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Ann Surg Oncol (2014) 21:29112919 DOI 10.1245/s10434-014-3708-4
ORIGINAL ARTICLE BREAST ONCOLOGY
The Target for Statins, HMG-CoA Reductase, Is Expressed in Ductal Carcinoma-In Situ and May Predict Patient Response to Radiotherapy
Salma Butt, MD, PhD1,2, Talha Butt, MD3, Karin Jirstrm, MD, PhD4,5, Linda Hartman, PhD3,4,5, Rose-Marie Amini, MD, PhD6, Wenjing Zhou, PhD7, Fredrik Warnberg, MD, PhD7, andSigne Borgquist, MD, PhD3,8
1Department of Surgery, Lund University, Skne University Hospital, Malm, Sweden; 2Division of Surgery, Institution of Clinical Sciences, Lund University, Malm, Sweden; 3Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden; 4Division of Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden;
5Regional Cancer Centre South Sweden, Lund, Sweden; 6Department of Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; 7Department of Surgical Science, Uppsala University, Uppsala, Sweden;
8Department of Oncology, Skne University Hospital, Lund, Sweden
ABSTRACTBackground. Patients with ductal carcinoma-in-situ (DCIS) are currently not prescribed adjuvant systemic treatment after surgery and radiotherapy. Prediction of DCIS patients who would benet from radiotherapy is warranted. Statins have been suggested to exert radio-sensitizing effects. The target for cholesterol-lowering statins is HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway. The aim of this study was to examine HMGCR expression in DCIS and study its treatment predictive value.Methods. A population-based cohort including 458 women diagnosed with primary DCIS between 1986 and 2004 were followed until November 2011 to study long-term survival. Tumor tissue microarrays were constructed, and immunohistochemical analyses were performed to detect cytoplasmic protein expression of HMGCR. The association between DCIS HMGCR expression and invasive breast cancer recurrence-free survival (RFSinv) and
overall survival (OS) was analyzed by KaplanMeier curves, log rank test, and Cox proportional hazard analysis.Results. HMGCR was strongly expressed in 24 % of the assessed DCIS samples, moderately expressed in 46 %, and weaklyexpressedin23 %;noexpressionwasdetectedin7 % of
the samples. During the follow-up time (median 13.8 years), 61 patients were diagnosed with an invasive breast cancer recurrence, and 80 patients died. A crude analysis showed no survival benet from radiotherapy. However, patients with strong HMGCR expression showed an improved RFSinv (log rank,
p = 0.03) and OS (log rank, p = 0.04) after radiotherapy. No statistically signicant interaction was observed for HMGCR and radiotherapy (RFSinv p = 0.69 and OS p = 0.29).
Conclusions. This...