Background The presence of stromal tumor-infiltrating lymphocytes (TILs) is associated with increased pathologic complete response (pCR) and improved outcomes in HER2-positive early-breast cancer (BC) treated with anti-HER2-based chemotherapy. In the absence of chemotherapy, the association of TILs with pCR following anti-HER2 therapy-only is largely unknown. Patients and methods The PAMELA neoadjuvant trial treated 151 women with HER2-positive BC with lapatinib and trastuzumab [and hormonal therapy if hormone receptor (HR)-positive] for 18 weeks. Percentage of TILs and tumor cellularity were determined at baseline (N = 148) and at day 15 (D15) of treatment (N = 134). Associations of TILs and tumor cellularity with pCR in the breast were evaluated. A combined score based on tumor cellularity and TILs (CelTIL) measured at D15 was derived in PAMELA, and validated in D15 samples from 65 patients with HER2-positive disease recruited in the LPT109096 neoadjuvant trial, where anti-HER2 therapy-only was administer for 2 weeks, then standard chemotherapy was added for 24 weeks. Results In PAMELA, baseline and D15 TILs were significantly associated with pCR in univariate analysis. In multivariable analysis, D15 TILs, but not baseline TILs, were significantly associated with pCR. At D15, TILs and tumor cellularity were found independently associated with pCR. A combined score (CelTIL) taking into account both variables was derived. CelTIL at D15 as a continuous variable was significantly associated with pCR, and patients with CelTIL-low and CelTIL-high scores had a pCR rate of 0% and 33%, respectively. In LPT109096, CelTIL at D15 was found associated with pCR both as a continuous variable and as group categories using a pre-defined cut-off (75.0% versus 33.3%). Conclusions On-treatment TILs, but not baseline TILs, are independently associated with response following anti-HER2 therapy-only. A combined score of TILs and tumor cellularity measured at D15 provides independent predictive information upon completion of neoadjuvant anti-HER2-based therapy. Clinical trial number NCT01973660.

中文翻译：

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基于无化学双重HER2阻断治疗的HER2阳性乳腺癌中肿瘤细胞和肿瘤浸润淋巴细胞（CelTIL）的病理反应的预测模型。

背景基质细胞浸润淋巴细胞（TILs）的存在与基于抗HER2的化学疗法治疗的HER2阳性早期乳腺癌（BC）的病理完全反应（pCR）增加和预后改善有关。在没有化疗的情况下，仅抗HER2治疗后TIL与pCR的关联尚不清楚。患者和方法PAMELA新辅助试验对151名HER2阳性BC，拉帕替尼和曲妥珠单抗[如果激素受体（HR）呈阳性的激素治疗）的妇女进行了18周的治疗。在治疗的基线（N = 148）和治疗的第15天（D15）（N = 134）确定TIL的百分比和肿瘤细胞的形成。评估了TIL和乳腺癌细胞与pCR的关联。在PAMELA中，根据在D15时测得的肿瘤细胞和TIL（CelTIL）得出综合评分，并在LPT109096新辅助试验中招募的65例HER2阳性患者的D15样本中进行了验证，该试验中仅进行抗HER2治疗2周，然后加入标准化疗24周。结果在单因素分析中，PAMELA中的基线和D15 TIL与pCR显着相关。在多变量分析中，D15 TIL（而非基线TIL）与pCR显着相关。在第15天，发现TIL和肿瘤细胞增多与pCR独立相关。得出将两个变量都考虑在内的综合得分（CelTIL）。在第15天，CelTIL作为连续变量与pCR显着相关，而CelTIL低和CelTIL高分的患者的pCR率分别为0％和33％。在LPT109096中，发现D15处的CelTIL与pCR相关联，既作为连续变量又作为小组类别（使用预先定义的临界值）（75.0％对33.3％）。结论接受治疗的TILs（而非基线TILs）与仅抗HER2治疗后的反应独立相关。在新辅助抗HER2疗法完成后，在D15时测得的TILs积分和肿瘤细胞数量的总和可提供独立的预测信息。临床试验编号NCT01973660。