Pathological Assessment of the Response of Locally Advanced Breast Cancer to Neoadjuvant Chemotherapy and Its Implications for Surgical Management

(Received for publication on Sept. 8, 1998; accepted on Sept. 17, 1999)     

Response to Induction Chemotherapy in Black and White Patients with Locally Advanced Breast Cancer

Abstract: Black women with breast cancer have significantly poorer survival rates, a more advanced stage distribution, and are diagnosed at younger ages compared to white patients in the United States. We evaluated tumor response and survival with respect to race and age after induction chemotherapy. The study population consisted of 303 patients (229 white, 74 black) registered in two prospective trials of induction chemotherapy for locally advanced breast cancer [stage II (T 4 cm), stage III (noninflammatory), and stage IV (supraclavicular lymph node involvement only)] between 1989 and 1996. Chemotherapy regimens utilized 5-fluorouracil, cyclophosphamide, and doxorubicin (FAC). Response was defined as complete (CR, no clinical/radiographic detectable disease), partial (PR, 50% reduction in disease), minor (MR, <50% reduction), no change (NC), or progressive disease (PD). Median follow-up was 58 months; survival was calculated using the Kaplan–Meier method. There was no significant difference in age at presentation (54% of black patients compared to 58% of white patients <50 years of age). The black patients had significantly more advanced stages of disease at diagnosis (50% of black patients compared to 30% of white patients with stage IIIB disease; p = 0.03). For both age groups together, tumor response, 5-year overall survival (OS), and 5-year disease-free survival (DFS) rates were similar between the black and white patients. A trend was noted that the younger black patients were more likely to have a clinical CR or PR; this did not translate into a survival advantage. Despite the more advanced stage distribution for black women with breast cancer, induction chemotherapy yields high response rates (especially for younger black patients) and survival rates equivalent to white patients.     

Breast Conserving Surgery after Primary Chemotherapy in Locally Advanced Breast Cancer

Purpose: Primary chemotherapy is being given in the treatment of locally advanced breast cancers (LABC), but a major concern is local recurrence after therapy. The aim of this study was to assess the role of breast conserving surgery (BCS) in patients with locally advanced breast cancer.

Material and Methods: Twenty-eight patients, presenting LABC (T any, N 012, M0) were treated with primary chemotherapy comprising of cyclophosphamide, doxorubicin and fluorouracil and then BCS followed by radiotherapy were examined between the years 1992-2002 retrospectively. Before neoadjuvant chemotherapy, seven patients (25%) were Stage IIB, 19 patients (68%) Stage IIIA and two patients (7%) Stage IiIB. Survival times and curves were established according to the Kaplan-Meier method and compared by means of the log-rank test. The chi-square test and log rank test were performed for univariate statistical analysis of each prognostic factor. P values in multivariate analysis were carried out by the Cox’s proportional hazards regression model. All p values were two-sided in tests and p values < 0.05 were considered significant.

Results: Clinical down staging was obtained in 25 (89%) of patients. Three (11%) patients had complete clinical response, 22 (78%) patients with partial response and 3 (11%) had stable disease. The primary tumour could not be palpated after chemotherapy in 6 (21%) of 28 patients presenting with palpable mass, therefore needle localization was performed for BCS. Median follow-up was 51.9 months (ranging 10 to 118 months). Local recurrence was detected in 4 (14%) patients. Distant metastasis developed in 5 (18%) patients. Three of the patients died of distant metastases and two of them are alive at 49 months. Five-year survival rate was 66%. Statistically, there were no significant factors in terms of local recurrence. Histological grade and menopause status were significantly associated with overall survival (p = 0.018) and nuclear grade was the one significant factor on distant disease-free survival in univariate analysis (p = 0.006). In multivariate analysis, there were no significant factors in terms of overall and distant disease-free survival Conclusions: Negative margin is more important than the clinical and histological parameters, such as pretreatment stage, clinical response rate, ER and PR in terms of local recurrence. BCS can be performed safely by achieving free surgical margin in patients who have small sized tumour and with either N2 axillary involvement or skin invasion.     

Combined Modality Treatment for Locally Advanced Breast Cancer

Purpose: To assess the value of aggressive loco-regional surgery in desperate situations with locally advanced breast cancer .

Methods: In this study there were considered 31 patients with locally advanced breast cancer who underwent surgery in a 5-year period. 10 of them received 3 cycles of chemotherapy and radiotherapy before surgical intervention; the rest of the 21 patients had systemic or local contra-indications for neo-adjuvant therapy. We describe clinical aspects and technical difficulties. Surgical intervention focused on tumour removal and lymph node dissection. Skin defect was covered with flaps according to the Mortimer-Show technique. Postoperatively, the outcome was influenced in a favourable way by the use of Detralex, a micronised flavonoid; all but 2 patients received chemotherapy and locoregional radiotherapy.

Results: 25 patients survived free of disease; from 6 patients who suffered recurrence, 2 are still living and 4 have died. Conclusions: In some forms of locally advanced breast cancer, aggressive surgery offers improvement in the quality of life and increases survival.     

Women with Locally Advanced Breast Cancer are Not at Higher Risk for Contralateral Synchronous Breast Cancer

Abstract: Breast magnetic resonance imaging (MRI) may provide a more accurate assessment of synchronous contralateral breast cancer in select cohorts of patients. The utility of this imaging technique for detecting synchronous contralateral breast cancers in patients with locally advanced breast cancer (LABC) has not previously been described. We report our experience in assessing contralateral disease in a cohort of women with LABC who had clinical assessment, mammography, ultrasound, and MRI prior to neo‐adjuvant therapy. Patients, who presented with LABC, stage IIB (T3N0), stage III A/B, were identified from a prospectively kept data base at a single tertiary care centre between November 2001 and August 2005. Charts were retrospectively reviewed and demographic, imaging and pathologic variables were abstracted. One hundred and one female patients with LABC were identified (median age 49). One hundred of 101 patients presented with a clinically obvious LABC. Three patients had LABC that was not visualized mammographically but was detected on ultrasound and MRI. Seventeen of 101 patients (17%) had contralateral imaging findings that required biopsy for diagnosis. Of the contralateral biopsies, 41% (7/17) were malignant. These malignant lesions were identified clinically in 4/7 patients, on 7/7 ultrasounds, 7/7 mammograms, and 5/5 MRI. Overall, 7% (7/101) patients had malignant synchronous contralateral disease. In our LABC patient cohort, 7% of patients presented with malignant contralateral disease. The incidence of contralateral disease in women with LABC is comparable with patients who present with early stage breast cancer. No single screening technique, ultrasound, mammogram or MRI, appeared to be superior for identifying contralateral synchronous malignancy.     

The Role of Radiation Therapy in Locally Advanced Breast Cancer

Abstract: The purpose of the study was to evaluate and compare the impact of postoperative radiotherapy, whether it was based on the clinical stage at presentation of the disease or on the pathological downstaged disease after initial chemotherapy for non‐inflammatory locally advanced breast cancer (LABC). We retrospectively analyzed locoregional recurrence (LRR), relapse free survival (RFS), overall survival (OS) and disease free survival (DFS) in 55 patients treated for non‐inflammatory LABC with neoadjuvant chemotherapy and surgery with or without radiotherapy. The mean follow‐up was 55 months. The 3‐year OS was 74%, DFS 73% and RFS 87%. The OS and DFS benefit was seen in those receiving radiation, with a mean OS of 89 months versus 68 months (p = 0.029) and mean DFS of 72 months versus 54 months (p = 0.029). Total LRR was 11% (8% versus 17% in the non‐radiotherapy group, p = 0.349) and mean RFS of 95 months versus 86 months (p = 0.164). If the treatment planning was to be based on the original extent of the disease, then all patients in our study should have received adjuvant radiotherapy. Significantly lower OS and DFS without the addition of radiotherapy suggests that indication for radiation treatment should be based on the clinical pre‐chemotherapy stage rather than the pathological post‐chemotherapy stage. Radiation should therefore always be considered regardless of the response to initial chemotherapy for non‐inflammatory LABC.     

The Integrated Evaluation of the Results of Oncoplastic Surgery for Locally Advanced Breast Cancer

The optimal surgical management of locally advanced breast cancer (LABC) remains undefined. The aim of the study was to obtain long‐term results of oncoplastic surgery in terms of overall survival, loco‐regional recurrence, and quality of life in case of LABC. Prospective cohort study enrolled 60 patients with stage III breast cancer. Forty‐two (70%) patients received neo‐adjuvant chemotherapy, 28 patients were considered suitable for surgery as initial treatment option. Type II oncoplastic surgery was performed for all patients: hemimastectomy and breast reconstruction with latissimus dorsi flap – for 29 (48.3%), lumpectomy – 31 (51.7%), and reconstruction with subaxillary flap for four (6.7%), with bilateral reduction mammoplasty – 14 (23.3%) and with J‐plastic – 13 (21.7%) patients. Adjuvant chemotherapy and hormonal therapy followed surgery for all, except one, patients. Sequential radiotherapy was administered for all patients. The mean period of follow‐up was 86 months. Postoperative morbidity rate was 5%. Local‐regional recurrence was detected in six (10%) patients. After reoperation no local relapse was diagnosed. However, three of these patients had systemic dissemination of the disease. Distant metastasis was detected in 23 (38.3%) patients. Distant metastasis‐free survival at 5 years was 61.7%. Fourteen patients died (23.3%). A total of 87.2% of the patients had good and excellent esthetic outcome. Oncoplastic breast‐conserving surgery can be proposed for selected patients with LABC with acceptable complication, local recurrence rate, and good esthetic results.     

Feasibility of Immediate Breast Reconstruction for Locally Advanced Breast Cancer

Background: Immediate breast reconstruction (IBR) has been considered contraindicated for patients with locally advanced breast cancer (LABC). Our goal was to determine whether IBR resulted in delayed postoperative chemotherapy, increased postoperative complications, or increased risk of recurrent disease.Methods: A prospective database of 540 modified radical mastectomies performed with IBR between 1990 and 1993 identified 50 patients with LABC. Postoperative management and outcome were compared to that of 72 patients undergoing modified radical mastectomy without IBR treated on a standardized LABC protocol using preoperative chemotherapy, postoperative chemotherapy, and radiotherapy during the same time period.Results: Results were evaluated by 2 analysis. The median ages for the patients with IBR versus those not undergoing IBR were 44 and 46 years, respectively. The stage distribution for the IBR patients versus patients not undergoing IBR was as follows: IIB, 46% versus 17%; IIIA, 44% versus 39%; and IIIB, 10% versus 44%. The types of IBR were transverse rectus abdominis myocutaneous (TRAM) flap (68%), latissimus dorsi flap (2%), and implants (30%). Chemotherapy was given to all IBR patients: 24% preoperatively and 96% postoperatively. Radiotherapy was used in 40%. Four postoperative complications (8%) necessitated prolongation of hospitalization, including two patients requiring surgical debridement for partial flap loss; there were no complete flap losses. The incidences of major and minor wound complications in the group not undergoing IBR were 7% and 4%, respectively. Of the 15 patients receiving implant reconstruction, 7 (47%) required subsequent implant removal because of contractures or infections. The median interval between surgery and postoperative chemotherapy was 35 days for the IBR patients and 21 days for the patients not undergoing IBR. This difference was marginally significant (P 5.05). With a median follow-up of 58.4 months, no significant differences in local or distant relapse rates were detected.Conclusions: IBR can be performed with low morbidity in patients with LABC. Use of autogenous tissue is preferable because of poor results with implants. IBR is associated with somewhat longer intervals to resumption of postoperative chemotherapy, but this does not appear to be clinically significant—the local and distant relapse rates are similar for LABC patients undergoing modified radical mastectomy with or without IBR.     

原发局部晚期乳腺癌的治疗

目的：分析女性原发局部晚期乳腺癌治疗结果及预后，以确定更完善的治疗。方法：对１４７例进行回顾性研究，对治疗及多种因素与预后的相关性进行分析。结果：与预后相关的因素为腋淋巴结转移（Ｐ＜０．０５），治疗失败的原因是血行转移（Ｐ＜０．０５）。单纯手术治疗５年及１０年生存率分别为２６．７％、２０．０％，综合治疗５年及１０年生存率分别为５２．６％、４７．７％（Ｐ＜０．０１）。结论：应采用综合治疗     

Sentinel Node Biopsy Before Neoadjuvant Chemotherapy for Determining Axillary Status and Treatment Prognosis in Locally Advanced Breast Cancer

Background Treatment of locally advanced breast cancer with neoadjuvant chemotherapy assesses an in vivo tumor response while increasing breast conservation. Axillary clearance of nodal disease after treatment defines prognostic stratification. Our study objective was to show that sentinel node staging before treatment can optimize posttreatment prognostic stratification in clinically N0 patients. Methods Eighty-nine patients with locally advanced breast cancer were treated with neoadjuvant chemotherapy. Of these, 42 (47%) clinically palpable or image-detected nodes (cN+) were histologically confirmed before treatment (group 1), and 47 (53%) patients without palpable lymph nodes (cN0) had a sentinel lymph node (SLN) biopsy before treatment (group 2). Survival analysis was conducted with the Kaplan-Meier method. Results In groups 1 and 2, 82 (92%) of 89 patients had node-positive disease before treatment. Seven (8%) of 89 had negative SLNs and no completion axillary lymph node dissection, 24 (27%) patients had a complete pathologic axillary response (pCR^AX; 11 [26%] of 42 in group 1 and 13 [33%] of 40 in group 2), and 58 (65%) of 89 had residual disease in the axilla. Breast-conserving therapy was applied to 27 (30%) of 89 patients. The seven SLN-negative patients had no axillary recurrence at 25 months, and pCR^AX patients had a significantly higher overall survival than patients with residual disease. Conclusions This study validates the prognostic stratification of patients with a complete pathologic axillary response to neoadjuvant chemotherapy. The addition of SLN biopsy to cN0 patients before treatment increased accurate nodal staging by 53%, eliminated completion axillary lymph node dissection in 15%, and demonstrated an improved prognosis in 28% of pCR^AX patients. SLN biopsy before treatment provides accurate staging of cN0 patients; allows acquisition of standard treatment markers, prognostic biomarkers, and microarray analysis; and affords prognostic stratification after treatment.     

Glutathione S-Transferase-pi Expression in Prechemotherapy and Postchemotherapy Tumor Samples from Patients with Locally Advanced Breast Carcinomas

Abstract: Early local disease recurrence and distant metastasis remain major problems in the management of locally advanced breast carcinoma (LABC). Glutathione S-transferase of the pi class (GST-pi) has been implicated as a potential prognostic predictor for breast carcinomas, and its expression has been reported in 40–70% of untreated human primary breast cancers. We examined GST-pi expression by immunohistochemis-try technique in 45 prechemotherapy biopsy samples and 26 postchemotherapy resection samples from patients with LABC and evaluated its relationship with response to treatment, disease recurrence, and other known prognostic factors. GST-pi expression was present in 56% and 58% of prechemotherapy and postchemotherapy samples, respectively. Of 26 postchemotherapy tumor samples, 15 cases showed positive GST-pi staining; these 15 patients had shorter overall survival times compared with the 11 patients whose tissue samples showed negative staining (p = 0.053). Eight cases showed a marked increase (more than double) of GST-pi expression from prechemotherapy samples to postchemotherapy samples, however, the increase did not correlate with survival time, response rate, or relapse rate. Our findings suggest that evaluation of GST-pi expression after induction chemotherapy for LABC may allow selection of patients who might benefit from different chemotherapeutic regimens or adjuvant chemotherapy.?     

Preoperative Paclitaxel and Radiotherapy for Locally Advanced Breast Cancer: Surgical Aspects

Introduction: Approximately 15% of breast cancer patients present with large tumors that involve the skin, the chest wall, or the regional lymph nodes. Multimodality therapy is required, to provide the best chance for long-term survival. We have developed a regimen of paclitaxel, with concomitant radiation, as a primary therapy in patients with locally advanced breast cancer.Methods: Eligible patients had locally advanced breast cancer (stage IIB or III). After obtaining informed consent, patients received paclitaxel (30 mg/m² during 1 hour) twice per week for 8 weeks and radiotherapy to 45 Gy (25 fractions, at 180 cGy/fraction, to the breast and regional nodes). Patients then underwent modified radical mastectomy followed by postoperative polychemotherapy.Results: Twenty-nine patients were enrolled. Of these, 28 were assessable for clinical response and toxicity, and 27 were assessable for pathological response. Objective clinical response was achieved in 89%. At the time of surgery, 33% had no or minimal microscopic residual disease. Chemoradiation-related acute toxicity was limited; however, surgical complications occurred in 41% of patients.Conclusions: Preoperative paclitaxel with radiotherapy is well tolerated and provides significant pathological response, in up to 33% of patients with locally advanced breast cancer, but with a significant postoperative morbidity rate.Presented at the 52nd Annual Meeting of Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999.     

多西他赛、环磷酰胺与多西他赛、吡柔比星新辅助化疗方案治疗局部晚期乳腺癌疗效分析

目的观察多西他赛、环磷酰胺（DC方案）与多西他赛、吡柔比星（DT方案）新辅助化疗方案治疗局部晚期乳腺癌的临床疗效和不良反应。方法经麦默通穿刺确诊局部晚期乳腺癌可手术患者73例,随机分为DC组（35例）,DT组（38例）,分别给予DC方案,DT方案化疗3个周期,DC组35例,DT组38例化疗结束2周后行乳腺癌改良根治术。比较DC组,DT组疗效和不良反应,治疗前、后TNM分变化、术后并发症及化疗前后ER、PR、HER2变化比较。结果临床疗效比较DT组优于DC组,其差异有统计学意义（P〈0．05）;TNM分期均较新辅助化疗前降低（P〈0．05）,不良反应比较差异无统计学意义（P〉0．05）;术后并发症比较差异无统计学意义（P〉0．05）,ER、PR均为阴性患者对化疗敏感,DT方案对于HER2高表达患者疗更敏感。结论DT及DC新辅助化疗方案疗对局部晚期乳腺癌均有效,DT方案优于DC方案。     

A Case of a Bilateral Inflammatory Breast Cancer: A Case Report

Cases of bilateral inflammatory breast cancer (IBC) are extremely rare. Our search criteria only found one other record of metachronous bilateral IBC (1). We present the case of a patient who was treated for IBC with neoadjuvant chemotherapy, modified radical mastectomy (MRM), and whole breast radiation. Less than 1 year later, the patient had a recurrence of IBC on the left chest wall with in the radiated field, as well as a new IBC on the contralateral side. Bilateral IBC is extremely rare. This entity can present challenges for the standard treatment of IBC with neoadjuvant chemotherapy, MRM, and whole breast radiation (2). Our case study shows the importance of scheduled routine imaging, screening with physical examination after IBC management, and good patient compliance in this aggressive disease (3).     

晚期乳腺癌新辅助化疗的临床报告

目的　探讨新辅助化疗在晚期乳腺癌治疗中的远期临床效果。方法　对 31例Ⅲ、Ⅳ期的乳腺癌患者行新辅助化疗 ,手术前行 2周期的CAF方案化疗〔CTX 5 0 0mg/m2 静脉推注 (第 1、8天 ) ,5 FU 5 0 0mg/m2 静脉推注 (第 1、8天 ) ,ADM 30mg/m2 静脉推注 (第 1天 ) ,每 2 1天为 1周期〕 ,并与同期未行任何术前治疗的可手术的30例Ⅲa期患者作对比分析。结果　新辅助化疗组的总有效率为 87.1% (2 7/31) ,有 6 1.3% (19/31)的患者分期降低 ,其中 6例降为Ⅲa期 ,8例降为Ⅱb期 ,4例降为Ⅱa期 ,1例降为 0期 ,临床完全缓解 1例 ,无病理完全缓解。新辅助化疗组的无病生存期为 5 6 .3个月 ,明显高于未行化疗组的 4 3.5个月 (P<0 .0 5 ) ,新辅助化疗组的 5年无病生存率为 38.7% ,略高于未化疗组的 33.3% ,两组间差异无显著性意义。结论　新辅助化疗能降低晚期乳腺癌患者的分期 ,为手术创造最佳机会 ,能明显延长晚期乳腺癌患者的无病生存期 ,减少或延缓肿瘤的复发、转移。     

术前区域动脉持续灌注化疗并栓塞治疗局部晚期乳腺癌的临床观察

目的：观察术前区域动脉持续灌注化疗并栓塞治疗局部晚期乳腺癌的效果。方法：应用术前超选择区域动脉插管持续灌注化疗结合次要供血动脉栓塞的方案,经治Ⅲａ,ｂ 期乳腺癌患者９ 例。结果：在治疗后的１ 个月内取得良好效果,有效率达８９ ％ （８／９） 。结论：局部晚期乳腺癌术前区域动脉持续灌注化疗配合次要供血动脉栓塞可有效提高术前化疗疗效,显著缩短疗程且毒副反应小、简便,值得推广应用。     

背阔肌肌皮瓣修复新辅助化疗后局部晚期乳腺癌组织缺损的疗效观察

目的:探讨我科12例局部晚期伴有皮肤侵犯导致溃疡形成的乳腺癌患者,术前行新辅助化疗后行改良根治术,即刻应用背阔肌肌皮瓣即时修复组织缺损的疗效观察。方法:12例患者均于术前行4~6周期新辅助化疗TEC方案,后达到临床部分缓解(PR)、创面缩小后,行乳腺癌改良根治术、即刻背阔肌肌皮瓣转移修复胸壁组织缺损。结果:12例患者手术均成功,接受新辅助化疗和术后放疗。随访l0~24个月,术后远处转移l例,无局部复发和死亡病例。结论:局部晚期乳腺癌新辅助化疗后,应用背阔肌肌皮瓣转移至胸壁修复组织缺损切实可行。