Tamoxifen is a hormonal therapy medicine given to pre- and post-menopausal women to lower the risk of hormone-receptor-positive, early-stage breast cancer coming back (recurrence). Hormonal therapy medicine given after surgery and other treatments (chemotherapy, radiation therapy) is called adjuvant hormonal therapy. Tamoxifen works by blocking the effects of estrogen on breast cancer cells.
The study reviewed here found that breast cancers with an activated form of estrogen receptor (ER alpha S118-P) benefited from tamoxifen treatment. Breast cancers without this activated form of estrogen receptor didn't benefit from treatment with tamoxifen.
The researchers tested cancer cells from 239 pre-menopausal women diagnosed with hormone-receptor-positive, early-stage breast cancer to see if the cells had activated estrogen receptors. Just over half (52%) of the cancers had activated hormone receptors. The women were then randomly divided into two groups with no regard for whether the cancers had activated estrogen receptors. Half of the women took tamoxifen for 2 years and the other half did not.
Cancers with the activated form of estrogen receptors that were treated with tamoxifen were 64% less likely to come back (recur) than the same type of cancers not treated with tamoxifen. This large reduction in recurrence seems to be because of the tamoxifen and not due to chance. So tamoxifen treatment significantly lowered the risk of recurrence of cancers with activated estrogen receptors.
Cancers without the activated form of estrogen receptors that were treated with tamoxifen were 13% less likely to come back (recur) than the same type of cancers not treated with tamoxifen. This small reduction in recurrence could possibly be due to chance and not because of the tamoxifen. So tamoxifen treatment didn't significantly lower the risk of recurrence of cancers without activated estrogen receptors.
These results suggest that testing for the activated form of estrogen receptors could help doctors figure out if tamoxifen makes sense for a pre-menopausal woman diagnosed with hormone-receptor-positive, early-stage breast cancer. This test also might be helpful in planning treatment for post-menopausal women diagnosed with hormone-receptor-positive breast cancer.
While testing breast cancer cells for estrogen receptors is done routinely, testing for the activated form of receptors isn't done routinely right now. More research is needed to figure out if doing this kind of testing could consistently improve treatment for women diagnosed with hormone-receptor-positive, early-stage breast cancer.
Studies like this offer promise for better ways to diagnose and treat breast cancer in the future. Stay tuned to Breastcancer.org for reports on cutting-edge research that moves promise closer to reality.
Estrogen receptor status may be a better predictor of tamoxifen response for premenopausal breast cancer patients if functionality of this drug target is considered, researchers found.
Women with tumors expressing an activated form of the estrogen receptor (ER) were 64% less likely to have a recurrence while taking tamoxifen than those not taking the drug, according to a study led by Göran Landberg, MD, PhD, of Lund University in Malmö, Sweden, and the University of Manchester, England.
But the same wasn't true for women with ER-positive tumors that didn't express the activated form, for whom the 13% reduction in recurrence risk was not significant compared with untreated women, the researchers reported online in the Journal of the National Cancer Institute.
Treatment guided by status of this ER type could prevent unnecessary treatment for half of the premenopausal breast cancer patients with ER-positive tumors while maintaining approximately the same 10-year, recurrence-free survival, the researchers said.
Although it's too early to suggest withholding tamoxifen from patients without the activated form, they might do better with alternative treatments, Landberg's group said.
Currently there are no validated biomarkers to predict which patients will fall into the half that express estrogen receptors -- specifically the alpha form found in breast cancer cells -- but are resistant to tamoxifen, the investigators said.
Preclinical studies had shown that phosphorylation of ER-alpha at a location known as serine-118 (ER-alpha S118-P) is required for the receptor to be activated by tamoxifen and regulate expression of genes as desired.
So Landberg's group evaluated this potential biomarker in a randomized, controlled trial of 239 premenopausal women with ER-alpha-positive stage II breast cancer.
These women had been randomly assigned to two years of adjuvant tamoxifen or no systemic treatment.
Compared with women who didn't get adjuvant hormonal therapy, adjuvant tamoxifen resulted in a recurrence-free survival benefit for women with high expression of ER alpha S118-P (23.7 versus 72.2 recurrences per 1,000 person-years, HR 0.36, 95% CI 0.20 to 0.65).
Low expression of ER alpha S118-P was associated with no significant benefit of tamoxifen versus no systemic adjuvant treatment (51.0 versus 57.0 recurrences per 1,000 person-years, HR 0.87, 95% CI 0.51 to 1.48).
Thus, adjuvant tamoxifen treatment for the 52% patients with high expression of activated ER-alpha, but not to the rest (who had a 10-year recurrence-free survival of 75% and 52%, respectively) would yield 10-year recurrence-free survival of 64% for patients with high ER-alpha S118-P expression, the researchers estimated.
"This value is equal to the estimated 10-year recurrence-free survival if all patients are treated with adjuvant tamoxifen irrespective of ER-alpha S118-P status," they said.
Among the women not treated with tamoxifen, ER alpha S118-P status had no significant impact on recurrence-free survival (HR 1.23, 95% CI 0.76 to 1.99).
But the researchers cautioned that the study could not rule out the possibility that activated ER-alpha might be associated with poor prognosis in untreated patients.
"High ER-alpha S118-P expression may reflect a highly active ER-alpha that induces enhanced transcription and subsequently proliferation and survival of breast cancer cells," they speculated.
The study was limited by loss of a substantial proportion of patients with lobular carcinoma due to too little tissue for analysis, and by the fact that patients in the trial were treated for only two years with tamoxifen rather than the standard five.
"However, if mechanisms of tamoxifen resistance are similar over time, then the absolute effect may extend to the current five-year regimen," they said.
Landberg's group noted that further study is needed to determine activated ER-alpha's role in tamoxifen response among postmenopausal women.
The study was supported, in part, by grants from the Top Institute Pharma, Pink Ribbon/A Sister's Hope, the Swedish Cancer Society, Malmö University Hospital Research Cancer Funds, and by Breakthrough Breast Cancer.
The cross-national component of the project was facilitated by the Marie Curie Transfer of Knowledge Industry-Academia Partnership research program, TargetBreast.
The researchers provided no information on conflicts of interest.
Primary source: Journal of the National Cancer Institute Source reference: Kok M, et al "Estrogen receptor-α phosphorylation at serine-118 and tamoxifen response in breast cancer" J Natl Cancer Inst 2009; 101.
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