Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen

Letrozole (2.5 mg) has shown superior efficacy over tamoxifen (20 mg) in first-line treatment of postmenopausal women with advanced breast cancer, and reduced the risk of progression by 30% compared with tamoxifen (J Clin Oncol. 2001;19:2596-606). Elevated serum HER-2/neu is associated with lower efficacy and shorter survival in advanced breast cancer patients treated with hormonal therapy (Lipton et al. Proc Am Soc Clin Oncol. 2001;87). Retrospectively, pretreatment serum samples (562/907 patients) from the first-line trial were analyzed for HER-2/neu levels (Bayer Immuno l automated assay) relative to efficacy. With a cutoff of 15 ng/mL as the upper limit of normal. 29% of patients had an elevated serum HER-2/neu level. Objective response rate (ORR), clinical benefit rate (CBR), time to disease progression (TTP) and time to treatment failure (TTF) were analyzed in elevated vs. normal serum HER-2/neu groups, regardless of treatment and separately by treatment arm. The ORR (15% vs. 31%, P=.0001) and CBR (30% vs. 50%, P=.0001) were lower in patients with an elevated serum HER-2/neu level. Median TTP (5.7 vs. 9.5 mos, P=.0001) and TTF (4.2 vs. 9.2 mos, P=.0001) were significantly shorter for these patients. Multivariate analyses revealed elevated serum HER-2/neu as a negative predictor of ORR, CBR, TTP, and TTF after adjusting for other variables. In the elevated HER-2/neu group, there was no significant difference in ORR (17% vs. 13%, P=.45), CBR (33% vs. 26%, P=.31), median TTP (6.1 vs. 3.3 mos, P=.14) and TTF (6.0 vs. 3.2 mos, P=.10) for patients treated with letrozole and tamoxifen, respectively. For patients with normal serum HER-2/neu, ORR (38% vs. 25%, P=.008), CBR (56% vs. 45%, P=.03), median TTP (13.0 vs. 8.5 months, P=.002) and TTF (11.8 vs. 6.2 months, P=.003) were significantly better in patients treated with letrozole vs. tamoxifen. This study reconfirms serum HER-2/neu as a negative predictive factor for response to endocrine therapy in this advanced breast cancer population. Although results favored letrozole in patients with elevated serum HER-2/neu, there was no significant difference between tamoxifen and letrozole in any efficacy endpoint analyzed. However, patients with normal serum HER-2/neu levels receiving letrozole demonstrated a significantly higher ORR, CBR, and longer TTP and TTF than those receiving tamoxifen.