TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer.
TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-16-0148
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发表时间：
2016-12-01
期刊：
影响因子：
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通讯作者：
Malorni L
中科院分区：
文献类型：
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作者：
Jeselsohn R;Barry WT;Migliaccio I;Biagioni C;Zhao J;De Tribolet-Hardy J;Guarducci C;Bonechi M;Laing N;Winer EP;Brown M;Leo AD;Malorni L
氟维司群是一种雌激素受体（ER）拮抗剂，是一种获批用于治疗转移性雌激素受体阳性（ER+）乳腺癌的药物。除ER水平外，尚无确定的氟维司群单药治疗应答的预测性生物标志物。我们试图确定晚期乳腺癌对氟维司群反应的基因特征。收集了134例入组III期CONFIRM研究的转移性ER+乳腺癌患者的原发性肿瘤样本，比较250 mg或500 mg氟维司群治疗，用于全基因组转录组学分析。基因表达谱分析使用Affyssin微阵列进行。进行了探索性分析，以确定与氟维司群应答相关的生物学途径和新特征。通路分析表明，EGF通路和FOXA 1转录信号传导的增加与对氟维司群的反应降低相关。使用多变量考克斯模型，我们确定了一组新的37个基因，其表达与无进展生存期（PFS）独立相关。TFAP 2C是一种已知的ER活性调节因子，在该基因集中排名第二，高表达与氟维司群应答降低相关。免疫组化证实TFAP2C蛋白表达的阴性预测值。我们在原发性ER+乳腺癌中确定了生物学途径和一种新的基因特征，可预测CONFIRM研究中对治疗的反应。这些结果提示了潜在的新治疗靶点，并值得进一步验证作为转移性乳腺癌中氟维司群治疗的预测生物标志物。
Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor positive (ER+) breast cancer. With the exception of ER levels, there are no established predictive biomarkers of response to single agent fulvestrant. We attempted to identify a gene signature of response to fulvestrant in advanced breast cancer. Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER+ breast cancer comparing treatment with either 250mg or 500mg fulvestrant were collected for genome-wide transcriptomic analysis. Gene expression profiling was performed using Affymetrix microarrays. An exploratory analysis was performed to identify biological pathways and new signatures associated with response to fulvestrant. Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model we identified a novel set of 37 genes whose expression is independently associated with progression free survival (PFS). TFAP2C, a known regulator of ER activity was ranked second in this gene set and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by immunohistochemistry. We identified biological pathways and a novel gene signature in primary ER+ breast cancers that predicts for response to treatment in the CONFIRM study. These results suggest potential new therapeutic targets and warrant further validation as predictive biomarkers of fulvestrant treatment in metastatic breast cancer.