Published: Dec 12, 2013
SAN ANTONIO -- Anastrozole (Arimidex) reduced the risk of breast cancer by 53% in high-risk postmenopausal women, a primary prevention trial showed.
The aromatase inhibitor cut the incidence to 2% over 5 years compared with 4% on placebo (P<0.0001), Jack Cuzick, PhD, of Queen Mary University of London, and colleagues found in the IBIS-II trial.
The number needed to treat was 36 to prevent one breast cancer in 7 years of follow-up, the researchers pointed out here at the San Antonio Breast Cancer Symposium and simultaneously online in The Lancet.
That primary prevention effect was larger than reported with tamoxifen or raloxifene (Evista) and similar to what was seen with fellow aromatase inhibitor exemestane (Arimidex) in the MAP.3 trial.
"This finding, along with the fact that most of the side-effects associated with estrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer," Cuzick's group argued.
The findings likely will put anastrozole in line to be added to breast cancer prevention guidelines, like exemestane was earlier this year, commented Matthew Goetz, MD, a medical oncologist at the Mayo Clinic in Rochester, Minn.
"I think the guidelines will probably be updated to reflect the fact that we now have level 1 evidence that both a steroidal (exemestane) and a nonsteroidal [anastrozole] aromatase inhibitor are effective in the primary prevention setting," he told MedPage Today, calling the results reassuring.
However, David A. Cameron, MD, MSc, of Scotland's Edinburgh Cancer Centre, wasn't so convinced.
The key question is whether any primary prevention drugs actually prevent breast cancer deaths and improve overall survival for the price in toxicity, which no trial has yet shown, he argued in a commentary accompanying the Lancet paper.
Instead of true prevention of clinically significant, life-threatening breast cancers, "the consistent finding of an increased effect of prevention therapy on hormone-receptor-positive tumors supports the prediction made by modelling data that pharmacological prevention of breast cancer is actually early treatment of extant subclinical tumors," he wrote.
"With two-thirds of the anastrozole benefit in screen-detected cancers, in view of their better outcomes, the likelihood of an eventual breast cancer mortality benefit seems small."
Goetz disagreed, though, pointing to the fact that anastrozole halved the risk of invasive cancers in the trial (rate 2% versus 3%, HR 0.50, 95% confidence interval 0.32-76).
The impact was driven by a 58% reduction in risk of invasive estrogen receptor (ER)-positive cancer, whereas no significant benefit accrued for invasive ER-negative tumors.
"It's premature to say the trial is not a success," he told MedPage Today. "This drug is reducing incidence of ER-positive breast cancer and for those often times the mortality effect is not seen for many years. Often recurrence is occurring in the second decade after being diagnosed."
The International Breast cancer Intervention Study II (IBIS-II) included 3,864 postmenopausal women at high risk of breast cancer, defined by family history or prior diagnosis of ductal carcinoma in situ, lobular carcinoma in situ, or atypical ductal hyperplasia.
They were randomized to take 1 mg anastrozole or placebo daily for 5 years.
The trial had a pragmatic design, with imaging and other follow-up at the end of the 5 years based on local practice without central review. Women had a mammogram and breast exam at baseline (unless recently done) and every 2 years thereafter during the study.
At the median 5 years of follow-up, 40 anastrozole-treated women compared with 85 on placebo had developed any breast cancer, for a hazard ratio of 0.47 (95% CI 0.32-0.68).
The cumulative incidence was predicted to rise to 2.8% and 5.6%, respectively, after 7 years.
The advantage of the aromatase inhibitor also was greater in preventing high-grade cancers, with no impact on intermediate- or low-grade tumors.
"Although highly significant, this finding could have been a result of chance, because other indicators of aggressive or fast growing tumours (eg, node positivity and large tumour size) were not differentially affected," the researchers warned.
Overall mortality was similar between groups (18 deaths with anastrozole versus 17 with placebo).
No specific causes of death were more common in one group than the other (P=0.836), but there were fewer cancers outside the breast, which the researchers called "surprising, especially for colorectal cancers, in which hormone replacement therapy is known to be protective and for which the ATAC trial suggested a non-significant increase with anastrozole compared with tamoxifen in the adjuvant setting."
Despite guideline support, uptake of primary prevention has been low among eligible women. And that's not likely to change with more of the same kind of efficacy data, Goetz suggested.
Side effects and cost are more likely to be deciding factors in the absence of any evidence that it will save women's lives, Cameron explained.
He was critical of the toxicity profile, noting that about half or more of the women in both groups in the trial had musculoskeletal and vasomotor symptoms, while about a fifth had gynecologic adverse events.
"Although the increase in frequency with anastrozole [versus placebo] was modest for musculoskeletal (6%) and vasomotor (8%) events, more than 100 to 200 additional women had these symptoms in the anastrozole group compared with the placebo group -- quite often to a moderate or severe level -- to prevent 15 symptomatically diagnosed breast cancers," Cameron argued.
The researchers took a different view of the same finding.
"Although many side-effects recorded have been associated with estrogen deprivation, they were only slightly more frequent in the anastrozole group than in the placebo group, indicating that most of these symptoms are not drug related," they wrote, suggesting that disseminating that fact could help curb dropouts.
The study was funded by Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca.
Cuzick reported having received funding for IBIS-II from Sanofi-Aventis and AstraZeneca, and being a paid member of a speaker's bureau for AstraZeneca.
Cameron and Goetz reported having no conflicts of interest to disclose.
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