除了HER2，还有更多指标也可预测早期乳腺癌新辅助抗HER2疗法效果

　　最新研究发现：除了ERBB2/HER2，是否联合拉帕替尼＋曲妥珠单抗、ER阴性、ESR1低、PAM50高、GGI高也可预测新辅助抗HER2疗法效果。

　　在新辅助试验（NeoALTTO）中，双重HER2阻断与单用各个靶向药物相比，可使HER2阳性乳腺癌治疗的病理学完全缓解（pCR）率和无事件生存（EFS）率提高。HER2扩增和/或过表达仍然是目前抗HER2治疗决策的唯一生物标志，但是其不足以解释抗HER2药物的不同疗效。

　　2016年9月29日，《美国医学会杂志肿瘤学分册》在线发表比利时布鲁塞尔自由大学、英国前沿科学、美国耶鲁大学、德国慕尼黑大学、秘鲁国家癌症研究所、中国台湾成功大学、南非伊斯特利乳腺诊疗中心、意大利国家肿瘤研究所、西班牙乳腺癌协作组、西班牙瓦尔德西布伦肿瘤学研究所、瑞士诺华、德国乌尔姆大学、美国纽约纪念斯隆-凯特林癌症中心、澳大利亚彼得·麦卡勒姆癌症中心的NeoALTTO随机临床试验二次分析报告，分析了通过RNA测序测定临床、生物学相关基因和基因特征预测抗HER2药物疗效的可行性。

　　在新辅助试验（NeoALTTO）中，455例HER2阳性早期乳腺癌女性随机接受曲妥珠单抗、拉帕替尼、曲妥珠单抗＋拉帕替尼6周，随后加用紫杉醇12周，术后氟尿嘧啶＋表柔比星＋环磷酰胺3个周期。该亚研究被计划于NeoALTTO主方案，评价了利用RNA测序检测出的治疗前基因表达水平相关生物标志，与抗HER2疗法效果（根据pCR率）和长期结局（根据EFS率）的相关性。

　　结果从254例（56%）NeoALTTO受试者获得测序数据（亚研究受试者平均年龄48.8±11.2岁）。

　　ERBB2/HER2表达为pCR率最显著的预测因子，随后为HER2富集亚型（PAM50）、雌激素受体α（ESR1）、治疗组、雌激素受体（ER）免疫组织化学分析评分、基因组学等级指数（GGI）、免疫、增殖、AKT/mTOR基因特征。

　　经过校正临床变量和治疗组，ERBB2/HER2表达、PAM50、ESR1、GGI仍然显著。

　　免疫基因特征与pCR率较高仅在联合治疗组有相关性（比值比：2.1，95%置信区间：1.2～4.0，交互检验P=0.01），而基质基因特征与单药治疗组pCR率较高和联合治疗组pCR率较低有显著相关性（比值比：0.46，95%置信区间：0.25～0.84，P=0.009）。

　　经过多变量校正后，无一评价变量与EFS率有相关性，但次分析把握度不足。

　　因此，高水平ERBB2/HER2、低水平ESR1与所有治疗组的pCR率有相关性。在联合治疗组中，免疫和基质的基因特征高表达分别与较高和较低的pCR率有显著相关性，并应被进一步探索作为候选预测标志。

JAMA Oncol. 2016 Sep 29. [Epub ahead of print]

RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial.

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 Pena L, Nuciforo P, Brase JC, Huober J, Baselga J, Piccart M, Loi S, Sotiriou C.

Université Libre de Bruxelles, Brussels, Belgium; Frontier Science Scotland, Kincraig, Inverness-shire, Scotland; Yale School of Medicine, New Haven, Connecticut; University of Munich, Munich, Germany; Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; National Cheng Kung University Hospital, Tainan, Taiwan; Eastleigh Breast Care Centre, Pretoria, South Africa; Istituto Nazionale Tumori, Milan, Italy; SOLTI-Breast Cancer Research Group, Barcelona, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Novartis Pharmaceutical, Basel, Switzerland; University of Ulm, Ulm, Germany; Memorial Sloan Kettering Cancer Center, New York, New York; Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia.

IMPORTANCE: 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.

OBJECTIVE: 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.

DESIGN, SETTING, AND PARTICIPANTS: 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).

MAIN OUTCOMES AND MEASURES: Gene expression-based biomarkers using RNA sequencing were examined for their association with response to anti-HER2 therapy and long-term outcome.

RESULTS: 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.

CONCLUSIONS AND RELEVANCE: 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.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00553358.

PMID: 27684533

DOI: 10.1001/jamaoncol.2016.3824