Four-Gene Model Predicts Response to Aromatase Inhibitor Therapy for Breast Cancer
As reported in the Journal of Clinical Oncology, Turnbull et al identified a four-gene predictive model of response to aromatase inhibitor therapy that was highly predictive of response on the basis of pretreatment and 2-week on-treatment measurements. The classifier was a significant predictor of recurrence-free and breast cancer–specific survival.
Study Details
In the study, 89 postmenopausal women who had estrogen receptor-alpha–positive breast cancer and were receiving neoadjuvant letrozole underwent biopsy for transcript profiling before letrozole treatment and at 2 weeks and 3 months after starting treatment. Dynamic clinical response was assessed by three-dimensional ultrasound measurements.
Classifier Accuracy
Molecular response to letrozole was characterized, and a four-gene classifier of clinical response was identified. The classifier consisted of levels of two genes before treatment (IL6ST, associated with immune signaling, and NGFRAP1, associated with apoptosis) and the levels of two proliferation genes (ASPM and MCM4) after 2 weeks of therapy.
The classifier had 96% accuracy, 96% sensitivity, and 94% specificity for response, with a positive predictive value of 98% and a negative predictive value of 89%. The area under the receiver operating characteristic curve was 0.96 units, with the classifier failing to predict response accurately in 3 of 73 patients. Use of pretreatment and matched 2-week on-treatment biopsies was associated with improved predictive power vs pretreatment biopsies alone. In a validation cohort of 44 patients treated with anastrozole, the classifier had accuracy of 91%, sensitivity of 90%, and specificity of 92%.
The classifier significantly predicted recurrence-free survival (P = .029) and breast cancer–specific survival (P = .009).
It was shown that testing for expression levels of the four genes can be performed by quantitative polymerase chain reaction or immunohistochemistry.
The investigators concluded: “A four-gene predictive model of clinical response to [aromatase inhibitors] by 2 weeks has been generated and validated. Deregulated immune and apoptotic responses before treatment and cell proliferation that is not reduced 2 weeks after initiation of treatment are functional characteristics of breast tumors that do not respond to [aromatase inhibitors].”
Andrew H. Sims, PhD, of the University of Edinburgh Cancer Research UK Centre, is the corresponding author of the Journal of Clinical Oncology article. Dr. Sims and J. Michael Dixon, MBChB, MD, of the University of Edinburgh Cancer Research UK Centre, contributed equally to the work described.
The study was supported by Breakthrough Breast Cancer and Edinburgh Breast Cancer Research Fund. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
