Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, England.
Duke University Medical Center, Durham, North Carolina.
JAMA Oncol. 2018 Apr 1;4(4):564-568. doi: 10.1001/jamaoncol.2017.3168.
Epidermal growth factor receptor (EGFR) (HER1) signaling depends on ligand binding and dimerization with itself or other HER receptors. We previously showed in a randomized trial that high EGFR ligand expression is predictive of panitumumab benefit in advanced colorectal cancer. Tumor expression of HER3 may further refine the RAS wild-type (wt) population benefitting from anti-EGFR agents.
To examine HER3 messenger RNA expression as a prognostic and predictive biomarker for anti-EGFR therapy in a randomized clinical trial of panitumumab.
DESIGN, SETTING, AND PARTICIPANTS: The study was a prospectively planned retrospective biomarker study of pretreatment samples from the PICCOLO trial that tested the addition of panitumumab to irinotecan therapy in patients with KRAS wt advanced colorectal cancer who experienced failure with prior fluoropyrimidine treatment. HER3 was assessed as a prognostic marker, then as a predictive biomarker in patients with RAS wt, first as a continuous variable and then as a binary (high vs low) variable. Relationship with MEK-AKT pathway mutations and EGFR ligands epiregulin and amphiregulin (EREG/AREG) were also assessed.
Primary end point was progression-free survival (PFS); secondary end points were response rate and overall survival (OS).
In 308 patients (mean age at randomization, 61.6 years; 193 men) higher HER3 was weakly prognostic for OS (hazard ratio [HR] per 2-fold change, 0.91; 95% CI, 0.83-0.99; P = .04) but not PFS (HR, 0.93; 95% CI, 0.83-1.05; P = .25). Higher HER3 was predictive, being associated with prolonged PFS on irinotecan plus panitumumab (IrPan) (HR, 0.71; 95% CI, 0.61-0.82; P < .001), but not irinotecan (HR, 0.96; 95% CI, 0.82-1.13; P = .65) in patients with RAS wt, with significant interaction between biomarker and treatment (P = .001). Similar interaction was seen for OS (P = .004). In an exploratory binary model, dividing the population at the 66th percentile, HER3 was predictive of panitumumab benefit: in patients with high HER3 expression, median PFS was 8.2 months (IrPan) vs 4.4 months (irinotecan) (HR, 0.33; 95% CI, 0.19-0.58; P < .001). Patients with low HER3 expression gained no benefit in PFS: 3.3 months (IrPan) vs 4.3 months (irinotecan) (HR, 0.96; 95% CI, 0.67-1.38; P = .84), with significant interaction (P = .002). The binary model was also predictive for OS, with significant interaction (P = .01). Combining HER3 and ligand data, patients with HER3-high, AREG/EREG-high tumors gained markedly from panitumumab (PFS HR, 0.24; 95% CI, 0.11-0.51; P < .005 and OS HR, 0.36; 95% CI, 0.18-0.73; P = .004). Conversely, patients with HER3-low, AREG/EREG-low tumors did not benefit (PFS HR, 1.14; 95% CI, 0.73-1.79; P = .57 and OS HR, 1.44; 95% CI, 0.92-2.26; P = .11).
High HER3 expression identified patients with RAS wt who gained markedly from panitumumab, and those who did not, with statistically significant biomarker-treatment interactions for PFS and OS. This finding provides insight into the mechanism of anti-EGFR agents and is of potential clinical utility.
表皮生长因子受体 (EGFR)（HER1）信号取决于配体结合及其自身或其他 HER 受体的二聚化。我们之前在一项随机试验中表明，高 EGFR 配体表达可预测晚期结直肠癌患者接受 panitumumab 治疗的获益。HER3 的肿瘤表达可能进一步细化从抗 EGFR 药物中获益的 RAS 野生型（wt）人群。
在 panitumumab 的随机临床试验中，作为预后和预测生物标志物，检查 HER3 信使 RNA 表达。
设计、设置和参与者：该研究是 PICCOLO 试验的前瞻性计划回顾性生物标志物研究，该试验测试了在 KRAS wt 晚期结直肠癌患者中添加 panitumumab 联合伊立替康治疗，这些患者在氟嘧啶治疗失败前接受了治疗。HER3 被评估为预后标志物，然后在 RAS wt 患者中作为预测生物标志物，首先作为连续变量，然后作为二进制（高与低）变量。还评估了与 MEK-AKT 通路突变和 EGFR 配体 epiregulin 和 amphiregulin (EREG/AREG) 的关系。
主要终点是无进展生存期 (PFS)；次要终点是反应率和总生存期 (OS)。
在 308 名患者（随机分组时的平均年龄为 61.6 岁；男性 193 名）中，较高的 HER3 对 OS 有微弱的预后作用（每增加 2 倍的风险比 [HR]，0.91；95%CI，0.83-0.99；P = .04），但对 PFS 没有影响（HR，0.93；95%CI，0.83-1.05；P = .25）。较高的 HER3 具有预测性，与伊立替康联合 panitumumab（IrPan）的 PFS 延长相关（HR，0.71；95%CI，0.61-0.82；P < .001），但与伊立替康（HR，0.96；95%CI，0.82-1.13；P = .65）在 RAS wt 患者中没有相关性，生物标志物和治疗之间存在显著的相互作用（P = .001）。OS 也存在类似的相互作用（P = .004）。在一个探索性的二进制模型中，将人群分为第 66 个百分位数，HER3 可预测 panitumumab 的获益：在高 HER3 表达的患者中，中位 PFS 为 8.2 个月（IrPan）与 4.4 个月（伊立替康）（HR，0.33；95%CI，0.19-0.58；P < .001）。低 HER3 表达的患者在 PFS 中没有获益：3.3 个月（IrPan）与 4.3 个月（伊立替康）（HR，0.96；95%CI，0.67-1.38；P = .84），存在显著的相互作用（P = .002）。该二进制模型也可预测 OS，存在显著的相互作用（P = .01）。结合 HER3 和配体数据，HER3 高、AREG/EREG 高的肿瘤患者从 panitumumab 中获益显著（PFS HR，0.24；95%CI，0.11-0.51；P < .005 和 OS HR，0.36；95%CI，0.18-0.73；P = .004）。相反，HER3 低、AREG/EREG 低的肿瘤患者没有获益（PFS HR，1.14；95%CI，0.73-1.79；P = .57 和 OS HR，1.44；95%CI，0.92-2.26；P = .11）。
高 HER3 表达可识别出从 panitumumab 中获益显著的 RAS wt 患者，以及那些不能获益的患者，PFS 和 OS 存在显著的生物标志物-治疗相互作用。这一发现为抗 EGFR 药物的作用机制提供了深入的了解，具有潜在的临床应用价值。
