乳腺癌辅助化疗的新进展

辅助化疗、内分泌治疗对乳腺癌远期无瘤生存率和总生存率有明显提高。目前乳腺癌辅助化疗应用最多的仍是蒽环类及紫杉类药物。已证明，单用紫杉类比单用蒽环类药物疗效更好。由于具有不同的抗癌机制，紫杉类与蒽环类联用可取得更好疗效。对于乳腺癌的辅助治疗，如何选择给药方式、给药密度，以达到最佳的远期疗效是目前关注的焦点之一。此外，利用生物标志物对临床早期乳腺癌预后的指导作用，在化疗及内分泌治疗中进行合理取舍，提高疗效、降低复发及治疗风险，也是目前的研究方向。     

乳腺癌药物治疗的现状与展望

术后辅助治疗能够提高乳腺癌病人的总生存率和无病生存率，含蒽环类药方案优于非蒽环类药方案，阿霉素为主方案中加入紫杉醇能进一步提高淋巴结阳性病人的生存率，化疗加用他莫昔芬（TAM）能进一步提高疗效，辅助化疗疗效与一定剂量强度相关，但强烈化疗联合造血干细胞 不能改善病人生存，新辅助化疗对Ⅲ期乳腺癌有效，合理应用内分泌治疗和化疗能改善晚期病人的生活质量，延长高质量的生存期。     

卡培他滨联合长春瑞滨治疗转移性乳腺癌的临床进展

蒽环类与紫杉类药物是目前乳腺癌化疗的基石,但由于肿瘤异质性,蒽环类与紫杉类药物治疗乳腺癌取得巨大进步的同时,耐药和复发转移有着日趋增多的态势,成为乳腺癌临床治疗的新难题.目前研究发现,卡培他滨与长春瑞滨无论作为一线治疗,还是作为既往蒽环类、紫杉类药物治疗失败的乳腺癌患者的二线治疗,疗效均满意,不良反应可以耐受,是一种有效可行的治疗手段.     

吉西他滨联合卡培他滨治疗复发转移性乳腺癌的临床观察

在我国，乳腺癌近年来发病率呈明显上升趋势，并已成为导致妇女死亡的主要肿瘤，含有蒽环类的联合化疗方案广泛用于乳腺癌的一线治疗或辅助治疗。此外，活性较高的紫杉类药物现已逐渐用于早期的辅助治疗，但对于紫杉类药物治疗后出现复发的病例，目前尚无公认的替代治疗方案。针对晚期复发转移性乳腺癌，给予正确的化疗、内分泌治疗、放疗等综合手段治疗可达到姑息性治疗的目的，提高患者的生活质量。其中化疗方案的选择是整个治疗中一个重要的环节。[第一段]     

Ki-67阳性或阴性表达乳腺癌不同辅助治疗方案的远期疗效比较

目的 探讨不同Ki-67表达情况下,乳腺癌术后不同辅助化疗方案及辅助化疗后接受不同内分泌药物治疗的远期疗效。方法 收集2008年1月至2009年12月694例乳腺癌患者,术后均接受蒽环类或蒽环类序贯紫杉类方案化疗;再选取其中ER阳性且绝经的261例患者,均接受选择性雌激素受体调节剂（SERM）或芳香化酶抑制剂（AI）内分泌治疗。对Ki-67不同表达情况下,不同辅助化疗方案及辅助化疗后不同内分泌药物治疗与无病生存期（DFS）和总生存期（OS）的关系进行分析。结果（1） 527例Ki-67阳性乳腺癌患者的中位DFS和OS分别为37.0个月和38.0个月,其中蒽环类方案组和序贯紫杉类方案组的中位DFS分别为36.5个月和38.0个月（P=0.046）,OS分别为38.0个月和39.0个月（P=0.045）;167例Ki-67阴性患者的中位DFS和OS分别为49.4个月和51.5个月,蒽环类方案组和序贯紫杉类方案组的中位DFS和OS差异均无统计学意义。在Ki 67和ER表达的4种组合中,仅Ki-67+ER-表达组蒽环类方案与序贯紫杉类方案的中位DFS（30.5个月vs.35.9个月,P=0.030）和中位OS（39.2个月vs.42.1个月,P=0.160）的差异有统计学意义。（2）261例ER阳性且绝经的患者中,200例Ki-67阳性者的中位DFS和OS分别为38.0个月和39.0个月,另外61例Ki-67阴性患者的中位DFS和OS分别为52.0个月和53.3个月;无论Ki-67阳性或阴性表达,接受SERM或AI治疗患者的DFS和OS均无显著差异。结论 在Ki-67阳性乳腺癌术后辅助化疗中,蒽环类序贯紫杉类方案疗效优于蒽环类方案。在ER阳性接受内分泌治疗的绝经患者中,SERM和AI在不同Ki-67表达者中的疗效相当。     

紫杉类药物在晚期乳腺癌治疗中的应用

复发或晚期乳腺癌治疗的主要目的是为了延长患者的生存期,控制症状,改善生活质量。该病的治疗以化疗为主,化疗药物包括蒽环类、紫杉类、抗代谢类、烷化剂类等,可以单药、联合或序贯使用。对于晚期乳腺癌患者,近30多年来临床上均以蒽环类药物为基础的方案作为标准化疗方案[1]。虽该方案取得较好的疗效,但由于阿霉素的毒性及累积剂量的限制性,仍需斟酌使用。近年来,紫杉类药物在乳腺癌治疗中已广泛应用,其具有疗效肯定、毒副反应较轻的特点,因而促使越来越多的临床医生在晚期乳腺癌的治疗中倾向于使用紫杉类药物。     

长春瑞滨或吉西他滨联合顺铂治疗耐药的晚期乳腺癌

乳腺癌是妇女常见的恶性肿瘤，含蒽环类和紫杉类药物的化疗方案广泛应用于乳腺癌的一线治疗，但对上述药物治疗后出现的复发、转移尚无公认的标准替代方案。如何治疗该类药物化疗失败的晚期乳腺癌患者成为临床医师面临的难题。从2002年2月～2007年3月，我们应用国产长春瑞滨与吉西他滨分别联合顺铂方案，治疗既往经蒽环类和／或紫杉类化疗后转移的乳腺癌患者66例，观察其近期疗效及不良反应，现报告如下。     

紫杉类联合蒽环类的新辅助化疗方案治疗三阴乳腺癌的疗效及预后

背景与目的:三阴乳腺癌(triple-negative breast cancer,TNBc)是一类不能受益于分子靶向治疗的高危乳腺癌.本研究比较紫杉类联合蒽环类新辅助化疗方案对TNBC和非TNBC的疗效及远期生存率.方法:对接受4个周期紫杉联合蒽环类新辅助化疗方案治疗的138例乳腺癌资料进行回顾性分析.用免疫组化法将雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体(Her-2)表达均阴性的肿瘤定义为TNBC,分析紫杉类联合蒽环类的新辅助化疗对TNBC和非TNBC的临床、病理疗效及其与远期生存的关系.结果:138例中37(26.8%)例为TNBC,101(73.2%)例为非TNBC.138例患者的总有效率(OR)为85.5%(118/138),其中临床完全缓解(cCR)为35.5%(49/138),临床部分缓解50.0%(69/138),病理完全缓解(pCR)30(21.7%)例.TNBC的cCR(51.4%)、pCR(45.9%)明显高于非TNBC的cCR(29.7%)、pCR(12.9%)(P<0.05).TNBC的5年无病生存率(DFS)为59.5%,低于非TNBC者(84.2%)(P=0.05);TNBC者的5年OS为75.7%,与非TNBC者(94.1%)相比差异无显著性(P=0.108).获得cCR、pCR的TNBC者的5年DFS及总生存率(OS)与非TNBC者间差异无显著性(P>0.05).相反,新辅助化疗后仍有残留病灶的TNBC的5年DFS及OS明显低于非TNBC(P<0.05). 结论:本研究结果表明,TNBC对紫杉联合蒽环类的新辅助化疗更敏感,更易获得cCR、pCR,获得cCR、pCR的TNBC患者预后好,未获得cCR、pCR的TNBC患者远期生存明显低于非TNBC.     

长春瑞滨单药周疗方案治疗既往应用过蒽环类和紫杉类药物的晚期乳腺癌临床观察

目的 观察长春瑞滨(NVB)单药治疗对既往应用过蒽环类和/或紫杉类药物的转移性乳腺癌的疗效和安全性.方法 我院从2008年1月至2011年7月共有31例既往应用过蒽环类和/或紫杉类药物的转移性乳腺癌患接受了NVB单药周疗方案治疗.结果 全组化疗共113个周期,中位化疗周期数为4个(2～6个周期).完全缓解(CR)1例(3%),部分缓解(PR)7例(22%),稳定(SD)4例(13%),进展(PD)19例(61%),总有效率(RR＝CR+PR)为26%,临床获益率(CR+PR+SD＞6个月)为32%,中位疾病进展时间(TTP)4.0个月,中位生存期为13个月.主要不良反应为骨髓抑制及胃肠道反应,无化疗相关死亡病例.结论 长春瑞滨单药治疗既往应用过蒽环类和/或紫杉类药物的转移性乳腺癌有一定疗效,且耐受性好.     

乳腺癌分子亚型预测新辅助化疗疗效的研究

目的:探讨不同乳腺癌分子亚型对紫杉联合蒽环类的新辅助化疗方案治疗疗效的预测价值.方法:对4周期紫杉联合蒽环类新辅助化疗方案治疗182例乳腺癌的资料进行回顾性分析.用免疫组化法将乳腺癌分为四个分子亚型,了解其与临床及病理疗效的关系.结果:单因素分析发现:雌激素受体(ER)阴性、孕激素受体(PgR)阴性及分子亚型可以预测临床完全缓解(cCR)和病理完全缓解(pCR)(P值均＜0.05),HER-2过表达可以预测cCR(P＜0.05).多因素分析发现只有乳腺癌分子分型是预测cCR及pCR的独立变量(P值均＜0.05).其中Luminal B亚型、basal-like亚型、HER2+/ER-亚型对新辅助化疗方案的疗效优于Luminal A亚型(P值均＜0.05).结论:Luminal B亚型、basal-like亚型及HER2+/ER-亚型对紫杉联合蒽环类新辅助化疗方案更敏感,乳腺癌分子亚型有可能成为该方案很好的疗效预测指标.     

Drug treatments for adjuvant chemotherapy in breast cancer: recent trials and future directions

Adjuvant chemotherapy with anthracycline-based regimens has been proven to decrease the risk of relapse and cancer-related mortality in women with early-stage breast cancer. The taxanes, paclitaxel and docetaxel, have been incorporated into several adjuvant chemotherapy regimens in recent studies. Some of these trials have matured and demonstrated a definitive benefit with the use of taxanes. The available studies reveal that the addition of a taxane after an anthracycline or the substitution of a taxane into a three-drug regimen, such as docetaxel, doxorubicin and cyclophosphamide, clearly demonstrate a benefit for taxanes in the adjuvant treatment of breast cancer. The toxicities of the taxanes are generally acceptable. Targeted therapy, such as with trastuzumab, has demonstrated a large benefit that previously has never been seen in adjuvant chemotherapy trials, and thus, should now be part of the standard in the treatment of HER-2/neu positive breast cancer. Newer agents are on the horizon.     

蒽环类药物及蒽环序贯紫杉类方案对乳腺癌辅助化疗后心脏毒性的影响

目的 研究蒽环类药物及蒽环序贯紫杉类两种化疗方案,对乳腺癌辅助化疗后引起的心脏毒性影响.方法 乳腺癌辅助化疗患者84例,根据化疗方案的不同,将其分为蒽环类组42例和蒽环序贯紫杉类组42例.蒽环类组患者接受蒽环类药物化疗方案治疗,而蒽环序贯紫杉类组则接受蒽环序贯紫杉类化疗方案治疗.试验过程中,分别于化疗前、首次化疗后及末次化疗次日3个实验时间点上,测定所有研究对象的静脉肌钙蛋白T和肌红蛋白含量,同时借助自制心脏毒性评级表评价患者心脏毒性级别,以评估上述两种化疗方案对患者引起的心脏毒性程度.结果 两种化疗方案组患者在进行辅助化疗后,静脉肌钙蛋白T含量均没有超出正常范围(P<0.1 ng/ml);在末次治疗后,蒽环序贯紫杉类组静脉肌钙蛋白T含量为(0.0210±0.0166)ng/ml,而另外一组为(0.0390±0.0168)ng/ml,前者低于后者,但无统计学意义(P>0.05);两组患者在3个实验时间点上的肌红蛋白含量均未发生明显变化,且均低于21 ng/ml;两组患者末次化疗后心脏毒性评级表情况,未出现明显差异.结论 蒽环序贯紫杉类化疗方案较蒽环类药物化疗方案,并没有引起患者心脏毒性的明显增大;静脉肌钙蛋白T含量及肌红蛋白含量在评估患者心脏毒性程度方面发挥一定的作用,但尚存在进一步优化之处.     

Emergence of nonanthracycline regimens in the adjuvant treatment of breast cancer

Long-term toxicity of adjuvant regimens is a critical consideration given improvements in survival and consequential management of treatment-related side effects. Despite their well-documented long-term side effects, including a cumulative dose-dependent cardiotoxicity and an increase in the incidence of secondary leukemia, anthracyclines remain an integral component of many adjuvant regimens for breast cancer. The utility of HER-2/TOP2A coamplification in predicting sensitivity to anthracycline chemotherapy has been widely suggested but requires substantiation. The recent maturation of two large phase III trials that directly examined the substitution of a taxane for an anthracycline in the adjuvant setting provides further data to critically evaluate the standard use of anthracyclines in the treatment of early-stage breast cancer. Results from both US Oncology 9735 and BCIRG 006 demonstrated equivalent efficacies in taxane- and anthracycline comparator arms. However, in both trials, the taxane-based regimen(s) resulted in less relative toxicity than the anthracycline-based regimen(s). These trial results pose legitimate questions regarding the future application of anthracyclines in the adjuvant breast cancer setting.     

Recent perspectives second-line chemotherapy for breast cancer

The recent development of chemotherapeutic agents for breast cancer will be reviewed. The paradigm shift from CMF to anthracycline containg regimens +/- taxanes in an adjuvant setting may be considered to decide the sequence of recommended chemotherapy for metastatic breast cancer. Recurrent breast cancer patients who never have undergone anthracycline-containing regimens should be treated with anthracycline regimens. Patients who have already received only an anthracycline-containing regimen in adjuvant therapy will be treated with taxane with or without capecitabine. For patients already having received both anthracycline and taxanes, capecitabine monotherapy will be indicated as a first-line treatment. Physicians will choose the best treatment option among chemotherapeutic agents for patients with distant metastasis.     

FOXP3 expression in cancer cells and anthracyclines efficacy in patients with primary breast cancer treated with adjuvant chemotherapy in the phase III UNICANCER-PACS 01 trial

BackgroundPredictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors.Patients and methodsExpression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan–Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells.ResultsFour hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline–taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy.ConclusionFOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.     

Progress in systemic chemotherapy of primary breast cancer: an overview.

Substantial progress has been made in the multidisciplinary management of primary breast cancer during the last 30 years. Adjuvant chemotherapy has been shown to significantly reduce the annual risk of cancer recurrence and mortality, and these effects persist even 15 years after diagnosis. Combination chemotherapy is superior to single-agent therapy and anthracycline-containing regimens. Those that combine an anthracycline with 5-fluorouracil and cyclophosphamide are more effective than regimens without an anthracycline. Six cycles of a single regimen appear to provide optimal benefit. Dose reductions below the standard range are associated with inferior results. Dose increases that require growth factor or hematopoietic stem cell support are under investigation; at this time, the existing results provide no compelling reason to use this strategy outside a clinical trial. Regimens using fixed crossover designs with two non-cross-resistant regimens are being evaluated. The addition of a taxane to anthracycline-containing regimens is currently under intense scrutiny, and preliminary analysis of the first three clinical trials has shown encouraging, albeit not compelling, results. For patients with estrogen receptor-positive breast cancer, the sequential administration of chemotherapy and 5 years of tamoxifen therapy provides additive benefits. No compelling evidence exists to combine ovarian ablation with chemotherapy. Most side effects and toxic effects are self-limited, although premature menopause requires monitoring and preventive interventions to preserve bone mineral density. The small risk of acute leukemia is of concern, and additional research to develop safer regimens is clearly indicated. The overall effect of optimal local/regional treatment combined with an anthracycline-containing adjuvant chemotherapy and a taxane (and, for patients with estrogen receptor-positive tumors, 5 years of tamoxifen therapy) is a greater than 50% reduction in annual risks of recurrence of and death from breast cancer. For most patients at intermediate or high risk of cancer recurrence, the benefits of adjuvant chemotherapy exceed by far its unwanted effects.     

A review of vinorelbine in the treatment of breast cancer

As combinations and sequences of anthracyclines and taxanes increasingly become standard adjuvant treatment for early breast cancer, a major need for new treatment options for metastatic breast cancer will arise. Vinorelbine is highly active in the treatment of metastatic breast cancer, both as a single agent and in combination regimens. Furthermore, it is well tolerated, with a low incidence of subjective toxicities. It is anticipated, therefore, that vinorelbine will become increasingly utilized for treating metastatic breast cancer due to its favorable safety profile, good tolerability, and promising results in combination with other chemotherapy agents. Combinations with trastuzumab and newer molecular targeting agents are being explored. Doublets or triplets of vinorelbine with drugs other than anthracyclines and taxanes could be considered in the next generation of adjuvant and neoadjuvant trials, where it is anticipated that anthracycline/taxane combinations are likely to replace anthracycline/cyclophosphamide combinations as the mainstay of adjuvant treatment.     

Adjuvant chemotherapy for early breast cancer: Is cyclophosphamide,methotrexate and 5‐fluorouracil still the standard?

Background: Oral cyclophosphamide, methotrexate and 5‐fluorouracil (CMF) was one of the first combination chemotherapy regimens used as adjuvant chemotherapy for early breast cancer. The value of CMF in reducing both recurrence and mortality from early breast cancer has been firmly established by the overviews of randomized trials of polychemotherapy, which have used CMF as their standard. The purpose of this review is to review the usage of oral CMF and the variants of CMF and to compare both the activity and side‐effects of CMF with more modern adjuvant chemotherapy regimens. Results: There are many variants of CMF but oral (or classical) CMF is probably more effective than intravenous (i.v.) CMF, at least in metastatic disease. When oral CMF is used in early breast cancer it reduces the annual hazard of recurrence by 24% and the annual hazard of mortality by 14% overall, although it appears more effective in younger patients. Anthracycline‐based regimens are more effective for reduction of recurrence and mortality than CMF but are associated with more severe acute toxicities and potentially greater risks of long‐term toxicities. Taxane‐based regimens have not been compared with CMF directly; however, in comparison with anthracycline‐based regimens, the early information suggests that taxane‐based regimens may be even more effective. The acute toxicities of taxane‐based regimens are probably less severe than anthracycline‐based regimens, but their long‐term toxicities are less well defined. Conclusion: Oral CMF as adjuvant chemotherapy for early breast cancer is the standard by which newer regimens are compared. Although newer regimens appear more effective than CMF, they may be associated with greater acute and potentially greater long‐term toxicities than CMF. Thus, CMF remains the standard by which future regimens should be judged, either directly or indirectly.     

Epirubicin in breast cancer: present and future

Epirubicin, a member of the anthracycline family of chemotherapeutic agents, has been widely used throughout the world both as adjuvant therapy in early breast cancer and in metastatic breast cancer. Clinical trials with epirubicin have examined the importance of a dose-response relationship, therapeutic dose, and optimum duration of chemotherapy. In addition, pharmacokinetic studies have provided data on ideal combinations with other agents. Epirubicin-containing regimens are considered to be superior to those containing cyclophosphamide, methotrexate, and fluorouracil (CMF) and are also used in patients with locally advanced stage IIIA/IIIB breast cancer. Combinations with other chemotherapeutic agents (eg, epirubicin plus a taxane, sequential or combined use of these agents) are being evaluated in ongoing clinical trials. Moreover, recent studies have suggested that biologic markers, such as tumor HER2/neu overexpression, predict responses to dose-intensive anthracycline chemotherapy, and combinations with nonchemotherapeutic regimens (eg, trastuzumab) may provide additional benefits, but such strategies require further evaluation.     

The emerging role of Lapatinib in HER2-positive breast cancer

In breast cancer, overexpression of HER2 is associated with an aggressive tumor phenotype and poor prognosis. Lapatinib has demonstrated benefit in combination with capecitabine in patients with HER2-positive locally advanced and metastatic breast cancer that has progressed after prior treatment with an anthracycline, a taxane, and trastuzumab. It has also demonstrated benefit with paclitaxel in patients with metastatic disease not previously treated with chemotherapy. This review discusses results from clinical trials suggesting an advantage with the use of lapatinib with other treatment modalities in the setting of metastatic and locally advanced disease.