Amplication of the estrogen receptor 1 (ESR1) gene in mastopathy predicts development of breast cancer.

Background: Mastopathy is a disease with fibrocystic changes (FCC) of the breast tissue commonly seen between the ages 30-50, but rare in postmenopausal women, and therefore suggestive of an association with estrogen stimulation. Whether FCC bears an elevated breast cancer risk is unclear. The role of ESR1 amplification in FCC has not previously been investigated. Material and Methods: Paraffin embedded tissues from 59 women with invasive breast cancer (BrCa) were analyzed. For all women, tissues with FCC taken at least 1.5 years before first diagnosis of BrCa (termed here "FCC old") were also available. Average latency between FCC and BrCa was 6years (range1.5-17y). Immunohistochemistry (IHC) with antibody against estrogen receptor alpha (ER) and FISH-analyses with a probe for ESR1 (Zytovision, Bremerhafen/Germany) were performed. As a control, tissues from 19 women with FCC without a diagnosis of in situ or invasive breast carcinoma in the observed time frame (12-18y) were taken. Clinicalpathological data, such as histological subtype, tumour stage, tumour diameter, BREgrade, patient's age and others, were available for statistical analysis. Results: After FISH analyses, 9 of 59 (15%) BrCa were amplified for ESR1. All ESR1-amplified BrCa were strongly positive for ER with IHC (at least 80% of tumour cells labelled). Tumour type or stage and BRE-grade did not correlate with ESR1-status. In all cases of ESR1 amplification in BrCa areas of amplification in FCC adjacent to the tumour were identified. Interestingly, in women with ESR1 amplification in BrCa, an amplification detectable in tissues with FCC prior to the first diagnosis of BrCa ("FCC old") was noted but was absent in tissues from women with FCC who did not develop BrCa in the observed time frame. Non-neoplastic ESR1 amplified cells within FCC were strongly positive for ER with IHC. In unaltered mammary glands ESR1 amplification was not observed. Discussion: In this preselected collective of women with BrCa and history of FCC we found amplification of the ESR1 gene in 15% of BrCa. In these women, ESR1 amplification was also detectable in tissue with FCC taken prior to the first diagnosis of BrCa. This investigation shows that ESR1 amplification is an early event in breast pathology and its occurrence in FCC predicts development of BrCa.