The target for statins, HMG-CoA reductase, is expressed in ductal carcinoma-in situ and may predict patient response to radiotherapy.
BACKGROUND
Patients with ductal carcinoma-in-situ (DCIS) are currently not prescribed adjuvant systemic treatment after surgery and radiotherapy. Prediction of DCIS patients who would benefit 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 Kaplan-Meier 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 weakly expressed in 23 %; no expression was detected in 7 % 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 benefit 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 significant interaction was observed for HMGCR and radiotherapy (RFSinv p = 0.69 and OS p = 0.29).


CONCLUSIONS
This study demonstrates HMGCR expression in DCIS and suggests HMGCR as a predictive marker of response to postoperative radiotherapy in DCIS, although the test for interaction was nonsignificant. Future DCIS studies addressing the potential of statin treatment targeting HMGCR are warranted.
Department of Surgery, Lund University, Skåne University Hospital, Malmö, Sweden, salma.butt@med.lu.se.
Salma
S
Butt
Talha
T
Butt
Karin
K
Jirström
Linda
L
Hartman
Rose-Marie
RM
Amini
Wenjing
W
Zhou
Fredrik
F
Wärnberg
Signe
S
Borgquist
D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008408:Mastectomy / Q000401:mortality*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D009367:Neoplasm Staging; D011183:Postoperative Complications / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D011879:Radiotherapy Dosage; D015996:Survival Rate
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases