Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, PSL Research University, Institut Curie, Paris.
INSERM, U932 Immunity and Cancer, Paris.
Ann Oncol. 2017 Sep 1;28(9):2233-2240. doi: 10.1093/annonc/mdx309.
The role of tumor-infiltrating lymphocytes (TILs) in breast cancer has been extensively studied over the last decade. High TILs levels have been associated with pathological response rate in the neoadjuvant setting and with better outcomes in the adjuvant setting. However, little attention has been paid to changes in TILs and residual TIL levels after neoadjuvant chemotherapy (NAC). We investigated TIL levels before, after chemotherapy, and their dynamics during treatment; and we assessed the correlation of these levels with response to NAC and prognosis.
We identified 175 patients with primary HER2-positive breast cancers receiving NAC+/- trastuzumab between 2002 and 2011. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Univariate and multivariate analyses were carried out to assess the association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival.
Baseline TIL levels were not significantly associated with pCR. TIL levels decreased during treatment in 78% of the patients. The magnitude of the decrease was strongly associated with pCR. After chemotherapy, TIL levels were high in tumors displaying aggressive patterns (high residual cancer burden score, mitotic index >22, tumor cellularity >5%). In the population with residual disease, TIL levels >25% at the end of NAC were significantly associated with an adverse outcome (TILs >25%, HR = 7.98, P = 0.009) after multivariate analyses including BMI, post-NAC mitotic index and tumor grade.
A decrease in TIL levels during chemotherapy was positively associated with response to treatment. In tumor failing to achieve pCR, post-NAC lymphocytic infiltration was associated with higher residual tumor burden and adverse clinical outcome. Further studies are required to characterize immune infiltration in residual disease to identify candidates who could benefit from second-line therapy trials including immune checkpoint inhibitors.
过去十年中，肿瘤浸润淋巴细胞（TILs）在乳腺癌中的作用已得到广泛研究。高 TILs 水平与新辅助治疗中的病理缓解率以及辅助治疗中的更好结局相关。然而，在新辅助化疗（NAC）后 TIL 水平和残留 TIL 水平的变化很少受到关注。我们研究了化疗前、化疗后以及治疗过程中的 TIL 水平，并评估了这些水平与 NAC 反应和预后的相关性。
我们确定了 175 名接受 NAC+/-曲妥珠单抗治疗的原发性 HER2 阳性乳腺癌患者，这些患者于 2002 年至 2011 年间接受治疗。对微活检标本和配对的手术样本进行了间质淋巴细胞浸润评估。进行了单变量和多变量分析，以评估临床和病理因素与病理完全缓解（pCR）和无病生存之间的关联。
基线 TIL 水平与 pCR 无显著相关性。在 78%的患者中，TIL 水平在治疗过程中下降。下降幅度与 pCR 密切相关。在化疗后，在显示侵袭性模式（残留癌症负担评分高、有丝分裂指数>22、肿瘤细胞密度>5%）的肿瘤中，TIL 水平较高。在残留疾病患者中，NAC 结束时 TIL 水平>25%与不良结局显著相关（TILs>25%，HR=7.98，P=0.009），多变量分析包括 BMI、NAC 后有丝分裂指数和肿瘤分级。
化疗过程中 TIL 水平的下降与治疗反应呈正相关。在未能达到 pCR 的肿瘤中，NAC 后淋巴细胞浸润与更高的残留肿瘤负荷和不良临床结局相关。需要进一步研究以确定残留疾病中的免疫浸润特征，以确定哪些患者可能受益于二线治疗试验，包括免疫检查点抑制剂。
