Abstract
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.
Highlights
About three quarters of breast cancers express the estrogen receptor (ER), which renders them susceptible to treatment by modulators/antagonists of ER activity such as the ER antagonist, tamoxifen
Treatment of ER-expressing (ER+) breast cancers by anti-estrogen drugs is the standard of care, with survival benefit even in very early breast cancers, as shown by the NSABP B-14 clinical trial in node-negative ER+ patients [1]
It is possible that a poor selection of potential candidates of tamoxifen therapy may have contributed to these counter-intuitive results, in that the benefit obtained from tamoxifen therapy in a subset of patients may have been obscured by the lack of benefit in another subset
Summary
About three quarters of breast cancers express the estrogen receptor (ER), which renders them susceptible to treatment by modulators/antagonists of ER activity such as the ER antagonist, tamoxifen. The MA. clinical trial was designed to answer the question of whether tamoxifen adjuvant therapy was of benefit in pre-menopausal women with early (pathologic stage I-III) but high-risk (high-risk node-negative or node-positive) breast cancer after the administration of cytotoxic chemotherapy. The results of this trial were recently reported: it was found that tamoxifen improved disease-free survival in these higher-risk early breast cancer patients, albeit not statistically significantly [2]. The search for candidate biomarkers of tamoxifen response will help to better define subsets of early breast cancer patients in whom tamoxifen therapy may either be withheld or administered with a greater certainty of its relative ineffectiveness or benefit
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