Clinical and pathological predictors of the response to neoadjuvant anthracycline chemotherapy in locally advanced breast cancer

Purpose The aim of this study is to determine clinical and histopathological characteristics correlated to responsiveness to anthracycline-based neoadjuvant chemotherapy in breast cancer. Patients and methods We studied primary tumor specimens with local advanced breast cancer from 40 patients. Patients received anthracycline-based chemotherapy. Neoadjuvant regimen consisted in 600 mg/m² 5-fluorouracil, 60 mg/m² doxorubicin, and 600 mg/m² cyclophosphamide (FAC). The World Health Organization criteria were used to classify the tumors. We performed immunohistochemical staining for ER, PgR, HER-2, PCNA (proliferation cell nuclear antigen), Ki-67, p53, and Bcl-2. Clinical and histopathological characteristics were associated with clinical response and histopathological changes induced by chemotherapy. Results The mean age was 47±14 yr. Twenty-three percent of patients were in stage IIB and 77% were in stages IIIA and IIIB. Seven percent of patients had progression of the disease. Stable disease was observed in 42% of patients and 45% had partial response. Only 7% of patients had a complete response. Factors associated with a better and major percentage of clinical response were the administration of doxorubicin-based chemotherapy, administration of more than three cycles, clinical N1, atypia, more than 10 mitosis per high-power field, moderate to severe SBR grade, and a major index of cellular proliferation. Conclusion We found that tumors with large volumes, N2 node status, low cellular proliferation rate, positive immunoreactivity to p53, and low differentiation grade have a lower response to neoadjuvant chemotherapy with anthracycline. These patients could benefit from a different chemotherapy scheme to obtain a better control and resection.     

MRI evaluation of primary chemotherapy response in breast cancer

The aim of this work was to evaluate the value of contrast enhanced MRI for determination of response to neoadjuvant chemotherapy (type FEC) in breast cancer according to two parameters: size of the enhancing tumor and the maximum relative enhancement curve (MRC) in the same tumor area. Twenty women with breast cancer (15 invasive ductal carcinomas and 5 invasive lobular carcinomas) T2 (n = 8) or T3 (n = 12) were evaluated by physical examination and MRI after a minimal of three courses of FEC and prior to surgery. Data from physical examination and imaging studies were compared to histopathological findings. Physical examination estimated correctly the residual tumor size in 45% of cases and MRI in 60% with 3 false negative cases. Among evaluated patients with MRI measurable residual tumor, tumor size was underestimated in 69% of the cases and overestimated in 31% of the cases. A MRC flattening was observed in 5 cases among the patients with a partial response or clinical stable disease correlated with a poor cellular density in the microscopic findings. MRI monitoring of chemotherapy response can be useful for guiding surgery. Therefore, underestimation of the residual tumor size and false negative rate are remaining problems.     

超声检查早期评价乳腺癌新辅助化疗疗效的临床研究

目的 探讨超声检查定量指标在早期评价乳腺癌新辅助化疗疗效中的价值。方法 收集在我院经超声引导下穿刺活检病理确诊的乳腺癌患者60例,共64个病灶。所有患者均行4～8个周期新辅助化疗后手术治疗。根据手术后病理组织检查结果, 将患者分为化疗有效组和无效组。分别在化疗前和化疗第1周期结束后3周（第2个周期开始前）进行超声检查。共观察4项定量指标：二维超声测量病灶最大径（D）、彩色多普勒测量最高血流速度（PSV）、阻力指数（RI）、弹性应变率比值（ESR）。采用配对样本t检验比较化疗前、后病灶4项指标的变化,绘制受试者工作特征（ROC）曲线并分析4项指标的灵敏度、特异度。结果 64个病灶中化疗有效组53例,化疗无效组11例。新辅助化疗后与化疗前相比,化疗有效组中D、PSV、RI、ESR的变化均有统计学意义（P＜0.001）,化疗无效组4项指标均无显著变化（P＞0.05）。根据ROC曲线分析拟合的数据,分别应用D缩小8.0％、PSV降低15.0％、RI下降3.6％及ESR下降15.7％为阈值,预测化疗有效的灵敏度为64.2％、63.4％、83.2％、88.7％,特异度为91.1％、100％、100％、100％。结论 通过超声监测D、PSV、RI和ESR的变化,可作为评价乳腺癌新辅助化疗早期疗效的可靠指标。     

Molecular predictors of response to chemotherapy in non-small cell lung cancer

Lung cancer is the leading cause of cancer-related mortality in the United States with 222,520 new cases and 157,300 deaths anticipated in 2010. The primary objective of any cancer treatment is to improve patient outcomes including overall survival and quality of life while minimizing treatment toxicity. As our knowledge of the molecular mechanisms involved in the pathogenesis of lung cancer evolves, improved methods of therapeutic selection may help clinicians better realize these goals. Such selection may be accomplished by examining biomarkers within patients' tumors that may provide prognostic information such as risk of recurrence in early stage disease or predict benefit from specific therapies regardless of disease stage. Three such biomarkers have emerged--excision repair cross-complementation group 1, the regulatory subunit of the ribonucleotide reductase enzyme, and thymidylate synthase--and are actively being evaluated in patients with non-small cell lung cancer. This review will focus on the role of these biomarkers as predictive and/or prognostic markers in the selection of chemotherapy regimens in non-small cell lung cancer patients.     

Clinical and pathological predictors of recurrence in breast cancer patients achieving pathological complete response to neoadjuvant chemotherapy

IntroductionDespite the excellent prognosis associated with pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), some patients still develop recurrence. Here, we investigated the outcomes of breast cancer patients with pCR, as well as the clinical and pathological predictors of cancer recurrence in these patients.Materials and methodsOf the 1599 breast cancer patients treated with NAC, we evaluated 394 patients who achieved pCR between January 2007 and December 2016. pCR was defined as no evidence of invasive cancer in breast. Residual in situ ductal and axillary lymph node diseases were not considered. We analyzed the outcomes using the Kaplan–Meier method. We assessed the association of clinical and pathological predictors with cancer recurrence using the cox proportional hazards regression model.ResultsThe median follow-up time was 63 months. The 5-year disease-free survival rate was 92.3%. Cancer recurrence was observed in 28 patients (7.1%): local recurrence 8 patients (2.0%), visceral metastasis 10 patients (2.5%), and brain metastasis 10 patients (2.5%). Brain metastases were found in patients with HER2 type breast cancer. The significant predictors of cancer recurrence were HER2 positivity (p = 0.04), clinical tumor size (p < 0.01), and lymph node metastasis (p < 0.01) before NAC on univariate analysis and only lymph node metastasis on multivariate analysis.ConclusionPatients achieving pCR to NAC showed excellent outcomes. Advanced clinical stage, large tumor size, presence of lymph node metastasis, and HER2 positivity before NAC were identified as significant predictors of cancer recurrence. Residual in situ ductal and lymph node diseases after NAC were not significant predictors.     

Metastasis from human breast cancer cell lines

Summary Immunodeficient animals, principally nude mice, when used in appropriately designed studies have been shown to be useful for the experimental analysis of human breast cancer metastasis. As with many other human tumors, the implantation of breast cancer cells into an anatomically appropriate tissue (the mammary fatpad) results in increased tumor take and incidence of metastasis for certain cell lines compared with subcutaneous injection. Testing a number of widely available human breast cancer cell lines identified the MDA-MB-435 cell line as the most metastatic, producing lung and lymph node metastases in a high proportion of nude and severe combined immunodeficient (SCID) mice after injection in the mammary fatpad. Mixing human breast cancer cells with normal fibroblasts or with Matrigel also increases the tumor incidence and growth rates in nude mice. Different routes of injection can be used to assess the ability of human breast cancer cells to form metastatic lesions in the lungs (i.v. injection), the liver (injection in the spleen), the brain (direct or intracarotid artery injection) and the bone marrow and bone (injection into the left ventricle of the heart). These different approaches demonstrate the potential of experimental studies of human breast cancer growth and metastasis using immunodeficient mice; this model is valuable for experiments that test the role of metastasis-associated genes and the efficacy of novel forms of therapy.     

Rank-based predictors for response and prognosis of neoadjuvant taxane-anthracycline-based chemotherapy in breast cancer

For neoadjuvant taxane and anthracycline-based chemotherapy for breast cancer, patients with pathological complete response (pCR) have a favorable prognosis compared with patients with residual disease (RD). Although a number of pCR predictors based on microarray profiles have been proposed to guide neoadjuvant chemotherapy, most of these have not been independently validated in inter-laboratory datasets, possibly owing to the fact that microarray measurements are sensitive to experimental batch effects and inter-array data normalizations. In this study, we developed a rank-based method to tackle this difficulty. First, we extracted from two datasets a combination of gene pairs, each of which had opposing relative expression orders in patients with pCR and those with RD, and used these to build a pCR predictor. This pCR predictor was found to have sensitivities of 74 and 86 % and specificities of 71 and 68 % in another two independent datasets from multiple laboratories, and these results were better than the performances of three previously reported predictors. Considering that patients with minimal RD also tend to have a good prognosis, we then developed a prognosis predictor for RD as a complement to the pCR predictor, in order to identify a group of patients likely to have a good prognosis, taking into account both the RD level and the intrinsic risk factors. In the independent validation, there was a significant difference (P = 0.001) in distant relapse-free survival between the patients likely to and those not likely to have a good prognosis according to our prognosis predictor. In conclusion, the rank-based predictors for response and prognosis can accurately and robustly predict patients with improved prognosis who might benefit from neoadjuvant taxane and anthracycline-based chemotherapy.     

Annexins in human breast cancer: Possible predictors of pathological response to neoadjuvant chemotherapy

Neoadjuvant chemotherapy is used in women who have large or locally advanced breast cancers. However, up to 70% of women who receive neoadjuvant chemotherapy fail to achieve a complete pathological response in their primary tumour (a surrogate marker of long-term survival). Five proteins, previously identified to be linked with chemoresistance in our in vitro experiments, were identified histochemically in pre-treatment core needle biopsies from 40 women with large or locally advanced breast cancers. Immunohistochemical staining with the five proteins showed no single protein to be a predictor of response to chemotherapy. However, pre-treatment breast cancer specimens that were annexin-A2 positive but annexin-A1 negative correlated with a poor pathological response (p = 0.04, Fisher’s exact test). The mechanisms by which annexins confer chemoresistance have not been identified, but may be due to inhibition of apoptosis. Annexin-A1 has been shown to enhance apoptosis, whilst annexin-A2, by contrast, inhibits apoptosis.     

乳腺癌新辅助化疗疗效评价方法的比较

目的 比较查体、超声和钼靶在乳腺癌新辅助化疗(NAC)疗效评价中的差异.方法 通过查体、超声和钼靶分别测量、记录141例NAC患者肿瘤状况,分析治疗前后原发灶、淋巴结的变化.结果 全组中晚期患者居多,Ⅰ期仅占8.5%.化疗前查体的乳腺肿块较超声检查明显偏大(P＜0.01).评价疗效时,原发灶查体误判完全缓解(CR)率高达46.8%(22/47),而超声误判残留率为84.0%(21/25).43例行钼靶检查患者中,有23例(53.5%)患者困难以测量肿块大小而无法评价疗效;5例有钙化的患者,虽化疗后肿块缩小,但钙化范围无变化.在治疗中,25例有效患者行原发灶空芯针穿刺,在9例穿刺病理阴性者中,仅有3例达pCR;16例穿刺阳性者均未达pCR.超声检查怀疑腋窝淋巴结转移的患者,通过空芯针穿刺的病理阳性率为88.3%(53/60),超声检查不怀疑者仍有20.0%(1/5)为阳性.24例超声未探及腋窝肿大淋巴结患者中,有9例(37.5%)前哨淋巴结活检阳性.化疗前淋巴结病理阳性患者64例,化疗后转阴36例(56.3%).全组原发灶及淋巴结均达病理完全缓解(pCR)者21例,占14.9%(21/141).结论 乳腺癌患者化疗前对腋窝淋巴结进行空芯针穿刺或前哨淋巴结活检明确病理状态非常重要,查体、超声及铜靶检查对原发灶肿瘤大小的判断都有相当的误差,可采用病灶穿刺来评价NAC的疗效,但对结果 的判断还需综合分析.     

Molecular predictors of response to chemotherapy in colorectal cancer

Colorectal cancer (CRC) is one of the leading causes of cancer mortality worldwide. In the last decade, median overall survival has increased significantly with the introduction of new cytotoxics and biologic therapies. Notably, the definition of molecular markers predicting benefit with epidermal growth factor receptor (EGFR)-targeted agents has led to important advances in the personalized treatment of CRC. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of response to anti-EGFR monoclonal antibodies. The predictive value of additional mutations and deregulations of the signaling pathways downstream of the EGFR such as BRAF, NRAS, PIK3CA, or PTEN is under intensive investigation. In addition, status of microsatellite instability and molecular markers related to the metabolism of chemotherapy agents has shown promising ability to select patients with higher chances of response to cytotoxic agents. Although attempts to identify predictive factors for efficacy to antiangiogenic therapies have been disappointing, further research on this field will maximize their therapeutic index. Determination of molecular predictive factors before selection of chemotherapy is rapidly approaching us to the paradigm of individualized treatment of CRC.     

Molecular predictors of chemotherapy response in non-small-cell lung cancer

Lung cancer is the number one cause of cancer-related mortality. In order to improve the outcome of patients, advances in the understanding of cancer biology and the development of therapeutic modalities that target key proliferation and survival mechanisms are needed. In vitro data have demonstrated that the genes RRM1 and ERCC1 are important components of these mechanisms. Recently, how these genes affect lung cancer therapy has been explored in the clinical setting with the goal of finding customized treatment algorithms to optimize efficacy, improve outcomes and minimize toxicity.     

Estrogen receptor-related genes as an important panel of predictors for breast cancer response to neoadjuvant chemotherapy

Purpose

Clinical data suggest that the estrogen receptor (ER) contributes to chemotherapeutic responsiveness. However, ER status alone is not consistently predictive. In this study, we used a microarray approach to find novel ER-related genes that predicted chemotherapy responses, with the hope of providing a robust multi-variable prediction method.

Methods

One hundred and ten patients with stages II and III breast cancer were included. They received four preoperative cycles of a weekly PCb (paclitaxel plus carboplatin) regimen. A total of 55 training cases were used for marker discovery and for identification of any ER-related genes that may have been associated with a chemotherapeutic response (“training cases”). The other 55 patients were available as an independent validation set (“validation cases”) to test, using immunohistochemistry (IHC).

Results

In the training set, 20 significantly differentially expressed genes were identified. Among these 20 genes, TFF1, ESR1, GATA3 and TFF3 were found to be ER-related. Among 55 independent validation cases, univariate analysis indicated that clinical variables and ER-related genes were all significantly associated with pCR. It was shown that the pCR rate was as high as 80% when these five factors were all negative. In contrast, these five factors were all positive in seven of nine chemo-resistant patients.

Conclusion

In conjunction with levels of ER-related genes, expression of ER protein may provide important predictive outcomes for responses to neoadjuvant chemotherapy and may allow for the identification of a subgroup of patients who could significantly benefit from chemotherapy (or who may be resistant to it).     

A radiometric method for evaluation of chemotherapy sensitivity: results of screening a panel of human breast cancer cell lines

We have used a radiometric method to screen for chemotherapy sensitivity among a panel of human breast cancer cell lines. This method utilizes the inhibition of conversion of [14C]glucose to 14CO2 as an index of cytotoxicity. Nine different breast cancer cell lines were exposed for 1 h to 4 different concentrations of several antineoplastic agents with and without documented clinical activity against breast cancer. Cytotoxic effects were analyzed as a function of the ratio of the concentration required to inhibit cell growth to 50% of control to 1/10 of the known peak plasma concentration in humans for each particular drug. The drug-induced inhibition of 14C production by breast cancer tumor cells correlated strongly with the drug-induced antiproliferative effect (P less than 0.002) and with the inhibition of colony formation in a soft agar cloning assay (P less than 0.05). The HS578T cell line and one of the MCF7 cell lines exhibited a chemosensitivity pattern consistent with the clinical responsiveness of human breast cancer to the agents tested. Most of the other cell lines exhibited resistance to clinically active agents, especially the cell lines obtained from patients exposed to prior chemotherapy. These results suggest that this radiometric method measures a drug-induced metabolic effect that correlates with the antiproliferative activity of antineoplastic agents on breast cancer cells. The HS578T and the MCF7-KO cell lines, tested in this system, could be a useful screen for new anticancer compounds with activity against human breast cancer.     

乳腺癌新辅助化疗疗效评估方法的研究进展

 乳腺癌新辅助化疗（NAC）是指对乳腺癌患者进行手术治疗前的药物治疗,可以提高病理完全缓解率和生存率,使保乳成为可能。乳腺癌NAC疗效评估方法一直是学科讨论的热点,现对其研究进展进行综述。     

Histone deacetylase inhibitors enhance retinoid response in human breast cancer cell lines

Solid tumors develop resistance to retinoids during carcinogenesis. One of the strategies to overcome this resistance may include the combination of these molecules with other differentiating, cytotoxic or chromatin-remodelling agents. We analysed the anti-proliferative activity of two histone-deacetylase inhibitors (HDACIs), Trichostatin A (TSA) and sodium phenylbutyrate (PB), alone or combined with retinoids, all-trans retinoic acid (ATRA) and Ro 41-5253, on two human breast cancer cell lines: the hormone-dependent MCF-7 and the hormone-independent MDA-MB-231. These lines responded differently to retinoids: MCF-7 were sensitive, whilst MDA-MB-231 were rather resistant. When the retinoids were combined with HDACIs, these molecules potentiated the retinoid activity on growth inhibition, especially for the association Ro 41-5253 and TSA. By FACS analysis, we observed that the anti-proliferative effects were only partially due to pro-apopotic mechanisms, suggesting a cell-cycle block. The efficacy of the retinoids/HDACIs combinations could represent a new strategy in breast cancer chemotherapy, allowing inhibition of both ER + and ER- cell populations.     

Clinical and histological predictors of contralateral breast cancer

AIMS: Women previously treated for primary operable breast cancer are at increased risk of developing cancer in the contralateral breast. The purpose of this study was to assess the annual incidence of metachronous contralateral breast cancer (CBC) and to identify factors that predict for its development. METHODS: A retrospective study was performed on 3211 women aged 相似文献   

Molecular predictors of response to therapy for breast cancer

For several decades, measurements from tumor tissue biomarkers have been used to identify subsets of breast cancer patients that may benefit from specific therapies. Since the 1980s, estrogen receptor testing has been routinely performed on breast carcinoma samples to determine whether hormonal therapy is indicated. Today, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 testing to guide treatment decisions are standard of care. In recent years, multigene assays have been introduced to predict breast tumor behavior. In particular, the OncotypeDx and MammaPrint assays have been commercialized and are used in North America and Europe to guide clinical decisions. Others, including the Breast Cancer Index (BCI; bioTheranostics) and PAM50 (Expression Analysis, Inc), are gaining acceptance as validated assays with associated clinical outcomes. In addition, certain germ line genetic tests are now reported to predict response to specific treatments (e.g., BRCA1, 2, CYP2D6). The optimal use of these novel molecular assays is a challenge to the practicing oncologist. In this review, we will focus on the role of biomarkers that predict response to treatment of breast cancer patients and provide a framework for oncologists to understand and evaluate these tools for use in clinical practice.     

Cultured cell lines from human breast cancer biopsies and xenografts

Summary Eighty-five breast cancer specimens were processed as part of a program in tumor acquisition, propagation, and preservation for biotherapy. Nine long-term culture cell lines were developed. Four cell lines were from solid tumor metastases, two lines were from pleural fluid specimens, and three were from xenograft tumors grown in nude mice. Two of the xenograft-derived cell lines were from biopsies which produced tumor cell lines as well. Success in establishing cultures did not correlate with the viability of the biopsy received. Poor tumor cell attachment to culture plastic was the most common problem. For certain specimens, attachment and growth were enhanced on collagen and extracellular matrix substrates. Collagen was beneficial in the development of one cell line. The cell lines were characterized and each of the lines contained more nuclear DNA than found in normal cells. Four of five lines tested were tumorigenic in nude mice. Five of nine were clonogenic in soft agar. Each of the cell lines tested reacted with at least two anti-tumor monoclonal antibodies. Xenograft and biopsy-derived cell lines from the same tumor were similar in their characteristics. While breast cancers are indeed difficult to establish and propagate in culture, the use of xenografts and special substrates appears to be beneficial in the development of cell lines from some tumors.     

The role of biological markers as predictors of response to preoperative chemotherapy in large primary breast cancer

The aim of this prospective study was to evaluate biological markers, their correlation with response and outcome, and the change in these markers under the influence of preoperative chemotherapy (PCT) in patients with a large primary breast cancer. One hundred and thirty-five women were treated with PCT, followed by locoregional therapy and adjuvant treatment. Estrogen receptor (ER), progesterone receptor (PgR), HER-2, p53, and cathepsin D were determined by immunohistochemistry (IHC) before and after PCT. The overall response (OR) was 70% and the pathologic complete response (pCR) was 13%. Forty-four percent of the patients could be offered breast-conserving surgery (BCS). At a median follow-up of 50 mo the overall survival is 82% and the disease-free survival is 70%. No local recurrence (LR) has developed following BCS. Invasive ductal carcinoma (IDC) was more frequently ER-negative and HER-2-positive than invasive lobular carcinoma (ILC). P53-negative and ER-negative patients seemed to be more chemosensitive compared to p53-positive patients (74% vs 53%) and ER-positive patients (75% vs 65%), but this difference did not reach statistical significance. A trend toward higher complete pathologic remission rate was seen for ER-negative patients (p=0.0609). PgR, HER-2, and cathepsin D were not related to response. The pattern of biological markers did not change with PCT, making repeated determination useless.