July 28, 2011 — The latest update of long-term data on tamoxifen in early-stage breast cancer confirm and further define the benefit of the drug.
In women with estrogen-receptor (ER)-positive disease, tamoxifen reduces the risk of dying from breast cancer by about a third over 15 years — during the 5 years it is taken and for 10 years after it is stopped, according to a meta-analysis published online July 29 in the Lancet.
The drug "can prevent a high proportion of recurrences and may potentially cure many patients, rather than simply delay an inevitable event," say a pair of experts in an editorial accompanying the study.
Overall survival approaches normal life expectancy for many of these women, note Stephen Chia, MD, from the University of British Columbia, Vancouver, Canada, and Antonio Wolff, MD, from the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.
"These mature and definite results allow clinicians to inform women confidently about the effect of tamoxifen on breast cancer events," they write.
Mature Data From Meta-Analysis
The findings come from a meta-analysis of individual patient data from more than 20,000 women with early-stage breast cancer enrolled in randomized controlled clinical trials evaluating adjuvant tamoxifen given daily for 5 years (with about 80% compliance). These trials began in the 1980s, and the Early Breast Cancer Trialists' Collaborative Group has been reporting results every 5 years.
In this latest report, the researchers report 15-year data.
In women who had ER-positive disease (n = 10,645), tamoxifen significantly reduced the long-term risk for breast cancer recurrence and death.
The relative risk (RR) for recurrence was nearly halved during tamoxifen treatment (0.53 during years 0 to 4). It was also significantly reduced, by about a third (RR, 0.68), during years 5 to 9, but then it plateaued (RR, 0.97) during years 10 to 14, suggesting that there was no further gain or loss after year 10, the researchers explain.
Remarkably, the reduction in the risk for death from breast cancer — by about one third — was seen throughout the 15 years of follow-up, with a "highly significant extra benefit" during each of the time periods, the researchers note. RR was reduced significantly during years 0 to 4 (RR, 0.71), during years 5 to 9 (RR, 0.66), and during years 10 to 14 (RR, 0.68).
At the same time, all-cause mortality was substantially reduced, the researchers note. Overall nonbreast cancer mortality was little affected, except for small absolute increases in thromboembolic and uterine cancer mortality (both seen only in women older than 55 years).
Elaborating on these 2 life-threatening adverse effects of tamoxifen, the researchers report that there is little uterine cancer risk or excess risk for fatal pulmonary embolus in women younger than 45 years, or in women 45 to 54 years. In contrast, for older women with an intact uterus, the excess risk for endometrial cancer or pulmonary embolus could be about 1%, they add.
Worldwide, half of all patients with breast cancer are younger than 55 years when they are diagnosed; for women who are pre- or perimenopausal with ER-positive breast cancer, tamoxifen in a major hormonal treatment option, they report.
Tamoxifen is "an attractive treatment option for many premenopausal and perimenopausal women, because at this age it carries little risk of endometrial cancer, and aromatase inhibitors are ineffective in women whose ovaries are still functioning," add the editorialists.
"Therefore, access to accurate ER testing and to tamoxifen ... is a public health imperative," they add.
Benefit Even in Weakly Positive Disease
One of the findings from this analysis is the strong evidence for substantial benefit, even in breast cancer that is only weakly ER-positive (10 to 19 fmol/mg).
This is relevant to current practice, according to the researchers. Although the guidelines for immunohistochemistry assays define ER-positive disease as that with 1% or more cells staining, there has been some uncertainty about whether to include the range from 1% to 10%. A low cutoff will minimize life-threatening false-negative ER results related to technical error, they note.
However, the benefit of tamoxifen at the lower ER levels was not significant, note the editorialists, although they add that the confidence interval is large and a sharp cutoff is not biologically plausible.
"Thus, another crucial message from this update is the need for accurate and sensitive immunohistochemistry assays ... to detect even low concentrations of ER and thus further identify potential candidates for adjuvant tamoxifen treatment," the editorialists write.
Lancet. Published online July 29, 2011.
In women with estrogen-receptor (ER)-positive disease, tamoxifen reduces the risk of dying from breast cancer by about a third over 15 years — during the 5 years it is taken and for 10 years after it is stopped, according to a meta-analysis published online July 29 in the Lancet.
The drug "can prevent a high proportion of recurrences and may potentially cure many patients, rather than simply delay an inevitable event," say a pair of experts in an editorial accompanying the study.
Overall survival approaches normal life expectancy for many of these women, note Stephen Chia, MD, from the University of British Columbia, Vancouver, Canada, and Antonio Wolff, MD, from the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.
"These mature and definite results allow clinicians to inform women confidently about the effect of tamoxifen on breast cancer events," they write.
Mature Data From Meta-Analysis
The findings come from a meta-analysis of individual patient data from more than 20,000 women with early-stage breast cancer enrolled in randomized controlled clinical trials evaluating adjuvant tamoxifen given daily for 5 years (with about 80% compliance). These trials began in the 1980s, and the Early Breast Cancer Trialists' Collaborative Group has been reporting results every 5 years.
In this latest report, the researchers report 15-year data.
In women who had ER-positive disease (n = 10,645), tamoxifen significantly reduced the long-term risk for breast cancer recurrence and death.
The relative risk (RR) for recurrence was nearly halved during tamoxifen treatment (0.53 during years 0 to 4). It was also significantly reduced, by about a third (RR, 0.68), during years 5 to 9, but then it plateaued (RR, 0.97) during years 10 to 14, suggesting that there was no further gain or loss after year 10, the researchers explain.
Remarkably, the reduction in the risk for death from breast cancer — by about one third — was seen throughout the 15 years of follow-up, with a "highly significant extra benefit" during each of the time periods, the researchers note. RR was reduced significantly during years 0 to 4 (RR, 0.71), during years 5 to 9 (RR, 0.66), and during years 10 to 14 (RR, 0.68).
At the same time, all-cause mortality was substantially reduced, the researchers note. Overall nonbreast cancer mortality was little affected, except for small absolute increases in thromboembolic and uterine cancer mortality (both seen only in women older than 55 years).
Elaborating on these 2 life-threatening adverse effects of tamoxifen, the researchers report that there is little uterine cancer risk or excess risk for fatal pulmonary embolus in women younger than 45 years, or in women 45 to 54 years. In contrast, for older women with an intact uterus, the excess risk for endometrial cancer or pulmonary embolus could be about 1%, they add.
Worldwide, half of all patients with breast cancer are younger than 55 years when they are diagnosed; for women who are pre- or perimenopausal with ER-positive breast cancer, tamoxifen in a major hormonal treatment option, they report.
Tamoxifen is "an attractive treatment option for many premenopausal and perimenopausal women, because at this age it carries little risk of endometrial cancer, and aromatase inhibitors are ineffective in women whose ovaries are still functioning," add the editorialists.
"Therefore, access to accurate ER testing and to tamoxifen ... is a public health imperative," they add.
Benefit Even in Weakly Positive Disease
One of the findings from this analysis is the strong evidence for substantial benefit, even in breast cancer that is only weakly ER-positive (10 to 19 fmol/mg).
This is relevant to current practice, according to the researchers. Although the guidelines for immunohistochemistry assays define ER-positive disease as that with 1% or more cells staining, there has been some uncertainty about whether to include the range from 1% to 10%. A low cutoff will minimize life-threatening false-negative ER results related to technical error, they note.
However, the benefit of tamoxifen at the lower ER levels was not significant, note the editorialists, although they add that the confidence interval is large and a sharp cutoff is not biologically plausible.
"Thus, another crucial message from this update is the need for accurate and sensitive immunohistochemistry assays ... to detect even low concentrations of ER and thus further identify potential candidates for adjuvant tamoxifen treatment," the editorialists write.
Lancet. Published online July 29, 2011.
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