Multi-Site Clinical Evaluation of DW-MRI as a Treatment Response Metric for Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

Purpose

To evaluate diffusion weighted MRI (DW-MR) as a response metric for assessment of neoadjuvant chemotherapy (NAC) in patients with primary breast cancer using prospective multi-center trials which provided MR scans along with clinical outcome information.

Materials and Methods

A total of 39 patients with locally advanced breast cancer accrued from three different prospective clinical trials underwent DW-MR examination prior to and at 3–7 days (Hull University), 8–11 days (University of Michigan) and 35 days (NeoCOMICE) post-treatment initiation. Thirteen patients, 12 of which participated in treatment response study, from UM underwent short interval (<1hr) MRI examinations, referred to as “test-retest” for examination of repeatability. To further evaluate stability in ADC measurements, a thermally controlled diffusion phantom was used to assess repeatability of diffusion measurements. MRI sequences included contrast-enhanced T1-weighted, when appropriate, and DW images acquired at b-values of 0 and 800 s/mm². Histogram analysis and a voxel-based analytical technique, the Parametric Response Map (PRM), were used to derive diffusion response metrics for assessment of treatment response prediction.

Results

Mean tumor apparent diffusion coefficient (ADC) values generated from patient test-retest examinations were found to be very reproducible (|ΔADC|<0.1x10^-3mm²/s). This data was used to calculate the 95% CI from the linear fit of tumor voxel ADC pairs of co-registered examinations (±0.45x10^-3mm²/s) for PRM analysis of treatment response. Receiver operating characteristic analysis identified the PRM metric to be predictive of outcome at the 8–11 (AUC = 0.964, p = 0.01) and 35 day (AUC = 0.770, p = 0.05) time points (p<.05) while whole-tumor ADC changes where significant at the later 35 day time interval (AUC = 0.825, p = 0.02).

Conclusion

This study demonstrates the feasibility of performing a prospective analysis of DW-MRI as a predictive biomarker of NAC in breast cancer patients. In addition, we provide experimental evidence supporting the use of sensitive analytical tools, such as PRM, for evaluating ADC measurements.     

Long-Term Treatment After Preoperative High-Dose Chemotherapy in a Lactating Breast Cancer Patient

Breast cancer during lactation is very rare, accounting for <3 % of all breast cancers. Its diagnosis and treatment is often delayed during pregnancy. We report a case of female lactating breast carcinoma in a 29-year old patient. The disease was stage IIIB (T4N1M0). The patient received preoperative induction chemotherapy and high-dose chemotherapy with peripheral blood stem cell support, followed by adjuvant chemotherapy and endocrine therapy. The metastases were detected 17 months after operation, palliative treatment including different chemotherapy for 60 cycles, locoregional radiotherapy and endocrine therapy. The total number of cycles of chemotherapy was 67, and the survival time was 118 months. We discuss the diagnosis and treatment options for breast cancer during lactation, based on a literature review.     

Cold Atmospheric Plasma-Activated Media Improve Paclitaxel Efficacy on Breast Cancer Cells in a Combined Treatment Model

Simple SummaryBreast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in females, with chemotherapy currently the only adjunctive therapy. However, the disadvantages of chemotherapy are represented by toxicity/side effects, and for many women the benefit is uncertain. Cold atmospheric plasma in in vitro and in vivo experiments proved that it is able to selectively inhibit the growth of cancer cells in various cancer types, with less deleterious side effects. Current guidelines include paclitaxel as a chemotherapy of choice for various types of breast cancers. The aim of the study was to evaluate in vitro, on human breast cancer cell lines, a plasma-activated media as a cytotoxic agent and as an associative agent in a combined treatment for breast cancer with paclitaxel. The collected data indicated that the plasma-activated media amplified the cytotoxic effect of paclitaxel.AbstractThe use of plasma-activated media (PAM), an alternative to direct delivery of cold atmospheric plasma to cancer cells, has recently gained interest in the plasma medicine field. Paclitaxel (PTX) is used as a chemotherapy of choice for various types of breast cancers, which is the leading cause of mortality in females due to cancer. In this study, we evaluated an alternative way to improve anti-cancerous efficiency of PTX by association with PAM, the ultimate achievement being a better outcome in killing tumoral cells at smaller doses of PTX. MCF-7 and MDA-MB-231 cell lines were used, and the outcome was measured by cell viability (MTT assay), the survival rate (clonogenic assay), apoptosis occurrence, and genotoxicity (COMET assay). Treatment consisted of the use of PAM in combination with under IC50 doses of PTX in short- and long-term models. The experimental data showed that PAM had the capacity to improve PTX’s cytotoxicity, as viability of the breast cancer cells dropped, an effect maintained in long-term experiments. A higher frequency of apoptotic, dead cells, and DNA fragmentation was registered in cells treated with the combined treatment as compared with those treated only with PT. Overall, PAM had the capacity to amplify the anti-cancerous effect of PTX.     

三阴型乳腺癌的化学治疗和靶向治疗进展

三阴型乳腺癌(Triple negative Breast cancer,TNBC)占乳腺癌总数的15%,是一种免疫组织化学亚型。通常发生于青年女性,有很高的复发率,内脏和中枢神经系统转移早,病程短、死亡率高。对大多数TNBC患者,常规化疗是主要的治疗方式。20%患者有很好的化疗敏感性,对化疗耐药的TNBC患者靶向治疗为当前研究的热点,寻找乳腺癌新的治疗靶点,提出TNBC新的治疗策略,有望去改善TNBC患者的预后。     

Decrease of Let-7f in Low-Dose Metronomic Paclitaxel Chemotherapy Contributed to Upregulation of Thrombospondin-1 in Breast Cancer

Low-dose metronomic (LDM) paclitaxel therapy displayed a stronger anti-angiogenic activity on breast tumors with fewer side effects. Upregulation of anti-angiogenic factor Thrombospondin-1 (TSP-1) accords for therapeutic potency of LDM paclitaxel, but its molecular mechanism has not been elucidated yet. microRNAs (miRNAs) have emerged as new important regulators of tumor growth and metastasis. Here, we hypothesize that miRNAs are involved in TSP-1 overexpression in paclitaxel LDM therapy of breast tumors. The miRNA profile of tumor tissues from control, LDM and MTD groups in 4T1 mouse breast cancer model was detected by microarray, and then verified by quantitative real-time PCR (qRT-PCR). Luciferase assay and western blot were employed to explore the mechanisms of miRNAs involved in this process. We found that let-7f, let-7a, miR-19b and miR-340-5p were reduced by >2 fold, and miR-543* and miR-684 were upregulated by at least 50% in paclitaxel LDM therapy. qRT-PCR verification revealed that let-7f level was reduced most significantly in LDM therapy. Computational prediction using TargetScan and miRanda suggested THBS1 which encodes TSP-1 as a potential target for let-7f. Luciferase activity assay further confirmed that let-7f may bind to 3''UTR of THBS1 gene and inhibit its activity. Moreover, forced expression of let-7f led to a decrease of TSP-1 at both mRNA and protein levels in MCF-7 cells. Contrastly, let-7f inhibition induced an increased expression of THBS1 mRNA and TSP-1 protein, but did not affect the proliferation and apoptosis of MCF-7 cells. Paclitaxel LDM therapy led to a decrease of let-7f and the elevation of TSP-1 protein expression in MCF-7 cells, while overexpression of let-7f may abolish LDM-induced the upregulation of TSP-1 in MCF-7 cells. In summary, let-7f inhibition contributed to the upregulation of TSP-1 in paclitaxel LDM therapy, independently of proliferation, cell cycle arrest and apoptosis of breast cancer. This study indicates let-7f as a potential therapeutic target for breast tumor.     

紫杉醇联合卡铂治疗局部晚期乳腺癌的临床研究

目的:探讨紫杉醇联合卡铂治疗局部晚期乳腺癌的临床疗效和安全性。方法:选取2010年3月~2012年8月在我院接受治疗的局部晚期乳腺癌患者80例,以其中采用紫杉醇联合卡铂治疗的40例患者作为实验组,紫杉醇联合表阿霉素治疗的40例患者作为对照组,化疗后患者行乳腺癌改良根治术或保乳术,观察和比较两组患者的治疗有效率、不良反应的发生情况及术后复发和转移情况。结果:两组患者的治疗有效率及不良反应的发生率比较均并无统计学差异(P>0.05),而实验组患者术后复发及转移的发生率明显低于对照组患者(P<0.05)。结论:紫杉醇联合卡铂治疗局部晚期乳腺癌的临床疗效及安全性与紫杉醇联合表阿霉素化疗相当,但是能够明显降低患者的术后复发率及转移率,改善患者的预后。     

High Bak Expression Is Associated with a Favorable Prognosis in Breast Cancer and Sensitizes Breast Cancer Cells to Paclitaxel

Breast cancer has become the leading cause of cancer-related death among women. A large number of patients become resistant to drug chemotherapy. Paclitaxel (Taxol) is an effective chemotherapeutic agent used to treat cancer patients. Taxol has been widely used in human malignancies including breast cancer because it can stabilize microtubules resulting in cell death by causing an arrest during the G2/M phase of the cell cycle. Pro-apoptotic Bcl-2 antagonist killer 1 (Bak) plays an important role in Taxol-induced apoptosis in breast cancer. In our present study, we investigated the expression of the Bak protein and clinicopathological correlations in a large sample of breast cancer tissues by immunohistochemistry. We found that the percentage of high scores of Bak expression in breast cancer was significantly lower than that of the non-cancerous breast control tissue. In addition, lower Bak expression was positively associated with the clinical TNM stage of breast cancer with a significant decrease in overall survival compared with those with higher Bak expression especially in the Luminal and HER2 subtypes. Importantly, higher Bak expression predicted a favorable clinical outcome in the cases treated with Taxol indicated by a higher overall survival than that of patients with lower Bak expression especially in Luminal and HER2 subtypes. Furthermore, these results were confirmed in vitro since overexpression of Bak sensitized breast cancer cells to Taxol by inhibiting proliferation and promoting apoptosis; in contrast, downregulation of Bak through siRNA transfection inhibited Taxol induced-apoptosis. Therefore, our results demonstrate that Bak acts as a sensitive biomarker and favorable prognostic factor for Taxol treatment in breast cancer. The restoration of Bak expression would be therapeutically beneficial for Taxol resistant breast cancer patients.     

乳腺癌新辅助化疗的研究进展

乳腺癌是一种女性最常见的恶性肿瘤,近年来我国乳腺癌的发病率呈逐年上升趋势。研究证实,新辅助化疗不仅可使不能手术的晚期乳腺癌患者获得手术机会,而且也增加了部分患者的保乳概率,但是约20%的乳腺癌患者不能从新辅助化疗中获益,并影响后续治疗效果。因此,制定合理的、个体化的新辅助化疗方案对于提高乳腺癌患者的生存质量和改善其预后尤为重要。目前,研究已发现的NCT相关的预测因子主要包块肿瘤类型、分子分型、ER、PR、Ki67等,而HER2、TOP2A、P53、PRAP单独作为预测因子的还存在争议。本文主要对乳腺癌新辅助化疗的现状、各种预测因子的作用及其不足之处进行了综述。     

Utilization of Neoadjuvant Chemotherapy Varies in the Treatment of Women with Invasive Breast Cancer

Background

Treatment with neoadjuvant chemotherapy (NAC) has made it possible for some women to be successfully treated with breast conservation therapy (BCT ) who were initially considered ineligible. Factors related to current practice patterns of NAC use are important to understand particularly as the surgical treatment of invasive breast cancer has changed. The goal of this study was to determine variations in neoadjuvant chemotherapy use in a large multi-center national database of patients with breast cancer.

Methods

We evaluated NAC use in patients with initially operable invasive breast cancer and potential impact on breast conservation rates. Records of 2871 women ages 18-years and older diagnosed with 2907 invasive breast cancers from January 2003 to December 2008 at four institutions across the United States were examined using the Breast Cancer Surgical Outcomes (BRCASO) database. Main outcome measures included NAC use and association with pre-operatively identified clinical factors, surgical approach (partial mastectomy [PM] or total mastectomy [TM]), and BCT failure (initial PM followed by subsequent TM).

Results

Overall, NAC utilization was 3.8%l. Factors associated with NAC use included younger age, pre-operatively known positive nodal status, and increasing clinical tumor size. NAC use and BCT failure rates increased with clinical tumor size, and there was significant variation in NAC use across institutions. Initial TM frequency approached initial PM frequency for tumors >30-40mm; BCT failure rate was 22.7% for tumors >40mm. Only 2.7% of patients undergoing initial PM and 7.2% undergoing initial TM received NAC.

Conclusions

NAC use in this study was infrequent and varied among institutions. Infrequent NAC use in patients suggests that NAC may be underutilized in eligible patients desiring breast conservation.     

紫杉醇、长春瑞滨联合顺铂方案治疗晚期乳腺癌的临床疗效

目的:探讨紫杉醇(PTX)、长春瑞滨(NVB)两药与顺铂(DDP)联用方案对晚期乳腺癌的临床疗效及副反应。方法:将2009年2月至2014年2月于我院就诊的60例晚期乳腺癌患者随机分为TP方案和NP方案两组,每组30例。TP方案组:顺铂25mg/m2,d1~d3,紫杉醇175 mg/m2,d1;NP方案组:顺铂25 mg/m2,d1~d3,长春瑞滨25 mg/m2,d1和d8。比较两组患者的临床有效率并记录相关不良反应。结果:TP方案有效率56.7%(17/30),中位缓解期7.5个月。NP方案有效率53.3%(14/30),中位缓解期7.7个月。组间疗效及缓解期差异无统计学意义(P0.05)。TP与NP方案组出现血小板减少、白细胞减少、贫血、恶心呕吐的发生率分别为26.7%、76.7%、56.7%、43.3%和26.7%、76.7%、56.7%、43.3%,两方案血液毒性差异无统计学意义(P0.05)。静脉炎及关节肌肉反应的发生率分别为30.0%、13.3%和16.7%53.3%,差异有统计学意义(P0.05)。结论:紫杉醇、长春瑞滨与顺铂联用治疗晚期乳腺癌疗效相当,不良反应可耐受,都可做为晚期乳腺癌治疗的一线用药方案。     

吉西他滨联合化疗方案治疗复发转移性乳腺癌的临床疗效观察

目的:观察吉西他滨与顺铂联合以及吉西他滨与紫杉醇联合治疗复发转移性乳腺癌的疗效和不良反应。方法:本研究收集65例女性乳腺癌术后复发转移的患者作为研究对象。随机分成两组,分别应用吉西他滨与顺铂(GP方案组)、吉西他滨与紫杉醇(GT方案组)联合进行治疗。GP方案组患者有30例,第1天、第8天用吉西他滨800mg~1000mg/m2溶于0.9%的100mL生理盐水中静脉滴注;第1天~第3天,21天重复用顺铂30mg/m2溶于0.9%的250mL生理盐水中静脉滴注;GT方案组患者有35例,吉西他滨的使用方法与GP方案组相同,第2天,21重复用紫杉醇135mg/m2溶于0.9%的500mL生理盐水中静脉滴注。对化疗时产生的不良反应进行对症处理。结果 :GP方案组化疗有效率为46.67%,疾病控制率为70.00%;GT方案组化疗有效率为42.86%,疾病控制率为68.57%,两组比较差异均无统计学意义(P0.05)。GT组脱发的发生率为62.86%,明显高于GP组的10.00%(P0.001),其他不良反应在两组之间差异无统计学意义(P0.05)。结论:GP方案和GT方案在治疗复发转移性乳腺癌有较好的疗效,不良反应较轻,可作为复方转移性乳腺的一种化疗方案。     

Predicting Treatment Response of Breast Cancer to Neoadjuvant Chemotherapy Using Ultrasound-Guided Diffuse Optical Tomography

PURPOSE: To prospectively investigate ultrasound-guided diffuse optical tomography (US-guided DOT) in predicting breast cancer response to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Eighty-eight breast cancer patients, with a total of 93 lesions, were included in our study. Pre– and post–last chemotherapy, size and total hemoglobin concentration (THC) of each lesion were measured by conventional US and US-guided DOT 1 day before biopsy (time point t0, THC THC0, SIZE S0) and 1 to 2 days before surgery (time point tL, THCL, SL). The relative changes in THC and SIZE of lesions after the first and last NAC cycles were considered as the variables ΔTHC and ΔSIZE. Receiver operating characteristic curve was performed to calculate ΔTHC and ΔSIZE cutoff values to evaluate pathologic response of 93 breast cancers to NAC, which were then prospectively used to predicate response of 61 breast cancers to NAC. RESULTS: The cutoff values of ΔTHC and ΔSIZE for evaluation of breast cancers NAC treatment response were 23.9% and 42.6%. At ΔTHC 23.9%, the predicted treatment response in 61 breast lesions for the time points t1 to t3 was calculated by area under the curve (AUC), which were AUC₁ 0.534 (P = .6668), AUC₂ 0.604 (P = .1893), and AUC₃ 0.674(P =. 0.027), respectively; for ΔSIZE 42.6%, at time points t1 to t3, AUC₁ 0.505 (P = .9121), AUC₂ 0.645 (P = .0115), and AUC₃ 0.719 (P = .0018). CONCLUSION: US-guided DOT ΔTHC 23.9% and US ΔSIZE 42.6% can be used for the response evaluation and earlier prediction of the pathological response after three rounds of chemotherapy.     

Inhibition of Paclitaxel-Induced Proteasome Activation Influences Paclitaxel Cytotoxicity in Breast Cancer Cells in a Sequence-Dependent Manner

Although the anti-tumour effects of paclitaxel result mainly from mitotic arrest, recent evidences suggest alternative mechanisms of cytotoxicity. Cell cycle, cell death, and gene expression assays were used to understand the molecular mechanisms of paclitaxel cytotoxicity in breast cancer cells. G₂/M cell cycle arrest and cell death coincided with the regulation of genes involved in cell death, cell cycle control, microtubule-based processes, oxidative stress, and ubiquitin-proteasome system. Induction of proteasome genes was also correlated with an accumulation of protein for proteasome subunits. Furthermore, a schedule-dependent regulation of paclitaxel-induced cytotoxicity was observed after combining paclitaxel and the proteasome inhibitor MG132. Proteasome inhibition after paclitaxel exposure induced the highest rate of growth inhibition and apoptosis, with no effect on mitotic arrest. These findings give support to clinical combinations of taxanes with proteasome inhibitors, outlining the importance of considering the sequence when designing such regimens.     

Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study)

Purpose

Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT).

Methods

Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m²), followed by 12 cycles of paclitaxel at 80 mg/m² weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug.

Results

This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted.

Trial Registration

University Hospital Medical Information Network. UMIN000003261.     

依西美坦治疗绝经后乳腺癌的临床疗效及安全性观察

目的:探讨依西美坦治疗绝经后乳腺癌的疗效及安全性进行观察.方法:观察84名病理明确证实绝经后乳腺癌且雌激素受体(ER)或孕激素受体(PgR)阳性患者,口服依西美坦25 mg/d,服药至病情进展或出现不能耐受的不良反应,观察依西美坦的疗效和不良反应.结果:84例患者均可评价疗效,客观有效率为(23/84)27.4％;疾病控制率为(34/84)41％;并且绝经的方式,前期化疗,手术与否与疗效的关系无明显统计学差异,但转移部位,前期内分泌治疗史可能对疗效有影响;依西美坦治疗后不良反应发生率低.结论:依西美坦对乳腺癌的疗效确切,且不良反应轻,耐受性好.     

TAC方案治疗晚期术后乳腺癌疗效观察

目的探讨分析TAC方案治疗晚期术后乳腺癌的临床疗效。方法选取我院自2008年1月至2010年6月收治的76例晚期术后乳腺癌患者,所有患者按随机数法分为实验组与对照组,两组均为38例。实验组接受TAC化疗方案,对照组接受CTF化疗方案,治疗6个疗程后比较两组患者的临床疗效及不良反应发生情况。结果实验组的无进展生存期、总生存期及1—3年生存率均明显优于对照组（P〈0．05）;实验组中性粒细胞减少与恶性呕吐的发生率明显高于对照组（P〈0．05）,两组其余髓内及髓外毒性反应及心脏毒性反应发生率的差异比较均无统计学意义（P〉0．05）。结论TAC方案治疗晚期术后乳腺癌的临床疗效显著,延长了患者术后的生存时间,且不良反应少,值得推广。