基因组分析显示，在北中部癌症治疗组n9831辅助曲妥珠单抗试验中，免疫功能基因与临床结局密切相关。

Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial.

作者信息

Perez Edith A, Thompson E Aubrey, Ballman Karla V, Anderson S Keith, Asmann Yan W, Kalari Krishna R, Eckel-Passow Jeanette E, Dueck Amylou C, Tenner Kathleen S, Jen Jin, Fan Jian-Bing, Geiger Xochiquetzal J, McCullough Ann E, Chen Beiyun, Jenkins Robert B, Sledge George W, Winer Eric P, Gralow Julie R, Reinholz Monica M

机构信息

Edith A. Perez, E. Aubrey Thompson, Yan W. Asmann, and Xochiquetzal J. Geiger, Mayo Clinic, Jacksonville, FL; Karla V. Ballman, S. Keith Anderson, Krishna R. Kalari, Jeanette E. Eckel-Passow, Kathleen S. Tenner, Jin Jen, Beiyun Chen, Robert B. Jenkins, and Monica M. Reinholz, Mayo Clinic, Rochester, MN; Amylou C. Dueck, and Ann E. McCullough, Mayo Clinic, Scottsdale, AZ; Jian-Bing Fan, Illumina, San Diego, CA; George W. Sledge, Stanford School of Medicine, Palo Alto, CA; Eric P. Winer, Harvard Medical School, Boston, MA; and Julie R. Gralow, Seattle Cancer Care Alliance, Seattle, WA.

出版信息

J Clin Oncol. 2015 Mar 1;33(7):701-8. doi: 10.1200/JCO.2014.57.6298. Epub 2015 Jan 20.

DOI:10.1200/JCO.2014.57.6298

PMID:25605861

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4334774/

Abstract

PURPOSE

To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer.

PATIENTS AND METHODS

DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme.

RESULTS

Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P < .001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P = .53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P = .64).

CONCLUSION

Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.

摘要

目的

开发一种基因组特征，以预测人表皮生长因子受体2阳性乳腺癌患者从曲妥珠单抗治疗中获益的情况。

患者与方法

采用DASL技术对1282例参加“乳腺癌治疗中含或不含曲妥珠单抗的联合化疗（北中部癌症治疗组N9831 [NCCTG-N9831]）”辅助曲妥珠单抗试验的患者样本中的mRNA进行定量分析。针对仅接受化疗的433例患者（A组）和接受化疗加曲妥珠单抗的849例患者（B组和C组），使用经显著临床病理危险因素校正的Cox比例风险比（HR）来确定每个基因与无复发生存期（RFS）的关联。采用网络和通路分析来识别与RFS相关的关键生物学过程。通过投票方案构建特征。

结果

网络和功能本体分析表明，RFS增加与免疫功能基因的一个子集相关。基于14个免疫功能基因中任意9个或更多基因在人群中的表达处于或高于0.40分位数，使用投票方案模型来定义免疫基因富集。该模型用于识别A组以及B组和C组中免疫基因富集的肿瘤。免疫基因富集与B组和C组中RFS增加相关（HR，0.35；95%CI，0.22至0.55；P <.001），而未表现出免疫基因富集的B组和C组患者未从曲妥珠单抗中获益（HR，0.89；95%CI，0.62至1.28；P =.53）。由我们的预测特征定义的富集免疫功能基因表达与A组中RFS增加无关（HR，0.90；95%CI，0.60至1.37；P =.64）。