"Estrogen-Related Genes in Malignant Breast Tumor Tissue Predict Responsiveness to Aromatase Inhibition: Presented at SABCS"
By Emma Hitt, PhD
SAN ANTONIO, TX -- December 18, 2006 -- Messenger RNA levels of estrogen-related genes in malignant breast tumor tissue appear to predict responsiveness to aromatase inhibitor treatment, according to the findings of a new study presented here at the 29[th Annual San Antonio Breast Cancer Symposium (SABCS).
Serdar E. Bulun, MD, professor and chief, division of reproductive biology research, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, presented the findings on December 14th.
Dr. Bulun and colleagues sought to identify molecular predictors of response to aromatase inhibitors by evaluating frozen primary breast carcinomas collected from 1989 to 1995 from 116 women who subsequently developed advanced breast cancer and were treated with an aromatase inhibitor.
Using Taqman-based real-time polymerase chain reaction, the researchers analyzed mRNA levels of estrogen-related genes -- AKR1C3 (converts androstenedione to testosterone); aromatase (converts testosterone to estradiol); estrogen receptor-alpha (ER-alpha, mediates estradiol action) -- and 3 estradiol/ERa-target genes -- BRCA1, cathepsin-D, and progesterone receptor (PR).
A receiver operating characteristic (ROC) analysis (ranging from a score of.5 for a marker with no predictive ability to 1.000 for a marker with perfect predictive ability) was used. The ROC curve was used to determine the specificity at 85% sensitivity.
Fifty of 78 (64%) ER-positive tumors and, more surprisingly, 7 of 38 (18%) ER-negative tumors responded favorably to treatment with the AIs (anastrozole or letrozole), with either a complete or partial response or stable disease for at least 6 months.
Overall, ER-alpha (P < .0001) and PR (P = .0008) mRNA levels were significantly higher in responders than in nonresponders. ER-alpha mRNA was the most powerful predictor for response to aromatase inhibitors (ROC area under the curve [AUC] 0.691).
In 38 ER-negative tumors, mRNA levels of ER-alpha (AUC = 0.691) and AKR1C3 (AUC = 0.700) were the most powerful predictors of response to an aromatase inhibitor. Combining ER-alpha, PR, and AKR1C3 improved the predictive power (AUC = 0.737, 61% specificity at 85% sensitivity).
"The findings suggest that potentially endocrine-responsive tumors exist in the ER-negative subgroup of patients and that mRNA analysis of estrogen-related genes is a useful clinical tool in predicting potential responders in this group," Dr. Bulun said.
According to Dr. Bulun, mRNA analysis in a receptor-unknown tumor does not offer any significant advantages over the current practice of assessing ER and/or PR proteins by immunohistochemistry. However, a combined analysis of PR protein and ER and BRCA1 mRNA in PR protein-negative tumors significantly improves specificity for response.
"Such an analysis would prevent 15% of nonresponders from being unnecessarily treated with an aromatase inhibitor without denying treatment to potential responders," he said.
[Presentation title: Messenger RNA Levels of Estrogen-Related Genes in Malignant Breast Tumor Tissue Predict Responsiveness to Aromatase Inhibitors. Abstract 14]
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