Adjuvant therapy of breast cancer

The treatment of early-stage breast cancer includes the use of chemotherapeutic and hormonal agents. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the United States are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen, a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors, compared to tamoxifen or an advantage of sequencing tamoxifen followed by an aromatase inhibitor (AI). The role of ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the HER2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early-stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an aromatse inhibitor in premenopausal women with breast cancer.     

Current status of therapy for breast cancer worldwide and in Japan

The results of clinical trials conducted in Europe and North America have been incorporated into treatment strategies for breast cancer in Japan. Despite the use of similar treatment regimens, why has mortality from breast cancer been increasing in Japan? Procedures for surgical treatment and sentinel lymph node biopsy in breast cancer do not differ between Japan and Western countries, but the strategies for radiotherapy differ slightly. Hormonal therapy is now selected on the basis of scientific evidence, and similar regimens are used in Japan and Western countries. As for postoperative adjuvant chemotherapy, an anthracycline plus cyclophosphamide and taxane-based regimens are standard treatments in Japan and Western countries. In 2009, however, the results of two large clinical studies designed to determine whether intravenous or oral treatment was superior for postoperative adjuvant chemotherapy were reported in Japan. Both studies showed that relapse-free survival and overall survival (OS) at 5 years after surgery were similar for a combination of cyclophosphamide, methotrexate, and 5-fluorouracil and for tegafur/uracil. Many chemotherapeutic agents that are used to treat recurrent or metastatic breast cancer have not yet been approved in Japan. As for molecular targeted therapy, some agents that target the human epidermal growth factor receptor family have been approved in Japan, whereas angiogenesis inhibitors have not. The results of many clinical trials have been incorporated into clinical practice in Japan, therefore, the outcomes of breast cancer therapy have surpassed those in other countries. Many pivotal clinical trials have been conducted outside Japan. Treatment regimens that have been developed on the basis of these studies might be suitable for the management of breast cancer in Western women, but not for Japanese women because of differences in genetic factors, physique, body mass index, pharmacokinetics, and drug metabolism. Such regimens should be modified on the basis of the characteristics of breast cancer in Japan to develop treatment that is optimally suited for Japanese women. In particular, local studies of pharmacokinetics, pharmacodynamics, and optimal dose levels and treatment intervals should be carefully performed. The establishment of treatment regimens optimally suited for Japanese patients with breast cancer could put the brakes on the trend towards increasing mortality from breast cancer in Japan.     

Adjuvant therapy for breast cancer — results from the USA consensus conference

The National Institutes of Health, USA sponsored a Consensus Development Conference on November 1-3, 2000 to review several major questions regarding the adjuvant treatment of breast cancer. A non-governmental group of oncology experts was selected to review clinical trial data and judge the evidence presented by 33 breast cancer researchers. Their conclusions resulted in the following recommendations: (1) Prognostic factors critical for determining risk of recurrence are age, axillary lymph node status, tumor size, histologic type and grade and hormone receptor status. (2) Tamoxifen, administered for 5 years, significantly improves long-term survival for women of all age groups with hormone receptor-positive tumors. Ovarian ablation also prolongs survival in premenopausal women. (3) Multi-agent chemotherapy of 4-6 months duration is associated with an improvement in survival in both hormone receptor-positive and -negative tumors. Anthracycline-containing regimens offer the greatest survival advantage. The role of taxanes is uncertain but they may be useful in selected patients with node-positive tumors. Women with small, node-negative tumors, women over age 70, and those with tumors of favorable histologic subtype (mucinous or tubular) may not require chemotherapy. (4) Adjuvant radiotherapy to the regional lymph nodes and chest wall following mastectomy is indicated for women with 4 or more axillary nodes. (5) Physicians should employ effective visual aids to help them present a complete and balanced view of the absolute benefits versus the side-effects of adjuvant treatments. Important avenues of future research were also discussed and suggestions were made.     

Current research topics in endocrine therapy for breast cancer

There are large-scale molecular differences between estrogen receptor (ER)-positive and ER-negative breast cancers. Endocrine therapy has become the most important treatment option for women with ER-positive breast cancer, and approximately 70% of primary breast cancers express ERα. Endocrine therapy has provided meaningful advances in breast cancer treatment and prevention. However, some patients continue to develop recurrence and die of the disease. New insights into ER biology and progress in the understanding of resistance mechanisms are generating tremendous promise for new therapeutic opportunities to target resistance and improve disease outcomes.     

The role of hormonal therapy in breast cancer

This review reassesses the role of hormonal therapy in breast cancer specifically the sequential or concurrent use of endocrine therapy and the combined use of chemotherapy with endocrine therapy. In advanced disease the sequential use of hormone therapies is generally recommended rather than the combined use of various hormonal agents, though combination hormonal therapy offers advantages in certain subsets of patients. The efficacy of combined chemo-endocrine therapy is questionable. Chemotherapy with estrogenic recruitment is an attractive but still experimental concept. However, in an adjuvant setting there is evidence that combined chemo-endocrine therapy causes a significant increase in disease-free and/or overall survival, particularly in postmenopausal patients with estrogen receptor (Expositive tumors. While hormonal treatment strategies have clearly benefitted from randomized studies, data regarding optimal endocrine therapy are still insufficient.     

Adjuvant radiation therapy following mastectomy for breast cancer

Many randomized clinical trials have been performed to address the effectiveness of postmastectomy radiation therapy (PMRT) to regional lymph nodes with or without chest wall irradiation. Although these studies have confirmed the usefulness of RT to reduce loco-regional recurrence, the benefit of postoperative RT for survival remains controversial. Recent prospective trials of PMRT in combination with systemic chemotherapy clearly demonstrated the benefit of this combined adjuvant therapy for both locoregional recurrence and survival outcomes. Based upon this new evidence, guidelines and recommendations for PMRT in the management of breast cancer have been proposed by the American Society of Clinical Oncology and by the International Consensus Panel at the International Conference on Adjuvant Therapy of Primary Breast Cancer in St. Gallen. PMRT is recognized as a standard adjuvant treatment for patients with more than 4 positive axillary nodes in these guidelines and recommendations. This re-appraisal of PMRT has not attracted much attention in Japan so far. Clinical studies are needed to determine how to best incorporate PMRT in the multimodal treatment of node-positive breast cancer.     

中国早期乳腺癌术后辅助治疗开展现状——一项基于110家医院的横断面调查研究

背景与目的：乳腺癌术后辅助治疗是乳腺癌综合治疗的重要组成部分之一。对中国乳腺癌诊疗现状进行基线调查,掌握早期乳腺癌术后辅助治疗的开展情况。方法：选取全国范围内110家乳腺癌年手术量超过200例的医疗机构,以问卷调查形式开展研究,调查内容包括手术医师及其所在科室和医院的基本情况、2017年乳腺癌手术开展情况,以及对乳腺癌术后辅助治疗相关热点问题的具体决策。结果：80.9%的受访医院使用常规病理学指标作为预后评价工具,多基因检测工具的使用比例不到20%。对于T 1a 期患者,48.2%的医院对人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）阳性型患者采用靶向治疗,77.3%的医院对三阴性乳腺癌（triple-negative breast cancer,TNBC）采用辅助化疗,蒽环类药物序贯紫杉类药物方案是最常用的化疗方案。对于高复发风险的患者,70.9%的受访医院主张密集化疗,但大部分医院的实际实施比例不到20%。对于激素受体阳性的患者,主张延长内分泌治疗时长至10年的医院占一半以上。绝经后患者联合应用双膦酸盐的比例在40%以内,绝经前患者使用卵巢功能抑制（ovarian function suppression,OFS）的比例总体也在40%以下,芳香化酶抑制剂（aromatase inhibitor,AI）是OFS的公认联合药物。结论：目前国内医院使用多基因预后预测工具的比例较低,对早期乳腺癌患者的辅助治疗决策较为保守,密集化疗、OFS和双膦酸盐等治疗方法和药物的应用比例较低。蒽环序贯紫杉方案和AI的临床应用已形成共识,延长内分泌治疗时长也成为新的趋势。     

Early switch with aromatase inhibitors as adjuvant hormonal therapy for postmenopausal breast cancer: pooled-analysis of 8794 patients

BACKGROUND: The magnitude of the survival benefit of aromatase inhibitors (AIs) after 2-3 years of tamoxifen as adjuvant hormonal therapy for early breast cancer is still unclear. We performed a literature-based meta-analysis, to look how much advantages adjuvant the "early switch" strategy add over standard tamoxifen for 5 years. METHODS: A pooled analysis of all phase-III trials was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived. Significant differences in primary outcome (EFS and RFS, event- and relapse-free survival), and secondary outcomes (OS, overall survival, deaths without progression, other cancers and toxicities), were explored. Magnitude outcome measures were absolute benefits and number of patients needed to treat. Heterogeneity test was applied as well. RESULTS: Five trials (8794 patients) were gathered. The risk of any event is reduced with AIs of 23%, with an absolute benefit of 3.8% (RR 0.67, 95% CI 0.59, 0.76). Again, RFS (RR 0.68, 95% CI 0.59, 0.79) or both LRFS and DFRS, were significantly improved with AIs. OS was significantly prolonged with AIs, with an absolute benefit of 1.2% (RR 0.76, 95% CI 0.62, 0.93), without significant heterogeneity. Bone fractures were significantly higher in patients receiving AIs (RR 1.50, 95% CI 1.12, 2.02), and endometrial cancer in patients who continued to receive tamoxifen (RR 0.32, 95% CI 0.13, 0.77), without significant heterogeneity. CONCLUSIONS: The early switch strategy improves survival over standard tamoxifen for 5 years, with a different toxicity profile. The lack of significant heterogeneity in the analysis underscores the homogenous effect across all trials.     

Recent perspectives of endocrine therapy for breast cancer

The choice of endocrine therapy for breast cancer depends on the menopausal status and stage of disease. Endocrine therapy remains the first choice and most important component in the treatment of hormone sensitive non-life threatening advanced breast cancer. In premenopausal women with metastatic disease, the combination of a luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen is reasonable as first-line endocrine therapy. In postmenopausal patients with recurrent disease progressing after or during adjuvant tamoxifen, third-generation aromatase inhibitors (AIs) are the preferred first-line endocrine treatment. Many premenopausal and postmenopausal women with hormone responsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Recent clinical trials designs have been implemented, employing AIs as monotherapy in postmenopausal breast cancer patients, as first-line adjuvant therapy, and in sequence either 2-3 or 5 years, with initial tamoxifen. Emerging results from these trials indicate an advantage to patients for any of these strategies, and most international guidelines now suggest the use of an AI in the adjuvant setting in postmenopausal women. The use of endocrine treatment for metastatic and early breast cancer will be reviewed here.     

Current status of adjuvant therapy for pancreatic cancer

In this article, we review the rationale for and outcomes associated with the use of adjuvant and neoadjuvant therapy for resectable and borderline resectable cancer of the pancreatic head and uncinate process. Localized pancreatic cancer is a systemic disease that requires nonoperative therapies to minimize the local and systemic recurrences that almost invariably occur in the absence of such therapy, even following complete surgical resection. A well-defined role exists for the systemic administration of gemcitabine or 5-fluorouracil in the postoperative setting. Although the survival benefit associated with adjuvant chemoradiation has not been as rigorously defined, its use is supported by extensive historic experience; chemoradiation should be considered particularly for patients at high risk for local recurrence. Delivery of chemotherapy and/or chemoradiation prior to surgery has multiple potential advantages, although the superiority of neoadjuvant therapy over standard postoperative therapy has yet to be demonstrated. Neoadjuvant therapy may be particularly beneficial among patients with borderline resectable cancers. Although the existing literature is confusing, and indeed controversial, available evidence suggests that systemic chemotherapy and/or chemoradiation should be offered to all patients with pancreatic cancer who undergo potentially curative resection. Well-designed prospective trials are needed to define the optimal adjuvant or neoadjuvant therapy strategy for these patients.     

Current status of antibody therapy for breast cancer

Antibody therapy with trastuzumab has greatly impacted breast cancer treatment. Combination treatment with trastuzumab is regarded currently as a first-line therapy for metastatic breast cancers that overexpress Her-2. It has become routine practice to examine the status of Her-2 expression in primary tumors. The impact of this therapy might be as great as that of endocrine therapy from a historical point of view. A number of new approaches using trastuzumab for seeking individualized treatment are being tested in current clinical trials. We reviewed recent advances in trastuzumab treatment and discuss the future of antibody therapy for breast cancer.     

Adjuvant therapy with high-dose medroxyprogesterone acetate for operable breast cancer

Background  Medroxyprogesterone acetate (MPA) produces a comparable or higher response rate in metastatic breast cancer compared with tamoxifen which is also commonly used for adjuvant endocrine therapy. Several studies in the West have indicated the efficacy of MPA when used as an adjuvant to surgery in certain subsets of patients. The present study was undertaken as a multicenter open study in Japan to investigate the safety and efficacy of MPA in adjuvant endocrine therapy. Method and Patients  A combination of 800 mg/day MPA and a fluorouracil compound for 6 months was given postoperatively tol 19 patients with stage II or Illa breast cancer in 32 participating hospitals between June 1987 and June 1989. Results  Among the 119 patients, 59 patients (49.6%) experienced some kind of adverse reaction. The major adverse reaction was abnormal menstruation, seen in 13 (25.0%) of the 52 premenopausal patients. Vaginal bleeding was a major adverse reaction in the 67 postmenopausal patients (8/67 or 11.9%). An increase in body weight and moon face were observed in 23 (19.3%) and 9 (7.6%) of the 1 19 patients, respectively. Administration of drugs was discontinued because of adverse reaction in 17 patients (14.3%), and dose reduction or temporary suspension was necessary in 7 patients (5.9%). Increase in body weight was the main reason for discontinuation of the treatment. No severe adverse reactions were observed. After a median follow-up of 74.5 months (range, 2.2–90.0 months), 84 of the 119 patients are alive with no evidence of disease. The 3-year and 5-year disease-free survival rates were 88.2% and 82.6% in stage II patients, and 64.7% and 52.9% in stage Illa patients, respectively. The 3-year and 5-year disease-free survival rates according to age were 87.8% and 79.3% in patients aged 50 years or more, and 78.6% and 71.4% in patients aged under 50 years. Conclusion  These results show that 800 mg/day MPA plus a fluorouracil compound can be administered with acceptable morbidity as an adjuvant treatment to selected breast cancer patients.     

再议乳腺癌内分泌治疗10项热点问题

近年来,乳腺癌的内分泌治疗数据更新较多,使临床工作中产生了新的问题,带来了新的思考。该文就绝经前乳腺癌患者内分泌治疗中卵巢功能抑制的适宜患者的选择,卵巢功能抑制联合口服内分泌药物方案的选择,内分泌治疗过程中不良反应管理,乳腺癌患者的生育问题和延长内分泌治疗等10项早期乳腺癌内分泌治疗中的热点问题,结合数据和笔者的临床经验进行再次阐述。     

乳腺癌新辅助内分泌治疗

随着内分泌治疗药物的发展,新辅助内分泌治疗成为近年来乳腺癌研究的又一热点.大量试验证明,新辅助内分泌治疗能降低肿瘤分期,提高乳腺癌的局部控制率,进一步提高保乳手术率,其中第3代芳香化酶抑制剂的疗效可能优于三苯氧胺.     

乳腺癌新辅助内分泌治疗的研究进展及展望

新辅助内分泌治疗（neoadjuvant endocrine therapy,NET）代替新辅助化疗（neoadjuvant chemotherapy therapy,NCT）对于雌激素受体（estrogen receptor,ER）阳性乳腺癌患者而言是一种有效的临床治疗策略,可以使肿瘤降期,从而接受乳腺癌保乳手术并减少术后的辅助化疗。本文旨在就NET的患者选择、NET效果对比、NET持续时间、NET与NCT效果对比及联合使用、NET联合靶向治疗、机会之窗试验、疗效评估预后指标及NET后辅助治疗决策等最新研究进展进行综述。     

Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer

BACKGROUND: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer has been emphasized, however, there is no general agreement as to how immunohistochemical assays should be evaluated. It is critical to evaluate hormone receptor status when considering response to endocrine therapy. METHODS: Estrogen receptor (ER) and progesterone receptor (PgR) expression was examined by immunohistochemistry using Allred's score for primary breast tumors from 75 metastatic breast cancer patients who received first-line treatment with endocrine therapy (56 patients received tamoxifen, 11 patients received aromatase inhibitors, and 8 patients received LH-RH agonist or other endocrine reagents) on relapse. Correlation between hormone receptor status and response to endocrine therapy as well as post-relapse survival was analyzed. RESULTS: The most significant correlation between positive ER expression and response to any endocrine therapy (p = 0.011) or tamoxifen only (p = 0.030) occurred when the cutoff score was set at 10%. When the evaluation was based on Allred's score (TS), a cutoff point of TS>or=4 showed a more significant association between positive ER expression and response to all kinds of endocrine therapy (p = 0.020) or tamoxifen only (p = 0.047). When evaluated at a cutoff point of 1% positive cells, there were fifteen patients with both ER- and PgR-negative tumors, and three patients (20.0%) responded to the therapy. Patients with 1% or more ER or PgR positive cells had better survival after relapse (p = 0.0005 and p = 0.0008, respectively). CONCLUSIONS: The proportion score alone might be enough to predict hormone responsiveness and post-relapse survival in metastatic breast cancer. The cutoff might be set low, for example 1%, especially for metastatic disease.     

Current status of experimental therapeutics for prostate cancer

Hormone refractory prostate cancer (HRPC) is the progression of disease in the presence of castrate serum levels of testosterone with a median survival of approximately 1 year. A variety of strategies have been developed to improve survival for the patients with advanced prostate cancer. Despite such efforts, the effective treatment modality for those patients has not been established other than chemotherapy. New experimental therapeutics such as gene therapy, vaccine therapy and target therapy use various mechanisms to kill tumor cells selectively while sparing surrounding normal tissues. Furthermore, new approaches in the field of chemoprevention are being made. Recent data from landmark studies, in particular vaccines, have shown improvements in overall survival of HRPC patients.