Letrozole or Tamoxifen for Initial Adjuvant Therapy in Breast Cancer?

Summary and Comment |
March 12, 2007

Letrozole or Tamoxifen for Initial Adjuvant Therapy in Breast Cancer?

  1. William J. Gradishar, MD

Long-term findings continue to support the conclusion that letrozole provides additional benefit over tamoxifen.

  1. William J. Gradishar, MD

The ongoing Breast International Group (BIG) 1-98 study is a large, industry-sponsored, multinational, randomized trial designed to compare breast cancer recurrence after initial adjuvant therapy with letrozole or tamoxifen. The treatment arms are:

  • Letrozole for 5 years

  • Tamoxifen for 5 years

  • Letrozole for 2 years, followed by tamoxifen for 3 years

  • Tamoxifen for 2 years, followed by letrozole for 3 years

Initial reports from this study included 2-year data on patients assigned to the monotherapy arms and data on those from the sequential-therapy arms that were censored at the time of therapy switch. The conclusions of this “primary core analysis” were that postmenopausal patients who were treated with initial letrozole, compared with tamoxifen, experienced fewer adverse events and had longer disease-free survival (N Engl J Med 2005; 3563:2747)

Now, researchers present an analysis of data from the 4922 patients in BIG 1-98 who received tamoxifen or letrozole monotherapy (median follow-up, 51 months) but excluding patient data from the “switching” arms. A total of 352 breast cancer–related events occurred among 2463 women receiving letrozole, and 418 events occurred among 2459 women receiving tamoxifen (relative risk reduction, 18%; hazard ratio, 0.82; 95% confidence interval, 0.71–0.95; P=0.007). More patients in the letrozole group than in the tamoxifen group discontinued therapy early due to adverse events (12.3% vs. 11.1%); however, more tamoxifen patients than letrozole patients discontinued treatment due to disease progression (11.5% vs. 7.9%). As in the primary core analysis, patients receiving tamoxifen experienced significantly more hot flashes, night sweats, vaginal bleeding, clots, and endometrial pathology. In contrast, patients receiving letrozole experienced significantly more arthralgias, bone fractures, low-grade cholesterol elevations, and adverse cardiovascular events (except ischemic heart disease and heart failures). Adverse cardiovascular events were predominantly grade 1 or 2 and included iliac artery stenosis, intermittent claudication, aortic dilatation, and hypertensive angiopathy.

Comment

The limitation of the primary core analysis was that emphasis was placed on early events. Although the initial conclusions were valid, comparison to other trials (such as ATAC [Cancer 2003; 98:1802], in which 5-year adjuvant endocrine therapy with tamoxifen or anastrozole was evaluated) was difficult. The current report provides longer follow-up on a significant population of patients who received only tamoxifen or letrozole. The longer-term findings continue to support the conclusion that letrozole provides additional benefit over tamoxifen and allow indirect comparisons with the ATAC results. Although event definitions varied slightly between the two trials, lengthening of time to disease recurrence and lack of survival benefit were similar. Caveats include the fact that more than 1000 patients in each treatment arm are still receiving therapy in BIG 1-98 and that longer follow-up of all the aromatase-inhibitor trials is required to determine whether they will provide a carry-over effect, like that of tamoxifen, beyond 5 years (after therapy is discontinued). Addressing the latter point, an updated analysis of the IES trial is instructive (Journal Watch Oncology and Hematology Mar 12 2007).

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