaxel and possibly other antineoplastic agents.

PMID: 17545614 [PubMed - indexed for MEDLINE]


Video clip from makers of Faslodex on hormonal aspects of BC:
http://www.hormonalaspectsofbc.com/p...211/index.html

Of note is that host says it can take 3 months before effectiveness is shown in hormonal therapy. Tumor can initially enlarge and Markers can rise even when eventually effective.



Med Oncol. 2010 Mar 20. [Epub ahead of print]
Prolonged time to progression with fulvestrant for metastatic breast cancer.

Mello CA, Chinen LT, da Silva SC, do Nascimento Matias C, Benevides CF, Gimenes DL, Fanelli MF.
Fundação Antônio Prudente, Hospital do Câncer A. C. Camargo, Rua Prof Antônio Prudente, 211, Liberdade, São Paulo, SP, 01509-900, Brazil, celso.mello@hcancer.org.br.
Although the incidence of breast cancer has been declining in recent years, the disease is still one of the leading causes of cancer deaths in women. Recently, breast cancer has been treated with innovative approaches that use hormone-sensitive therapies. This is because in at least one-third of breast cancers, estrogens mediated via the estrogen receptor pathway act as endocrine growth factors. Fulvestrant has been studied as both first- and second-line therapy for locally advanced and metastatic breast cancer, but few studies have shown its effect as third-line therapy alone. To observe the disease time to progression (TTP) obtained with fulvestrant when used on metastatic breast cancer as first-, second-, and also third-line therapy. We also aimed to correlate the TTP obtained with fulvestrant with hormone receptor, HER2 expression, and metastatic site. This was a cohort study that retrospectively examined medical records of 73 postmenopausal women with advanced breast cancer who were treated with fulvestrant (250 mg/month i.m. injection) and followed at the Department of Medical Oncology at Hospital do Cancer A. C. Camargo in São Paulo, Brazil from August 2003 to December 2006. The median TTP with fulvestrant was about 11 months. When used as the first-line therapy, TTP was about 13 months; when used as second-line, TTP was about 6 months; and when used as third-line, it was about 12 months. No statistically significant difference was observed regarding the therapy line. In patients with positive ER tumors, TTP was 11 months. No significant difference in TTP was observed in negative ER tumors (TTP = 10 months). In patients with positive PgR tumors, TTP was 13 months and for negative PgR, TTP was 6 months (P = 0.008). According to the HER2 status, the TTP was 5 months for HER2+ and 10 months for HER2-. Our findings indicate that fulvestrant is an effective alternative for treatment of metastatic breast cancer.

PMID: 20306159 [PubMed - as supplied by publisher]

[Rich66]

Breast Cancer Res. 2010;12(3):R43. Epub 2010 Jun 28.
The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells.

Ikeda H, Taira N, Hara F, Fujita T, Yamamoto H, Soh J, Toyooka S, Nogami T, Shien T, Doihara H, Miyoshi S.
Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama-city, Okayama, Japan. yashima_hirokuni@msn.com


FREE TEXT

Abstract

INTRODUCTION: Microtubule-associated protein tau (MAPT) inhibits the function of taxanes and high expression of MAPT decreases the sensitivity to taxanes. The relationship between estrogen receptor (ER) and MAPT in breast cancer is unclear. In this study, we examined the correlation of MAPT expression with the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT.
METHODS: The correlation between MAPT expression and sensitivity to taxanes was investigated in 12 human breast cancer cell lines. Alterations in cellular sensitivity to taxanes were evaluated after knockdown of MAPT expression. ER expression was knocked down or stimulated in MAPT- and ER-positive cell lines to examine the relationship between ER and MAPT. The cells were also treated with hormone drugs (tamoxifen and fulvestrant) and taxanes.
RESULTS: mRNA expression of MAPT did not correlate with sensitivity to taxanes. However, expression of MAPT protein isoforms of less than 70 kDa was correlated with a low sensitivity to taxanes. Downregulation of MAPT increased cellular sensitivity to taxanes. MAPT protein expression was increased by stimulation with 17-beta-estradiol or tamoxifen, but decreased by ER downregulation and by fulvestrant, an ER inhibitor. The combination of fulvestrant with taxanes had a synergistic effect, whereas tamoxifen and taxanes had an antagonistic effect.
CONCLUSIONS: Expression of MAPT protein isoforms of less than 70 kDa is correlated with a low sensitivity to taxanes in breast cancer cells. ER influences MAPT expression and fulvestrant increases the sensitivity to taxanes in MAPT- and ER-positive breast cancer cells.

1: Breast Cancer Res Treat. 2009 Jul 22. [Epub ahead of print] Links

Fulvestrant (ICI 182,780) sensitizes breast cancer cells expressing estrogen receptor alpha to vinblastine and vinorelbine.

Sui M, Jiang D, Hinsch C, Fan W.
Program of Innovative Cancer Therapeutics, First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China.
Cumulative data suggest that some chemotherapeutic agents may be less effective in estrogen receptor alpha positive (ER+) breast tumors than ER negative (ER-) tumors, which has raised a clinically relevant question as to how to reverse this ER-mediated chemoresistance in ER+ breast tumors. This study is to investigate the possible influence of estrogen receptor alpha (ERalpha) on the therapeutic effects of vinblastine and vinorelbine on breast cancer cells and explore whether combination of anti-estrogen agent fulvestrant (ICI 182, 780) may enhance the sensitivity of ERalpha+ cells to these chemotherapeutic agents. Through comparing ER+ with ER- human breast tumor cells or through stable transfection of an ERalpha expression vector into ER negative human breast cancer BCap37 cells, a series of assays were applied to determine the sensitivity of ER+ and ER- breast tumor cells to vinblastine and vinorelbine in the presence or absence of 17-beta-estradiol and/or fulvestrant. 17-beta-Estradiol showed no effect on the sensitivity of ER- MDA-MB-468 and BCap37 cells to the treatment of vincristine or vinblastine, but it significantly reduced the sensitivity of ER+ T47D cells and BCap37 cells expressing ERalpha to the two drugs mentioned. Further analyses show that ERalpha has little effect on vinca alkaloids-induced mitotic arrest, but dramatically affects their ability to induce tumor cell apoptosis. Moreover, through a series of assays, we also demonstrated that the combination of fulvestrant, a selective ER down-regulator, could reverse the resistance of ER+ breast tumor cells to vinca alkaloids and even produce synergistic effects. The findings obtained from this study have provided important evidence that expression and subsequent activation of ERalpha are associated with resistance of breast cancer cells to vinca alkaloids. This study also suggested that the combination of anti-estrogen agents, such as fulvestrant, might be a novel strategy to reverse ER-mediated chemoresistance or sensitize ER+ breast tumors to vinca alkaloids and possibly other chemotherapeutic agents.

Surg Today. 1999;29(2):149-56.
Effects of experimental chemoendocrine therapy with a combination of a pure antiestrogen and 5-fluorouracil on human breast cancer cells implanted in nude mice.

Ogasawara Y, Doihara H, Shiroma K, Kanaya Y, Shimizu N.
Department of Surgery II, Okayama University Medical School, Japan.
The antitumor effects of an experimental chemoendocrine therapy combining a new pure antiestrogen ICI 182780 and 5-fluorouracil (5-FU) were studied on MCF-7 human breast cancer cells implanted in nude mice. ICI 182780 had a dose-dependent antitumor activity, which was potentiated by the concomitant use of 5-FU. When compared with the control group, the estrogen receptor (ER) level in the ICI 182780 group was lower and that in the combination group was markedly lower. Cell cycle analysis by flow cytometry (FCM) resulted in a lower percentage of S-phase cells (%S) in the treated mice. No significant difference was observed in the 5-FU concentrations in tumor cells, while the 5-FU content in RNA was significantly higher in the combination group. The changes in free thymidylate synthetase (TS) concentration indicated TS synthesis after the administration of 5-FU to be more greatly suppressed in the combination group than in the 5-FU group. These results suggest that ICI 182780 and 5-FU exert their combination effect mainly on ER-positive cells, and that the suppression of TS synthesis in tumor cells and the potentiation of the 5-FU-induced metabolic dysfunction of RNA are thus involved in the mode of action of this combination therapy.

PMID: 10030740 [PubMed - indexed for MEDLINE]


Breast Cancer Res Treat. 2009 Sep;117(1):69-75. Epub 2008 Nov 23.
Activity of fulvestrant versus exemestane in advanced breast cancer patients with or without visceral metastases: data from the EFECT trial.

Mauriac L, Romieu G, Bines J.
Institut Bergonié, Centre Régional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, France. mauriac@bergonie.org


TEXT

Abstract

PURPOSE: Patients with visceral metastases (VM: lung and/or liver metastases) are generally regarded as being less responsive to hormonal therapy, and chemotherapy often becomes the default treatment. This paper reports a subgroup analysis from EFECT (The Evaluation of Faslodex versus Exemestane Clinical Trial) examining the efficacy of fulvestrant and exemestane in patients with or without VM.
METHODS: EFECT is a randomised, double-blind, multicentre, Phase III trial in postmenopausal women with advanced breast cancer progressing or recurring after prior non-steroidal aromatase inhibitor therapy.
RESULTS: Overall, approximately 57% of patients in EFECT had visceral involvement. Fulvestrant and exemestane demonstrated clinical benefit in 29.1% and 27.2% of patients with VM, respectively. Median duration of response was 13.5 vs 10.8 months and median duration of clinical benefit was 9.9 vs 8.1 months, respectively.
CONCLUSIONS: These results encourage the use of endocrine agents such as fulvestrant in treating patients with advanced breast cancer and VM.

PMID: 19030986 [PubMed - indexed for MEDLINE]

[Rich66]

FDA Approves New Dosing for Fulvestrant in Treatment of Metastatic Breast Cancer in HR+ Postmenopausal Women

WILMINGTON, Del -- September 10, 2010 -- The US Food and Drug Administration (FDA) has approved the 500-mg dose of fulvestrant (FASLODEX Injection), replacing the previously approved monthly dose of fulvestrant 250 mg, for the treatment of hormone receptor-positive (HR+) metastatic breast cancer in postmenopausal women with disease progression following anti-oestrogen therapy.

The FDA approval of fulvestrant 500 mg was based on results from the phase 3 Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) study, which demonstrated that fulvestrant 500 mg significantly reduced the risk of disease progression in patients with metastatic breast cancer, when compared with the 250-mg dose. Safety and tolerability profiles of both doses were comparable.

The CONFIRM study, presented for the first time at the annual San Antonio Breast Cancer Symposium in December 2009, showed fulvestrant 500 mg reduced the risk of disease progression (assessed as progression-free survival) by 20% (hazard ratio [HR] = 0.80; 95% confidence interval [CI], 0.68-0.94; P = .006) when compared with fulvestrant 250 mg. Fulvestrant 500 mg significantly increased median progression-free survival to 6.5 versus 5.4 months with 250 mg (P = .006).

Objective response rates calculated in patients with measurable disease were not significantly different between fulvestrant 500 mg (13.8%) and 250 mg (14.6%) (HR = 0.94; 95% CI, 0.57-1.55; P = .795). Median overall survival was 25.1 months with fulvestrant 500 mg and 22.8 months with fulvestrant 250 mg (HR = 0.84; 95% CI, 0.69-1.03; P = .091). At the time of analysis, overall survival was not statistically significant. A preplanned second survival analysis will occur as data mature when approximately 75% of patients have had an event.

The recommended dose of fulvestrant 500 mg should be administered intramuscularly into the buttocks as two 250-mg injections, one in each buttock, on days 1, 15, 29, and once monthly thereafter. A dose of 250 mg is recommended in patients with moderate hepatic impairment.

Fulvestrant 500 mg will be supplied as 2 x 250 mg/5 mL packaged together in early fourth quarter 2010. During this time, fulvestrant 250 mg will still be available.

SOURCE: AstraZeneca





High dose Fulvestrant more effective than anastrozol for 1st line mets

---

Robertson JFR et al. – First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.
Methods

• Phase II, randomized, open-label, multicenter study
• HD fulvestrant regimen (500 mg/mo + 500 mg on d 14 of mo 1) vs. anastrozole (1 mg/d)
• Primary analysis 6 mos after last patient assigned

Results

• CBR was similar for fulvestrant HD and anastrozole (72.5% vs. 67.0%, respectively)
• ORR was similar for fulvestrant HD and anastrozole (36.0% vs. 35.5%, respectively)
• TTP was significantly longer for fulvestrant vs. anastrozole (median TTP for fulvestrant HD was not reached; 12.5 mos for anastrozole)
• Duration of OR and CB favored fulvestrant HD
• Both treatments were well-tolerated, with no significant differences in the incidence of pre-specified adverse events

Activity of Fulvestrant 500 mg Versus Anastrozole 1 mg As First-Line Treatment for Advanced Breast Cancer: Results From the FIRST Study

John F.R. Robertson,^* Antonio Llombart-Cussac, Janusz Rolski, David Feltl, John Dewar, Euan Macpherson, Justin Lindemann, and Matthew J. Ellis
From the Division of Breast Surgery, University of Nottingham, Nottingham; Department of Oncology, Ninewells Hospital and Medical School, Dundee; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom; Hospital Arnau de Vilanova, Lérida, Spain; Centrum Onkologii, Instytut im M. Skodowskiej-Curie, Krakow, Poland; Fackultni Nemocnice Ostrava, Radioterapeutická klinika, Ostrava-Poruba, Czech Republic; Washington University School of Medicine, St Louis, MO.

^* To whom correspondence should be addressed. E-mail: john.robertson@nottingham.ac.uk

Purpose: To compare the clinical activity of the pure antiestrogen fulvestrant at 500 mg/mo (double the approved dose) with the aromatase inhibitor anastrozole as first-line endocrine therapy for advanced hormone receptor–positive breast cancer in postmenopausal women.
Patients and Methods: FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) is a phase II, randomized, open-label, multicenter study of a fulvestrant high-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month 1) versus anastrozole (1 mg/d). The primary efficacy end point was clinical benefit rate (CBR), defined as the proportion of patients experiencing an objective response (OR) or stable disease for 24 weeks. The primary analysis was performed 6 months after the last patient was randomly assigned.
Results: CBR was similar for fulvestrant HD (n = 102) and anastrozole (n = 103), 72.5% v 67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P = .386). Objective response rate (ORR) was also similar between treatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Time to progression (TTP) was significantly longer for fulvestrant versus anastrozole (median TTP not reached for fulvestrant HD v 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39 to 1.00; P = .0496). Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well tolerated, with no significant differences in the incidence of prespecified adverse events.
Conclusion: First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.


Breast. 2008 Apr;17 Suppl 3:S16-21. Epub 2008 Mar 18. Links

Fulvestrant: expanding the endocrine treatment options for patients with hormone receptor-positive advanced breast cancer.

Chia S, Gradishar W.
Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. SChia@bccancer.bc.ca
With the aromatase inhibitors (AIs) replacing tamoxifen as the first-line treatment for postmenopausal women with hormone receptor-positive early and advanced breast cancer, there is a need to evaluate appropriate endocrine treatment options following AI failure. However, until recently, there were no Phase III trial data in this area. Fulvestrant (Faslodex) is an oestrogen receptor antagonist utilised for the treatment of postmenopausal women with locally advanced or metastatic breast cancer following progression or recurrence on anti-oestrogen therapy. Fulvestrant has a mode of action that is distinct from the AIs and the selective oestrogen receptor modulators, and thus may offer an effective treatment option in the post-AI setting. The Evaluation of Faslodex and Exemestane Clinical Trial (EFECT) is the first Phase III trial to evaluate the efficacy and tolerability of fulvestrant and the steroidal AI, exemestane, in patients with locally advanced or metastatic breast cancer who have progressed or recurred while receiving a non-steroidal AI. EFECT confirmed that fulvestrant and exemestane offer effective treatment options in this setting. Similar efficacy was seen in both treatment groups and there were no significant differences in reported adverse events between fulvestrant and exemestane. The EFECT data provide further evidence for the activity of fulvestrant in the treatment of advanced breast cancer. Other ongoing fulvestrant trials will further define its full role, including the potential for a high-dose regimen, combination of fulvestrant with an AI, and identification of clinical and biological markers to help in targeting those patients who are most likely to respond to treatment.
PMID: 18353647 [PubMed - indexed for MEDLINE]

CONFIRM Trial: Fulvestrant 500 mg Better Than Standard Dosing

Elsevier Global Medical News. 2009 Dec 11, B Jancin

SAN ANTONIO (EGMN) - Fulvestrant at 500 mg per dose is significantly more effective and no more toxic than the approved 250-mg dose in postmenopausal women with estrogen receptor-positive advanced breast cancer, according to the phase III CONFIRM trial.
"We believe that based on the results of this study, treatment and practice should change. Patients should routinely receive the 500-mg dose," Dr. Angelo Di Leo declared in presenting the findings of CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) Dec. 10 at the San Antonio Breast Cancer Symposium.
CONFIRM was a randomized, double-blind, multicenter trial involving 736 postmenopausal women with estrogen receptor-positive advanced breast cancer. Their median age was 61 years, with a median 3.3 years since diagnosis of their malignancy. Nearly two-thirds had visceral involvement. All participants had prior therapy with an aromatase inhibitor or an antiestrogen hormonal treatment.
Patients were randomized to fulvestrant on the approved schedule of a 250-mg intramuscular injection on days 0, 14, 28, and monthly thereafter, or to two 250-mg injections on the same schedule. Patients on the standard dosing regimen also got a placebo intramuscular injection at the same time. (Technical limitations in the ability to concentrate the drug make it impossible to deliver more than 250 mg per injection.)
The primary end point in CONFIRM was time to disease progression from the start of fulvestrant therapy. It was a median of 6.5 months in the high-dose group, for a highly significant 20% improvement over the 5.5 months in the standard-dose group (P = .006), reported Dr. Di Leo, director of oncology at the Hospital of Prato (Italy).
The improvement in time to progression resulted from a combination of an increased clinical benefit rate (defined as complete or partial response or stable disease lasting at least 24 weeks) and longer duration of disease stabilization. Clinical benefit was documented in 45.6% of the fulvestrant 500-mg group (median duration, 16.6 months), compared with a 39.6% clinical benefit rate (median duration, 13.9 months) with fulvestrant 250 mg. There was no difference in tumor-shrinkage rates between the two study arms, as reflected in objective response rates of 9%-10%.
Median overall survival at the point in the trial when half of all patients had died was 25.1 months in the high-dose fulvestrant group, compared with 22.8 months with standard dosing, a 16% relative risk reduction that fell short of significance (P = .09). Another analysis of overall survival is prespecified when 75% of participants have died, which is expected to be in mid-2011.
The incidence and severity of adverse effects were closely similar in the two study arms. The toxicity was far less than that typically seen with chemotherapy, which is the next step in patients with hormone receptor-positive metastatic breast cancer who don't respond to antiestrogen therapy, Dr. Di Leo noted. He stressed the relevance to patients of time to progression while on fulvestrant as a clinically meaningful end point. The most common adverse events associated with fulvestrant were GI disturbances (affecting 20% of patients in each study arm) and joint disorders (about 19%).
Time to progression was consistent across all prespecified subgroups. It didn't vary according to progesterone receptor status, patient age, visceral involvement, presence or absence of measurable disease, the last endocrine therapy given before fulvestrant use, or the response to prior endocrine therapy.
Nevertheless, the investigators have embarked on Trans-CONFIRM, a preplanned exploratory substudy involving detailed analysis of 150 archived primary tumor samples from CONFIRM participants. The hypothesis is that it will be possible to define (biologically or clinically) a subset of patients who are particularly likely to benefit from high-dose fulvestrant, and another subgroup unlikely to benefit from down-regulation of the estrogen receptor. The roughly one-half of patients with acquired - as opposed to intrinsic - resistance to fulvestrant are the ones who are unlikely to benefit from the antiestrogen, the oncologist explained.
Symposium president Dr. C. Kent Osborne said in an interview that CONFIRM leaves him convinced that 500 mg of fulvestrant is the optimal dose.
"It's a really expensive drug, though, and I don't know if insurers will pay for the second dose. That'll probably be the determining factor in how much impact this study has on clinical practice," said Dr. Osborne, director of the cancer center at Baylor College of Medicine, Houston.
He added that he'd really like to see fulvestrant at this more favorable dose undergo study as adjuvant therapy in women with early breast cancer. That could conceivably result in much larger benefits than those seen when the drug is used in the setting of metastatic disease.
Dr. Di Leo disclosed that he is on the advisory board of AstraZeneca, which supported the CONFIRM study. Dr. Osborne has no relevant financial interests.


Breast Cancer Res Treat. 2010 Sep;123(2):453-61. Epub 2010 Jul 15.
Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2).

Pritchard KI, Rolski J, Papai Z, Mauriac L, Cardoso F, Chang J, Panasci L, Ianuli C, Kahan Z, Fukase K, Lindemann JP, Macpherson MP, Neven P.
Sunnybrook Odette Cancer Centre and University of Toronto, 2075 Bayview Avenue, M4N 3M5, Toronto, ON, Canada. kathy.pritchard@sunnybrook.ca


LINK

Abstract

The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of three fulvestrant dosing regimens. FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy. Primary endpoint: objective response rate (ORR); secondary endpoints: time to progression (TTP), clinical benefit rate (CBR), tolerability, and PK parameters. Patients were randomized to receive fulvestrant: 250 mg/month (approved dose [AD]); 250 mg plus loading dose (loading dose [LD]; 500 mg on day 0, 250 mg on days 14, 28, and monthly thereafter); or 500 mg (high dose [HD]; 500 mg/month plus 500 mg on day 14 of Month 1). Treatment continued until disease progression or discontinuation. 144 patients were randomized: fulvestrant AD (n = 47); LD (n = 51); HD (n = 46). ORRs were: 8.5% (95% confidence interval [CI]: 2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8% (32.9, 63.1%) for the AD, LD, and HD arms, respectively. Median TTP (months) was numerically longer for HD (6.0) and LD (6.1) versus AD (3.1). Tolerability was similar across dosing regimens. Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD. While there appeared to be a trend toward improved efficacy with HD and LD versus AD, no significant differences could be shown. A parallel study (FINDER1) has reported similar findings in Japanese patients.

PMID: 20632084 [PubMed - in process]

[Rich66]

Breast Cancer Res Treat. 2005 Jul;92(2):169-74.
Sensitivity to further endocrine therapy is retained following progression on first-line fulvestrant.

Robertson JF, Howell A, Gorbunova VA, Watanabe T, Pienkowski T, Lichinitser MR.
Unit of Surgery, City Hospital, NG5 1PB, Nottingham, UK. John.Robertson@nottingham.ac.uk
There is a need for new endocrine agents that lack cross-resistance with currently available treatments to extend the endocrine treatment window and delay the need for cytotoxic chemotherapy. This retrospective analysis evaluated the response of postmenopausal patients with previously untreated metastatic/locally advanced breast cancer to further endocrine treatment following progression on first-line fulvestrant or tamoxifen. Patients received fulvestrant 250 mg (intramuscular injection every 28 days) plus matching tamoxifen placebo (once daily), or tamoxifen 20 mg (orally once daily) plus matching fulvestrant placebo (every 28 days) in a double-blind, randomized, phase III trial. Treatment continued until disease progression or withdrawal, when further endocrine therapy was initiated (at the treating physician's discretion). Information regarding subsequent therapies and responses was obtained by follow-up questionnaire. Two-hundred-and-forty-five questionnaires were returned (from 587 patients), 149 of which yielded follow-up data on patients receiving second-line endocrine therapy following fulvestrant (n=83) and tamoxifen (n=66). Second-line therapy produced objective responses (OR) in 6/44 (13.6%) and clinical benefit (CB) in 25/44 (56.8%) patients who had CB with fulvestrant and produced OR in 5/41 (12.2%) patients and CB in 27/41 (65.8%) patients who had CB with first-line tamoxifen. For patients deriving no CB from trial therapy, second-line therapy produced OR in 3/39 (7.7%) and CB in 15/39 (38.5%) patients in the fulvestrant group and OR in 4/25 (16.0%) and CB in 12/25 (48.0%) patients in the tamoxifen group. Results from this questionnaire-based study suggest that postmenopausal women with advanced breast cancer who respond to first-line fulvestrant or tamoxifen retain sensitivity to subsequent endocrine therapy.

PMID: 15986127 [PubMed - indexed for MEDLINE]


Breast Cancer Res Treat. 2003 May;79(2):207-11.
Postmenopausal women who progress on fulvestrant ('Faslodex') remain sensitive to further endocrine therapy.

Vergote I, Robertson JF, Kleeberg U, Burton G, Osborne CK, Mauriac L; Trial 0020 Investigators; Trial 0021 Investigators.
Department of Gynecologic Oncology, University Hospitals, Leuven, Belgium. Ignace.Vergote@uz.kuleuven.ac.be
PURPOSE: This retrospective evaluation of data from two randomized, multicenter trials examined whether tumor responses to further endocrine therapy were seen in postmenopausal women with advanced breast cancer who had progressed on both initial endocrine therapy, usually tamoxifen, and on the estrogen receptor (ER) antagonist fulvestrant ('Faslodex'). PATIENTS AND METHODS: A combined total of 423 patients received fulvestrant 250 mg as a monthly intramuscular injection. After progression on fulvestrant, some patients received another endocrine therapy. Responses to subsequent endocrine therapy were assessed using a questionnaire sent to the trial investigators. Best responses were classified as a complete or partial response (CR or PR), stable disease (SD) lasting > or = 24 weeks, or disease progression. RESULTS: Follow-up data were available for 54 patients who derived clinical benefit (CB, defined as CR, PR or SD) from fulvestrant and who received subsequent endocrine therapy, resulting in a PR in 4 patients, SD in 21 patients, and disease progression in 29 patients. Data were available for 51 patients who derived no CB from fulvestrant and who received further endocrine therapy, resulting in a PR in 1 patient, SD in 17 patients, and disease progression in 33 patients. Aromatase inhibitors were used as subsequent endocrine therapy in > 80% of patients. CONCLUSIONS: After progression on fulvestrant, patients may retain sensitivity to other endocrine agents. Fulvestrant provides an additional option to existing endocrine therapies for the treatment of advanced or metastatic breast cancer in postmenopausal women, and may provide the opportunity to extend the sequence of endocrine regimens before cytotoxic chemotherapy is required.

PMID: 12825855 [PubMed - indexed for MEDLINE]




Endocr Relat Cancer. 2006 Mar;13(1):251-5.
Endocrine response after prior treatment with fulvestrant in postmenopausal women with advanced breast cancer: experience from a single centre.

Cheung KL, Owers R, Robertson JF.
Division of Breast Surgery, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. kl.cheung@nottingham.ac.uk

FREE TEXT

The pure anti-oestrogen fulvestrant has now been licensed for use in advanced breast cancer which has progressed on an anti-oestrogen. Optimal sequencing of various endocrine agents becomes very important in the therapeutic strategy. We report our experience of further endocrine response with another endocrine agent after prior fulvestrant treatment. Among all patients with advanced breast cancer who had been entered into five phase II/III trials using fulvestrant as first- to ninth-line endocrine therapy in our Unit since 1993, 54 patients who fulfilled the following criteria were studied for their subsequent endocrine response: (i) oestrogen receptor positive or unknown; (ii) having been on a subsequent endocrine therapy for > or =6 months unless the disease progressed before; and (iii) with disease assessable for response according to International Union Against Cancer criteria. Eleven patients had received an aromatase inhibitor prior to fulvestrant, which resulted in five CBs (clinical benefit = objective remission/stable disease (SD)) for > or =6 months). Twenty-eight patients achieved CB on fulvestrant. They went on subsequent endocrine therapy with two partial responses, 11 SDs and 15 PDs (progressive disease) at 6 months. The median survival from starting fulvestrant and subsequent endocrine therapy was respectively 46.6 and 18.2 months. Among the remaining 26 patients who progressed at 6 months on fulvestrant, there were three SDs and 23 PDs at 6 months on subsequent endocrine therapy. The median survival from starting fulvestrant and subsequent endocrine therapy was respectively 12.5 and 9.3 months. Of all these 54 patients, 30% (n = 16) therefore achieved CB using another (second- to tenth-line) endocrine agent (anastrozole = 26; tamoxifen = 12; megestrol acetate = 11; others = 5). It would thus appear that further endocrine response can be induced in a reasonable proportion of patients after failing fulvestrant.

PMID: 16601292 [PubMed - indexed for MEDLINE]

[Rich66]

Int J Oncol. 2007 Feb;30(2):509-20.
Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer.

Osipo C, Meeke K, Cheng D, Weichel A, Bertucci A, Liu H, Jordan VC.
Department of Pathology, Oncology Institute, Cardinal Bernadin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
Tamoxifen resistance is common for estrogen receptor alpha (ERalpha) positive breast cancer. Second-line therapies include aromatase inhibitors or fulvestrant. We have shown previously that fulvestrant reversed 17beta-estradiol-induced tumor regression of tamoxifen-stimulated MCF-7 xenografts (MCF-7TAMLT) treated for >5 years with tamoxifen in athymic mice and paradoxically stimulated growth. We investigated mechanisms responsible for growth by fulvestrant in the presence of physiologic estradiol and therapeutic strategies in vivo. The results demonstrated that only estradiol increased expression of the estrogen-responsive genes, c-myc, igf-1, cathepsin D, and pS2 mRNAs, in MCF-7E2 and MCF-7TAMLT tumors. Tamoxifen or fulvestrant decreased the estradiol-induced increase of these mRNAs in both tumor models. However, tyrosine-phosphorylated HER2/ neu, HER3, phospho-extracellular-regulated kinase-1/2 (ERK-1/2), and phospho-glycogen synthetase kinase 3alpha (GSK3alpha) and beta proteins were increased in MCF-7TAMLT tumors treated with fulvestrant compared to estradiol, control, or tamoxifen. Phospho-HER2/neu interacted with HER3 protein in MCF-7TAMLT tumors. In order to determine whether the functional interaction of HER2/neu with HER3 is critical for growth of fulvestrant-stimulated MCF-7TAMLT tumors, pertuzumab (an antibody that blocks HER2/neu-HER3 interaction) was used in an in vivo xenograft growth assay. Only growth of fulvestrant-treated MCF-7TAMLT xenografts was decreased significantly by 37.2% in response to pertuzumab (P=0.004). Pertuzumab specifically decreased the interaction of HER2/neu protein with HER3 in fulvestrant-stimulated MCF-7TAMLT tumors. These results suggested growth of MCF-7TAMLT tumors by tamoxifen or fulvestrant is potentially independent of ERalpha transcriptional activity as evidenced by lack of induction of four estrogen-responsive genes. The results suggested that growth of MCF-7TAMLT tumors treated with fulvestrant in the presence of physiologic estradiol is in part mediated through enhanced signaling from the HER2/neu-HER3 pathway as pertuzumab partially inhibited growth and the interaction of HER2/neu with HER3 in vivo.

PMID: 17203234 [PubMed - indexed for MEDLINE]



Cancer Biol Ther. 2010 Mar 11;9(5). [Epub ahead of print]
Estrogen receptor-alpha-interacting cytokeratins potentiate the antiestrogenic activity of fulvestrant.

Long X, Fan M, Nephew KP.
Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA; School of Biotechnology, Jiangnan University, Wuxi, China; Zhongnan Hospital, Wuhan University, Wuhan, China.
Fulvestrant (ICI 182, 780) is a selective estrogen receptor downregulator (SERD) and potent antiestrogen. In estrogen receptor alpha positive ERalpha(+) breast cancer, the drug immobilizes ERalpha in the nuclear matrix, inducing receptor polyubiquitination and subsequent degradation via the 26S proteasome. We previously reported that fulvestrant-induced ERalpha degradation depends on the interaction of ERalpha with cytokeratins 8 and 18 (CK8/CK18). Here we further investigate the role of these two cytokeratins in the antagonistic activity of the SERD. Using ER-responsive reporter assays, we demonstrate greater antiestrogenic activity of fulvestrant in CK8/CK18(+) vs. CK8/CK18(-) cancer cells and loss of CK8/CK18 expression was observed in a breast cancer cell model for acquired fulvestrant resistance. In contrast, the presence of CK8/CK18 had no effect on the antiestrogenic activity of 4-hydroxytamoxifen, which was unable to induce an interaction between these CKs and ERalpha. By utilizing the ligand activity inversion ERalpha mutant L540Q to further examine the mechanism of fulvestrant action, we demonstrate that the ERalpha mutant does not interact with CK8/CK18 in the presence of fulvestrant and L540Q is not immobilized to the nuclear matrix after antiestrogen treatment. In transcription assays, fulvestrant displayed agonist activity, stimulating L540Q-mediated gene expression. In addition, fulvestrant did not induce an ERbeta interaction with CK8/CK18 and subsequent ERbeta degradation. Collectively, these results suggest that CK8/18 play an important role in the antiestrogenic action of fulvestrant in breast cancer cells and that these two cytokeratins could serve as prognostic markers for SERD therapy response in breast cancer patients.

PMID: 20061804 [PubMed - as supplied by publisher]



Case Rep Oncol. 2010 Apr 29;3(2):131-136.
Low-Dose Fulvestrant Maintained Long-Term Complete Remission after Poor Response to Previous Endocrine Therapies in a Patient with Advanced Breast Cancer.

Hawle H, Hess D, Mueller A, Thuerlimann B.
Department of Medical Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.


FREE TEXT

Abstract

We report a case of long-term (9 years) response to 4th-line endocrine treatment with fulvestrant given for advanced breast cancer after no or poor response to prior endocrine therapies. Complete remission was achieved with full dose and maintained even after dose reduction due to unanticipated intensity of mucosal toxicity. Complete remission was temporarily lost after fulvestrant was tentatively withdrawn (63 months after treatment start), but was re-achieved after renewal of half-dose treatment and last reconfirmed 90 months after treatment start. The pharmacokinetic profile provides evidence to hypothesize a unique sensitivity to fulvestrant in this patient which might explain both: toxicity and extraordinary efficacy.

PMID: 20740185 [PubMed]PMCID: PMC2919988Free PMC Article


Fulvestrant loading, tumor markers,and ongoing trials
Letter to editor COMMUNITY ONCOLOGY ■ November 2007
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