Significance of 17bHSD Type 14 as a Predictive Factor for Adjuvant Tamoxifen Treatment Response in Breast Cancer.
Authors: T. Sivik, O. Stål, T. Fornander, L. Skoog, B. Nordenskjöld, A. Jansson
Journal: Cancer Research (2009)

Abstract Background: Peripheral sex steroid synthesis in target organs from adrenally derived steroid precursors is believed to be an ongoing event throughout life, but becomes exceedingly important as the gonadal sources of sex steroids cease, as is the case for estrogen synthesis in women after menopause. 17β hydroxysteroid dehydrogenases (17bHSDs) comprise a family of 14 enzymes catalyzing the stereospecific oxidation/reduction at position C17 of estrogens and androgens. Due to their importance in fine-tuning estrogen levels, the 17bHSDs have been studied in breast cancer. In a previous study examining mRNA of 17bHSD type 14, an enzyme driving the oxidation of estradiol into less potent estrone, from a cohort of stage 2 tumors, high levels were associated with longer disease-free survival. The present study was conducted in order to investigate whether this result could be repeated in another group of patients examining protein expression and to investigate whether 17bHSD type 14 has any prognostic or predictive importance in breast cancer patients systemically treated or untreated with tamoxifen. Material and Methods: A peptide sequence corresponding to amino acids 255 to 269 of human 17bHSD type 14 was synthesized and used for immunization of rabbits with the subsequent purification of a polyclonal antibody towards the antigen. A randomized tamoxifen trial comprising 1780 breast cancer patients was conducted in Stockholm, Sweden, 1976-1990. All patients had lymph node negative primary breast cancer and were postmenopausal at the time of diagnosis. We analyzed the protein expression of 17bHSD type 14 with immunohistochemistry using tissue microarrays, which were constructed from paraffin blocks originating from 912 patients. Results: Results were obtained from 847 patients. Among patients with estrogen receptor positive tumors, high expression of 17bHSD type 14 was associated with a significantly better benefit from tamoxifen as shown by a higher local recurrence-free probability (RR 0.38; 95% C.I. 0.19-0.77, p=0.006) when compared to patients bearing tumors with intermediate, low or negative expression levels (RR 1.20; 95% C.I. 0.54-2.60; p=0.67). The interaction test was significant (p=0.03). No significant difference in tamoxifen response was found when looking at 17bHSD type 14 in relation to breast cancer specific mortality. Furthermore, for untreated patients no prognostic significance for 17bHSD type 14 was found. Discussion: In the current study we show that intratumoral levels of 17bHSD type 14, an enzyme potentially involved in lowering the levels of potent estradiol, is a predictive factor in determining the local response to adjuvant tamoxifen treatment. The fact that patients with ER positive tumors have a greater possibility of responding well to tamoxifen when the expression levels of 17bHSD type 14 are high suggests that some patients would gain better from other treatments than tamoxifen, e.g. aromatase inhibitors and/or inhibitors of reducing 17bHSD enzymes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2015.