Dieci M V, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, Ficarra G, Mathieu M C, Delaloge S, Curigliano G, Andre F
INSERM Unit U981, Institut Gustave Roussy, Villejuif, France; Department of Oncological and Surgical Sciences, University of Padua, Padua; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova.
Early Drug Development for Innovative Therapies Division, Department of Medicine, Istituto Europeo di Oncologia, Milano.
Ann Oncol. 2014 Mar;25(3):611-618. doi: 10.1093/annonc/mdt556. Epub 2014 Jan 8.
BACKGROUND: There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Three hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%. RESULTS: TIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77-0.96, P = 0.01 and HR 0.85, 95% CI 0.75-0.98, P = 0.02 for Str-TIL and It-TIL, respectively] and overall survival (HR 0.86, 95% CI 0.77-0.97, P = 0.01 and HR 0.86, 95% CI 0.75-0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06-0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample. CONCLUSIONS: The presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse.
背景：在新辅助治疗环境中，需要开发治疗效果的替代指标，以加速药物研发并根据结果对患者进行分层。临床前研究表明，化疗可诱导抗肿瘤免疫反应。为了开发新的药物疗效替代指标，我们评估了三阴性乳腺癌（TNBC）患者新辅助化疗（NACT）后肿瘤浸润淋巴细胞（TIL）对残留疾病的预后价值。 患者与方法：回顾性纳入三家不同医院的304例NACT后有残留疾病的TNBC患者。对化疗后手术标本的苏木精和伊红染色切片进行瘤内（It-TIL）和基质（Str-TIL）TIL评估。如果It-TIL和/或Str-TIL>60%，则病例分类为高TIL。 结果：278例患者的TIL可评估。在多变量模型中，连续的It-TIL和Str-TIL变量是强有力的预后因素，无论是无转移生存[风险比（HR）分别为0.86，95%置信区间（CI）0.77-0.96，P = 0.01和HR 0.85，95%CI 0.75-0.98，P = 0.02，分别为Str-TIL和It-TIL]还是总生存（HR分别为0.86，95%CI 0.77-0.97，P = 0.01和HR 0.86，95%CI 0.75-0.99，P = 0.03，分别为Str-TIL和It-TIL）。高TIL患者（n = 27）的5年总生存率为91%（95%CI 68%至97%），低TIL患者为55%（95%CI 48%至61%）（HR 0.19，95%CI 0.06-0.61，对数秩P = 0.0017）。TIL的主要预后影响见于NACT后肿瘤负荷大的患者（残留肿瘤>2 cm和/或淋巴结转移）。除一例高TIL病例外，化疗前样本中的It-TIL和Str-TIL值均较低。 结论：NACT后残留疾病中TIL的存在与TNBC患者较好的预后相关。该参数可能代表新辅助治疗环境中测试研究药物的药物疗效新替代指标，以及选择复发高风险患者的新预后标志物。
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