肿瘤浸润性淋巴细胞比例在乳腺癌新辅助化疗中的意义

目的 探讨肿瘤浸润性淋巴细胞比例与乳腺癌新辅助化疗疗效的关系。方法 收集南京医科大学第一附属医院2010年12月—2013年11月期间接受新辅助化疗后可确认手术切除的59例女性乳腺癌患者资料,采用肿瘤浸润淋巴细胞计数评分检测化疗前每个患者的肿瘤内与间质内淋巴细胞计数总得分及术后间质内淋巴细胞计数得分,并采用Miller和Payne（MP）治疗反应评价方法评价术后乳腺癌组织的病理治疗反应,统计分析两者间的关系。结果 浸润淋巴细胞高比例组（3~6级）的新辅助化疗有效率明显高于低比例组（0~2级）,差异具有统计学意义（P＝0.001),化疗后间质淋巴细胞比例提高组化疗有效率高于比例无变化组,差异具有统计学意义（P＝0.031)。结论 肿瘤浸润淋巴细胞和化疗反应之间存在较强的相关性,肿瘤浸润性淋巴细胞可望成为预测新辅助化疗疗效的一个重要参数。     

肿瘤浸润淋巴细胞在三阴性乳腺癌新辅助化疗预测价值中的研究进展

三阴性乳腺癌（triple negative breast cancer,TNBC）是一种具有高度侵袭性特征的乳腺癌,总体预后不良。肿瘤浸润淋巴细胞（tumor infiltrating lymphocytes,TILs）在肿瘤微环境（tumor microenvironment,TME）中发挥重要作用,可通过细胞免疫调节作用起到对肿瘤细胞增进或抑制。新辅助化疗（neoadjuvant chemotherapy,NAC）是TNBC常见的且有效的治疗手段,其可以通过缩小原发肿瘤达到降期保乳、保腋窝或使“不可手术乳腺癌”转变为“可手术乳腺癌”,为患者治疗提供更多可选的临床思路。目前,TNBC的NAC疗效及预后的预测价值是临床研究的重点和难点,肿瘤浸润淋巴细胞作为重要的生物免疫标志物,在这方面具有较为重要的意义。本文将对TILs在TNBC的NAC疗效及预后方面的预测价值进行综述。     

肿瘤浸润淋巴细胞对食管鳞癌术后辅助化疗的影响

目的；探讨肿瘤浸润淋巴细胞对食管鳞癌术后辅助化疗的影响。方法：９７例食管鳞癌患者根河后随机分为辅助化疗组（顺铂加５～氟脲嘧啶）和单纯手术组。比较两组患者生存率，分析肿瘤淋巴细胞浸润与辅助化疗患者生存斯的关系。结果：辅助化疗组２年、５年生存率（７４．０３％，２６．９％）低于单纯手术组（８２．０２％、４９．６％，Ｐ〈０．０５＿。辅助化疗组生存期与肿瘤的生长方式、炎细胞浸润程度、淋巴结转移率和ＴＮＭ分期     

CD8+T淋巴细胞浸润与三阴性乳腺癌新辅助化疗疗效的关系

目的 探讨三阴性乳腺癌组织CD8+T淋巴细胞浸润（CD8+Tils）的特点与患者预后的关系。方法 回顾性分析术前行新辅助化疗的126例三阴性乳腺癌患者的临床病理资料,采用免疫组织化学法分析CD8+Tils与临床病理特征的关系;Kaplan-Meier法绘制生存曲线,Cox风险比例回归模型分析患者无病生存时间（DFS）的预后影响因素。结果 高密度CD8+Tils浸润与年龄<60岁、病理高分级、临床高分期显著相关（P<0.05）。CD8+Tils高密度浸润患者术后pCR率较低密度组高（66.7% vs. 19.8%, P=0.000）。高密度组中位DFS显著长于CD8+Tils低密度组（49 vs. 25月, P<0.05）。多因素分析显示病理高分级、肿瘤直径>2 cm 、淋巴结转移、脉管侵犯、CD8+Tils低密度浸润均为预后不良影响因素（P<0.05）,CD8+Tils为独立预后因素。结论 CD8+Tils有可能是三阴性乳腺癌患者独立预后指标,高密度浸润患者术后pCR率高、DFS长、远期疗效更优。     

肿瘤浸润淋巴细胞对食管鳞癌术后辅助化疗的影响

目的 :探讨肿瘤浸润淋巴细胞对食管鳞癌术后辅助化疗的影响。方法 :97例食管鳞癌患者根治术后随机分为辅助化疗组 (顺铂加 5-氟脲嘧啶 )和单纯手术组。比较两组患者生存率 ,分析肿瘤淋巴细胞浸润与辅助化疗患者生存期的关系。结果 :辅助化疗组 2年、5年生存率 ( 74 0 3%、2 6 9% )低于单纯手术组 ( 82 0 2 %、4 9 6% ,P <0 0 5)。辅助化疗组生存期与肿瘤的生长方式、炎细胞浸润程度、淋巴结转移率和TNM分期有关 (P <0 .0 5)。特别是肿瘤 <3cm、分化程度Ⅰ级、膨胀型生长、无淋巴结转移或Ⅰ ⅡA期时 ,肿瘤间质常伴有明显炎细胞浸润 ,辅助化疗组与单纯手术组相比患者生存率降低更为明显 (P <0 .0 5)。反之 ,淋巴结转移率 >50 %和Ⅳ期患者肿瘤间质缺乏炎细胞浸润 ,辅助化疗组 2年生存率与单纯手术组比较分别提高于 2 2 2 2 %和 37 50 % (P <0 0 5)。两组其他参数相比生存率无明显差异 (P >0 0 5)。结论 :肿瘤浸润淋巴细胞是影响辅助化疗和预后的一个重要因素 ,可作为食管鳞癌患者根治术后选择合理治疗方案的指标     

2023 ASCO肿瘤浸润淋巴细胞预测乳腺癌疗效的研究进展

在2023年美国临床肿瘤学会（ASCO）大会上,肿瘤浸润淋巴细胞（tumor infiltrating lymphocytes,TILs)成为关注的焦点,大会主旨报告中的A505、A507、A508分别报道TILs在Luminal型、三阴性及HER2阳性乳腺癌的抗肿瘤治疗疗效方面具有较好的预测作用。壁报会议中也有多项研究围绕TILs在不同亚型乳腺癌中的作用展开探索。研究报告提示TILs与乳腺癌进展转移相关,TILs可作为乳腺癌临床生物标志物。全文就2023 ASCO关于TILs在乳腺癌疗效预测作用的最新进展进行报道。     

外周血淋巴细胞和单核细胞比值与乳腺癌新辅助化疗疗效关联性

目的新辅助化疗(neoadjuvant chemotherapy,NAC)已成为局部晚期乳腺癌的标准治疗选择,然而化疗前缺乏有效的疗效预测评估手段。部分研究表明,外周血淋巴细胞与单核细胞比值(lymphocyte-monocyte ratio,LMR)与多种癌症的预后相关。本研究探讨化疗前外周血LMR对乳腺癌新辅助化疗疗效的预测价值。方法收集西南医科大学乳腺外科2018-01-31—2019-03-08接受新辅助化疗后可确认手术切除的55例女性乳腺癌患者资料,采用受试者工作曲线,将约登指数最大值对应的外周血LMR作为截断值,分为高、低比值组。并采用乳腺癌新辅助化疗后组织学评估评价系统(Miller-Payne分级系统)评价术后乳腺癌组织的病理治疗反应,统计分析两者间的关系。结果NAC疗效与肿瘤大小(χ^2=0.007,P=0.931)、淋巴结转移情况(χ^2=2.208,P=0.154)、组织分级(χ^2=0.931,P=0.335)、临床分期(χ~2=0.026,P=0.871)、病理分型(χ^2=5.519,P=0.063)、Ki-67水平(χ^2=0.004,P=0.953)无关联性;仅与LMR比值有关联性,外周血LMR高比例组(≥4.87)的新辅助化疗有效率为90.6%,高于低比例组(<4.87)的43.5%,差异有统计学意义,χ^2=14.420,P<0.001。多因素Logistic回归分析显示,化疗前高LMR是影响新辅助化疗的保护性因素,OR=0.073,95%CI为0.016~0.333,P=0.001。结论化疗前高外周血LMR患者新辅助化疗疗效可能更佳。     

乳腺癌新辅助化疗中肿瘤标志物检测的临床意义

目的检测肿瘤标志物在新辅助化疗乳腺癌中的表达,探讨新辅助化疗患者中ER、PR、c-erbB2和Ki67的表达及临床意义.方法用免疫组织化学法检测ER、PR、c-erbB2和Ki67在89例新辅助化疗乳腺癌组织中的表达状况,分析上述指标与化疗的关系.结果新辅助化疗总有效率89.9%,其中完全缓解CR32.6%,部分缓解PR57.3%,病理完全缓解pCR17.9%,疾病稳定SD10.5%,无恶化病例.ER/PR表达与疗效有关（P〈0.05）,c-erbB2、Ki67表达与化疗疗程无关.结论激素受体阴性者对新辅助化疗的敏感性较高,新辅助化疗肿瘤标志物的检测可以为临床评价疗效判断预后提供依据.     

外周血淋巴细胞和单核细胞比值对三阴性乳腺癌新辅助化疗疗效的预测价值

目的:探讨外周血淋巴细胞和单核细胞比值(lymphocyte-to-monocyte ratio,LMR)对三阴性乳腺癌(triple negative breast cancer,TNBC)患者新辅助化疗(neoadjuvant chemotherapy,NAC)疗效的预测价值.方法:收集2017年01月至2019年...     

乳腺癌新辅助化疗的疗效预测因子

乳腺癌的新辅助化疗已经成为乳腺癌治疗策略的一部分,并逐渐应用于早期乳腺癌[1],通过减少肿瘤体积,部分可达到保乳目的 ,而且理论上可以减少微小转移灶的播散,并观察药物的疗效。新辅     

Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy.

PURPOSE: Neoadjuvant chemotherapy for breast cancer creates new possibilities for the analysis of biological factors in the tumor and/or host, which may play a role in the response to treatment. In this study we analyzed whether changes in local antitumor immunity take place after neoadjuvant paclitaxel therapy and if they correlate with response to treatment. EXPERIMENTAL DESIGN: Neoadjuvant chemotherapy (paclitaxel, 200 mg/m2 q2w, 4 treatments) was followed by definitive surgical management. Histological sections from the pre- and post-treatment surgical specimens of 25 patients were analyzed for the extent of lymphocytic infiltration and presence of tumor infiltrating lymphocytes (TILs). The cumulative apoptotic response in the tumor after the first dose of paclitaxel was also studied in 10 of 25 patients. RESULTS: Pretreatment lymphocytic infiltrate in the tumor was minimal in the majority of patients and showed no relationship with clinical response. In the patients without TILs before treatment, development of TILs after treatment was noted in 0/3 (0%) patients with stable disease, 3/12 (25%) patients with clinical partial response, and 4/6 (67%) patients with clinical complete response and pathological residual disease. These correlated with the tumor cell apoptotic response to the first dose of paclitaxel. CONCLUSIONS: These results suggest that development of TILs after treatment correlates with clinical response to neoadjuvant paclitaxel therapy. The possible mechanism(s) whereby neoadjuvant chemotherapy may lead to induction of antitumor T cells is discussed. Immunological processes may influence the response of breast cancer patients to neoadjuvant treatment.     

Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy

The androgen receptor (AR) has been shown to be of potential prognostic importance in retrospective cohorts. We evaluated immunohistochemical AR expression on a tissue microarray of 673 core biopsies from primary breast cancer patients treated with neoadjuvant docetaxel/doxorubicin/cyclophosphamide (TAC) chemotherapy in the prospective GeparTrio phase-III trial. AR was detected in 53.2% of tumours. Lowest AR expression was detected in triple-negative breast cancers (TNBC) with 21.2%. Highest AR expression was observed in Luminal A-like tumours with 67%. In AR-positive tumours, pathological complete response (pCR) rate was 12.8% compared to 25.4% in AR-negative tumours (P < 0.0001). In multivariate analysis, AR independently predicted pCR (OR 1.86; 95% CI [1.16-2.79] P = 0.0086). Overall patients with an AR-positive tumour had a significant better disease-free (DFS) (AR-positive 78.9% vs. AR-negative 72.5%; log-rank P = 0.0329) and overall survival (OS) (88.8% vs. 82.7%; log-rank P = 0.0234) than those with AR-negative tumours. Stratified analysis revealed that in the TNBC subgroup, but not in the other subgroups defined by ER, PgR and HER2, AR expression predicted a better DFS (AR-positive 85.7% vs. AR-negative 65.5% log-rank P = 0.0544) and OS (95.2% vs. 76.2%; log-rank P = 0.0355). Within the non-pCR subgroup, AR positivity selected a group with a significant better DFS (P = 0.045) and OS (0.021) but not within the pCR group. Patients with an AR-negative tumour have a higher chance of achieving a pCR than those with an AR-positive one. But, patients with AR-positive tumours have a better survival especially if they did not achieve a pCR.     

Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy

BackgroundFor primary triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), higher pretreatment tumor-infiltrating lymphocytes (TILs) correlates with increased pathologic complete response (pCR) rates, and improved survival. We evaluated the added prognostic value of residual disease (RD) TILs to residual cancer burden (RCB) in predicting survival post-NAC.Patients and methodsWe combined four TNBC NAC patient cohorts who did not achieve pCR. RD TILs were investigated for associations with recurrence-free survival (RFS), and overall survival (OS) using Cox models with stromal TILs as a continuous variable (per 10% increment). The likelihood ratio test was used to evaluate added prognostic value of RD TILs.ResultsA total of 375 RD TNBC samples were evaluable for TILs and RCB. The median age was 50 years, with 62% receiving anthracycline/taxane chemotherapy. The RCB class after NAC was 11%, 50%, and 39% for I, II, and III, respectively. The median RD TIL level was 20% (IQR 10–40). There was a positive correlation between RD TIL levels and CD8+ T-cell density (ρ = 0.41). TIL levels were significantly lower with increasing post-NAC tumor (P = 0.005), nodal stage (P = 0.032), but did not differ by RCB class (P = 0.84). Higher RD TILs were significantly associated with improved RFS (HR: 0.86; 95% CI 0.79–0.92; P < 0.001), and improved OS (HR: 0.87; 95% CI 0.80–0.94; P < 0.001), and remained significant predictors in multivariate analysis (RFS P = 0.032; OS P = 0.038 for OS). RD TILs added significant prognostic value to multivariate models including RCB class (P < 0.001 for RFS; P = 0.021 for OS). The positive prognostic effect of RD TILs significantly differed by RCB class for RFS (P_Int=0.003) and OS (P_Int=0.008) with a greater magnitude of positive effect observed for RCB class II than class III.ConclusionsTIL levels in TNBC RD are significantly associated with improved RFS and OS and add further prognostic information to RCB class, particularly in RCB class II.     

A gene signature to predict high tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple-negative breast cancer

BackgroundIn patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after neoadjuvant chemotherapy (NACT) is associated with better prognosis. Our objective was to develop a gene signature from pretreatment samples to predict the extent of TILs after NACT and then to test its prognostic value on survival.Patients and methodsUsing 99 pretreatment samples, we generated a four-gene signature associated with high post-NACT TILs. Prognostic value of the signature on distant relapse-free survival (DRFS) was first assessed on the training set (n = 99) and then on an independent validation set (n = 115).ResultsA four-gene signature combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 was developed in baseline samples to predict the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, this signature was associated with DRFS [hazard ratio (HR): 0.28, for a one-unit increase in the value of the four-gene signature, 95% confidence interval (CI): 0.13–0.63)]. In a multivariate analysis performed on an independent validation set, the four-gene signature was significantly associated with DRFS (HR: 0.17, 95% CI: 0.06–0.43). The four-gene signature added significant prognostic information when compared with the clinicopathologic pretreatment model (likelihood ratio test in the training set P = 0.004 and in the validation set P = 0.002).ConclusionsA four-gene signature predicts high levels of TILs after anthracycline-containing NACT and outcome in patients with TNBC and adds prognostic information to a clinicopathological model at diagnosis.     

Sentinel node biopsy in breast cancer patients treated with neoadjuvant chemotherapy

A sentinel node biopsy (SNB) has been proved to be an accurate method to estimate the axillary lymph node status as a replacement for axillary lymph node dissection (AxLND) in patients with early breast cancer who have not been treated with neoadjuvant chemotherapy (NAC). We examined the feasibility and accuracy of performing SNB after NAC. Seventy breast cancer patients treated with NAC were enrolled in the current study during the period between March 2001 and June 2005. NAC performed preoperatively consisted of three to four times of CAF chemotherapy. Moreover, intra-arterial (subclavian artery and internal mammary artery) infusion of epirubicin and 5-fluorouracil was performed in addition to systemic CAF chemotherapy once to three times in patients with large breast tumors or bulky axillary lymph node metastases. The sentinel nodes were successfully identified in 63 out of 70 patients (identification rate: 90%). The mean number of sentinel nodes removed per patient was 1.5 (range 1-6). Of the 43 patients in whom AxLND was performed after the sentinel nodes were identified, 19 (44.2%) had positive sentinel nodes. In 8 of those 19 patients, the sentinel node was the only cancer positive lymph node. Among the 24 patients who had negative sentinel nodes it was found that one patient had a confirmed false negative result, thus yielding a false negative rate of 5%, and a sensitivity of 95%. There was no false negative patient who had a clinically negative lymph node status (N0) before NAC (17 patients), whereas the false negative rate was 6.3% in the subgroup of patients with a clinically positive lymph node status (N1, N2) before NAC (26 patients). As a result, SNB after NAC is thus considered to be able to effectively predict the axillary lymph node status in patients with a clinically negative lymph node status before NAC.     

Prognostic value of Bcl‐2 in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy

We have analyzed the predictive/prognostic value of Bcl‐2 protein in breast cancer patients treated with neoadjuvant chemotherapy. One hundred and ten patients were submitted to two different chemotherapeutic regimens: a) 5‐fluorouracil, adriamycin or epirubicin, and cyclophosphamide (FAC/FEC) during 2–6 cycles before surgery and 3 or 4 additional cycles of FAC/FEC after surgery (n=40) and b) doxorubicin (D) 75mg/m2 or epirubicin (E) 120mg/m2 during 4 cycles before surgery, and 6 cycles of cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF) after surgery (n=70). Bcl‐2 expression, evaluated by immunohistochemistry, did not change significantly after chemotherapy and was not related to clinical/pathological response. In FAC/FEC group, Bcl‐2 positive expression after chemotherapy correlated with better disease free survival (DFS) and overall survival (OS) (P=0.008 and P=0.001). In D/E group, Bcl‐2 also correlated with better DFS and OS (P=0.03 and P=0.054) in the post‐chemotherapy biopsies. An unusual nuclear localization of Bax was observed in some biopsies, but this localization did not correlate with the tumor response or outcome of the patients. We found that a high Bcl‐2 expression had no predictive value but had prognostic value in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy.     

Sentinel lymph node biopsy in breast cancer patients treated with neoadjuvant chemotherapy

BACKGROUND:

Sentinel lymph node biopsy (SLNB) is a widely used staging method for patients with early breast cancer. Neoadjuvant chemotherapy modifies the anatomical conditions in the breast and axilla, and thus SLNB remains controversial in patients treated preoperatively. The aim of this study was to demonstrate the reliability and accuracy of this procedure in this particular group of patients.

METHODS:

The retrospective study analyzed medical records of patients diagnosed with primary breast cancer between the years 2005 and 2009. Of the patients treated by neoadjuvant therapy, 343 underwent lymphatic mapping to identify sentinel lymph nodes, and these were included in the analysis.

RESULTS:

The overall detection rate of sentinel lymph nodes was 80.8%. It was strongly influenced by clinical lymph node status (significantly higher success rate in lymph node‐negative patients); higher detection rates were also associated with age <50 years, estrogen receptor positivity, lower proliferation index, and absent lymphovascular space invasion. The false‐negative rate was 19.5% and was only marginally significantly dependent on lymphovascular space invasion. The overall accuracy of the method was 91.5%.

CONCLUSIONS:

By using the present technique, sentinel lymph node biopsy cannot be recommended as a reliable predictor of axillary lymph node status when performed at the authors' institution after neoadjuvant chemotherapy. Infrequent use of blue dye for lymphatic mapping, low number of resected sentinel lymph nodes, and absence of any selection among patients included in the study could be the main factors responsible for the low detection rate and high false‐negative rate. Cancer 2011;. © 2011 American Cancer Society.     

Prediction of survival after neoadjuvant chemotherapy for breast cancer by evaluation of tumor-infiltrating lymphocytes and residual cancer burden

Background

The tumor immune environment not only modulates the effects of immunotherapy, but also the effects of other anticancer drugs and treatment outcomes. These immune responses can be evaluated with tumor-infiltrating lymphocytes (TILs), which has frequently been verified clinically. On the other hand, residual cancer burden (RCB) evaluation has been shown to be a useful predictor of survival after neoadjuvant chemotherapy (NAC). In this study, RCB and TILs evaluations were combined to produce an indicator that we have termed “RCB-TILs”, and its clinical application to NAC for breast cancer was verified by subtype-stratified analysis.

Methods

A total of 177 patients with breast cancer were treated with NAC. The correlation between RCB and TILs evaluated according to the standard method, and prognosis, including the efficacy of NAC, was investigated retrospectively. The RCB and TILs evaluations were combined to create the “RCB-TILs”. Patients who were RCB-positive and had high TILs were considered RCB-TILs-positive, and all other combinations were RCB-TILs-negative.

Results

On multivariable analysis, being RCB-TILs-positive was an independent factor for recurrence after NAC in all patients (p < 0.001, hazard ratio = 0.048), triple-negative breast cancer (TNBC) patients (p = 0.018, hazard ratio = 0.041), HER2-positive breast cancer (HER2BC) patients (p = 0.036, hazard ratio = 0.134), and hormone receptor-positive breast cancer (HRBC) patients (p = 0.002, hazard ratio = 0.081).

Conclusions

The results of the present study suggest that RCB-TILs is a significant predictor for breast cancer recurrence after NAC and may be a more sensitive indicator than TILs alone.