Predictive markers for tamoxifen response in primary breast cancer

Abstract: It is well-known that a majority of breast cancers are hormone-dependent, making endocrine therapy an important adjuvant treatment after surgery. Susceptibility to endocrine treatment is determined by the presence of estrogen receptors (ER) and progesterone receptors (PR) in the tumors. Tamoxifen is the most well-established endocrine treatment available, inhibiting tumor growth and improving survival. Resistance to tamoxifen despite ER/PR positivity is a well-known clinical problem. Cyclin D1, initially described as a cell cycle regulator, also functions as a co-factor to the ER, activating the receptor in the absence of ligand. We investigated the predictive impact of cyclin D1 on tamoxifen treatment response in tumors from patients previously enrolled in randomized trials and found that high levels of cyclin D1 in tumors of tamoxifen treated patients predicted for poor response and reduced recurrence-free survival despite ER positivity. Furthermore, amplification of the cyclin D1 gene (CCND1) was associated with an adverse outcome upon tamoxifen treatment. P27 is a cell cycle regulator, acting as a cdk-inhibitor but also as an assembly factor to the cyclin D1-cdk4/6 complex. We found that low levels of p27 correlated to a poor tamoxifen response but had no prognostic value in untreated patients. ER and PR are the only clinical tools available for predicting treatment response, with a cut-off at 10% positive tumor cell nuclei. We investigated if a more detailed mapping of hormone receptor levels could provide additional information and found that it was predominantly tumors with high levels of PR (>75%) that responded well to tamoxifen treatment. Further studies, confirming cyclin D1, p27 and other factors possibly inducing tamoxifen treatment resistance, are needed. In the meantime, a more precise assessment of hormone receptor status could be informative.