Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with postmastectomy radiation.
Reported rates of local failure after adjuvant radiation for women with inflammatory breast cancer (IBC) and triple-negative non-IBC are higher than those of women with receptor-expressing non-IBC. These high rates of locoregional recurrence are potentially influenced by the contribution of radioresistant cancer stem cells to these cancers. Statins have been shown to target stem cells and improve disease-free survival among IBC patients. We examined simvastatin radiosensitization of multiple subtypes of breast cancer cell lines in vitro in monolayer and mammosphere-based clonogenic assays and examined the therapeutic benefit of statin use on local control after postmastectomy radiation (PMRT) among IBC patients. We found that simvastatin radiosensitizes mammosphere-initiating cells (MICs) of IBC cell lines (MDA-IBC3, SUM149, SUM190) and of the metaplastic, non-IBC triple-negative receptor cell line (SUM159). However, simvastatin radioprotects MICs of non-IBC cell lines MCF-7 and SKBR3. In a retrospective clinical study of 519 IBC patients treated with PMRT, 53 patients used a statin. On univariate analysis, actuarial 3-year local recurrence-free survival (LRFS) was higher among statin users, and on multivariate analysis, triple negative breast cancer, absence of lymphatic invasion, neoadjuvant pathological tumor response to preoperative chemotherapy, and statin use were independently associated with higher LRFS. In conclusion, patients with IBC and triple-negative non-IBC breast cancer have the highest rates of local failure, and there are no available known radiosensitizers. We report significant improvement in local control after PMRT among statin users with IBC and significant radiosensitization across triple-negative and IBC cell lines of multiple subtypes using simvastatin. These data suggest that simvastatin should be justified as a radiosensitizing agent by a prospective clinical trial.
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Lara
L
Lacerda
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Jay P
JP
Reddy
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Diane
D
Liu
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Richard
R
Larson
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Li
L
Li
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Hiroko
H
Masuda
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Takae
T
Brewer
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Bisrat G
BG
Debeb
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Wei
W
Xu
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Gabriel N
GN
Hortobágyi
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Thomas A
TA
Buchholz
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Naoto T
NT
Ueno
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic and the Departments of Radiation Oncology, Biostatistics, and Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA wwoodward@mdanderson.org.
Wendy A
WA
Woodward
D000328:Adult; D000368:Aged; D002454:Cell Differentiation; D016009:Chi-Square Distribution; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008408:Mastectomy; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000528:radiation effects*; D016016:Proportional Hazards Models; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D012307:Risk Factors; D019821:Simvastatin / Q000627:therapeutic use*; D018874:Spheroids, Cellular; D013997:Time Factors; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D055815:Young Adult
D011838:Radiation-Sensitizing Agents; D019821:Simvastatin
Inflammatory breast cancer; Local recurrence; Radiation; Statins