Breast cancer spatial heterogeneity in near-infrared spectra and the prediction of neoadjuvant chemotherapy response

We describe an algorithm to calculate an index that characterizes spatial differences in broadband near-infrared [(NIR), 650-1000 nm] absorption spectra of tumor-containing breast tissue. Patient-specific tumor spatial heterogeneities are visualized through a heterogeneity spectrum function (HS). HS is a biomarker that can be attributed to different molecular distributions within the tumor. To classify lesion heterogeneities, we built a heterogeneity index (HI) derived from the HS by weighing the HS in specific NIR absorption bands. It is shown that neoadjuvant chemotherapy (NAC) response is potentially related to the tumor heterogeneity. Therefore, we correlate the heterogeneity index obtained prior to treatment with the final response to NAC. From a pilot study of 15 cancer patients treated with NAC, pathological complete responders (pCR) were separated from non-pCR according to their HI (-44 ± 12 and 43 ± 17, p = 3 × 10(-8), respectively). We conclude that the HS function is a biomarker that can be used to visualize spatial heterogeneities in lesions, and the baseline HI prior to therapy correlates with chemotherapy pathological response.     

超声显像技术对乳腺癌新辅助化疗后病理反应性的预测作用

探讨不同超声显像技术在预测乳腺癌新辅助化疗(neoadjuvant chemotherapy,NAC)病理反应性方面的研究进展。目前用于预测NAC病理反应性的超声技术有二维灰阶超声、多普勒超声、超声造影、弹性成像、近红外光谱及光散射成像。超声可通过上述不同的技术模式从肿物形态、血流、硬度、及氧含量等不同方面对乳腺癌的生物学特性进行评估,进而对NAC后病理反应性进行预测,其在该领域应用前景广阔。     

乳腺癌新辅助化疗组织学疗效评价研究

目的 探讨乳腺癌新辅助化疗后根治标本的组织学疗效评价标准.方法 收集2005年6月至2007年6月乳腺癌新辅助化疗154例档案,其中改良根治术139例,保乳手术15例.化疗结束后4周内实施乳腺根治术.按照Miller and Payne(MP)分级系统的标准规范进行取材、制片和按该系统组织学疗效评价标准进行分级评价,同时与既往应用的肿瘤治疗反应评价系统(既往评价系统)进行比较.对所有病例进行常规随访.应用SPSS 13.0软件进行统计学处理.结果 (1)154例手术标本所获得的组织学疗效评价信息:MP分级系统1级12例(7.8%)、2级33例(21.4%)、3级64例(41.6%)、4级31例(20.1%)、5级14例(9.1%);既往评价系统分别为轻度治疗反应51例(33.1%)、中度治疗反应71例(46.1%)、重度治疗反应32例(20.8%).MP分级系统与既往评价系统各组病例比例之间存在统计学相关(X2=186.660,P<0.01).(2)154例患者中147例获得随访信息(95.5%),随访时间16～38个月;其中14例出现术后复发、远处转移或死亡.MP分级系统5个级别组与患者生存状态均相关(X2=11.612,P=0.020),既往评价系统3个级别组与患者生存状态均无关(X2=0.881,P=0.644).结论 MP分级系统可以用于肿瘤化疗后的组织学疗效评价,与预后相关.     

In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival

Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. However, the predictive value of tumour-infiltrating lymphocytes after neoadjuvant chemotherapy for breast cancer remains unknown. We hypothesized that the nature of the immune infiltrate following neoadjuvant chemotherapy would predict patient survival. In a series of 111 consecutive HER2- and a series of 51 non-HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy, we studied by immunohistochemistry tumour infiltration by FOXP3 and CD8 T lymphocytes before and after chemotherapy. Kaplan-Meier analysis and Cox modelling were used to assess relapse-free survival (RFS) and overall survival (OS). A predictive scoring system using American Joint Committee on Cancer (AJCC) pathological staging and immunological markers was created. Association of high CD8 and low FOXP3 cell infiltrates after chemotherapy was significantly associated with improved RFS (p = 0.02) and OS (p = 0.002), and outperformed classical predictive factors in multivariate analysis. A combined score associating CD8/FOXP3 ratio and pathological AJCC staging isolated a subgroup of patients with a long-term overall survival of 100%. Importantly, this score also identified patients with a favourable prognosis in an independent cohort of HER2-negative breast cancer patients. These results suggest that immunological CD8 and FOXP3 cell infiltrate after treatment is an independent predictive factor of survival in breast cancer patients treated with neoadjuvant chemotherapy and provides new insights into the role of the immune milieu and cancer.     

The CXCR4/CXCL12 axis in endometrial cancer

Chemokines and their receptors seem to act as important regulators of the metastatic cascade. CXCL12 and its receptor CXCR4 were shown to be involved in human cancer progression. There is increasing evidences suggesting that the expression of CXCR4 in human cancers is correlated with poor patient prognosis and that CXCR4 neutralization can prevent metastases in vivo. Here we tested the role of the CXCR4/CXCL12 axis in a neoplasia with a reduced risk of metastatic progression, such as human endometrial cancer. CXCR4 and CXCL12 mRNA expression was measured in 41 endometrial cancers and in corresponding not affected tissues. The expression of CXCR4 was predominant in endometrial cancer (P = 0.035) whereas CXCL12 was overexpressed in normal mucosae (P = 0.002). CXCR4 expression (P = 0.035), but not CXCL12, was significantly related to cancer differentiation. Endometrial cancer cells (HEC1A) were able to generate diffuse metastases in peritoneum, lung and liver of CD-1 nude mice, but the simultaneous treatment with a neutralizing anti-CXCR4 monoclonal antibody dramatically reduced the number and the size of metastases in the animals. In conclusion, our data seem to indicate that the CXCR4-CXCL12 axis can play a role in the progression of endometrial carcinoma and that specific therapies with antagonists of chemokines receptors could be of help in the treatment of metastatic patients.     

乳腺癌新辅助化疗后临床评价与病理评价的差异分析

目的 探讨乳腺癌新辅助化疗后,临床疗效评价与病理评价之间存在差异的病理学基础.方法 收集中国医学科学院肿瘤医院2005年6月至2007年12月施行乳腺癌新辅助化疗的209例.新辅助化疗前均行核芯针穿刺活检.化疗结束后4周内实施乳腺癌根治术.新辅助化疗前后均对乳腺原发灶进行临床体检、乳腺X线检查和(或)超声检查.实施新辅助化疗后,依实体瘤的疗效评价标准(RECIST,1.1版)对乳腺癌原发灶进行临床疗效评价,依Miller和Payne(MP)分级系统进行病理评价.应用SPSS 15.0软件分析临床评价与病理评价的相关性.结果 (1)新辅助化疗后依临床体检结果进行临床评价:完全缓解33例,部分缓解124例,疾病稳定41例,疾病进展11例.(2)新辅助化疗前后均行乳腺X线检查87例,依乳腺X线检查进行临床评价:完全缓解8例,部分缓解42例,疾病稳定37例.(3)新辅助化疗后MP分级病理评价:1级14例,2级35例,3级106例,4级36例,5级18例.(4)临床体检相关的临床评价与病理评价存在统计学相关性(x2=33.668,P=0.001),乳腺X线检查相关的临床评价与病理评价存在统计学相关性(x2=22.404,P=0.004).(5)新辅助化疗病理评价与X线检查相关临床评价存在差异的病理学改变有:残存浸润癌以脉管瘤栓为主要表现形式;伴有大片黏液湖形成的黏液腺癌;导管内癌残存,伴明显沙砾样钙化及周围组织的沙砾样钙化;间质结节状纤维化等.结论 乳腺癌新辅助化疗的临床评价与病理评价存在统计学相关性.两者之间的差异有相应的病理学基础.伴有大片黏液湖形成的黏液腺癌、导管内癌的残存伴沙砾样钙化及间质结节状纤维化可能是临床评价低估治疗疗效的原因之一;而残存癌表现为脉管瘤栓可能是临床评价高估治疗疗效的原因之一.     

乳腺癌新辅助化疗后临床评价与病理评价的差异分析

目的 探讨乳腺癌新辅助化疗后,临床疗效评价与病理评价之间存在差异的病理学基础.方法 收集中国医学科学院肿瘤医院2005年6月至2007年12月施行乳腺癌新辅助化疗的209例.新辅助化疗前均行核芯针穿刺活检.化疗结束后4周内实施乳腺癌根治术.新辅助化疗前后均对乳腺原发灶进行临床体检、乳腺X线检查和(或)超声检查.实施新辅助化疗后,依实体瘤的疗效评价标准(RECIST,1.1版)对乳腺癌原发灶进行临床疗效评价,依Miller和Payne(MP)分级系统进行病理评价.应用SPSS 15.0软件分析临床评价与病理评价的相关性.结果 (1)新辅助化疗后依临床体检结果进行临床评价:完全缓解33例,部分缓解124例,疾病稳定41例,疾病进展11例.(2)新辅助化疗前后均行乳腺X线检查87例,依乳腺X线检查进行临床评价:完全缓解8例,部分缓解42例,疾病稳定37例.(3)新辅助化疗后MP分级病理评价:1级14例,2级35例,3级106例,4级36例,5级18例.(4)临床体检相关的临床评价与病理评价存在统计学相关性(x2=33.668,P=0.001),乳腺X线检查相关的临床评价与病理评价存在统计学相关性(x2=22.404,P=0.004).(5)新辅助化疗病理评价与X线检查相关临床评价存在差异的病理学改变有:残存浸润癌以脉管瘤栓为主要表现形式;伴有大片黏液湖形成的黏液腺癌;导管内癌残存,伴明显沙砾样钙化及周围组织的沙砾样钙化;间质结节状纤维化等.结论 乳腺癌新辅助化疗的临床评价与病理评价存在统计学相关性.两者之间的差异有相应的病理学基础.伴有大片黏液湖形成的黏液腺癌、导管内癌的残存伴沙砾样钙化及间质结节状纤维化可能是临床评价低估治疗疗效的原因之一;而残存癌表现为脉管瘤栓可能是临床评价高估治疗疗效的原因之一.     

ALDH1 and tumor infiltrating lymphocytes as predictors for neoadjuvant chemotherapy response in breast cancer

Many studies have reported that Aldehyde dehydrogenase 1 (ALDH1) and tumor-infiltrating lymphocytes (TIL) are related to breast cancer prognosis. However, the clinical significance of ALDH1 and tumor-infiltrating immune cells in breast cancer has not been fully investigated in patients who received neoadjuvant chemotherapy (NAC). We studied the significance of the expression of ALDH1 and the population of TIL for predicting the prognosis and chemotherapeutic response of patients with breast cancer who had received NAC. Forty patients who underwent NAC were enrolled in this study. ALDH1 and TIL (T cells and tumor associated macrophages) were evaluated before and after NAC. The influences of ALDH1 expression status and TIL populations on both prognosis and chemotherapeutic response were evaluated. ALDH1 positivity was related to estrogen receptor (p?=?0.026) and progesterone receptor negativity (p?=?0.025). Positive change of ALDH1 after NAC tended to be associated with a poor NAC response (p?=?0.078). Patients with more CD8+ T cells before NAC and fewer CD68 (+) macrophages after NAC tended to have better OS, respectively (p?=?0.086, p?=?0.096). The chemotherapeutic response and prognosis of patients with breast cancer who received NAC are thought to be determined by the tumor microenvironment. Further research with more patients and a longer study period is needed.     

动态增强MRI对乳腺癌新辅助化疗的疗效评价及预测

【摘要】目的:探讨动态增强MRI评价和预测乳腺癌新辅助化疗（NAC）疗效的价值。方法:回顾性分析45例经手术病理 证实为浸润性乳腺癌并行术前NAC的患者资料。依据化疗前后组织病理学改变进行的疗效评价,将病人分为病理完全 缓解组和病理非完全缓解组。对比分析化疗前后两组动态增强MRI检查参数数值变化的差异,以病理反应性标准分组 为金标准,对其中有统计学意义的参数进行ROC曲线分析,并计算ROC曲线下面积（AUC）,评价各参数对NAC疗效的 评价效能,最后根据分析结果建立乳腺癌NAC疗效预测模型Logist P。结果:病理完全缓解组有16例患者,而病理非完 全缓解组有29例患者。两组间肿瘤最大经线变化率、肿瘤体积变化率、早期强化程度变化、时间信号强度曲线最大线性 斜率变化率、时间信号强度曲线类型的变化差异均有统计学意义（P<0.05）。最大经线变化率、肿瘤体积变化率、早期强化 程度变化、时间信号强度曲线最大线性斜率变化率、时间信号强度曲线类型的变化的AUC分别为0.711、0.759、0.711、 0.795、0.692,灵敏度/特异度分别为0.38/0.97、0.81/0.66、0.56/0.83、0.75/0.76、0.69/0.62,联合肿瘤体积变化率和最大线性 斜率变化率的Logist P模型的AUC为0.793（95%CI 0.644~0.942）。结论:早期动态增强MRI参数能用于评价和预测乳腺 癌NAC疗效。     

Dynamic contrast‐enhanced MRI texture analysis for pretreatment prediction of clinical and pathological response to neoadjuvant chemotherapy in patients with locally advanced breast cancer

The aim of this study was to investigate the potential of texture analysis, applied to dynamic contrast‐enhanced MRI (DCE‐MRI), to predict the clinical and pathological response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC) before NAC is started. Fifty‐eight patients with LABC were classified on the basis of their clinical response according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines after four cycles of NAC, and according to their pathological response after surgery. T₁‐weighted DCE‐MRI with a temporal resolution of 1 min was acquired on a 3‐T Siemens Trio scanner using a dedicated four‐channel breast coil before the onset of treatment. Each lesion was segmented semi‐automatically using the 2‐min post‐contrast subtracted image. Sixteen texture features were obtained at each non‐subtracted post‐contrast time point using a gray level co‐occurrence matrix. Appropriate statistical analyses were performed and false discovery rate‐based q values were reported to correct for multiple comparisons. Statistically significant results were found at 1–3 min post‐contrast for various texture features for the prediction of both the clinical and pathological response. In particular, eight texture features were found to be statistically significant at 2 min post‐contrast, the most significant feature yielding an area under the curve (AUC) of 0.77 for response prediction for stable disease versus complete responders after four cycles of NAC. In addition, four texture features were found to be significant at the same time point, with an AUC of 0.69 for response prediction using the most significant feature for classification based on the pathological response. Our results suggest that texture analysis could provide clinicians with additional information to increase the accuracy of prediction of an individual response before NAC is started. Copyright © 2014 John Wiley & Sons, Ltd.     

15-PGDH expression as a predictive factor response to neoadjuvant chemotherapy in advanced gastric cancer

Given the various clinical and pathologic responses to neoadjuvant chemotherapy (NACT) in gastric cancer (GC), potential biomarkers that reflecting the efficacy of NACT on GC should be investigated. The aim of this study was to investigate the 15-PGDH expression response to NACT in GC patients and its relationship with prognosis of GC. Immunohistochemical method was used to assess the level of 15-PGDH expression in 56 GC patients who received NACT before surgery and 46 patients who underwent surgical treatment without NACT as well as their corresponding adjacent non-neoplastic tissues. We found that there was no correlation of 15-PGDH expression between non-cancerous gastric tissues and GC tissues (P=0.519), while 15-PGDH expression level in NACT group was higher than that in nNACT group (P=0.015). In patients with NACT, the higher level of 15-PGDH expression was significantly associated with well-moderately differentiated grade (P=0.023), I/II stage (P=0.014) and with no lymph node metastasis (P=0.016). Moreover, statistically significant differences in overall survival (OS) were found among 15-PGDH expression (log-rank test, P<0.001) and TNM stage (log-rank test, P=0.032). Most importantly, expression of 15-PGDH was found to be an independent predictive factor by multivariate analysis (Hazard ratio (HR) 0.315 [0.120-0.827], P=0.019). These findings indicated that NACT could increase 15-PGDH expression in advanced GC patients, and 15-PGDH may serve as a candidate prognostic biomarker of advanced GC response to NACT.     

The pathological response to neoadjuvant chemotherapy with FOLFOX-4 for colorectal liver metastases: a comparative study

FOLFOX-4 (folinic acid/5-fluorouracil/oxaliplatin) chemotherapy is used to treat patients with colorectal liver metastases. We aimed to assess hepatic histopathological responses to neoadjuvant FOLFOX-4 chemotherapy in patients with colorectal liver metastases. We selected all patients (n = 54) treated with FOLFOX-4 for colorectal liver metastases between June 2002 and June 2005. Only 25 underwent hepatectomy and formed the study group. Histological responses were assessed in the study group and a matched control group (n = 25) that did not receive neoadjuvant chemotherapy. The median (IQR) body mass index in the study and control groups was 24 (22–26) and 24 (23–25) kg/m², respectively, (P = NS). Complete histological resolution of tumour occurred in six (24%) patients in the study group. Median residual tumour cellularity was less (35 vs 70%) and fibrosis greater (50 vs 5%) in patients in the study group when compared with controls (P < 0.001). The liver surrounding the tumour was steatotic in 17 (68%) patients in the study group and five (20%) controls (P = 0.001). Hepatic sinusoidal dilatation was more pronounced in patients in the study group than in controls (P < 0.001). The response to FOLFOX-4 was associated with tumour necrosis, fibrosis and inflammation. More than two thirds of patients undergoing hepatectomy after FOLFOX-4 had steatosis despite being non-obese.     

Pathological complete response and prognosis after neoadjuvant chemotherapy in patients with HER2-low breast cancer

BackgroundThe development of novel human epidermal growth factor receptor 2 (HER2) antibody drug conjugates brings encouraging opportunities for the treatment of HER2-low breast cancer. In this study, we investigated the clinical factors and prognosis of HER2-low breast cancer after neoadjuvant chemotherapy (NAC).MethodsData from patients diagnosed with HER2-zero or HER2-low breast cancer at a single center between January 2017 and December 2021 who underwent NAC followed by surgery were retrospectively reviewed. HER2 status was detected by immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH), and classified as HER2-zero (IHC 0), HER2-low (IHC 1+ or IHC 2+ and FISH–), and HER2-positive (IHC 3+ or IHC 2+ and FISH+). Baseline characteristics were analyzed and compared between the HER2-low and HER2-zero groups. Survival outcomes were analyzed using the Kaplan–Meier method with the log-rank test and Cox proportional-hazards regression analysis.ResultsThe sample comprised 132 patients with HER2-zero [n = 62 (47.0 %)] and HER2-low [n = 70 (53.0 %)] breast cancer. Relative to the HER2-zero group, the HER2-low group contained larger proportions of patients with hormone receptor (HR) positivity (37.1 % vs. 75.7 %, P < 0.001) and low nuclear grades and Ki-67 indices (both P < 0.05). The pathological complete response (pCR) rate was significantly lower in the HER2-low group than in the HER2-zero group (20.0 % vs. 37.1 %, P = 0.03). At the final follow-up [median 20 (range 4–66) months], patients with HER2-low status had significantly favorable disease-free survival (DFS) and overall survival (OS) outcomes relative to those with HER2-zero status (87.1 % vs. 71.0 %, P = 0.02 and 94.3 % vs. 82.3 %, P = 0.02, respectively). HER2-low status and pCR were independent prognostic factors for DFS [hazard ratio (HR) = 0.31, 95 % confidence interval (CI) 0.13–0.75, P = 0.009 and HR = 0.08, 95 % CI 0.01–0.67, P = 0.02, respectively].ConclusionThis analysis revealed that HER2-low status is associated significantly with HR positivity and low nuclear grades, Ki-67 indices, and pCR rate. It is also associated with favorable DFS and OS outcomes after NAC. HER2-low status and pCR are independent prognostic factors for DFS.