Evaluation of radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy

The Danish Breast Cancer Cooperative Groups DBCG 82b and c randomized trials are analyzed in order to illustrate the influence of radiotherapy after modified radical mastectomy in high-risk pre- and postmenopausal patients also receiving systemic therapy with respect to loco-regional tumor control, disease-free and overall survival and cardiac mortality. The results from the present randomized studies indicate that adjuvant systemic treatment does not sufficiently prevent local recurrence. An effective loco-regional treatment is therefore required in order to achieve maximal survival benefit from systemic therapy. However the temporary and persistent toxicity following each treatment modalities have to be weighed against the outcome of obtaining an optimum quality of life.     

The choice of systemic adjuvant therapy in receptor-positive early breast cancer

Patients with endocrine-responsive breast cancer represent a distinct population for which tailored adjuvant treatments are needed. Endocrine therapy is mandatory for this population. For premenopausal patients, ovarian ablation or tamoxifen can be recommended; the combination of both, as well as the combination of ovarian ablation and aromatase inhibitors is under investigation. For postmenopausal patients, tamoxifen for 5 years is the 'standard of care'. Anastrozole can be recommended for patients with a contraindication to tamoxifen. The addition of 5 years of letrozole after 5 years of tamoxifen has yielded benefits in terms of disease-free survival. The sequential use of tamoxifen and exemestane was superior to tamoxifen for 5 years. However, in both studies, long-term toxicity is still not fully evaluated. The addition of chemotherapy to endocrine treatment can be recommended for patients at high risk of relapse and in young patients. Chemotherapy should consist of 3-6 cycles of cyclophosphamide, methotrexate, 5-fluorouracil or of an anthracycline-containing regimen. The addition of taxanes cannot be routinely recommended in this population. Endocrine treatment should start after completion of chemotherapy.     

Progress in systemic adjuvant therapy of early-stage breast cancer

Despite major improvements in the treatment of early-stage breast cancer over the past 15 years, many controversies exist surrounding the optimal adjuvant therapies for these patients. Adjuvant chemotherapy has been demonstrated to reduce recurrence and improve mortality, but questions persist as to what is the optimal regimen and how much adjuvant therapy should be administered. Among the adjuvant chemotherapy issues that remain controversial are the role of the taxanes and the optimal number of adjuvant chemotherapy treatment cycles. In the realm of adjuvant endocrine therapy, the early results of the Anastrozole, Tamoxifen and Combination (ATAC) trial have led to confusion as to how best to treat postmenopausal patients with estrogen receptor-positive, early-stage breast cancer. Clinicians are faced with the decision of choosing between tamoxifen and anastrozole. The enthusiasm for so-called targeted therapies, such as trastuzumab, in patients with metastatic disease, is now being carried over into the adjuvant setting. Multiple clinical trials around the world are evaluating the potential benefit of adding trastuzumab to chemotherapy in patients with HER2-positive, early-stage breast cancer. In the United States, clinicians are faced with many decisions on how to optimally treat patients with early-stage breast cancer. Evidence-based treatment guidelines such as those developed by the National Comprehensive Cancer Network (NCCN) provide a useful algorithm for assisting in making treatment decisions. It is hoped that, in the next few years, the results of ongoing clinical trials now underway will lead to further improvements in the outcome of patients with early-stage breast cancer.Presentation made at the ASCO-JSCO Joint Symposium held at Tokyo, Japan, on October 18, 2002.     

Controversies in the adjuvant systemic therapy of endocrine-non-responsive breast cancer

Treatment of breast cancer requires a fully integrated multidisciplinary management as well as an ongoing dialogue with laboratory scientists. The growing amount of data generated by randomized clinical trials need to be interpreted by the clinicians and discussed with patients, so that treatment decisions might be better individualized. In early breast cancer, three consensus panels have been developed to help with this task: the Early Breast Cancer Trialists Collaborative Group or Oxford Overview, the NIH Consensus Conference on Adjuvant Therapy for Breast Cancer and the St. Gallen International Consensus Panel on the Treatment of Primary Breast Cancer. Nevertheless, even these panels leave us with a good deal of uncertainty about the optimal adjuvant systemic treatment of the disease, especially when it is classified as "endocrine non-responsive". The two most problematic issues regarding the management of endocrine non-responsive breast cancer are: (1) which fit woman should not be treated, with two major "to treat or not to treat" dilemmas, (a) women above 70 years of age, where available evidence is scant and co-morbid conditions more often come into the equation of benefit/risk, and (b) women who have very small invasive tumours (<1 cm); and (2) what is the optimal chemotherapy regimen (type, doses, schedule, timing and duration). The aim of this review is to examine these controversial issues. Two difficult clinical cases, which are representative of those frequently encountered in daily practice, will also be presented and discussed, with the help of a panel of 48 breast cancer experts from different regions of the world.     

Node-negative minimal invasive breast cancer patients are not candidates for routine systemic adjuvant therapy

Ninety-one patients with invasive breast carcinoma with a diameter of 1 cm or less and histologically negative axillary nodes were treated between 1976 and 1986 with radical surgery alone (67), or with conservative surgery (24). Cases were analyzed in relation to tumor size, steroid receptors, histologic and nuclear grade, age, and type of therapy, none of which showed a significant relationship to relapse or survival. There were 22% well-differentiated, 20% moderately differentiated, and 56% poorly differentiated or anaplastic tumors. Estimated disease-free survival (DFS) for this group was 91% at 7 years, and overall survival 96% for the same period. There were five relapses (all among poorly differentiated tumors) and three deaths unrelated to breast cancer. With the three deaths censored, 100% of the well-differentiated and moderately differentiated tumors were disease-free at 7 years versus 91% for poorly differentiated and anaplastic tumors (P = 0.076). These data suggest that node-negative patients with minimal invasive breast cancer are highly curable by primary surgical therapy alone, and the authors believe that these patients are not appropriate candidates for adjuvant therapy until such time as subgroups at high risk of recurrence can be identified.     

Recent advances in systemic therapy. Advances in adjuvant systemic chemotherapy of early breast cancer

Adjuvant treatment for early breast cancer is an evolving field. Since the advent of the initial cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimens, which reduced risk for recurrence and death, anthracyclines and subsequently taxanes were added to the cytotoxic armamentarium for use sequentially or in combination in the adjuvant setting. The efficacy and toxicity of each chemotherapy regimen must be viewed within the context of host co-morbidities and the specific biologic phenotype of the tumor. In the era of mammographic screening, small, node-negative breast cancer is the most frequent presentation of the disease. Patient selection for adjuvant chemotherapy has become a key issue. Traditional prognostic factors continue to be of value in determining the risk for relapse, but new and sophisticated genomic tools (such as Oncotype Dx^® and Mammaprint^®) are now available and may improve our ability to select patients. For those patients who do require adjuvant chemotherapy, the 'one size fits all' paradigm should never again feature in the treatment of early breast cancer, following the important insights yielded by biomarker research to identify those who will benefit the most from a particular drug. In this review we focus on some of the current controversies and potential future steps in adjuvant chemotherapy for treatment of early breast cancer.     

Quality of life and adjuvant systemic therapy for early-stage breast cancer

Adjuvant chemotherapy and hormonal therapy reduce the risk of recurrence and death due to breast cancer, but often at considerable cost to the health-related quality of life (HRQL) of patients. The short-term effects of chemotherapy on HRQL are well known and are accepted by most patients for modest gains in survival. The long-term effects of chemotherapy-induced menopause and hormonal therapy on HRQL are poorly recognized. Vasomotor symptoms and altered sexual function are common, distressing and inadequately treated. HRQL information is helpful in describing likely effects of adjuvant treatment, facilitating informed decision-making, identifying health problems to guide research into potential solutions, guiding treatment strategies for interventions with equivalent survival and guiding resource allocation. New technologies will make HRQL information increasingly available for individual patient care.     

Quality of life and adjuvant systemic therapy for early-stage breast cancer

Adjuvant chemotherapy and hormonal therapy reduce the risk of recurrence and death due to breast cancer, but often at considerable cost to the health-related quality of life (HRQL) of patients. The short-term effects of chemotherapy on HRQL are well known and are accepted by most patients for modest gains in survival. The long-term effects of chemotherapy-induced menopause and hormonal therapy on HRQL are poorly recognized. Vasomotor symptoms and altered sexual function are common, distressing and inadequately treated. HRQL information is helpful in describing likely effects of adjuvant treatment, facilitating informed decision-making, identifying health problems to guide research into potential solutions, guiding treatment strategies for interventions with equivalent survival and guiding resource allocation. New technologies will make HRQL information increasingly available for individual patient care.     

Receipt of adjuvant systemic therapy among patients with high-risk breast cancer detected by mammography screening

Background Few studies have compared screen-detected (SD) breast cancer patients with symptomatic patients for the frequency and determinants of receipt of adjuvant systemic therapy according to accepted guidelines. Methods Depending on the date of diagnosis, adjuvant therapy guidelines from the 5th, 6th, and 7th St. Gallen International Conferences were used as standards to audit the treatment of 598 node-negative high-risk patients (59% SD) and 430 node-positive patients (40% SD) aged 50–69 years from an Italian cancer registry (1997–2001). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using backward stepwise logistic regression models. Results Among node-negative high-risk patients, SD cancers were smaller (P = 0.000) and of lower grade (P = 0.003). Downgrading was generally from grade 3 to grade 2, with an increased proportion of patients placed in the high-risk category due to grade 2 alone. The total rates of adjuvant systemic therapy were similar (58 vs. 60%) whereas SD patients were less often treated according to the guidelines (34 vs. 45%; OR = 0.61; 95% CI, 0.44–0.86). After adjustment for tumour size and other weaker confounders, the OR was 0.99 (95% CI, 0.67–1.46). Among node-positive patients, the OR of receiving the standard adjuvant systemic therapy did not differ between SD and symptomatic cancers. Conclusions SD cancers amplified the prognostic heterogeneity of node-negative high-risk patients. Their lower likelihood of being treated according to the guidelines was largely explained by their lower risk profile. No evidence was found to suggest that physicians held a priori assumptions about the relative biological indolence of SD cancers.     

Cost-effectiveness of new guidelines for adjuvant systemic therapy for patients with primary breast cancer.

BACKGROUND: In this study, the potential impact of a new national guideline for adjuvant systemic therapy in breast cancer (introduced in The Netherlands in 1998) was assessed, as well as the modifications of this guideline, issued in 2001. Both the change in total number of patients eligible for adjuvant therapy, as well as the cost-effectiveness of the changed clinical management of these patients were analysed. PATIENTS AND METHODS: Percentages of patients who would be eligible for adjuvant therapy in 1994, 1998 and 2001 were estimated, based on clinical data from 127 patients, who were operated on in 1994. Ten-year overall survival rates were used as a measure of effectiveness, based on the two most recent EBCTCG meta-analyses. Actual resource costs were calculated. With a decision analytic model, the incremental cost-effectiveness ratios (1998 versus 1994, and 2001 versus 1998) were calculated. RESULTS: The introduction of the 1998 guideline resulted in a relative increase of 80% in the total number of patients eligible for adjuvant therapy, compared with 1994 (from 40% to 72% of all patients with primary breast cancer). With an estimated absolute increase of 10-year overall survival of 2%, the 1998 guideline was found to have an expected incremental cost-effectiveness ratio of about 4837 per life-year gained. CONCLUSIONS: Introduction of the new guideline considerably affected the number of patients eligible for adjuvant systemic therapy for breast cancer. The associated incremental cost-effectiveness ratio is well within the range of values that are generally considered acceptable.     

淋巴结阴性乳腺癌患者辅助治疗的研究进展

淋巴结阴性乳腺癌患者中有20%～30%经手术治疗后复发和转移.本文综述了如何选择需要内分泌治疗和/或化疗的淋巴结阴性乳腺癌患者,以及如何选择正确的治疗模式.     

Understanding the utility of adjuvant systemic therapy for primary breast cancer.

PURPOSE: Physicians and patients require quantitative information on the expected benefits of adjuvant therapy for primary breast cancer to make appropriate treatment decisions. To date, there has not been any widely available method for estimating the benefits from adjuvant systemic therapy, in terms of long-term disease-free survival probabilities, in patients with primary breast cancer. METHODS: Baseline prognostic information for primary breast cancer patients was estimated by asking 11 breast cancer specialists to complete a questionnaire on baseline prognosis and then using mean values. Data on the relative benefits of adjuvant therapy were culled from systematic reviews and randomized controlled trials. A computer algorithm was developed to calculate 10-year absolute outcome data. Results from this evaluation were compared with a previously described actuarial algorithm. RESULTS: Individual prognostic estimates varied within a group of breast cancer specialists, but mean values of their estimates closely followed published data. Translation of expected benefits of adjuvant therapy from relative to absolute terms was performed with a simple computer algorithm. The data were translated into tabular forms to facilitate user-friendly clinical use. CONCLUSION: The provided data should facilitate a better understanding of the absolute magnitude of benefit for available systemic adjuvant therapies in individual women with primary breast cancer. This should allow patients to make more informed decisions about their options.     

Updates in adjuvant systemic treatment of breast cancer

Breast cancer is a significant public health burden with more than 200,000 new cases diagnosed in the United States each year. Although many incident cases represent localized disease, a significant proportion of women with early stage breast cancer eventually experience a distant relapse and ultimately die of metastatic breast cancer complications. Consequently, investigators strive to improve the adjuvant treatment paradigm and thus, optimize outcomes for women with early stage breast cancer. Within the last year a study describing a decline in incident breast cancer cases in the United States was reported. In addition, the results from a number of notable adjuvant treatment studies were reported or updated. Innovations in taxane-containing strategies and dose dense chemotherapy strategies were prominently featured. In addition, a number of insights pertaining to the treatment of women with HER2-positive breast cancer were reported. An overview of selected recently reported studies will be reviewed here.     

Targeted adjuvant therapy in breast cancer

Introduction: The potential of molecular targeted therapy to improve the clinical outcomes of patients with early-stage breast cancer (BC) as adjuvant therapy has been first demonstrated through endocrine treatment. The introduction of HER2 blockade, through the successful clinical development of trastuzumab, changed the natural history of HER2-positive BC subtype.

Areas covered: There are ongoing efforts to augment further the use of targeted agents as adjuvant treatment in BC, hoping that early introduction of targeted therapy blocking key oncogenic drivers of micro-residual disease, will significantly improve clinical outcomes. In the present Review, we present data through extensive search of PubMed about the following targeted adjuvant therapeutic strategies in BC: i) HER2 blockade and ongoing efforts to further augment its efficacy for patients with HER2-positive disease, ii) angiogenesis inhibition, iii) PI3K-mTOR- AKT pathway inhibition, iv) CDK4/6 inhibition, v) PARP inhibition.

Expert commentary: we provide insights about challenges and potential ways to overcome them, in terms of successful clinical development of targeted agents as adjuvant therapy for patients with BC. In particular, we emphasize the need to systematically assess minimal residual cancer burden as a way to increase the rates of successful clinical development of targeted agents in the adjuvant setting.     

Cost-effectiveness of adjuvant systemic therapy in low-risk breast cancer patients with nodal isolated tumor cells or micrometastases

BackgroundThe cost-effectiveness of adjuvant systemic therapy in patients with low-risk breast cancer and nodal isolated tumor cells or micrometastases is unknown.Patients and methodsA cost-effectiveness analysis of adjuvant systemic therapy was carried out using the costs per 1% event prevented after 5 years of follow-up as incremental cost-effectiveness ratio (ICER). Secondary objective was to establish when adjuvant systemic therapy becomes cost saving. Patients included in the MIRROR study with isolated tumor cells or micrometastases who had a complete 5-year follow-up and who either did or did not receive systemic therapy were eligible. Sensitivity analyses were carried out.ResultsIn the no adjuvant therapy cohort (N = 366), 24.9% of patients had an event within 5 years versus 16.8% of patients in the adjuvant therapy cohort (N = 483) (P < 0.01). The ICER was €363 per 1% event prevented. Beyond 18 years after diagnosis, the extrapolated mean cumulative costs per patient in the no adjuvant therapy cohort exceeded those of the adjuvant therapy cohort.ConclusionsIn this population of breast cancer patients with isolated tumor cells or micrometastases, €36 300 had to be invested to prevent one event in 5 years of follow-up. Adjuvant systemic therapy was cost saving beyond 18 years after diagnosis.     

ER阳性乳癌病人全身辅助治疗的研究

目的研究雌激素受体阳性(ER+)乳癌病人接受不同全身辅助治疗的预后,以期指导病人的治疗。方法387例ER+乳癌病人分成三组辅助内分泌治疗组(178例)绝经后(绝经前病人先切除卵巢)病人服用三苯氧胺(TAM)5年。辅助化疗组(154例)主要化疗方案有CMFVP;CMF;CF;FVC等。联合治疗组(55例)化疗+TAM,其中绝经前病人未切除卵巢。采用生命表的方法观察三组病人的5年无病生存率(DFS)和总生存率(OS)。结果在不同年龄、不同月经状态、不同局部肿瘤T期及不同转移淋巴结数目的病人中,都显示出辅助内分泌治疗的5年无病生存率和总生存率明显好于辅助化疗者,差异有显著意义。在转移淋巴结≥10个组内,虽然仍是内分泌治疗结果好于化疗组,但未显示统计学意义。联合治疗的病人,在各个亚组分析中,都不优于辅助内分泌治疗。结论ER及绝经状态应作为决定取舍辅助内分泌治疗的主要依据,对于ER阳性乳癌病人,术后内分泌治疗为最合适。     

Bilateral primary breast cancer in patients treated with adjuvant therapy

Between 1974 and 1986, 1036 patients with operable breast cancer were treated with doxorubicin-containing combination chemotherapy regimens. Of these, 44 patients had bilateral breast cancer prior to initiation of adjuvant therapy (prechemotherapy) and 17 patients developed primary breast cancer on the contralateral side during or after completion of adjuvant therapy (postchemotherapy). The objectives of the study were twofold: to determine the incidence of bilateral primary breast cancer and to determine the effect of second primary breast cancer on prognosis of patients treated for disease in the contralateral breast. The estimated disease-free and overall survival of patients with prechemotherapy bilateral disease was similar to the patients with unilateral breast cancer. Four hundred eight patients received tamoxifen in addition to combination chemotherapy during adjuvant therapy. The incidence of contralateral breast cancer at 2 years in patients treated with tamoxifen was 0.4% in comparison to 0.8% in patients treated with chemotherapy alone. Time to development of second breast cancer in patients treated with or without tamoxifen was not significantly different (p = 0.41). We conclude that patients with bilateral breast cancer have a prognosis similar to that of patients with comparably staged unilateral disease. Although the rate of bilateral disease observed among patients treated with adjuvant chemotherapy and tamoxifen was somewhat lower than for those receiving chemotherapy only, the difference was not statistically significant.