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.     

Predictive value of biologic parameters for primary chemotherapy in operable breast cancer

Primary chemotherapy represents an ideal model to evaluate the relationships between treatments and the prognostic and predictive parameters provided by the new technologies. First- and second-generation trials have shown that primary chemotherapy significantly improves the rate of breast conservation without increasing the risk of ipsilateral recurrence and while assuring survival rates comparable with those achieved with postoperative chemotherapy. Moreover, patients who exhibited a pathologic complete response (pCR) showed better progression-free survival and overall survival. The third-generation trials were aimed at improving the percentage of pCR, identifying and validating gene and protein biomarkers of chemotherapy sensitivity, and better defining the individual risk of relapse. Several parameters, such as index of proliferation and apoptosis, expression of proteins (eg, p53 and Bcl-2), and hormone receptor and epidermal growth factor family receptors, have been related to response to primary chemotherapy. Negative hormone receptors and greater proliferative activity seem to be the only parameters more consistently associated with greater chemotherapy sensitivity. However, the strength of this association is not sufficient to differentiate patients at different degrees of risk and does not allow for an individualized therapeutic choice. Newer technologies offer the possibility of evaluating thousands of genes and identifying clusters of gene expression associated with significantly different risks of relapse and patterns of sensitivity/resistance to specific drugs. The primary chemotherapy model is the ideal clinical setting in which to validate the relationship between tumor molecular profiling and treatment outcomes and to design tailored therapies based on observed effects on individual tumors.     

Neoadjuvant chemotherapy in operable breast cancer

Primary chemotherapy in localised breast cancer may prevent tumour spread during surgical treatment and reduce proliferation of micrometastases. A randomised clinical trial, in 196 premenopausal and postmenopausal patients with operable (T2-3, N0-1b) breast cancer, was started in November 1983 at the Institut Curie to compare neoadjuvant and adjuvant regimens of chemotherapy with radiotherapy with or without surgery. The patients have been followed up for 35–70 months (median 54). A neoadjuvant group received two monthly cycles of intravenous doxorubicin/cyclophosphamide/5-fluorouracil before locoregional therapy and four cycles subsequently. Six months cycles following locoregional therapy were administered to the adjuvant group. Because of inclusion of postmenopausal and/or node-negative patients, compliance was less than optimal in 39 patients who were analysed separately according to actual dose received. Tumour response, evaluated after two cycles of neoadjuvant chemotherapy, was significantly associated with dose (P = 0.003). Survival showed a slight non-significant advantage for the neoadjuvant group. Survival plotted by actual dose was also similar. Neoadjuvant chemotherapy was safe and at least as effective as the adjuvant regimen. Patients have been accrued to a subsequent larger trial of chemotherapy as first-line treatment.     

Neo-adjuvant chemotherapy for operable breast cancer induces apoptosis

The use of neo-adjuvant chemotherapy (often referred to as pre-operative or primary chemotherapy) represents a major change in the management of breast cancer as a systemic disease. Laboratory studies have shown that many anti-cancer agents with differing modes of action achieve cytotoxic effects by inducing apoptosis. In this study, we investigated the induction of apoptosis by neo-adjuvant chemotherapy in human breast cancer. The aim was to determine whether a correlation existed between post chemotherapy apoptotic index (AI) and clinical response and patients' survival. Our results indicate that apoptosis is induced by neo-adjuvant chemotherapy and that the response is variable. Our data show that post chemotherapy AI correlated with clinical response and increased patient survival, including both relapse (disease) free survival and overall survival. Post-neo-adjuvant chemotherapy AI levels in primary breast cancer may possibly predict an individual patient's overall response.     

可手术的乳腺癌术前化疗的近期临床观察

Eighty-one patients with operable breast cancers received the short-term and intensive preoperative chemotherapy, followed by radical mastectomy are presented. The total response rate in the primary tumor to chemotherapy was 59%. Seven patients (8.6%) had complete remission, 41 (50.6%) partial remission and 33 (40.7%) stable lesions. No cancer cells were found histopathologically by serial sections from two primary lesions after chemotherapy. The authors found that tumor with small size, short course and regular shape had a better response rate. Histopathological type, firmness and boundary of tumor, menopausal status, and estrogen receptor (ER) status were not related to the chemotherapeutic effect. No obvious toxicity and side effects were found during the chemotherapy. The chemotherapy did not influence the wound healing. The results indicate that the chemotherapy has a favorable effect on breast cancer and is safe and valid. The response rate of breast cancer to chemotherapy before operation can be used as breast cancer chemosensitivity test in vivo.     

可手术乳腺癌的新辅助化疗

新辅助化疗已被广泛用于局部晚期乳腺癌,早期可手术乳腺癌的新辅助化疗应用价值还在探讨之中。本文综述了新辅助化疗治疗可手术乳腺癌基础及临床方面的最新进展,认为新辅助化疗应用于早期可手术乳腺癌,可明显消退肿瘤,提高乳房保留治疗率,可获得至少与辅助化疗同样的总生存率。     

可手术的乳腺癌术前化疗的远期效果

目的探讨术前化疗对可手术的乳腺癌的远期疗效。方法可手术的乳腺癌患者５３７例,分为两组：术前化疗组（Ａ组）２５３例;术后辅助化疗组（Ｂ组）２８４例。Ａ组术前联合化疗,每周一次共４次,休２周行根治性手术。两组患者术后两周内开始化疗、化疗方案和完成化疗周期相同。结果（１）Ⅲ期患者,Ａ组５年总生存率（ＯＳ）５９％,无病存活率（ＤＦＳ）５４．９％,均明显高于Ｂ组２８．３％和２０．８％（Ｐ＜０．０５）。（２）Ⅱ期患者,Ａ组８年ＯＳ８１．４％,ＤＦＳ７６．３％,均高于Ｂ组６７．４％和６２．９％（Ｐ＜０．０５）。Ⅲ期患者,Ａ组８年ＯＳ４６．９％,ＤＦＳ４０．６％,也高于Ｂ组２０．７％和１３．３％（Ｐ＜０．０５）。（３）Ａ组Ｔ３、Ｔ４和转移淋巴结数≥４个的患者,５年、８年生存率均高于Ｂ组（Ｐ＜０．０５）。结论可手术的Ⅲ期乳腺癌,术前化疗可提高患者５年、８年生存率,明显改善Ⅱ期患者的远期疗效。     

可手术乳腺癌的新辅助全身治疗

新辅助全身治疗(neoadjuvant systemic treatment, NST)也称术前全身治疗。以全身治疗为原发性乳腺癌的首治方法兴起于上世纪70年代,其初衷是为了解决不可切除或切除困难的局部晚期乳腺癌(locally advanced breast cancer,LABC)和炎性乳腺     

Second neoplasms after adjuvant chemotherapy for operable breast cancer

Between 1974 and 1982, 797 patients who had operable breast cancer were treated at the University of Texas M.D. Anderson Hospital and Tumor Institute at Houston with three adjuvant chemotherapy trials consisting of fluorouracil, doxorubicin, and cyclophosphamide (FAC). The incidence of second primary malignant tumors in this group of patients was evaluated and compared with that in a historical control group of patients who had stages II and III disease (n = 186) and who did not receive adjuvant chemotherapy following surgery. Radiotherapy was given to 54% (n = 433) of the chemotherapy-treated patients and to 96% (n = 178) of the controls. The median age of the patients was 49.6 and 55 years for the treated and control groups, respectively. Second neoplasms developed in 10 chemotherapy-treated patients and in nine control patients; rates at 5 years from initiation of therapy based on actuarial curves were 1.9 and 5.0%, respectively. These second tumors developed after a median latency period of 17.5 months for the FAC-treated group and 13 months for the controls. Two cases of leukemia developed in each of the two treatment groups. The rate of second malignancy in the chemotherapy-treated patients was not increased compared with that in the historical controls.     

可手术乳腺癌NEF方案新辅助化疗的临床观察

目的评价NEF方案用于可手术乳腺癌新辅助化疗的近期疗效及其不良反应.方法 2000至2004年应用NEF方案治疗Ⅱb～Ⅲ期可手术乳腺癌患者52例.NEF 方案长春瑞滨(NVB) 30 mg/ m2,d1,5;EPI 50 mg/ m2 ,d1;5-Fu 500 mg/ m2 ,d1～5.28 d为1 个周期,所有患者完成2 个周期新辅助化疗后评价疗效,化疗结束后2～3周手术.结果 34例(65.4%)降低了临床分期;其中完全缓解(CR)3例(5.8%),病理完全缓解(pCR) 2例(3.8%),部分缓解(PR)35例(67.3%),病变稳定(SD)14例(26.9%),全组无疾病进展(PD)者,总有效率(CR+PR)为73.1%.Ⅱb期、Ⅲa期、Ⅲb期有效率分别为83.3% (15/18)、69.6%(16/23)和63.6%(7/11),Ⅱb期有效率高于Ⅲa期和Ⅲb期.新辅助化疗2个周期后有42.0%(21/50) 未触及肿大淋巴结;46.0%(23/50)肿大淋巴结明显缩小,腋窝淋巴结总有效率为88.0%(44/50).毒副反应为白细胞下降、恶心呕吐、脱发、神经毒性和周围静脉炎等,患者均可耐受.结论 NEF方案用于可手术乳腺癌新辅助化疗,对原发灶和腋窝淋巴结均有较高的有效率,而且可以降低临床分期,不良反应可耐受,值得推广.     

Prediction of response to primary systemic chemotherapy involving weekly paclitaxel followed by FEC 100 for advanced breast cancer

To predict the response to primary systemic chemotherapy (PSC) involving weekly paclitaxel (PTX) followed by FEC100, we analyzed the therapeutic effects of PSC on 58 cases of stage II - III advanced breast cancer, 2 cases of PD, 4 cases of suspension due to adverse events, and 52 successful cases (89.7%). As for clinical effect, CR was observed in 12 cases (23.1%) and PR in 33 cases (63.5%) and for histological effects, grade 3 (pCR) was observed in 7 cases (13.5%) and grade 2 in 13 cases (25.0%). At the time of completion of 4 courses of PTX, SD was observed in 34 out of 52 cases, but the number of SD decreased to 28 cases on completion of 8 courses of PTX, to 19 cases on completion of 12 courses of PTX, and to 7 cases on completion of 4 courses of FEC. In examining the 7 cases of pCR in whom the histological effect was observed, 3 cases of SD were observed on completion of 4 courses of PTX and 2 cases on completion of 8 courses of PTX. Unless PD is observed during the course of PSC, continuation of therapy would be indicated because of the delayed response.     

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.     

Prognostic significance of a complete pathological response after induction chemotherapy in operable breast cancer

Only a few papers have been published concerning the incidence and outcome of patients with a pathological complete response after cytotoxic treatment in breast cancer. The purpose of this retrospective study was to assess the outcome of patients found to have a pathological complete response in both the breast and axillary lymph nodes after neoadjuvant chemotherapy for operable breast cancer. Our goal was also to determine whether the residual pathological size of the tumour in breast could be correlated with pathological node status. Between 1982 and 2000, 451 consecutive patients were registered into five prospective phase II trials. After six cycles, 396 patients underwent surgery with axillary dissection for 277 patients (69.9%). Pathological response was evaluated according to the Chevallier's classification. At a median follow-up of 8 years, survival was analysed as a function of pathological response. A pathological complete response rate was obtained in 60 patients (15.2%) after induction chemotherapy. Breast tumour persistence was significantly related to positive axillary nodes (P=5.10(-6)). At 15 years, overall survival and disease-free survival rates were significantly higher in the group who had a pathological complete response than in the group who had less than a pathological complete response (P=0.047 and P=0.024, respectively). In the absence of pathological complete response and furthermore when there is a notable remaining pathological disease, axillary dissection is still important to determine a major prognostic factor and subsequently, a second non cross resistant adjuvant regimen or high dose chemotherapy could lead to a survival benefit.     

Adjuvant chemotherapy for primary breast cancer

For patients with hormone-unresponsive or higher-risk operable early-stage breast cancer, adjuvant chemotherapy significantly reduces the risks of relapse and death. The prognosis for such patients, especially those presenting with extensive axillary lymph node involvement, remains poor. New chemotherapy agents and novel administration schedules have recently been shown to improve clinical outcome. This overview provides a summary of the state of the art and the most recent developments regarding adjuvant chemotherapy for primary breast carcinoma.     

原发性乳腺癌新辅助化疗的临床研究

目的　探讨以 5 氟脲嘧啶 (5 Fu)和蒽环类药物为主的联合化疗对原发性乳腺癌新辅助化疗的应用价值。方法　 111例患者的 114个原发性乳腺癌 ,于手术前应用 5 Fu和蒽环类药物 (吡柔比星或表柔比星 )为主的联合化疗 2～ 6个周期 ,观察其疗效和毒副反应 ,并分析疗效与肿瘤特征的关系。结果　全组总有效率为 87.7% ,其中临床完全缓解率为 39.5 % ,病理学完全缓解率为 2 3.7% ,疾病进展率为 0 .9%。吡柔比星方案较表柔比星方案疗效更佳 ,两方案病理学完全缓解者差异有显著性 (P <0 .0 5 )。吡柔比星方案的脱发反应轻微 ,但骨髓抑制较表柔比星方案严重。肿瘤激素受体表达与疗效有关 ,激素受体表达阴性者病理学完全缓解率为 33.3% ,而激素受体表达阳性者仅为 7.5 %(P <0 .0 0 5 )。肿瘤大小和HER 2表达与疗效无关。结论　 5 Fu和蒽环类药物为主的联合方案用于乳腺癌新辅助化疗 ,近期疗效满意 ,且副反应较轻。吡柔比星方案的疗效优于表柔比星方案 ,激素受体表达阴性者对化疗更敏感     

Accuracy of mammography and echography versus clinical palpation in the assessment of response to primary chemotherapy in breast cancer patients with operable disease

The response to primary chemotherapy is an important prognostic factor in patients with non metastatic breast cancer. In this study we compared the assessment of response performed by clinical palpation to that performed by echography and mammography in 141 out of 157 consecutive breast cancer patients (T2-4, N0-1, M0) submitted to primary chemotherapy. A low relationship was recorded between tumor size assessed clinically and that evaluated by either mammography: Spearman R=0.38 or echography: R=0.24, while a greater correlation was found between the tumor dimension obtained by the two imaging techniques (R=0.62). According to the WHO criteria, the grade of response of breast cancer to primary chemotherapy, showed by mammography and echography, was less marked than the grade of response seen at clinical examination. Residual tumor size assessed clinically depicted a stronger correlation with pathological findings (R=0.68) than the residual disease assessed by echography (R=0.29) and mammography (R=0.33). Post-chemotherapy histology evaluation revealed pathological complete response in three cases (2.1%). Two of these cases were judged as complete responders by clinical palpation but only one was recognized by mammography, and none by echography. Clinical response, but not the response obtained by the two imaging techniques, was a significant predictor for longer disease free survival (p=0.04). To conclude, physical examination measurements remain the method of choice in evaluating preoperatively the disease response in trials of primary chemotherapy. Prediction of pathological outcome is not improved by echography and mammography.     

Randomized phase II study of primary systemic chemotherapy and trastuzumab for operable HER2 positive breast cancer

BackgroundIn primary systemic therapy in patients with human epidermal growth factor receptor 2 positive (HER2⁺) breast cancer, improvements in pathologic complete response (pCR) rate have been achieved by administering trastuzumab.Patients and MethodsPatients with stage II or IIIA HER2⁺ operable breast cancer were randomly assigned to receive four 3-weekly cycles of FEC (5-fluorouracil 500 mg/m², epirubicin 100 mg/m², cyclophosphamide 500 mg/m²) followed by 4 cycles of 3-weekly trastuzumab (8 mg/kg week 1 and then 6 mg/kg) with either 12 weekly doses of paclitaxel 80 mg/m² (FEC-PH) or 4 cycles of 3-weekly docetaxel 75 mg/m² (FEC-DH).ResultsBetween March 2007 and June 2008, 102 patients were enrolled. Forty-nine patients receiving FEC-PH and 47 receiving FEC-DH were assessable for efficacy and safety. Eighty-four patients completed treatment and underwent surgery. There was no significant difference in the pCR rate between the 2 groups (46.9% [95% CI, 33.7%-60.6%] with FEC-PH vs. 42.6% [95% CI, 29.5%-56.8%] with FEC-DH; P = .67). Analysis by hormone receptor (HR) status showed pCR rates of 54.2% (32/59) in HR^? tumors and 29.7% (11/37) in HR⁺ tumors (P = .02). Among HR^? tumors, the pCR rates were 65.4% and 45.5% in patients treated with FEC-PH and FEC-DH, respectively (P = .13).ConclusionsThere was no significant difference in pCR rate between FEC-PH and FEC-DH. Both regimens achieved higher pCR rates in HR^? than HR⁺ breast cancer, and there was a trend toward higher pCR in HR^? tumors with FEC-PH compared with FEC-DH. Further investigation is warranted to explore the relationship between efficacy and HR status.     

Prognostic factors for survival after neoadjuvant chemotherapy in operable breast cancer. the role of clinical response

The aim of this retrospective study was to assess predictive factors for clinical response to preoperative chemotherapy and prognostic factors for survival. From 1981 to 1992, 936 patients with T2-T3, N0-N1 breast cancer who received 2-6 months (median 4) of preoperative chemotherapy were selected from the Institute Curie database. Preoperative treatment was followed by surgery and/or radiotherapy. Median follow-up was 8.5 years (range 7-211 months). The objective response rate before surgery and/or radiotherapy was 58.3%. In stepwise multivariate analysis (Cox model), favourable prognostic factors for survival were the absence of pathological axillary lymph node involvement (Relative Risk (RR) 1.54; P=0.0004), low histological tumour grade (RR=1.54; P=0.0017), clinical response to preoperative chemotherapy (RR=1.45, P=0.0013), positive progesterone receptor (PR) status (RR=1.56; P=0.0001), smaller tumour size (RR=1.37; P=0.005) and lack of clinical lymph node involvement (RR=1.42; P=0.007). The association of clinical tumour response with survival is independent of the baseline characteristics of the tumour. Clinical response could be used as a surrogate marker for evaluation of the efficacy of neoadjuvant chemotherapy before assessment of the pathological response.