Neoadjuvant endocrine therapy for postmenopausal patients with hormone receptor-positive early breast cancer: a new concept

Patients with resectable, nonmetastatic (stage I–IIIA) breast cancer usually receive adjuvant (postoperative) systemic therapy to control micrometastasis and prevent recurrence. Neoadjuvant (preoperative) chemotherapy is a standard treatment for resectable breast cancer, potentially enabling patients to undergo partial dissection. However, it has been reported that neoadjuvant chemotherapy has a limited effect in patients with hormone receptor-positive disease in terms of pathologic complete response rate, and in elderly patients there may be safety concerns. Furthermore, the appropriateness of chemotherapy for luminal early breast cancer [defined as hormone receptor-positive and human epidermal growth factor receptor-2 (HER2)-negative tumors] is an important clinical issue. We determine the need for chemotherapy in postmenopausal patients with hormone receptor-positive, HER2-negative, lymph node-negative early breast cancer according to clinicopathologic factors, including multigene signature. The National Surgical Adjuvant Study of Breast Cancer (N-SAS-BC06) New primary Endocrine-therapy Origination Study (NEOS) is a randomized phase III trial conducted in Japanese centers. It is evaluating adjuvant endocrine therapy, with or without chemotherapy, in patients with postmenopausal breast cancer that has responded to neoadjuvant letrozole. The aims of this trial are to: define patients who might not require chemotherapy by using their response to neoadjuvant endocrine therapy; analyze the relationship between neoadjuvant endocrine therapy and long-term prognosis; and analyze the correlation between clinical and pathologic response to neoadjuvant hormonal therapy with additional postoperative chemotherapy. We hope that the results of this trial will lead to the development of a new clinical strategy of pre- and postsurgical treatment for luminal breast cancer.     

Neoadjuvant chemotherapy for operable breast cancer

Adjuvant systemic chemotherapy has been shown to prolong survival in all subsets of patients with breast cancer. In addition, among patients with locally advanced breast cancer, neoadjuvant orpreoperative chemotherapy has improved the ability to perform breast-conserving therapy. This observation, combined with multiple preclinical hypotheses and the results of laboratory studies, has prompted investigation of neoadjuvant chemotherapy as a treatment strategy for operable breast cancer. In this article, both the evidence supporting this treatment approach and some of the problems associated with it are reviewed. Currently, seven randomized studies comparing neoadjuvant chemotherapy followed by surgery or surgery followed, in turn, by adjuvant chemotherapy have been completed and their results analyzed. Despite exciting preclinical evidence, no trial to date has shown a survival advantage for the neoadjuvant treatment approach. Nonetheless, evidence from more recent phase III trials and the fact that neoadjuvant chemotherapy is not harmful topatients validate its use in operable breast cancer.     

乳腺癌新辅助化疗中MCM7和C—erbB-2的表达及其临床意义

目的：探讨乳腺癌新辅助化疗前后MCM7和C—erbB-2蛋白的表达状况,分析其与化疗疗效的关系。方法：采用免疫组化法检测55例乳腺癌新辅助化疗前后标本中MCM7和C—erbB-2的表达。结果：新辅助化疗有效率为76．4％。化疗前MCM7蛋白阳性表达显著高于化疗后（P〈0．01）,而化疗前后C—erbB-2蛋白阳性表达差异无显著性（P〉0．05）。化疗有效组（42例）MCM7蛋白阳性表达显著高于无效组（13例）（P〈0．01）,而化疗有效组C—erbB-2蛋白阳性表达显著低于无效组（P〈0．01）。结论：ET方案新辅助化疗有较好的疗效,可能通过抑制MCM7蛋白表达来阻止乳腺癌细胞的增殖。MCM7高表达,C—erbB-2阴性者化疗更为敏感,二者可作为临床指导乳腺癌化疗并预测化疗敏感性的分子生物学指标。     

乳腺癌新辅助化疗中肿瘤标志物检测的临床意义

目的检测肿瘤标志物在新辅助化疗乳腺癌中的表达,探讨新辅助化疗患者中ER、PR、c-erbB2和Ki67的表达及临床意义.方法用免疫组织化学法检测ER、PR、c-erbB2和Ki67在89例新辅助化疗乳腺癌组织中的表达状况,分析上述指标与化疗的关系.结果新辅助化疗总有效率89.9%,其中完全缓解CR32.6%,部分缓解PR57.3%,病理完全缓解pCR17.9%,疾病稳定SD10.5%,无恶化病例.ER/PR表达与疗效有关（P〈0.05）,c-erbB2、Ki67表达与化疗疗程无关.结论激素受体阴性者对新辅助化疗的敏感性较高,新辅助化疗肿瘤标志物的检测可以为临床评价疗效判断预后提供依据.     

影响乳腺癌新辅助化疗后病理完全缓解的临床因素分析

目的:探讨影响乳腺癌新辅助化疗后病理完全缓解（pathological complete response,pCR）的临床因素。方法:回顾分析新辅助化疗并行根治性手术的120例女性乳腺癌患者的临床资料;所有患者均接受6~8周期EC-T方案化疗,化疗结束后2~4周行根治性手术。采用χ2检验及 Logistic 回归分析影响pCR和非pCR的临床因素。结果:疗效结果单因素分析显示:T分期、N分期、乳腺癌分子分型、治疗前Ki-67表达水平、治疗前血小板水平与乳腺癌新辅助化疗后肿瘤pCR率显著相关。Logistic二元回归分析发现乳腺癌非Luminal分子亚型和新辅助化疗前高血小板水平是影响乳腺癌新辅助化疗后pCR的独立预测因素。结论:乳腺癌非Luminal分子亚型和新辅助化疗前高血小板水平是影响乳腺癌新辅助化疗后pCR的决定性因素。     

Initial medical treatment for breast cancer]

Rationale for primary medical treatment of breast cancer relies on experimental data showing that the incidence of metastatic disease is dependent on the primary tumour mass and tumoral angiogenesis. Although this concept may be applied to both chemotherapy and hormonotherapy, only the first was extensively explored for patients with locally advanced breast cancer, and more recently in smaller tumours. Despite high clinical +/- radiological response rates, only pathologic information, carefully assessed in both the primary and axillae lymph nodes, stands out as the major source of prognostic information on patients' outcome. Recent developments in chemotherapy (dose-intensity, new drugs) do not seem to influence these results, indicating the possible limitations of conventional chemotherapy. Of 6 published randomized trials comparing neo versus adjuvant strategy, none showed any significant impact of primary chemotherapy on survival, with in some a trend towards delayed and/or distant recurrences if neoadjuvant treatment given. That some recent reports suggest that local relapse rate might be increased after conservative treatment following induction chemotherapy in subgroups analyses should cause oncologists to revise the role for post neoadjuvant treatment conservative surgery without calling into question the global strategy. Through sequential samplings, neoadjuvant medical treatment provides indeed the opportunity (a) to identify molecular mechanisms associated with pathologic response and (b) to study the possibility to guide the choices for induction treatment and patients' populations submitted to primary medical treatment.     

Current and future roles of neoadjuvant chemotherapy in operable breast cancer

Neoadjuvant chemotherapy was initially used only as treatment for locally advanced breast cancer. However, because breast cancer is considered to be a systemic disease in which distant micrometastases are already present at the time of the initial diagnosis, primary systemic therapy may be beneficial in the eradication of these micrometastatic lesions. Despite the fact that no survival benefit of neoadjuvant chemotherapy over adjuvant chemotherapy has yet been demonstrated, the clinical indication for neoadjuvant chemotherapy is being extended not only to stage T3/4 tumors but also to some stage T1/2 operable breast cancers. The current clinical benefits of the use of neoadjuvant chemotherapy are that (1) the safety of neoadjuvant chemotherapy is comparable with that of adjuvant chemotherapy, (2) neoadjuvant chemotherapy increases the possibility of the use of breast-conserving surgery, and (3) pathologic complete response may be a predictive indicator of better survival. Importantly, the response to neoadjuvant chemotherapy in vivo could provide a useful prediction of prognosis and help define strategies for an individual patient's future treatment with alternative chemotherapy regimens or molecular-targeting agents. Furthermore, the discovery of predictive markers for tumor response to neoadjuvant chemotherapy through the analysis of complementary DNA microarrays and proteomics may also help facilitate individualized chemotherapy, particularly by improving survival in patients with breast cancer with a poor prognosis. Herein we review the current status and future role of neoadjuvant chemotherapy in operable breast cancer in terms of its survival benefit and the potential for the individualization of adjuvant therapy for these patients.     

Staging of breast cancer in the neoadjuvant setting

The use of neoadjuvant chemotherapy has become more prevalent in the treatment of breast cancer patients. The finding of a pathologic complete response to neoadjuvant chemotherapy (no evidence of residual invasive cancer in the breast and lymph nodes at the time of surgical resection) has been shown to correlate with improved survival. The current version of the American Joint Committee on Cancer (AJCC) staging for breast cancer has a pretreatment clinical stage designation that is determined by clinical and radiographic examination of the patient and a postoperative pathologic stage classification based on the findings in the breast and regional lymph nodes removed at surgery. Pathologic staging has not been validated for patients receiving neoadjuvant chemotherapy; thus, prognosis is determined for these patients based on the pretreatment clinical stage. We hypothesized that clinical and pathologic staging variables could be combined with biological tumor markers to provide a novel means of determining prognosis for patients treated with neoadjuvant chemotherapy. Two scoring systems, based on summing binary indicators for clinical and pathologic substages, negative estrogen receptor status, and grade 3 tumor pathology, were devised to predict 5-year patient outcomes. These scoring systems facilitated separation of the study population into more refined subgroups by outcome than the current AJCC staging system for breast cancer, and provide a novel means for evaluating prognosis after neoadjuvant therapy.     

乳腺癌新辅助化疗再认识

近年来随着乳腺癌新辅助化疗研究的深入,该治疗手段已在临床被广泛应用。新辅助化疗使不可手术的局部晚期乳腺癌患者获得手术治疗的机会,并且提高具有较大肿瘤体积患者的保乳率,从而明显改善患者的生存质量,但仍有许多问题存在争议。本文将对乳腺癌新辅助化疗相关临床研究、以及对新辅助化疗的再认识进行综述。      

Neoadjuvant endocrine therapy of breast cancer: a surgical perspective

Neoadjuvant treatment with chemotherapy or endocrine agents is being used increasingly to downstage locally advanced and large operable breast cancers. Following these treatments, inoperable breast cancer often becomes fully resectable, and initially operable tumours requiring mastectomy may be successfully removed by breast-conserving surgery. Patient selection is important to optimise neoadjuvant endocrine therapy: only patients with oestrogen receptor (ER)-rich breast cancer are candidates, and postmenopausal women are likely to benefit the most. Such patients can expect a high probability of responses over a 3-month treatment period. Response to therapy should be monitored by clinical examination as well as by ultrasound, mammography, or other imaging procedures. Third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen in this treatment setting. In a large randomised trial of neoadjuvant endocrine therapy in postmenopausal women, letrozole achieved significantly higher response rates than tamoxifen, and a correspondingly higher rate of breast-conserving surgery was possible in the letrozole-treated patients. There is some evidence to suggest that the nature of the tumour response is different for preoperative endocrine therapy compared with chemotherapy. This difference may result in a higher rate of complete tumour excisions following breast-conserving surgery after neoadjuvant endocrine treatment. There appears to be a low rate of subsequent local recurrence in patients having breast-conserving therapy after neoadjuvant endocrine therapy.     

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.     

Primary (neoadjuvant) chemotherapy with docetaxel in breast cancer

The use of primary or neoadjuvant chemotherapy for locally advanced breast cancer, including those patients with inflammatory breast cancer, is well established. The use of primary chemotherapy has also been investigated in patients with operable breast cancer. The potential benefit of using primary chemotherapy is the opportunity to administer systemic therapy at an earlier timepoint, where it may be more effective against microscopic disease. In addition, primary chemotherapy for patients with operable breast cancer may also result in higher rates of breast conservation, axillary nodal downstaging, and potential improvement in patient outcome. A variety of different chemotherapy drugs have been evaluated in the primary chemotherapy setting. One of the most common approaches is to use an anthracycline-based regimen for 4 or more cycles of treatment before considering definitive local therapy. Although high tumor response rates have been reported using anthracycline-based regimens, the fraction of patients actually attaining a pathologic complete response has remained small (less than 20%). With the introduction of new chemotherapy drugs, such as docetaxel, which is associated with a very high tumor response rate in metastatic disease, a natural evolution of clinical investigation is to use docetaxel in the neoadjuvant or primary chemotherapy setting. Some of the recent trials that have evaluated single-agent docetaxel, docetaxel-based chemotherapy combinations, and novel sequencing strategies that include docetaxel in the neoadjuvant setting are reviewed. The results from these trials clearly suggest that docetaxel-containing treatment strategies can be considered a standard in the primary chemotherapy setting     

乳腺癌新辅助治疗策略的研究进展

新辅助治疗作为乳腺癌的重要治疗手段,其适应证已不仅限于局晚期乳腺癌。病理完全缓解(pathologic complete response,pCR)与新辅助治疗后患者总生存率(overall survival,OS)及无病生存率(disease-free survival,DFS)的提高显著相关,是新辅助治疗最为客观高效的疗效评价指标。经新辅助治疗后的患者可以达到肿瘤降期、提高保乳率、有效观察肿瘤药物敏感性等重要的诊疗目的。精准的疗效分析可以帮助临床医生及时转换诊疗策略,为病人提供个体化治疗方案,避免治疗不足或过度治疗。本文综述了新辅助化疗中的去蒽环问题、HER2阳性乳腺癌新辅助靶向治疗、三阴性乳腺癌新辅助免疫治疗、手术时机及方式的选择等问题的最新研究进展。     

局部晚期食管癌新辅助治疗的研究进展

近年来,食管癌的治疗越来越倾向于多学科的综合治疗。多项研究已证明在手术的基础上加入放疗、化疗或免疫治疗可提高食管癌的生存获益。对于局部晚期食管癌患者,新辅助联合手术治疗效果明显,新辅助放化疗以及新辅助化疗均能够提高生存获益,但目前这两种治疗模式孰优孰劣尚存在争议。随着诱导化疗和新辅助免疫的加入,新辅助治疗模式更加多样化,进一步提高了病理完全缓解率,为局晚期食管癌患者的治疗提供了新思路。因此,本文旨在对近年来局晚期食管癌的新辅助治疗模式进行探讨,为进一步优化综合治疗策略提供参考。     

Neoadjuvant taxanes in the treatment of non-metastatic breast cancer: a systematic review

In recent years the role of neoadjuvant (primary, preoperative) chemotherapy has undergone rapid progress. Initially, neoadjuvant chemotherapy use was limited to those patients with inoperable locally advanced breast cancer in an attempt to try to down-size the tumour to make effective surgery possible. The advent of more effective chemotherapy regimens has led to an increased use of neoadjuvant therapy to shrink potentially operable tumours to allow for breast conservation when a mastectomy would have been required previously. While neoadjuvant treatment for operable tumours has indeed allowed increased rates of breast conserving surgery, it has not yet demonstrated any survival benefit over standard postoperative anthracycline-based chemotherapy. Echoing the evolution of taxane based chemotherapy from the metastatic setting through to the adjuvant situation, there has been increased interest in the role of taxanes in neoadjuvant regimens. The use of taxane-based therapies in this setting has so far shown improvements over more standard regimens in terms of clinical response rates, breast conservation, pathologic response rates, disease free survival, and overall survival. The aim of this review is to systematically summarize and interpret the results of published randomized controlled trials of neoadjuvant taxane chemotherapy for women with non-metastatic breast cancer.     

Efficacy of Neoadjuvant Single or Dual Anti-HER-2 Therapy Combined with Chemotherapy in Patients with HER-2-Positive Breast Cancer: A Single-Center Retrospective Study

Background: Studies have shown that neoadjuvant anti-HER-2 therapy and chemotherapy can increase pathologic complete response (pCR) rate in HER-2-positive breast cancer patients and improve prognosis. However, data from Chinese patients are limited. Therefore, we conducted a single-center retrospective study to evaluate the effects of neoadjuvant single or dual anti-HER-2 therapy and chemotherapy in Chinese HER-2-positive breast cancer patients and to explore the prognostic indicators of pCR and progression-free survival (PFS). Methods: We included patients with HER-2-positive breast cancer treated with neoadjuvant anti-HER-2 therapy and chemotherapy at the First Affiliated Hospital of Chongqing Medical University in China from January 2016 to July 2020. We analyzed the relationship between patient characteristics and the pCR rate or PFS. Results: Forty-seven patients with HER-2-positive breast cancer receiving neoadjuvant anti-HER-2 therapy and chemotherapy were included. Univariate analysis suggested that compared with patients receiving neoadjuvant single anti-HER-2 therapy, patients receiving neoadjuvant dual anti-HER-2 therapy tended to have a higher pCR rate and better PFS. Patients who achieved pCR also tended to have longer PFS. Multivariate analysis indicated that patients with greater systemic inflammation response index (SIRI) reduction (>0.54) during neoadjuvant treatment (NAT) and patients with a lower T stage were more likely to achieve pCR. Patients aged ≤60 years with lower Ki-67 had longer PFS. Conclusion: Greater SIRI reduction during NAT was an independent influencing factor for pCR. Patients receiving neoadjuvant dual anti-HER-2 therapy and chemotherapy tended to have higher pCR rates and longer PFS. Patients who achieved pCR also tended to have longer PFS.     

乳腺癌术前化疗疗效及其对分子标记物的影响

[目的]通过研究乳腺幅术前化疗疗效及其对分子标记物的影响，进一步评价新辅助化疗的临床价值：[方法]对100例经窄芯针穿刺收材病理确诊的乳腺癌患者，给于术前化疗（新辅助化疗）方案2周期，继之行根治术，术后免疫组化测分子标记物ER、PR和c—erb B-2，并与化疗前的检查结果比对．[结果]经新辅助化疗后，乳腺癌原发灶明显缩小，11％（11例）达到完全缓解（CR）；腋窝淋巴结阳性率下降，21．6％（8／37）达到完全缓解（CR）；ER、PR和c-erb B-2的表达与新辅助化疗前不相符，不符合率分别为46％、37％和12％、[结论]新辅助化疗对降低病期、争取保乳机会、筛选敏感的化疗药物大有益处．但因其影响了术后ER，PR和c-erbB-2等分子标记物结果，不利于医生制定放疗、内分泌治疗及基因治疗等方案，有待于进一步研究解决此矛盾。     

CT findings of breast cancer with clinically complete response following neoadjuvant chemotherapy--histological correlation

In breast cancer patients, several regimens of neoadjuvant chemotherapy have been developed in order to achieve prognostic advantages for individual patients. Though some percentages of breast cancer patients show clinically complete response to neoadjuvant chemotherapy, the histopathological specimens of these patients demonstrate a considerably high frequency of the existence of residual disease. In this study, we aimed to evaluate the therapeutic effect of neoadjuvant chemotherapy for breast cancer patients showing clinically complete response (cCR) to neoadjuvant chemotherapy, using thin-section (5 mm) helical CT (prone position) with bolus injection of contrast agent. Between April 1994 and March 2002, 9 patients with breast cancer showing cCR to the neoadjuvant chemotherapy, who had undergone thin-section CT study both before and following neoadjuvant chemotherapy, enrolled in the study. The mean age of the patients was 46.2 years and all of them were female. The clinical stages were, 8 patients in stage II, and one in stage IIIA. In the CT evaluation, residual disease was visualized in 5 out of the 9 patients. Histopathological examination disclosed the existence of residual cancers in 6 out of the 9 patients, but only non-invasive cancer was revealed in 1 out of the 6. As patients having residual disease composed only of non-invasive cancer are classified into the pathologically complete response group according to the WHO classification, 4 out of these 9 patients showing clinically complete response to the neoadjuvant chemotherapy were classified into pCR (pathologically complete response) group, and another 5 were classified into the pPR (pathologically partial response) group. As a result, the diagnostic accuracy of the second CT study performed after neoadjuvant chemotherapy was evaluated as 77.8%, with a sensitivity of 80.0%, a specificity of 75.0%, a positive predictive value (PPV) of 80.0%, and a negative predictive value (NPV) of 75.0%. Therefore, for precise evaluation of the neoadjuvant chemotherapeutic effect for breast cancer, thin-section CT studies are considered to be essential.     

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.     

多西紫杉醇联合表柔比星新辅助化疗治疗乳腺癌的疗效分析

目的探讨多西紫杉醇联合表柔比星(ET方案)在乳腺癌新辅助化疗应用中的临床效果。方法选取70例原发性乳腺癌患者作为研究对象,所有患者均采用ET方案进行新辅助化疗,治疗4个疗程后,分析治疗效果和不良反应的发生情况。结果 ET方案新辅助化疗治疗乳腺癌的有效率为75.8%,治疗后患者发生不同程度的呕吐、粒细胞减少和脱发等不良反应。结论对乳腺癌患者行多西紫杉醇联合表柔比星新辅助化疗能够有效提高肿瘤治疗的有效率,不良反应患者可耐受,ET方案是新辅助化疗治疗乳腺癌较为理想的选择。