Department of Oncology, Region Jönköping County, Jönköping, Sweden.
Department of Clinical Sciences Lund, Division of Oncology, Lund University, Lund, Sweden.
Breast Cancer Res. 2020 Dec 23;22(1):140. doi: 10.1186/s13058-020-01364-w.
Tumour-infiltrating lymphocytes (TILs) are of important prognostic and predictive value in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) and triple-negative breast cancer (TNBC), but their clinical relevance in oestrogen receptor-positive/HER2-negative (ER+/HER2-) remains unknown. The primary study aim was to analyse the prognostic effect of TILs on the BC-free interval (BCFi) in premenopausal patients stratified by BC subtypes. The secondary aim was to investigate if TILs are predictive of tamoxifen (TAM) benefit.
Archival tissues from primary breast tumours were collected from patients from the SBII:2pre trial, in which 564 premenopausal women were randomised to 2 years of adjuvant TAM or no systemic treatment, regardless of hormone receptor status. TILs were scored on whole tissue sections from 447 patients with available ER status. Tumours were divided into ER+/HER2-, HER2+ and TNBC subtypes by immunohistochemistry and in situ hybridisation. The prognostic value of TILs was analysed in systemically untreated patients (n = 221); the predictive information was investigated in the ER+ subgroup (n = 321) by cumulative incidence curves and Cox regression analyses. The median follow-up was 28 years.
High (≥ 50%) infiltration of TILs was a favourable prognostic factor in terms of BCFi (univariable analysis: hazard ratio (HR) 0.40; 95% confidence interval (CI) 0.22-0.71; P = 0.002). Similar effects were observed across all BC subtypes. The effect of adjuvant TAM was stronger in patients with ER+ tumours and TILs < 50% (HR 0.63; 95% CI 0.47-0.84; P = 0.002) than in patients with high immune infiltration (≥ 50%) (HR 0.84; 95% CI (0.24-2.86); P = 0.77). However, evidence for differential effects of TAM in categories of TILs, i.e. interaction, was weak.
We demonstrate a long-term favourable prognostic value of high infiltration of TILs in a cohort of premenopausal BC patients and the positive prognostic effect was extended to the ER+/HER2- subgroup. A beneficial effect of TAM in ER+ patients was observed in patients with tumours of low TIL infiltration, but evidence for a treatment predictive effect was weak.
This trial is registered in the ISRCTN database, trial ID: ISRCTN12474687 .
肿瘤浸润淋巴细胞（TILs）在人表皮生长因子受体 2 阳性（HER2+）乳腺癌（BC）和三阴性乳腺癌（TNBC）中具有重要的预后和预测价值，但它们在雌激素受体阳性/HER2 阴性（ER+/HER2-）中的临床相关性尚不清楚。主要研究目的是分析 TILs 在按 BC 亚型分层的绝经前患者中对 BC 无复发生存期（BCFi）的预后影响。次要目的是研究 TILs 是否可以预测他莫昔芬（TAM）的获益。
从 SBII:2pre 试验中的原发性乳腺肿瘤的存档组织中收集了可获得 ER 状态的 447 例患者中有 TILs 评分的组织切片。564 例绝经前妇女被随机分配接受 2 年辅助 TAM 或无全身治疗，无论激素受体状态如何。通过免疫组化和原位杂交将肿瘤分为 ER+/HER2-、HER2+和 TNBC 亚型。在未接受系统治疗的患者（n=221）中分析 TILs 的预后价值；通过累积发生率曲线和 Cox 回归分析在 ER+亚组（n=321）中研究预测信息。中位随访时间为 28 年。
高（≥50%）TIL 浸润是 BCFi 的有利预后因素（单变量分析：风险比（HR）0.40；95%置信区间（CI）0.22-0.71；P=0.002）。在所有 BC 亚型中均观察到类似的效果。在 ER+肿瘤和 TILs<50%的患者中（HR 0.63；95%CI 0.47-0.84；P=0.002），TAM 的作用强于在高免疫浸润（≥50%）的患者（HR 0.84；95%CI（0.24-2.86）；P=0.77）。然而，TAM 在 TIL 分类中的作用存在差异的证据较弱，即交互作用。
我们在绝经前 BC 患者队列中证明了高 TIL 浸润具有长期有利的预后价值，并且这种积极的预后影响扩展到了 ER+/HER2-亚组。在 ER+患者中观察到 TAM 有获益作用，但其在 TIL 浸润较低的患者中获益作用的证据较弱。
本试验在 ISRCTN 数据库中注册，试验 ID：ISRCTN86551034。
