Extending adjuvant letrozole treatment may reduce breast cancer recurrence: The MA.17R trial

1. Extended-use adjuvant letrozole therapy was associated with significant reduction in breast cancer-free survival but not overall survival, compared to placebo.

2. Extended-use adjuvant letrozole therapy was associated with significantly more bone toxicity side effects compared to placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Anti-estrogen therapies like tamoxifen, and aromatase inhibitors like letrozole have been used as adjuvant therapies to reduce recurrence of hormone receptor positive breast cancer. Typically, an aromatase inhibitor is used as either up-front monotherapy or used after a five-year course of tamoxifen therapy. In this double-blind, placebo controlled randomized trial, researchers evaluated the effects of extending adjuvant letrozole therapy by an additional five years to the standard of care in reducing breast cancer recurrence. Researchers found that extended use of letrozole for five years reduced the recurrence of breast cancer in women, independent of nodal status, previous adjuvant chemotherapy and duration of prior anti-estrogen or aromatase inhibitor therapy. However, no overall difference in overall survival was seen between participants treated with letrozole compared to placebo. Additionally, researchers noted significantly more bone toxic events in the letrozole group.

Click to read the study, published today in NEJM

Relevant Reading: A randomized trial of letrozole in postmenopausal women after five ears of tamoxifen therapy for early-stage breast cancer.

In-Depth [randomized controlled trial]: In this study, 1918 participants were randomized to receive either letrozole (n = 959) or placebo (n = 959). The primary study end-point was disease free survival from the time of randomization to the time of recurrence of either primary breast cancer or development of new primary breast cancer in the contralateral breast. Of the 165 participants that experienced disease recurrence, 40% were in the letrozole group and 60% were in the placebo group. In terms of death from disease recurrence, 31 and 34 deaths occurred in the letrozole and placebo groups, respectively. The 5-year disease free survival rate was 95% (95%CI 93-96) for the letrozole group and 91% (95%CI 89-93) for the placebo group, with a HR of 0.66 (95%CI 0.48-0.91; p = 0.01). However, the difference between the overall 5-year survival rate between the letrozole (93% rate; 95%CI 92-95) and control group (94% rate, 95%CI 92-95) was not significant (HR 0.97; p = 0.83).

The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95%CI 0.1-0.32) compared to the placebo rate of 0.49% (95%CI 0.32-0.67) with a hazard ratio of 0.42 (95%CI 0.22-0.81; p = 0.007). Bone related toxic effects occurred more frequently in the letrozole group. In the letrozole group, 10% of participants compared to 7% of placebo group participants had lumbar spine T-scores less than -2.5 at any time after baseline (p = 0.03). Additionally, new onset osteoporosis occurred in 109 (11%) of letrozole group participants compared to 54 (6%) of placebo group patients (p < 0.001). No significant differences between the groups were noted for overall SF-36 scores and corollary subscale scores (completed by 85% of participants). However, reduction in scores over time was greater in the letrozole group for the bodily-pain subscores. Only 5.4% and 3.7% of participants discontinued treatment in the letrozole and control groups, respectively.

Image: PD

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