Most women with
estrogen receptor expressing breast
cancers receiving anti-
estrogens such as
tamoxifen may not need or benefit from them. Besides the
estrogen receptor, there are no predictive
biomarkers to help select
breast cancer patients for
tamoxifen treatment. CCND1 (cyclin D1) gene amplification is a putative candidate
tamoxifen predictive
biomarker. The RSF1 (remodeling and spacing factor 1) gene is frequently co-amplified with CCND1 on chromosome 11q. We validated the predictive value of these
biomarkers in the
MA.12 randomized study of adjuvant
tamoxifen vs. placebo in high-risk premenopausal early
breast cancer. Premenopausal women with node-positive/high-risk node-negative early
breast cancer received standard
adjuvant chemotherapy and then were randomized to
tamoxifen (20 mg/day) or placebo for 5 yrs. Overall survival (OS) and relapse-free survival (RFS) were evaluated. Fluorescent in-situ hybridization was performed on a tissue microarray of 495
breast tumors (74% of patients) to measure CCND1 and RSF1 copy number. A multivariate Cox model to obtain hazard ratios (HR) adjusting for clinico-pathologic factors was used to assess the effect of these
biomarkers on Os and RFS. 672 women were followed for a median of 8.4 years. We were able to measure the
DNA copy number of CCND1 in 442 patients and RSF1 in 413 patients. CCND1 gene amplification was observed in 8.7% and RSF1 in 6.8% of these patients, preferentially in
estrogen receptor-positive breast
cancers. No statistically significant interaction with treatment was observed for either CCND1 or RSF1 amplification, although patients with high RSF1 copy number did not show benefit from adjuvant
tamoxifen (HR = 1.11, interaction p = 0.09). Unlike CCND1 amplification, RSF1 amplification may predict for outcome in high-risk premenopausal
breast cancer patients treated with adjuvant
tamoxifen.