Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of residual breast cancer

<b>Background:</b> Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes. It is not known, however, whether treatment with various chemotherapeutic agents with different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in residual cancer. <b>Methods:</b> One hundred and twenty breast carcinoma cases with residual disease that were treated with one of three types of pre-operative chemotherapy regimens were selected for the study. The percentage of StrTIL was evaluated in pretreatment core biopsies (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL). TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL. <b>Results:</b> When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we detected significant StrTIL increase independently of the treatment applied. Based on distant metastases-free survival analysis, both post-StrTIL and ΔStrTIL was found to be independent prognostic factor in HR negative cases. <b>Conclusions:</b> Significant increase of StrTIL in the residual disease was observed in patients treated with the highly (platinum), moderately (cyclophosphamide) and marginally mutagenic chemotherapeutic agents (taxane, anthracycline). Increase in StrTIL in residual cancer compared to pretreatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.

**研究背景：** 化疗药物多具有致突变性。学界认为，化疗可通过诱导突变相关新表位这一机制，增加肿瘤浸润淋巴细胞的数量。然而，针对不同致突变能力的各类化疗药物，是否会在残余癌组织中诱导产生数量存在显著差异的基质肿瘤浸润淋巴细胞（stromal tumor-infiltrating lymphocytes, StrTIL），目前尚无定论。**研究方法：** 本研究纳入120例经三种术前化疗方案之一治疗后仍存在残余病灶的乳腺癌病例。分别在治疗前的核心穿刺活检标本（pre-StrTIL）以及治疗后的手术切除肿瘤标本（post-StrTIL）中，对基质肿瘤浸润淋巴细胞的占比进行评估。通过计算post-StrTIL与pre-StrTIL的差值，得到肿瘤浸润淋巴细胞变化量（ΔStrTIL）。**研究结果：** 对三组治疗队列的pre-StrTIL与post-StrTIL进行分析后发现，无论接受何种化疗方案，患者的StrTIL水平均出现显著升高。基于无远处转移生存分析结果，在激素受体（HR）阴性的病例中，post-StrTIL与ΔStrTIL均被证实为独立预后因素。**研究结论：** 接受高致突变性（铂类）、中致突变性（环磷酰胺）及弱致突变性化疗药物（紫杉类、蒽环类）治疗的患者，其残余癌组织中的StrTIL水平均出现显著升高。在HR阴性乳腺癌病例中，与治疗前肿瘤组织相比，残余癌组织的StrTIL水平升高与更长的无远处转移生存期显著相关。