Breast radiologic complete response is associated with favorable survival outcomes after neoadjuvant chemotherapy in breast cancer

BackgroundThe aim of this study was to examine the accuracy of radiologic complete response (rCR) in predicting pathologic complete response (pCR), and determine whether rCR is a predictor of favorable survival outcomes.Materials and methodsWe retrospectively reviewed breast cancer patients treated with neoadjuvant chemotherapy (NAC) followed by surgery from September 2007 to June 2016. Breast lesions and axillary nodes were measured by MRI and categorized into either disappeared (breast rCR) or residual disease (breast non-rCR) and either normalized (axillary rCR) or abnormal findings (axillary non-rCR) in the axillary nodes. Correlation between rCR and pCR were compared using Cohen’s Kappa statistics, and the recurrence-free survival (RFS) and overall survival (OS) rates were calculated by the Kaplan-Meier method.ResultsOut of the 1017 eligible patients, 287 (28.2%) achieved breast pCR, 165 (16.2%) achieved breast rCR, 529 (52.0%) had axillary pCR, and 274 (26.9%) achieved axillary rCR. The correlation between a breast rCR and pCR showed a Cohen’s Kappa value of 0.459, and between axillary rCR and pCR, the value was 0.384. During a median follow-up time of 48.0 months, the 5-year RFS rates were 90.6% for breast rCR, and 69.2% for breast non-rCR. The 5-year RFS rates were 82.3% for axillary rCR, and 68.8% for axillary non-rCR. Patients without breast rCR had a 2.4-fold significant increase in the risk of recurrence (p = 0.004) compared to patients with breast rCR.ConclusionAlthough rCR correlated with pCR by only moderate to fair degrees, breast rCR was a strong predictor for a favorable RFS outcome.     

The role of neoadjuvant chemotherapy for breast cancer treatment

Neoadjuvant chemotherapy has become popular, especially for patients with advanced breast cancer. The pros and cons of neoadjuvant chemotherapy for treating breast cancer patients are reviewed. The advantages of neoadjuvant chemotherapy are 1) overall survival and recurrence-free survival rate are the same as post-operative chemotherapy, 2) serves as an in vivo sensitivity test, 3) increases the rate of breast conserving therapy, 4) facilitates the study of cancer biology. On the other hand, the disadvantages of neoadjuvant chemotherapy are 1) it modifies the stage, 2) treatment delay of PD cases, 3) residual intraductal component may be left behind after breast conserving surgery, 4) there are some cases of over-treatment. Combination chemotherapy is one possible way to increase the pathological CR rate, although the optimal order and cycles have not been determined. To avoid residual cancer cells after breast conserving surgery, the shrinkage pattern should be evaluated by MRI. Core needle biopsy should be performed before neoadjuvant chemotherapy to avoid over-treatment. It is essential to develop more effective regimens and stratify patients based on predictive factors.     

乳腺癌新辅助化疗86例临床观察

目的：观察乳腺癌新辅助化疗的临床效果,并探讨其临床价值。方法：2004年6月-2007年2月收治乳腺癌患者86例,予以新辅助化疗（rIThpC方案）,即：多西紫杉醇（艾素）100mg,d1;吡柔比星60mg,d1;环磷酰胺0．8g,d1。21d为1周期,2—5个周期后观察客观有效率、病理缓解率及新辅助化疗前后免疫组化指标的变化。结果：新辅助化疗后临床完全缓解（cCR）者19例,占22．09％,部分缓解（cPR）者51例,占59．30％,病情稳定（SD）者16例,占18．60％,无疾病进展（PD）患者;病理学完全缓解（pCR）者7例,占8．14％。21例患者新辅助化疗后的ER、PR、C-erbB-2的阳性表达率均低于新辅助化疗前,但未达到统计学差异（P〉0．05）。结论：乳腺癌新辅助化疗可以有效的缩小肿瘤,降低肿瘤分期,提高行改良根治术及保乳术几率,逆转可能存在的全身转移,为化疗方案提供药敏依据;新辅助化疗可使乳腺癌患者ER、PR、C-erbB-2的阳性表达降低,临床应根据术前免疫组化结果制定相关术后辅助治疗方案,才可能使患者有更大的获益。     

Treg细胞和IDO在HPV感染相关宫颈疾病组织中表达及意义

目的 探讨HPV感染相关宫颈疾病患者宫颈组织中Treg细胞和吲哚胺2,3-二氧酶(IDO)的表达及其临床意义.方法 对194例患者行HPV检测、宫颈TCT检查及宫颈病理学检查,然后按病变程度分为正常宫颈(对照组)、HPV阴性(HPV-)宫颈炎、HPV阳性(HPV+)宫颈炎、CINⅠ、CINⅡ、CINⅢ和宫颈癌6组实验组,应用Q-PCR、流式细胞术,检测各组宫颈组织中Treg细胞和吲哚胺2,3-二氧酶(IDO)的表达水平.结果 宫颈癌中Treg细胞占CD4+ T细胞的比例及IDO表达水平高于其他组;CINⅢ、CINⅡ 、CINⅠ及HPV(+)宫颈炎组Treg细胞比例高于HPV(-)宫颈炎组及对照组;CINⅢ及CINⅡ组宫颈组织中IDO mRNA表达水平高于CINⅠ、HPV(+)宫颈炎、HPV(-)宫颈炎组及对照组.结论 高危型HPV感染持续存在,Treg细胞数增加,促进宫颈病变进行性发展;HPV感染的CINⅢ、CINⅡ及宫颈癌组织中,IDO呈过表达;IDO和Treg细胞在宫颈癌免疫逃逸机制中发挥重要作用.     

新辅助化疗对乳腺癌细胞凋亡和增殖的影响

目的：观察乳腺癌新辅助化疗后癌细胞凋亡及增殖程度的变化,判断化疗疗效.方法：新辅助化疗手术标本44例和术前未接受化疗的对照组37例,进行Ki67及PCNA免疫组织化学染色和TUNEL原位细胞凋亡检测,并进行统计学处理.结果：化疗组Ki67、PCNA和AI的阳性细胞数比率分别为11.8%、31.3%和69.8%,对照组分别为21.6%、62.8%和52.8%,化疗组和对照组相比均有显著性差异.结论：新辅助化疗能抑制乳腺癌细胞的增殖,诱导凋亡.     

影像学评估乳腺癌新辅助化疗反应的研究进展

传统用于评估肿瘤对于新辅助化疗反应的常规成像方式有一定的局限性,功能成像能够早期预测新辅助化疗反应,从而个性化的指导治疗。但目前对于新辅助化疗随访患者的影像学评估方法并无标准。本文旨在讨论用于评价乳腺癌新辅助化疗患者化疗反应情况的各种影像学方法尤其是功能成像的准确性、优势、局限性和未来发展方向。     

Predictive markers of response to neoadjuvant chemotherapy in breast cancer

Several randomized prospective studies on breast cancer patients have proved the safety of neoadjuvant chemotherapy. These trials have also demonstrated that tumor down staging does indeed improve the eligibility for breast conservative surgery without increasing local recurrence rates with possibly an improved survival. However, complete pathologic remissions are noted in only 3–30% of patients. About 20% of patients do not benefit from different chemotherapy regimens currently in use and are thus subjected to toxic drugs. This often leads to progression of disease and thereby the surgeon may lose a window of opportunity to obtain durable locoregional control of disease. Identification of predictive markers associated with pathologic complete response can help to distinguish patients with high or low probability of a response to treatment so that an individualized treatment plan can be implemented. It could also streamline the development of new alternative regimens for those who are unlikely to benefit from existing drugs. It is expected that a combination of markers will be more informative than a single one. So far, several factors have been studied as predictors for response to cytotoxic treatment, viz., tumor size, hormone (estrogen and progesterone) receptor status, tumor type and differentiation, HER2/cerB-2, tumor proliferation Ki-67, apoptosis related genes p53, bcl-2 and BAX; certain subgroups of breast cancer, and the latest in this category is gene expression profiling. However, in terms of prediction of drug responsiveness, data reported are still very limited.This review aims to discuss the current relevant literature on the subject.     

Optimal timing of surgery following breast cancer neoadjuvant chemotherapy: A systematic review and meta-analysis

BackgroundAdministration of chemotherapy before breast surgery has the potential to reduce the risk of distant recurrence by targeting micrometastasis as well as allowing a more minimalistic approach to surgical intervention. We performed a systematic review to determine the optimum timing of surgery post breast cancer neoadjuvant chemotherapy (NACT).MethodsThe primary outcome was to determine whether the timing of surgery post NACT impacted overall survival (OS) and disease-free survival (DFS). We compared patient outcomes between those who had surgery within 8 weeks of completion of NACT to those that had surgery after 8 weeks. An outcome comparison between <4 weeks and 4–8 weeks was also performed. Secondary outcome included complete pathological response (pCR) post NACT. A meta-analysis was performed using the Mantel-Haenszel method.ResultsFive studies, including 8794 patients were eligible for inclusion. Patients that had surgery within 8 weeks of completion of NACT had a statistically significant improved OS(OR 0.47, 95% c. i 0.34–0.65) and DFS(OR 0.71 (95% c. i 0.52–0.98, P = 0.04). There were no survival advantages associated with having surgery less than 4 weeks post completion of NACT (OR 0.78, 95% c. i 0.46–1.33, P = 0.37). There was no difference in pCR rate between those that had surgery <4 weeks and 4–8 weeks (OR 1.01, 95% c. i 0.80–1.28, P = 0.93).ConclusionThis meta-analysis shows that the optimum timing of surgery post completion of NACT is 4–8 weeks as it is associated with increased OS and DFS.     

Breast-conserving treatment after neoadjuvant chemotherapy in large breast cancer

Several recent trials have demonstrated that neoadjuvant chemotherapy can allow more patients to successfully undergo breast-conserving treatment (BCT), and does not confer a survival disadvantage compared with standard adjuvant chemotherapy. In addition, the pathological response of primary breast tumors to neoadjuvant chemotherapy appears to be a surrogate marker for patient outcome. In our series, during the period from May 1995 to December 2000, 86 patients with tumors between 3.1 and 6.0 cm in diameter received epirubicin-based neoadjuvant chemotherapy. There were 55 (64.0%) responders and ultimately 64 patients (74.4%) were treated with BCT. The margin positive rate was 14.1%(9/64), similar to the rate after BCT for early-stage breast cancers, the largest diameter of which was smaller than 3 cm. At a median follow-up of 30 months, only 3 patients in the BCT group have developed local recurrence; the local recurrence rate appears to be comparable to that after BCT for early stage breast cancers. Long term follow-up is required, however, to establish whether this procedure is a safe alternative to mastectomy for patients with large breast cancers.     

The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer

Purpose To compare the prognostic significance of proliferation, as assessed by Ki67 expression, in breast cancer before and after neoadjuvant chemotherapy. Methods A retrospective search of a prospectively maintained clinical database was performed to identify patients treated with neoadjuvant chemotherapy at the Royal Marsden Hospital. The expression of Ki67 was assessed using immunohistochemistry in pre-therapy core-needle biopsy and post-therapy surgical excision specimens. The following factors were considered pre- and post-chemotherapy for their relationship with relapse-free and overall survival: age, menstrual status, T and N stage, pre-therapy operability, Ki67, ER, PgR, HER2, grade, histological subtype, vascular invasion, clinical response, chemotherapy regimen, type of surgery performed, adjuvant therapy, pathological tumour size and nodal involvement. Results In a matched cohort of 103 patients, on multivariate analysis of relapse-free survival, post-therapy Ki67 was the only significant independent prognostic factor. On multivariate analysis for overall survival, both pre- and excision Ki67 were significant independent predictors but the latter showed a stronger prognostic impact. The highest and lowest tertiles of excision Ki67 had different prognosis for both 5-year relapse-free (27% vs. 77%) and overall (39% and 93%) survival. In a cohort of 284 patients with only excision samples, post-therapy Ki67 was a significant independent prognostic factor on multivariate analysis. Conclusion Post-chemotherapy Ki67 is a strong predictor of outcome for patients not achieving a pathological complete response.     

Metabolomics approach for predicting response to neoadjuvant chemotherapy for breast cancer

Breast cancer is a clinically heterogeneous disease, which necessitates a variety of treatments and leads to different outcomes. As an example, only some women will benefit from chemotherapy. Identifying patients who will respond to chemotherapy and thereby improve their long-term survival has important implications to treatment protocols and outcomes, while identifying non responders may enable these patients to avail themselves of other investigational approaches or other potentially effective treatments. In this study, serum metabolite profiling was performed to identify potential biomarker candidates that can predict response to neoadjuvant chemotherapy for breast cancer. Metabolic profiles of serum from patients with complete (n = 8), partial (n = 14) and no response (n = 6) to chemotherapy were studied using a combination of nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography–mass spectrometry (LC–MS) and statistical analysis methods. The concentrations of four metabolites, three (threonine, isoleucine, glutamine) from NMR and one (linolenic acid) from LC–MS were significantly different when comparing response to chemotherapy. A prediction model developed by combining NMR and MS derived metabolites correctly identified 80% of the patients whose tumors did not show complete response to chemotherapy. These results show promise for larger studies that could result in more personalized treatment protocols for breast cancer patients.     

Ki-67在乳腺癌新辅助化疗中的作用及临床意义

新辅助化疗主要应用于局部晚期乳腺癌的治疗,疗效评价常用的指标为临床上缓解和病理学上缓解的程度.Ki-67是与细胞分裂增殖有关的核蛋白,已广泛应用于各种肿瘤的诊断及预后.多项临床研究资料表明Ki-67在判断乳腺癌新辅助化疗是否有效中显示出潜在的价值,现就Ki-67在乳腺癌新辅助化疗中的作用及临床意义作一综述.     

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 lymphadenectomy for the staging of clinical axillary node-negative breast cancer before neoadjuvant chemotherapy

Background

Several authors reported sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NC). Nevertheless, the ideal time of SLNB is still a matter of debate.

Methods

We evaluated the feasibility and the accuracy of SLNB before NC using a combined procedure (blue dye and radio-labelled detection) before NC. Axillary lymph node dissection (ALND) was performed after completion of NC in a homogeneous cohort study with clinically axillary node-negative breast cancer.

Results

Among the 20 women who had metastatic SLNB (65%), 4 (20%) had additional metastatic node on ALND. By contrast, all the 11 women who had no metastatic SLNB had no involved nodes in the ALND. The SLN identification rate before NC was 100% with any false negative.

Conclusions

SLNB before NC is a feasible and an accurate diagnostic tool to predict the pre-therapeutic axilla status. These findings suggest that ALND may be avoided in patients with a negative SLNB performed before NC.     

新辅助化疗对乳腺癌患者调节性T细胞的影响

目的探讨新辅助化疗对乳腺癌患者外周血中CD4+CD25+Foxp3+调节性T细胞(Treg细胞)的影响。方法采集68例乳腺癌患者新辅助化疗前1d和化疗后第10天的外周静脉血,应用流式细胞仪检测外周血中Treg细胞及CD3+、CD4+及CD8+T细胞占T淋巴细胞的百分比。定量资料分别采用独立样本或配对样本t检验进行统计分析。结果化疗前,乳腺癌患者外周血Treg细胞占T淋巴细胞的百分比较健康对照组明显增高[(4.77±0.76)%比(0.68%±0.36)%,t=21.176,P=0.000]。化疗后CD4+/CD8+较化疗前升高[(1.95±0.72)%比(1.19±0.43)%,t=8.280,P=0.000];化疗后Treg细胞较化疗前明显降低[(1.59±0.58)%比(4.77±0.76)%,t=19.041,P=0.000]。化疗有效组Treg细胞较无效组明显降低,差异有统计学意义(t=8.227,P=0.000)。结论新辅助化疗可调控乳腺癌患者机体的肿瘤免疫耐受,改善其免疫功能,从而达到治疗肿瘤的效果。     

血清HER2-ECD水平在乳腺癌新辅助化疗中的应用价值分析

背景与目的：人类表皮生长因子受体-2（human epidermal growth factor receptor-2,HER2）是一种原癌基因所表达的蛋白,HER2阳性往往预示着肿瘤进展快、容易发生淋巴结或血道转移,对新辅助化疗不敏感,预后不佳。本研究通过对乳腺癌患者血清HER2胞外段（extracellular domain,ECD）水平与患者临床新辅助化疗的反应性的比较,来评估血清HER2-ECD在新辅助化疗评估中的价值。方法：收集507例乳腺癌患者的治疗前血清样本,利用χ2检验比较血清HER2-ECD与患者年龄、分期、组织雌激素受体、孕激素受体、Ki-67及HER2的关系,对其中48例HER2表达阳性的行新辅助化疗的乳腺癌患者予以随访,单因素分析治疗前后血清HER2-ECD水平变化与新辅助化疗疗效之间的关系。结果：通过对507例患者血清HER2-ECD和临床病理特征的比较发现,在年龄>50岁、Ⅲ~Ⅳ期、组织雌激素受体（-）、孕激素受体（-）、Ki-67>20%及HER2（+）的患者中血清HER2-ECD阳性率较高。对48例组织HER2阳性的患者随访发现,血清HER2-ECD在治疗2个周期后即出现大幅下降,从18.10 ng/mL（13.20~28.95 ng/mL）降低到11.20 ng/mL（9.80~12.75 ng/mL）（P<0.01）。对48例患者进行疗效评估发现,新辅助化疗2个周期后血清HER2-ECD阴性的患者其客观缓解率（94.7%,36/38）显著高于治疗后血清HER2-ECD阳性的患者（60.0%,6/10）（P<0.05）。结论：乳腺癌患者血清HER2-ECD升高与其年龄、分期、组织雌激素受体、孕激素受体及Ki-67相关,且新辅助化疗2个周期后的血清HER2-ECD水平对新辅助化疗的疗效有一定的评估作用。     

生存素乳腺癌耐药蛋白和人表皮生长因子受体2基因的表达与乳腺癌新辅助化疗疗效的关系

目的 探讨生存素(Survivin)、乳腺癌耐药蛋白(BCRP)以及人表皮生长因子受体2(HER-2)基因表达对乳腺癌TE方案新辅助化疗疗效的预测价值.方法 对56例乳腺癌患者行TE方案新辅助化疗,应用RT-PCR法检测TE方案化疗前后Survivin、BCRP和HER-2 mRNA的表达差异,并结合化疗疗效进行相关性分析.结果 56例乳腺癌患者经TE方案新辅助化疗后的总有效率为71.4％.全组完全缓解5例,病理完全缓解4例,部分缓解35例,稳定13例,进展3例.Survivin mRNA的阳性表达率由化疗前的60.7％降至化疗后的35.7％ (P =0.008);BCRP mRNA的阳性表达率由化疗前的37.5％降至化疗后的19.6％(P=0.036);HER-2 mRNA的阳性表达率由化疗前的41.1％降至化疗后的21.4％ (P =0.025).Survivin或BCRP单独阴性表达的患者化疗的有效率均较阳性表达者高(均P＜0.05).HER-2 mRNA的单独表达状况与化疗疗效无关(P =0.144).Survivin、BCRP和HER-2 mRNA均为阴性表达的患者化疗疗效高于其他各组(P =0.003).在乳腺癌组织中,Survivin、BCRP和HER-2 mRNA的表达之间不存在相关关系(P＞0.05).结论 联合检测Survivin、BCRP和HER-2的表达可作为预测乳腺癌TE方案新辅助化疗敏感性的分子生物学指标.