早期治疗转录谱分析作为改善HER2阳性炎性乳腺癌病理反应预测的工具。

Early on-treatment transcriptional profiling as a tool for improving pathological response prediction in HER2-positive inflammatory breast cancer.

作者信息

Pernas Sonia, Guerriero Jennifer L, Naumenko Sergey, Goel Shom, Regan Meredith M, Hu Jiani, Harrison Beth T, Lynce Filipa, Lin Nancy U, Partridge Ann, Morikawa Aki, Hutchinson John, Mittendorf Elizabeth A, Sokolov Artem, Overmoyer Beth

机构信息

Susan F. Smith Center for Women's Cancers, Inflammatory Breast Cancer Program, Dana-Farber Cancer Institute, Boston, MA, USA.

Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA.

出版信息

Ther Adv Med Oncol. 2022 Jul 30;14:17588359221113269. doi: 10.1177/17588359221113269. eCollection 2022.

DOI:10.1177/17588359221113269

PMID:35923923

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9340890/

Abstract

BACKGROUND

Inflammatory breast cancer (IBC) is a rare and understudied disease, with 40% of cases presenting with human epidermal growth factor receptor 2 (HER2)-positive subtype. The goals of this study were to (i) assess the pathologic complete response (pCR) rate of short-term neoadjuvant dual-HER2-blockade and paclitaxel, (ii) contrast baseline and on-treatment transcriptional profiles of IBC tumor biopsies associated with pCR, and (iii) identify biological pathways that may explain the effect of neoadjuvant therapy on tumor response.

PATIENTS AND METHODS

A single-arm phase II trial of neoadjuvant trastuzumab (H), pertuzumab (P), and paclitaxel for 16 weeks was completed among patients with newly diagnosed HER2-positive IBC. Fresh-frozen tumor biopsies were obtained pretreatment (D1) and 8 days later (D8), following a single dose of HP, prior to adding paclitaxel. We performed RNA-sequencing on D1 and D8 tumor biopsies, identified genes associated with pCR using differential gene expression analysis, identified pathways associated with pCR using gene set enrichment and gene expression deconvolution methods, and compared the pCR predictive value of principal components derived from gene expression profiles by calculating and area under the curve for D1 and D8 subsets.

RESULTS

Twenty-three participants were enrolled, of whom 21 completed surgery following neoadjuvant therapy. Paired longitudinal fresh-frozen tumor samples (D1 and D8) were obtained from all patients. Among the 21 patients who underwent surgery, the pCR and the 4-year disease-free survival were 48% (90% CI 0.29-0.67) and 90% (95% CI 66-97%), respectively. The transcriptional profile of D8 biopsies was found to be more predictive of pCR (AUC = 0.91, 95% CI: 0.7993-1) than the D1 biopsies (AUC = 0.79, 95% CI: 0.5905-0.9822).

CONCLUSIONS

In patients with HER2-positive IBC treated with neoadjuvant HP and paclitaxel for 16 weeks, gene expression patterns of tumor biopsies measured 1 week after treatment initiation not only offered different biological information but importantly served as a better predictor of pCR than baseline transcriptional analysis.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT01796197 (https://clinicaltrials.gov/ct2/show/NCT01796197); registered on February 21, 2013.

摘要

背景

炎性乳腺癌（IBC）是一种罕见且研究不足的疾病，40%的病例为人类表皮生长因子受体2（HER2）阳性亚型。本研究的目的是：（i）评估短期新辅助双HER2阻断联合紫杉醇治疗的病理完全缓解（pCR）率；（ii）对比与pCR相关的IBC肿瘤活检的基线和治疗期间转录谱；（iii）确定可能解释新辅助治疗对肿瘤反应影响的生物学途径。

患者与方法

对新诊断的HER2阳性IBC患者完成了一项新辅助曲妥珠单抗（H）、帕妥珠单抗（P）和紫杉醇治疗16周的单臂II期试验。在添加紫杉醇之前，于治疗前（D1）和单剂量HP治疗8天后（D8）获取新鲜冷冻的肿瘤活检样本。我们对D1和D8肿瘤活检样本进行了RNA测序，使用差异基因表达分析确定与pCR相关的基因，使用基因集富集和基因表达反卷积方法确定与pCR相关的途径，并通过计算D1和D8亚组的曲线下面积比较从基因表达谱得出的主成分的pCR预测价值。

结果

招募了23名参与者，其中21名在新辅助治疗后完成了手术。从所有患者处获取了配对的纵向新鲜冷冻肿瘤样本（D1和D8）。在接受手术的21名患者中，pCR率和4年无病生存率分别为48%（90%CI 0.29 - 0.67）和90%（95%CI 66 - 97%）。发现D8活检样本的转录谱比D1活检样本更能预测pCR（AUC = 0.91，95%CI：0.7993 - 1）（AUC = 0.79，95%CI：0.5905 - 0.9822）。