Breast Cancer Res Treat. 2010 Jul 1. [Epub ahead of print]
Potent CYP2D6 Inhibiting drugs do not increase relapse rate in early breast cancer patients treated with adjuvant tamoxifen.
Siegelmann-Danieli N,
Kurnik D,
Lomnicky Y,
Vesterman-Landes J,
Katzir I,
Bialik M,
Loebstein R.
Department of Specialized Medicine, Maccabi Healthcare Services, Tel Aviv, Israel.
Abstract
Endoxifen, the most active metabolite of the prodrug tamoxifen, is produced by cytochrome P450 CYP2D6. Breast cancer patients treated with tamoxifen who have reduced CYP2D6 activity, related to either genetic variation or drug inhibition, may have inferior outcomes. To assess the effect of concomitant CYP2D6 inhibiting drug use on clinical outcomes of breast cancer patients treated with adjuvant tamoxifen. We conducted a retrospective database analysis. Women with non-metastatic estrogen receptor positive tumors who had completed adjuvant tamoxifen therapy for 2 years, without treatment with adjuvant aromatase inhibitors or early relapse, were included. Patients were classified as users of CYP2D6 inhibitors if they purchased strong CYP2D6 inhibiting drugs for >/=4 consecutive months during tamoxifen treatment. Tumors were classified as "high risk" if adjuvant chemotherapy was prescribed. Primary endpoint was disease free (DFS) and secondary endpoint was overall survival (OS). 902 patients treated with tamoxifen (median duration, 4.9 years) were followed for a median period of 5.9 years. Fifty-nine (6.5%) patients were users of CYP2D6 inhibitors (median duration, 23 months). DFS at 3 years (corresponding to 5 years after tamoxifen initiation) did not differ between users and non-users of CYP2D6 inhibiting drugs (92.7 vs. 93.0%, respectively; adjusted P = 0.44). OS at 3 years was lower in the patients using CYP2D6 inhibiting drugs: 89.4 vs. 93.8%, but after adjustment for age and comorbidities this difference was not significant (P = 0.20).
Overall recurrence rates did not differ between users and non-users of CYP2D6 inhibiting drugs (11.8 vs. 19.0% respectively, P = 0.23). Concomitant prolonged therapy with strong CYP2D6 inhibiting drugs does not affect adversely DFS and recurrence rates in tamoxifen-treated early breast cancer patients.
PMID: 20593233 [PubMed - as supplied by publisher]
Ann N Y Acad Sci. 2009 Feb;1155:99-111.
Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen.
Lazarus P,
Blevins-Primeau AS,
Zheng Y,
Sun D.
Cancer Control and Population Sciences Program, Penn State Cancer Institute, Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.
plazarus@psu.edu
Tamoxifen (TAM) is a selective estrogen receptor modulator that is widely used in the prevention and treatment of estrogen receptor-positive (ER(+)) breast cancer. Its use has significantly contributed to a decline in breast cancer mortality, since breast cancer patients treated with TAM for 5 years exhibit a 30-50% reduction in both the rate of disease recurrence after 10 years of patient follow-up and occurrence of contralateral breast cancer. However,
in patients treated with TAM there is substantial interindividual variability in the development of resistance to TAM therapy, and in the incidence of TAM-induced adverse events, including deep vein thrombosis, hot flashes, and the development of endometrial cancer. This article will focus on the UDP glucuronosyltransferases, a family of metabolizing enzymes that are responsible for the deactivation and clearance of TAM and TAM metabolites, and how interindividual differences in these enzymes may play a role in patient response to TAM.
PMID: 19250197 [PubMed - indexed for MEDLINE]
Scientists crack the code to tamoxifen resistance
WEDNESDAY 12 NOVEMBER 2008
Cancer Research UK Press Release
CANCER RESEARCH UK scientists have discovered the molecular basis for
tamoxifen response in
breast cancer cells - and the reason why some women can develop resistance to the treatment, according to a study published in Nature* today (Wednesday).
Tamoxifen is given to most women for five years after they are first diagnosed with breast cancer to help prevent the disease from coming back but some women develop resistance to the treatment after time, meaning their cancer is more likely to return.
Researchers at the Cancer Research UK Cambridge Research Institute have discovered for the first time the mechanism by which the breast cancer therapy tamoxifen operates. It switches off a breast cancer gene ErbB2 via a protein called Pax2. Pax2 acts as a 'switch' to keep ErbB2 switched off. Tamoxifen resistance occurs when ErbB2 remains switched on.
Previously it was known that tamoxifen worked by blocking oestrogen from causing unchecked cell growth in breast cancer by switching certain genes on but the mechanism by which this occurred was unknown.
Lead author,
Dr Jason Carroll said: "We knew that women developed resistance to tamoxifen but previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked. Now we understand how all the engine parts operate and we can try to think about ways to make repairs.
"We have discovered that for tamoxifen to work it has to block the gene ErbB2 and it does this by using a control switch that is hidden in the background of the genome, within the ErbB2 gene itself. In order for tamoxifen to be effective, this switch must be held in the off position by Pax2. Now we understand how women can develop tamoxifen resistance."
The production of oestrogen can cause breast cancer cells to grow and divide but tamoxifen prevents oestrogen from causing breast cancer cells to grow, helping to lower the risk of the disease returning. Most women have breast cancers that are stimulated to grow by oestrogen but not all.**
Breast cancer is the most common cancer in women in the UK. More than 45,500 women are diagnosed with the disease each year – 125 women a day, and the disease causes almost 12,500 deaths each year. Eight in 10 cases of breast cancer are diagnosed in women over the age of 50.
Professor Sir David Lane, Cancer Research UK's chief scientist said: "Cancer Research UK's early clinical trials of tamoxifen helped transform the way that women were treated for early breast cancer saving ten's of thousands of lives, and this work is yet another step forward.
"More women are surviving breast cancer than ever before thanks to improvements in diagnosis and treatment as well as important fundamental science discoveries like this."
He added: "Tamoxifen has been a huge success story helping to prevent breast cancer recurring for many women.
"Understanding why it occasionally stops working is really important because it allows us to identify new targets for drug development and who will need such treatments."
ENDS
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Notes to Editors:
Listen to Dr Carroll talking about his work:
Antoni Hurtado et al. *ERBB2 regulation by Estrogen Receptor-Pax2 determines tamoxifen response. (2008) Nature. Wednesday 12 November.
The scientists used microarray technology (genomic technology) to define a genomic map of where oestrogen receptor interacts with the genome. The oestrogen receptor was found to interact with unexpected areas in the genome, which were then identified as the 'switches' for gene regulation. This provided insight into how oestrogen receptor worked. Using this information, the scientists could find the switch for the important cancer related gene, ErbB2.
Microarray technology involves scanning millions of DNA sequences to detect the association with a target sequence of DNA (in this case the regions of the genome that make contact points with the oestrogen receptor).
New Take On Growth Factor Signaling In Tamoxifen Resistance
ScienceDaily (June 22, 2009) — Differences in growth factor (GF) signaling may cause the poor prognosis in some breast cancer cases. A new study, published in the open access journal BMC Medical Genomics, suggests that some estrogen receptor-positive breast cancers respond poorly to tamoxifen because of increased GF signaling.
Sherene Loi, from the Peter MacCallum Cancer Centre, Melbourne, worked with a team of Australian and Belgian researchers to investigate the differences between those estrogen receptor positive (ER+) cancers that respond well to tamoxifen (luminal-A) and those that do not (luminal-B). She said, “This is the first study specifically investigating the biology of the luminal-B, ER+ breast cancer subtype. We propose that activation of GF signaling contributes to this highly proliferative, relatively tamoxifen-insensitive, phenotype and that this exists independently of HER2 overexpression. Targeting this pathway and its upstream mediators could prove to be a useful therapeutic strategy”.
The researchers used a new computational method of analysis of gene expression data called gene set enrichment analysis (GSEA) to determine that there is increased growth factor activation from the gene expression profiles of nearly 100 luminal-B breast cancers samples. They then validated this finding by showing that treatment with the growth factor heregulin, which induced growth factor signaling an in-vitro model, could overcome tamoxifen-induced cell cycle arrest.
This research represents a departure from the informative, but sometimes not terribly useful, process of identifying genes associated with given conditions. Dr Loi said, “Although gene expression data has demonstrated its ability to identify subsets of disease and predict outcomes or drug responses, identifying new therapeutic approaches based on whole genome microarray profiling has, to date, been a significant challenge. By using GSEA, we’ve been able to use gene expression data to identify that activation of GF signaling pathways as a possible therapeutic target for further exploration in the clinical setting for these particular breast cancer patients”.
Menin, a product of the MENI gene, binds to estrogen receptor to enhance its activity in breast cancer cells: possibility of a novel predictive factor for tamoxifen resistance
Breast Cancer Research and Treatment, 11/04/09
Imachi H et al. – Menin can function as a transcriptional regulator of ER? and is a possible predictive factor for tamoxifen resistance.
Methods - Menin is a tumor suppressor encoded by Men1 that is mutated in the human-inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1); it also serves as a critical link in the recruitment of nuclear receptor-mediated transcription.
Results - Menin expressed in breast cancer cell line MCF-7 is colocalized with ER? and functions as a direct coactivator of ER-mediated transcription in breast cancer cells
- In MCF-7 cells, coexpression of menin and estrogen-response element-luciferase induced the activity of the latter in a hormone-dependent manner
- Cells knocked down for ER? exhibited impaired ERE-luciferase activity induced by menin
- Mammalian two-hybrid assay and GST pull-down assays indicated that menin could interact with the AF-2 domain of ER?
- Tamoxifen inhibited the binding of menin to AF-2 in mammalian two-hybrid assay, but in menin-overexpressing clones, tamoxifen suppressed ERE-luciferase activity only to the levels of nontreated wild-type MCF-7
- In a clinical study with 65 ER-positive breast cancer samples—all of which had been treated with tamoxifen for 2–5 years as adjuvant therapies—menin-positive tumors had a worse outcome than menin-negative ones
GDPawel on Tam resistance