Optimal use of aromatase inhibitors comes into focus

ABSTRACT: New studies suggest better outcomes when patients are switched to an AI after two to three years of tamoxifen or start adjuvant therapy with an AI.

The suggestion that aromatase inhibitors (AIs) are superior to tamoxifen was solidified by two meta-analyses of nearly 20,000 patients, presented by James Ingle, MD, of the Mayo Clinic, Rochester, Minn. (abstract 12). AIs were better at reducing recurrences, whether given as initial monotherapy, where they reduced the risk by 23% over tamoxifen, or in a “switching” strategy (given after two to three years of tamoxifen), where they reduced the risk by 29% relative to those women who continued on tamoxifen. The study was based on data from six major trials submitted to the Early Breast Cancer Trialists’ Collaborative Group.

In the monotherapy cohort (n = 9,856), recurrences were documented in 15.3% of AI users eight years after diagnosis, compared with 19.2% of tamoxifen users (P < .00001), representing a highly significant absolute gain of 2.9% at five years and 3.9% at eight years in patients who remained free of breast cancer recurrence, and a nonsignificant gain in survival (breast cancer mortality) of 1.1% at five years and 0.5% at eight years.

In the switching cohort (n = 9,015), breast cancer recurred in 12.6% of patients switched to an AI, compared with 16.1% of those who continued on tamoxifen. The overall comparison of time to recurrence was highly significant (P < .00001). Breast cancer mortality was significantly reduced with the use of AIs in the switching cohort, yielding an absolute reduction of 0.7% at three years and 1.6% at six years (P = .02), Dr. Ingle reported. Most benefit occurred while patients were on active treatment. “There is a change when patients go off therapy, but AIs are still better,” he noted. “Duration of AI treatment is now a major question to be answered.”

Letrozole vs tamoxifen
The phase III Breast International Group (BIG) 1-98 trial (n = 8,010) also found improved outcomes with an AI, compared with tamoxifen. Five years of adjuvant letrozole (Femara) was associated with improved survival, and no advantage was found for treating patients first with tamoxifen, then switching to an AI, according to Henning Mouridsen, MD, of Copenhagen University Hospital (abstract 13).

At a median follow-up of 76 months, mortality risk was reduced by 13% with letrozole, though the results fell short of significance (P = .08) due to the 25% crossover to letrozole after 18 months on tamoxifen, according to Dr. Mouridsen.

Sequential adjuvant hormonal therapy (two years of letrozole or tamoxifen followed by two to three years of the other drug) was not more effective than five years of letrozole (median follow-up of 71 months).

DFS was 87.9% for letrozole monotherapy, 87.6% for letrozole followed by tamoxifen, and 86.2% for tamoxifen followed by letrozole. There was a trend toward lower early (two-year) recurrence rates when letrozole was administered first, according to the authors.

Sequencing tamoxifen and anastrozole
Mature results from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8 (n = 3,714) confirmed a survival difference for the sequencing strategy of tamoxifen followed by anastrozole (Arimidex), compared with five years of tamoxifen (abstract 14).

At a median follow-up of 72 months, a sequencing strategy of two years of tamoxifen followed by two to three years of anastrozole improved recurrence-free survival, compared with five years of tamoxifen. Recurrences were reduced by 21% regardless of whether patients actually received their assigned treatment (P = .038), and by 27% in patients who received treatment as planned (P = .001).

Overall survival was also significantly improved with sequential treatment, with mortality reduced by 22% in the intent-to-treat analysis (P = .032), reported Raimund Jakesz, MD, of Vienna Medical University.

“Switching from tamoxifen to anastrozole after two years of tamoxifen significantly improves recurrence-free and overall survival,” Dr. Jakesz concluded.

“This trial clearly shows a survival benefit over five years of adjuvant tamoxifen,” he said.

Endpoints of TEAM
Results for exemestane (Aromasin) were less robust, according to the first planned analysis of the international TEAM (Tamoxifen, Exemestane, Adjuvant, Multinational) trial. TEAM enrolled 9,775 subjects.

Exemestane had numerically better outcomes, but the primary endpoint has not reached statistical significance in the preliminary analysis, according to Stephen Jones, MD, of US Oncology Research in Houston (abstract 15).

The analysis presented at SABCS was for disease-free survival at 2.75 years in patients randomized to initial treatment with tamoxifen or exemestane. Disease-free survival was reduced by 11% with exemestane over tamoxifen, but the difference was not statistically significant, according to Jones and colleagues’ results.

When adjusting the primary disease-free survival analysis to account for discontinuation rates and patients who switched from tamoxifen to exemestane before 2.5 years (n = 754), however, the investigators found a 17% reduction in risk of disease-free survival events with exemestane, which did reach significance. “Exemestane was associated with important DFS benefits in patients who were on the assigned study drug,” Dr. Jones emphasized.

Initiation of treatment with exemestane also significantly improved recurrence-free survival and time to distant metastasis.

The risk reduction for recurrence-free survival came in at 15%. The risk reduction for time to distant metastasis was 19%, according to the results.

“The TEAM trial provides the missing link in the comparison of tamoxifen and aromatase inhibitors,” Dr. Jones pointed out. “Now we have data on exemestane with similar endpoints to other AIs versus tamoxifen as initial therapy,” he concluded.