Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia.
Division of Medical Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia.
JAMA Oncol. 2016 Feb;2(2):242-6. doi: 10.1001/jamaoncol.2015.5482.
There is a paucity of immune signatures identifying patients with human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer (IBC) at risk for treatment failure following trastuzumab and chemotherapy.
To determine whether circulating anti-HER2 CD4-positive (CD4+) T-helper type 1 (Th1) immunity correlates with recurrence in patients with completely treated HER2-positive IBC.
DESIGN, SETTING, AND PARTICIPANTS: Hypothesis-generating exploratory translational analysis at a tertiary care referral center of patients with completely treated HER2-positive IBC with median (interquartile range) follow-up of 44 (31) months. Anti-HER2 Th1 responses were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II-promiscuous peptides via interferon-γ (IFN-γ) enzyme-linked immunospot assay.
T-helper type 1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFCs]/106 cells). Anti-HER2 Th1 responses in treatment-naive patients (used as an immunologic baseline) were compared with those in patients completing trastuzumab and chemotherapy; in the latter group, analyses were stratified by recurrence status. Recurrence was defined as any locoregional or distant breast event, or both. Cox regression analysis estimated the instantaneous hazard of recurrence (ie, disease-free survival [DFS]) stratified by anti-HER2 Th1 responsivity.
In 95 women with HER2-positive IBC (median [range] age, 49 [24-85] years; 22 treatment-naive, 73 treated with trastuzumab and chemotherapy), depressed anti-HER2 Th1 responsivity (recurrence, 2 of 25 [8%], vs nonrecurrence, 40 of 48 [83%]; P < .001), mean (SD) repertoire (0.1 [0.1] vs 1.5[0.2]; P < .001), and mean (SD) cumulative response (14.8 [2.0] vs 80.2 [11.0] SFCs/106 cells; P < .001) were observed in patients incurring recurrence (n = 25) compared with patients without recurrence (n = 48). After controlling for confounding, anti-HER2 Th1 responsivity remained independently associated with recurrence (P < .001). This immune disparity was mediated by anti-HER2 CD4+T-bet+IFN-γ+ (Th1)-not CD4+GATA-3+IFN-γ+ (Th2) or CD4+CD25+FoxP3+ (Treg)-phenotypes, and not attributable to immune incompetence. When stratifying trastuzumab plus chemotherapy-treated patients by Th1 responsivity, Th1-nonresponsive patients demonstrated a worse DFS (median, 47 vs 113 months; P < .001) compared with Th1-responsive patients (hazard ratio, 16.9 [95% CI, 3.9-71.4]; P < .001).
Depressed anti-HER2 Th1 response is a novel immune correlate to recurrence in patients with completely treated HER2-positive IBC. These data underscore a role for immune monitoring in patients with HER2-positive IBC to identify vulnerable populations at risk of treatment failure.
目前缺乏识别接受曲妥珠单抗和化疗治疗后 HER2 阳性浸润性乳腺癌（IBC）治疗失败风险的免疫特征。
确定完全治疗的 HER2 阳性 IBC 患者中循环抗 HER2 CD4+阳性（CD4+）T 辅助 1 型（Th1）免疫是否与复发相关。
设计、地点和参与者：在一家三级转诊中心进行假设生成的探索性转化分析，中位（四分位间距）随访 44（31）个月，完全治疗的 HER2 阳性 IBC 患者。通过干扰素-γ（IFN-γ）酶联免疫斑点测定，使用与 6 个 HER2 衍生的 II 类混杂肽脉冲的外周血单核细胞来检测抗 HER2 Th1 反应。
Th1 反应指标包括抗 HER2 反应性、反应谱（反应肽数量）和 6 个肽的累积反应（斑点形成细胞[SFC]/106 细胞）。将治疗前患者的抗 HER2 Th1 反应（用作免疫基线）与完成曲妥珠单抗和化疗的患者进行比较；在后一组中，根据复发情况进行分层分析。复发定义为任何局部或远处乳房事件或两者兼有。Cox 回归分析估计了抗 HER2 Th1 反应性分层的瞬时复发风险（即无病生存[DFS]）。
在 95 例 HER2 阳性 IBC 患者中（中位[范围]年龄，49[24-85]岁；22 例为治疗前，73 例接受曲妥珠单抗和化疗），观察到抗 HER2 Th1 反应性降低（复发 25 例[8%]，非复发 48 例[83%]；P <.001）、平均（标准差）反应谱（0.1[0.1]比 1.5[0.2]；P <.001）和平均（标准差）累积反应（14.8[2.0]比 80.2[11.0] SFC/106 细胞；P <.001）在复发患者（n = 25）中与无复发患者（n = 48）相比。在控制混杂因素后，抗 HER2 Th1 反应性仍与复发独立相关（P <.001）。这种免疫差异是由抗 HER2 CD4+T-bet+IFN-γ+（Th1）而不是 CD4+GATA-3+IFN-γ+（Th2）或 CD4+CD25+FoxP3+（Treg）表型介导的，而不是由于免疫无能。当根据 Th1 反应性对接受曲妥珠单抗联合化疗的患者进行分层时，Th1 无反应患者的无病生存率（中位时间，47 比 113 个月；P <.001）比 Th1 反应患者差（危险比，16.9[95%CI，3.9-71.4]；P <.001）。
抗 HER2 Th1 反应降低是完全治疗的 HER2 阳性 IBC 患者复发的新免疫相关性。这些数据强调了对 HER2 阳性 IBC 患者进行免疫监测以识别治疗失败风险高的脆弱人群的作用。
