RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial.
RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial.
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DOI：
10.1001/jamaoncol.2016.3824
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发表时间：
2017-02-01
期刊：
影响因子：
28.4
通讯作者：
Sotiriou C
中科院分区：
文献类型：
--
作者：
Fumagalli D;Venet D;Ignatiadis M;Azim HA Jr;Maetens M;Rothé F;Salgado R;Bradbury I;Pusztai L;Harbeck N;Gomez H;Chang TW;Coccia-Portugal MA;Di Cosimo S;de Azambuja E;de la Peña L;Nuciforo P;Brase JC;Huober J;Baselga J;Piccart M;Loi S;Sotiriou C
在新辅助治疗试验中，与单独使用每种靶向药物相比，使用双重HER 2阻断剂治疗人表皮生长因子受体2（HER 2）阳性乳腺癌导致病理完全缓解（pCR）率增加。HER 2的扩增和/或过表达目前仍然是治疗决策的唯一生物标志物，但不足以解释对抗HER 2药物的异质性应答。研究通过RNA测序测量的临床和生物学相关基因和基因特征（GS）预测抗HER 2药物疗效的能力。新辅助治疗NeoALTTO试验将455名HER 2阳性早期乳腺癌女性随机分配至曲妥珠单抗、拉帕替尼或联合治疗6周，随后每周添加紫杉醇治疗12周，术后接受3个周期的氟尿嘧啶、表阿霉素和环磷酰胺治疗。在NeoALTTO主要方案中计划的当前子研究评价了使用RNA测序定义的治疗前基因表达水平与pCR和无事件生存期（EFS）的相关性。使用RNA测序检查基于基因表达的生物标志物与抗HER 2治疗应答和长期结局的相关性。254例（56%）NeoALTTO受试者的测序数据可用（子研究受试者的平均[SD]年龄为48.8 [11.2]岁）。ERBB 2/HER 2的表达是pCR的最显著预测因子，其次是HER 2富集亚型、ESR 1、治疗组、ER免疫组织化学分析评分、基因组分级指数、免疫、增殖和AKT/mTOR GS。调整临床病理学变量和治疗组后，ERBB 2/HER 2、HER 2富集亚型、ESR 1和基因组分级指数仍具有显著性。免疫GS仅在联合治疗组中与较高的pCR相关（比值比，2.1; 95%CI，1.2-4.0;相互作用检验P = .01），而基质GS在单治疗组中与较高的pCR显著相关，在联合治疗组中与较低的pCR显著相关（比值比，0.46; 95%CI，0.25-0.84; P = .009）。经多重检验校正后，评价的变量均与EFS无关，但该分析的效力不足。在所有治疗组中，高水平ERBB 2/HER 2和低水平ESR 1与pCR相关。在联合治疗组中，免疫和间质GS的高表达分别与较高和较低的pCR率显著相关，应进一步探索其作为候选预测标志物。clinicaltrials.gov标识符：NCT 00553358
In neoadjuvant trials, treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancers with dual HER2 blockade resulted in increased pathologic complete response (pCR) rates compared with each targeted agent alone. Amplification and/or overexpression of HER2 currently remains the only biomarker for therapeutic decisions, but it is insufficient to explain the heterogeneous response to anti-HER2 agents. To investigate the ability of clinically and biologically relevant genes and gene signatures (GSs) measured by RNA sequencing to predict the efficacy of anti-HER2 agents. The neoadjuvant NeoALTTO trial randomized 455 women with HER2-positive early-stage breast cancer to trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The present substudy, which was planned in the NeoALTTO main protocol, evaluated the association of pretreatment gene expression levels defined using RNA sequencing with pCR and event-free survival (EFS). Gene expression–based biomarkers using RNA sequencing were examined for their association with response to anti-HER2 therapy and long-term outcome. Sequencing data were available for 254 (56%) of the NeoALTTO participants (mean [SD] age of substudy participants, 48.8 [11.2] years). The expression of ERBB2/HER2 was the most significant predictor of pCR, followed by HER2-enriched subtype, ESR1, treatment arm, ER immunohistochemical analysis scores, Genomic Grade Index, immune, proliferation, and AKT/mTOR GSs. Adjusting for clinicopathological variables and treatment arms, ERBB2/HER2, HER2-enriched subtype, ESR1, and Genomic Grade Index remained significant. Immune GSs were associated with higher pCR only in the combination arm (odds ratio, 2.1; 95%CI, 1.2–4.0; interaction test P = .01), while the stroma GSs were significantly associated with higher pCR in the single arms and with lower pCR in the combination arm (odds ratio, 0.46; 95%CI, 0.25–0.84; P = .009). None of the evaluated variables was associated with EFS after correction for multiple testing, but this analysis was underpowered. High levels of ERBB2/HER2 and low levels of ESR1 were associated with pCR in all treatment arms. In the combination arm, high expression of immune and stroma GSs were significantly associated with higher and lower pCR rates, respectively, and should be further explored as candidate predictive markers. clinicaltrials.gov Identifier: NCT00553358