Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Clin Cancer Res. 2016 Jan 15;22(2):337-45. doi: 10.1158/1078-0432.CCR-15-0757. Epub 2015 Sep 30.
In spite of improvements of average benefit from adjuvant/neoadjuvant treatments, there are still individual patients with early breast cancer at high risk of relapse. We explored the association with outcome of robust gene cluster-based metagenes linked to proliferation, ER-related genes, and immune response to identify those high-risk patients.
A total of 3,847 publicly available gene-expression profiles were analyzed (untreated, N = 826; tamoxifen-treated, N = 685; chemotherapy-treated, N = 1,150). Genes poorly performing in formalin-fixed samples were removed. Outcomes of interest were pathologic-complete response (pCR) and distant metastasis-free survival (DMFS). In ER(+)HER2(-), the proliferation and ER-related metagenes were combined to define three risk groups. In HER2(+) and ER(-)HER2(-) risk groups were defined by tertiles of an immune-related metagene.
The high-proliferation/low-ER group of ER(+)HER2(-) breast cancer had significantly higher pCR rate [OR, 5.01 (1.76-17.99), P = 0.005], but poorer outcome [HR = 3.73 (1.63-8.51), P = 0.0018] than the low-proliferation/high-ER. A similar association with outcome applied to patients with residual disease (RD) after neoadjuvant chemotherapy (P = 0.01). In ER(-)HER2(-) and HER2(+) breast cancer, immune metagene in the high tertile was linked to higher pCR [33.7% vs. 11.6% in high and low tertile, respectively; OR, 3.87 (1.79-8.95); P = 0.0009]. In ER(-)HER2(-), after adjuvant/neoadjuvant chemotherapy, 5-year DMFS was 85.4% for high-tertile immune metagene, and 43.9% for low tertile. The outcome association was similar in patients with RD (P = 0.0055). In HER2(+) breast cancer treated with chemotherapy the association with risk of relapse was not significant.
We developed metagene-based predictors able to define low and high risk of relapse after adjuvant/neoadjuvant therapy. High-risk patients so defined should be preferably considered for trials with investigational agents.
尽管辅助/新辅助治疗的平均获益有所提高，但仍有部分早期乳腺癌患者存在复发风险较高的情况。我们通过探索与增殖、ER 相关基因和免疫反应相关的稳健基因簇元相关的预后之间的关系，确定这些高危患者。
共分析了 3847 个公开的基因表达谱（未治疗，N = 826；他莫昔芬治疗，N = 685；化疗治疗，N = 1150）。去除在福尔马林固定样本中表现不佳的基因。感兴趣的结果是病理完全缓解（pCR）和远处无病生存（DMFS）。在 ER(+)HER2(-)中，增殖和 ER 相关的元基因联合定义了三个风险组。在 HER2(+)和 ER(-)HER2(-)风险组中，通过免疫相关元基因的三分位法来定义。
在 ER(+)HER2(-)乳腺癌中，高增殖/低 ER 组的 pCR 率显著更高[比值比（OR），5.01（1.76-17.99），P = 0.005]，但预后较差[风险比（HR）= 3.73（1.63-8.51），P = 0.0018]。对于新辅助化疗后残留疾病（RD）的患者，也存在类似的预后相关性（P = 0.01）。在 ER(-)HER2(-)和 HER2(+)乳腺癌中，免疫元基因在高三分位组与更高的 pCR 相关[分别为 33.7%和 11.6%，OR，3.87（1.79-8.95）；P = 0.0009]。在 ER(-)HER2(-)患者中，在辅助/新辅助化疗后，高免疫元基因三分位组的 5 年 DMFS 为 85.4%，低三分位组为 43.9%。在 RD 患者中，预后相关性相似（P = 0.0055）。在接受化疗的 HER2(+)乳腺癌患者中，与复发风险的相关性不显著。
我们开发了基于元基因的预测因子，能够在辅助/新辅助治疗后定义复发的低风险和高风险。如此定义的高危患者应优先考虑参加针对研究性药物的临床试验。
