Di Cosimo Serena, Ciniselli Chiara M, Pizzamiglio Sara, Cappelletti Vera, Silvestri Marco, El-Abed Sarra, Izquierdo Miguel, Bajji Mohammed, Nuciforo Paolo, Huober Jens, Cameron David, Chia Stephen, Gomez Henry L, Iorio Marilena V, Vingiani Andrea, Pruneri Giancarlo, Verderio Paolo
Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Unit of Bioinformatics and Biostatistics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Front Oncol. 2023 Jan 31;12:1028825. doi: 10.3389/fonc.2022.1028825. eCollection 2022.
The absence of breast cancer cells in surgical specimens, , pathological complete response (pCR), is widely recognized as a favorable prognostic factor after neoadjuvant therapy. In contrast, the presence of disease at surgery characterizes a prognostically heterogeneous group of patients. Here, we challenged circulating microRNAs (miRNAs) at the end of neoadjuvant therapy as potential prognostic biomarkers in the NeoALTTO study.
Patients treated within the trastuzumab arm (, pre-operative weekly trastuzumab for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks; post-operative FEC for 3 cycles followed by trastuzumab up to complete 1 year of treatment) were randomized into a training (= 54) and testing (= 72) set. RT-PCR-based high-throughput miRNA profile was performed on plasma samples collected at the end of neoadjuvant treatment of both sets. After normalization, circulating miRNAs associated with event free survival (EFS) were identified by univariate and multivariate Cox regression model.
Starting from 23 circulating miRNAs associated with EFS in the training set, we generated a 3-circulating miRNA prognostic signature consisting of miR-185-5p, miR-146a-5p, miR-22-3p, which was confirmed in the testing set. The 3-circulating miRNA signature showed a C-statistic of 0.62 (95% confidence interval [95%CI] 0.53-0.71) in the entire study cohort. By resorting to a multivariate Cox regression model we found a statistical significant interaction between the expression values of miR-194-5p and pCR status (p.interaction =0.005) with an estimate Hazard Ratio (HR) of 1.83 (95%CI 1.14- 2.95) in patients with pCR, and 0.87 (95%CI 0.69-1.10) in those without pCR. Notably, the model including this interaction along with the abovementioned 3-circulating miRNA signature provided the highest discriminatory capability with a C-statistic of 0.67 (95%CI 0.58-0.76).
Circulating miRNAs are informative to identify patients with different prognosis among those with heterogeneous response after trastuzumab-based neoadjuvant treatment, and may be an exploitable tool to select candidates for salvage adjuvant therapy.
手术标本中不存在乳腺癌细胞，即病理完全缓解（pCR），被广泛认为是新辅助治疗后一个良好的预后因素。相比之下，手术时存在疾病则表明这是一组预后异质性的患者。在此，我们在NeoALTTO研究中对新辅助治疗结束时的循环微小RNA（miRNA）作为潜在的预后生物标志物进行了研究。
在曲妥珠单抗治疗组（术前每周使用曲妥珠单抗6周，随后每周添加紫杉醇12周；术后使用FEC方案化疗3个周期，随后继续使用曲妥珠单抗直至完成1年治疗）接受治疗的患者被随机分为训练组（n = 54）和测试组（n = 72）。对两组新辅助治疗结束时采集的血浆样本进行基于RT-PCR的高通量miRNA分析。标准化后，通过单变量和多变量Cox回归模型确定与无事件生存期（EFS）相关的循环miRNA。
从训练组中与EFS相关的23种循环miRNA开始，我们生成了一个由miR-185-5p、miR-146a-5p、miR-22-3p组成的3种循环miRNA预后特征，该特征在测试组中得到了验证。在整个研究队列中，3种循环miRNA特征的C统计量为0.62（95%置信区间[95%CI] 0.53 - 0.71）。通过多变量Cox回归模型，我们发现miR-194-5p的表达值与pCR状态之间存在统计学显著的相互作用（p相互作用 = 0.005），在pCR患者中的估计风险比（HR）为1.83（95%CI 1.14 - 2.95），在无pCR患者中为0.87（95%CI 0.69 - 1.10）。值得注意的是，包含这种相互作用以及上述3种循环miRNA特征的模型具有最高的鉴别能力，C统计量为0.67（95%CI 0.58 - 0.76）。
循环miRNA有助于在基于曲妥珠单抗的新辅助治疗后反应异质性的患者中识别出具有不同预后的患者，并且可能是一种可用于选择挽救性辅助治疗候选者的工具。
