Sinn Bruno V, Loibl Sibylle, Hanusch Claus A, Zahm Dirk-Michael, Sinn Hans-Peter, Untch Michael, Weber Karsten, Karn Thomas, Becker Clemens, Marmé Frederik, Schmitt Wolfgang D, Müller Volkmar, Schem Christian, Treue Denise, Stickeler Elmar, Klauschen Frederik, Burchardi Nicole, Furlanetto Jenny, van Mackelenbergh Marion, Fasching Peter A, Schneeweiss Andreas, Denkert Carsten
Department of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institut of Health, Berlin, Germany.
Berlin Institute of Health (BIH), Berlin, Germany.
Clin Cancer Res. 2021 May 1;27(9):2584-2591. doi: 10.1158/1078-0432.CCR-20-3113. Epub 2021 Feb 16.
We evaluated mRNA signatures to predict response to neoadjuvant PD-L1 inhibition in combination with chemotherapy in early triple-negative breast cancer.
Targeted mRNA sequencing of 2,559 transcripts was performed in formalin-fixed, paraffin-embedded samples from 162 patients of the GeparNuevo trial. We focused on validation of four predefined gene signatures and differential gene expression analyses for new predictive markers.
Two signatures [GeparSixto signature (G6-Sig) and IFN signature (IFN-Sig)] were predictive for treatment response in a multivariate model including treatment arm [G6-Sig: OR, 1.558; 95% confidence interval (CI), 1.130-2.182; = 0.008 and IFN-Sig: OR, 1.695; 95% CI, 1.234-2.376; = 0.002), while the CYT metric predicted pathologic complete response (pCR) in the durvalumab arm, and the proliferation-associated gene signature in the placebo arm. Expression of PD-L1 mRNA was associated with better response in both arms, indicating that increased levels of PD-L1 are a general predictor of neoadjuvant therapy response. In an exploratory analysis, we identified seven genes that were higher expressed in responders in the durvalumab arm, but not the placebo arm: , and . These genes were associated with cellular antigen processing and presentation and IFN signaling.
Immune-associated signatures are associated with pCR after chemotherapy, but might be of limited use for the prediction of response to additional immune checkpoint blockade. Gene expressions related to antigen presentation and IFN signaling might be interesting candidates for further evaluation.
我们评估了mRNA特征，以预测早期三阴性乳腺癌患者新辅助PD-L1抑制联合化疗的反应。
对GeparNuevo试验中162例患者的福尔马林固定石蜡包埋样本进行了2559个转录本的靶向mRNA测序。我们专注于四个预定义基因特征的验证以及新预测标志物的差异基因表达分析。
在包括治疗组的多变量模型中，两个特征[GeparSixto特征（G6-Sig）和IFN特征（IFN-Sig）]可预测治疗反应[G6-Sig：比值比（OR），1.558；95%置信区间（CI），1.130 - 2.182；P = 0.008，IFN-Sig：OR，1.695；95%CI，1.234 - 2.376；P = 0.002]，而CYT指标可预测度伐利尤单抗组的病理完全缓解（pCR），安慰剂组的增殖相关基因特征可预测pCR。PD-L1 mRNA的表达与两组的更好反应相关，表明PD-L1水平升高是新辅助治疗反应的一般预测指标。在探索性分析中，我们鉴定出7个在度伐利尤单抗组而非安慰剂组的反应者中高表达的基因： 、 和 。这些基因与细胞抗原加工呈递和IFN信号传导相关。
免疫相关特征与化疗后的pCR相关，但对于预测额外免疫检查点阻断的反应可能用途有限。与抗原呈递和IFN信号传导相关的基因表达可能是进一步评估的有趣候选指标。
