Expression of estrogen-related gene markers in breast cancer tissue predicts aromatase inhibitor responsiveness.
Aromatase inhibitors (AIs) are the most effective class of drugs in the endocrine treatment of breast cancer, with an approximate 50% treatment response rate. Our objective was to determine whether intratumoral expression levels of estrogen-related genes are predictive of AI responsiveness in postmenopausal women with breast cancer. Primary breast carcinomas were obtained from 112 women who received AI therapy after failing adjuvant tamoxifen therapy and developing recurrent breast cancer. Tumor ERα and PR protein expression were analyzed by immunohistochemistry (IHC). Messenger RNA (mRNA) levels of 5 estrogen-related genes-AKR1C3, aromatase, ERα, and 2 estradiol/ERα target genes, BRCA1 and PR-were measured by real-time PCR. Tumor protein and mRNA levels were compared with breast cancer progression rates to determine predictive accuracy. Responsiveness to AI therapy-defined as the combined complete response, partial response, and stable disease rates for at least 6 months-was 51%; rates were 56% in ERα-IHC-positive and 14% in ERα-IHC-negative tumors. Levels of ERα, PR, or BRCA1 mRNA were independently predictive for responsiveness to AI. In cross-validated analyses, a combined measurement of tumor ERα and PR mRNA levels yielded a more superior specificity (36%) and identical sensitivity (96%) to the current clinical practice (ERα/PR-IHC). In patients with ERα/PR-IHC-negative tumors, analysis of mRNA expression revealed either non-significant trends or statistically significant positive predictive values for AI responsiveness. In conclusion, expression levels of estrogen-related mRNAs are predictive for AI responsiveness in postmenopausal women with breast cancer, and mRNA expression analysis may improve patient selection.
Northwestern University, Department of Obstetrics and Gynecology, Chicago, Illinois, United States of America.
Irene
I
Moy
Zhihong
Z
Lin
Alfred W
AW
Rademaker
Scott
S
Reierstad
Seema A
SA
Khan
Serdar E
SE
Bulun
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D012372:ROC Curve; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D005819:Genetic Markers; D009570:Nitriles; D011980:Receptors, Progesterone; D014230:Triazoles; D013629:Tamoxifen; D000077384:Anastrozole; D000077289:Letrozole; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001141:Aromatase