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.
Older abstract, but maybe still relevant:
Clin Ther. 2005 Nov;27(11):1671-84.
Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer.
Berry J.
MacNeal Cancer Center, 3340 South Oak Park Avenue, Berwyn, IL 60402, USA.
jberry@macneal.com
BACKGROUND: Five years of tamoxifen therapy has been the standard of care for the adjuvant treatment of estrogen receptor-positive early-stage breast cancer for many years and was the first hormonal treatment for postmenopausal women with advanced or metastatic disease. The third-generation aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole offer new treatment options, although their efficacy has not been compared directly in randomized, double-blind, controlled trials in any breast cancer treatment setting. OBJECTIVE:: The goal of this article was to review the results of recent randomized, controlled clinical trials of the AIs in the settings of neoadjuvant, adjuvant, and advance d/metastatic breast cancer. METHODS: MEDLINE was searched for descriptions of randomized, controlled clinical trials published from 1990 to 2005 using the terms breast cancer, aromatase, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from the proceedings of several oncology meetings held between 2001 and 2005 were searched to capture relevant emerging data. RESULTS: In 2 Phase III trials comparing an AI with tamoxifen for the adjuvant treatment of breast cancer in postmenopausal women, disease-free survival was significantly improved with anastrozole and letrozole compared with tamoxifen as initial adjuvant treatment (P = 0.01 and P = 0.003, respectively). A switch to either anastrozole (2 Phase III trials) or exemestane (1 Phase III trial) after 2 to 3 years of adjuvant tamoxifen therapy was more effective in reducing the risk of recurrence than continued tamoxifen therapy (P = 0.006, P < 0.002, and P < 0.001, respectively); data on switching to letrozole are expected soon. In another Phase III trial, letrozole was found to improve disease-free survival in the extended adjuvant setting (P < or = 0.001) and was the only AI consistently more effective than tamoxifen in the neoadjuvant setting. In 3 Phase III studies (1 letrozole vs tamoxifen, 2 anastrozole vs tamoxifen), both anastrozole and letrozole were more efficacious than tamoxifen in the first-line setting, and some patients receiving letrozole had better overall response rates compared with those receiving anastrozole in the second-line setting (19.1% vs 12.3%, respectively; P = 0.013).
In a patient-preference study, those receiving letrozole reported fewer adverse events than those receiving anastrozole (43% vs 65%; P < 0.003), and more patients preferred letrozole to anastrozole (68% vs 32%; P < 0.01). CONCLUSIONS: Currently, anastrozole and letrozole are associated with the most complete data over the breast cancer care continuum, with efficacy in early-stage, locally advanced, and metastatic disease.
In-direct comparisons suggest stronger evidence for the use of letrozole compared with other AIs for breast cancer in postmenopausal women who require estrogen-deprivation therapy. Data from randomized, double-blind comparative studies will help clarify the differences between AIs.
PMID: 16368441 [PubMed - indexed for MEDLINE]
Hormone sensitivity of breast stem cells presents drug target
Featured In:
Disease Research
By EurekAlert Sunday, April 11, 2010
Researchers at the Walter and Eliza Hall Institute have discovered that breast stem cells are exquisitely sensitive to the female hormones oestrogen and progesterone, a finding that opens the way for the development of new preventions and treatments for breast cancer.
The discovery, by scientists in the institute's Stem Cells and Cancer and Bioinformatics divisions, also explains decades of evidence linking breast cancer risk to exposure to female hormones.
It has been published online today in the international journal
Nature.
Dr Jane Visvader, who led the research with Dr Geoff Lindeman, said sustained exposure to oestrogen and progesterone was a well-established risk factor for breast cancer. "There is a clear evidence that the more menstrual cycles a woman has the greater her breast cancer risk," Dr Visvader said. "There is even an increase in breast cancer risk in the short-term following pregnancy. However the cellular basis for these observations has been poorly understood."
In the mid-2000s, Drs Visvader and Lindeman discovered breast stem cells in both mice and humans. Unexpectedly, however, they also found that breast stem cells lacked 'receptors' that would allow them to be directly controlled by the female hormones oestrogen and progesterone.
Now, work by Drs Visvader and Lindeman in collaboration with Drs Marie-Liesse Asselin-Labat, Gordon Smyth and others at the institute, has revealed that
despite lacking receptors for oestrogen and progesterone, breast stem cells are still remarkably sensitive to female hormones.
Using mouse models, they showed that when the ovaries were removed or the animals were treated with hormone inhibitors (which are in clinical use as anti-breast cancer agents), breast stem cell numbers dropped and the cells appeared to become dormant.
Dr Lindeman, who is also a medical oncologist at the Royal Melbourne Hospital, said this finding helped to explain why the effects of 'chemoprevention' – a treatment aimed at breast cancer prevention continued long after anti-estrogen tablets have been stopped.
"Our research also revealed that during pregnancy there is a profound increase in breast stem cell numbers," Dr Lindeman said.
"This might account for the short-term increase in cancer risk associated with pregnancy."
Further studies, in collaboration with Dr Jack Martin at St Vincent's Institute Melbourne and Dr Hisataka Yasuda at the Nagahama Institute for Biochemical Science,
identified the RANK ligand pathway as the key cell-signalling pathway responsible for the indirect control of breast stem cells in pregnancy.
Dr Lindeman said inhibitors of RANK signalling have been developed and are currently in clinical trials to help maintain bone strength and treat breast cancer that has spread to the bones. "Our discovery suggests that inhibitors of RANK or other stem cell pathways represent possible therapeutic strategies that could also be investigated as breast cancer prevention agents," Dr Lindeman said.
http://www.biosciencetechnology.com/...lls-presents-/
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.