Changes to Adjuvant Systemic Therapy in Breast Cancer: A Decade in Review

Breast cancer is the second most common cause of cancer death in women among the United States. Fortunately, it continues to be an active area of research. Today, it is well recognized that breast cancer can often be a systemic disease, with micrometastatic involvement at diagnosis in many patients. Over the past decade, adjuvant systemic therapy has been used to eradicate micrometastatic disease, and it has been shown to decrease the rates of recurrence and improve the survival of patients with early-stage, resected breast cancer. Some of the success of modern adjuvant systemic therapy has come from the advent of new chemotherapy and endocrine agents but also from the development of targeted therapies, which have improved the efficacy of conventional, cytotoxic therapy. There has also been increasing awareness that the dosing and schedule of administration of systemic therapies are equally important factors in achieving better outcomes in patients with early-stage breast cancer. Growing research into the biology and genomics of breast cancer has fueled the development of more accurate risk stratification tools and helped individualize the decision to recommend adjuvant systemic therapy. Herein, we present a review of salient developments over the past decade that have helped shape the adjuvant systemic therapy of today.     

Prognostic and predictive factors in early-stage breast cancer

Breast cancer is the most common malignancy among American women. Due to increased screening, the majority of patients present with early-stage breast cancer. The Oxford Overview Analysis demonstrates that adjuvant hormonal therapy and polychemotherapy reduce the risk of recurrence and death from breast cancer. Adjuvant systemic therapy, however, has associated risks and it would be useful to be able to optimally select patients most likely to benefit. The purpose of adjuvant systemic therapy is to eradicate distant micrometastatic deposits. It is essential therefore to be able to estimate an individual patient's risk of harboring clinically silent micrometastatic disease using established prognostic factors. It is also beneficial to be able to select the optimal adjuvant therapy for an individual patient based on established predictive factors. It is standard practice to administer systemic therapy to all patients with lymph node-positive disease. However, there are clearly differences among node-positive women that may warrant a more aggressive therapeutic approach. Furthermore, there are many node-negative women who would also benefit from adjuvant systemic therapy. Prognostic factors therefore must be differentiated from predictive factors. A prognostic factor is any measurement available at the time of surgery that correlates with disease-free or overall survival in the absence of systemic adjuvant therapy and, as a result, is able to correlate with the natural history of the disease. In contrast, a predictive factor is any measurement associated with response to a given therapy. Some factors, such as hormone receptors and HER2/neu overexpression, are both prognostic and predictive.     

Breast cancer chemotherapy

Chemotherapy can be an integral component of the adjuvant management strategy for women with early-stage breast cancer. Modern adjuvant strategies now comprises one or more chemotherapy agents, hormonal maneuvers, immunotherapy agents, or experimental agents. The use of adjuvant chemotherapy is generally based on estimates of an individual's risk of recurrence and the expected benefit of therapy. However, risk-benefit calculations have recently become increasingly sophisticated as a result of advances in genetic testing and molecular marker identification as well as ongoing refinements in chemotherapy strategies. In this article we will review the role of important prognostic and predictive factors and the rationale for adjuvant systemic therapy and modern chemotherapy regimens in the management of women with early-stage breast cancer.     

Changing Beliefs and Practices in Women With Breast Cancer in China

The trends of surgical therapy for breast cancer in China between 1999 and 2008 show persistent use of modified radical mastectomy and slow uptake of sentinel node mapping for women with early-stage breast cancer. Additional health care programs must be developed and implemented in China to promote awareness and a multidisciplinary approach to treating breast cancer, including adoption of screening mammography, breast-conserving surgery, and sentinel node mapping and biopsy.In this issue of The Oncologist, Dr. Qiao and colleagues report on the trends of surgical therapy for breast cancer in China between 1999 and 2008 [1]. Their data reflect the results of women treated for breast cancer in a single university hospital from each of the seven geographic regions in China. What is most striking about their report is the persistent use of modified radical mastectomy and slow uptake of sentinel node mapping for women with early-stage breast cancer. Equally striking is that the highest incidence of early breast cancer in China occurs at the age of 45 years, which is a full decade earlier than women in the U.S. There are many reasons for the delay in widespread adoption of breast-conserving surgical techniques in China. Reviews like this one shed light on important factors that will help shape progress in this area and emphasize the need for urgent health care redesign in the treatment of breast cancer in China.In 1985, the first randomized trial demonstrating equivalent efficacy between breast-conserving surgery (BCS) and mastectomy was published in the U.S. [2]. Between 1985 and 1989, approximately 35% of women with stage I and 19% with stage II breast cancer were treated with BCS. In 1990, the National Institutes of Health consensus development conference published recommendations for using BCS for the treatment of early-stage breast cancer [3]. Within 5 years, the proportion of women undergoing BCS had increased to 60% for stage I and 39% for stage II breast cancer patients. Over the past decade, the proportion of women with early-stage disease undergoing BCS has remained fairly stable at approximately 70%. Recently, however, the proportion of mastectomies done for early-stage breast cancer appears to be increasing. The reasons behind this shift are multifactorial but largely due to improvements in reconstruction techniques and options that avoid long-term surveillance and prolonged years of endocrine therapy. Changes in practice occur faster today than in the past because of advances in technology, global dissemination of information, and public awareness. Physicians and patients have similar access to information regarding new techniques for cancer diagnoses and treatments. An increasing number of productive women in China are affected by this disease each year. With the assistance of modern technology and more health care resources, women in China will hopefully soon be able to look forward to a change in the perception of what breast cancer surgery should look like in the 21st century and similarly realize that they can expect a good outcome and future after breast cancer.Measuring quality of breast cancer care by the percentage of BCS may not be an accurate assessment of the landscape in China. Surgery remains a vital component of breast cancer care, yet improved survival and prevention of a second breast cancer are now closely linked to screening and the benefits of adjuvant therapies including radiation, chemotherapy, and endocrine therapy [4]. Treating breast cancer in the U.S. and in many other Western countries is done in a multidisciplinary setting. Incorporating adjuvant therapies into the treatment algorithm comes at a cost not only to the health care system but also to the patient. Adapting the multidisciplinary approach used in the U.S. to treat breast cancer in China will not only involve changing surgical options but also having adjuvant therapy resources available and a willingness to accept the loss of productivity during treatment and in some cases long term.Another milestone in the surgical practice for breast cancer has been the impact that sentinel node mapping and biopsy (SNB) has had on reducing morbidity. Sentinel node mapping in breast cancer began in 1991, and the first article was published by Giuliano et al. in 1994 [5]. Numerous studies have validated the technique, and there is general acceptance for the use of sentinel node biopsy in early-stage breast cancer to select patients with occult lymph node metastases who may benefit from further regional or systemic therapy. SNB reduces the morbidity of treatment and improves quality of life following treatment without compromising local control and the accuracy of staging. In developing countries, there are barriers to using this technique. Availability of the contrast materials necessary to perform the procedure and pathologists to interpret the results limit its use in areas where there are competing economic issues and lack of resources. The results of a SNB generally help physicians make decisions about systemic therapy and aid in the planning of appropriate radiation therapy fields of treatment. Having this information may be somewhat irrelevant if these adjuvant therapies are not available. On the other hand, there is a fairly widespread consensus that a full axillary dissection is unnecessary in approximately 80% of women with early-stage breast cancer because their nodes are not involved. Once patient advocates in the U.S. learned about the reduced morbidity associated with SNB they helped tremendously to move this part of the field forward by querying their surgeons about the technique. The health care system in China needs to embrace SNB by making resources and training available for physicians to learn this technique. Increasing public awareness of this option may also help to encourage surgeons to incorporate this technique into their practices.Breast cancer is the most commonly diagnosed cancer in woman worldwide. The breast cancer incidence rate in China has steadily increased over the past 20 years and is projected to double within the next decade. This increase in incidence parallels that in the U.S., which increased slowly between 1940 and 1980, sharply increased in the early 1980s because of wider use of screening mammography, then stabilized in the 1990s, and began to decrease in 2000 after the decline in use of hormone replacement therapy. The incidence of breast cancer in the U.S. has remained stable since 2007, at approximately 124 cases per 100,000 women. Most importantly, however, mortality from breast cancer in the U.S. has decreased since 1975 because of the contributions of regular screening mammography and adjuvant therapy. The increasing incidence and the simultaneously increasing mortality rates associated with breast cancer in China should be a stimulus to increase the pace of change.Breast cancer screening has been shown to reduce rates of breast cancer mortality. A meta-analysis of 13 randomized trials found a 26% reduction in the relative risk of breast-cancer related mortality when women aged 50–74 years received screening mammography [6]. Other reviews have estimated a relative risk reduction of only 15%. It is likely that adoption of screening mammography in China would initially result in a shift toward earlier stage diagnoses of breast cancer and a drop in mortality. However, it is possible that the benefit may be blunted compared with its benefit in the U.S. because of the earlier age of diagnosis and the accompanying increased breast density which reduces the sensitivity of mammography. It may be that breast ultrasound is ultimately a better imaging tool for screening premenopausal women in China. The health care system in China will hopefully embrace the benefits of what technology can offer to increase awareness among its citizens regarding the incidence of breast cancer, the availability and recommendations for screening for breast cancer, and the curability of this disease if identified at an early stage.Earlier diagnosis will lead to increased survival and should be the highest priority in any health care system. The second priority in breast cancer care should be reducing the extent of surgery as long as there is access to adjuvant therapies that maintain the same level of treatment efficiency and long-term survival. In Western countries, the percentage of patients surviving at least 5 years after diagnosis and treatment is more than 90%. As life expectancy worldwide increases, our treatments for breast cancer need to be long lasting and impose less morbidity. Individual choices regarding the extent of treatment may depend upon education level, availability to centers with radiation, adjuvant therapy options, competing obstacles in life, and family structure. Patient preference may also vary based upon the physician-patient interaction, which is an increasingly complicated and evolving dynamic that we all need to embrace. Recognizing that it is possible to save more women’s lives and simultaneously minimize the morbidity of treatment will hopefully continue to stimulate those in the Chinese health care system to develop and implement additional health care programs to promote awareness, screening, and a multidisciplinary approach to treating breast cancer.     

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.     

The prognostic and predictive role of 21-gene recurrence scores in hormone receptor-positive early-stage breast cancer

Over the past two decades, gene expression profiling of breast cancer has emerged as an important tool in early-stage breast cancer management. The approach provides important information on underlying biological mechanisms, breast cancer classification, future risk potential of developing recurrent metastatic disease, and provides beneficial clues for adjuvant chemotherapy in hormone receptor (HR) positive breast cancer. Of the commercially available genomic tests for breast cancer, the prognostic and predictive value of 21-gene recurrence score tests have been validated using both retrospective data and prospective clinical trials. In this paper, we reviewed the current evidence on 21-gene expression profiles for HR-positive HER2-negative early-stage breast cancer management. We show that current evidence supports endocrine therapy alone as an appropriate adjuvant systemic therapy for approximately 70% of women with HR-positive, HER2-negative, node-negative breast cancer. Evolving evidence also suggests that 21-gene recurrence scores have predictive values for node-positive breast cancer and that chemotherapy can be avoided in more than half of women with nodes 1 to 3 positive HR-positive breast cancer. Furthermore, retrospective data also supports the predictive role of 21-gene recurrence scores for adjuvant radiation therapy. A prospective trial in this area is ongoing.     

Operable breast cancer

Opinion statement Breast cancer is the most common malignancy among American women. As a result of widespread screening, most patients present with operable breast cancer that is treated with curative intent. It is well established that the appropriate use of adjuvant therapy improves the disease-free and overall survival of patients with breast cancer. Adjuvant systemic therapy options include tamoxifen for hormone receptorpositive patients, and systemic polychemotherapy. It is standard clinical practice to administer adjuvant systemic therapy to patients with node-positive and high-risk, node-negative breast cancer.     

The quality of early-stage breast cancer treatment: what can we do to improve?

Early-stage breast cancer is a highly curable disease with well-established protocols, including surgery, and the adjuvant modalities of regional radiation therapy, chemotherapy, and hormonal therapy. Yet, there is clear evidence that these adjuvant modalities are underused significantly. This article reviews the evidence that supports the use of efficacious local and systemic therapies in early-stage breast cancer, reasons for underuse, and interventions that have proven to be effective in ensuring the delivery of appropriate breast cancer care and suggests strategies to improve the quality of breast cancer care.     

Adjuvant breast cancer treatment and cognitive function: current knowledge and research directions

Evidence is mounting that potentially curative systemic adjuvant therapy for early-stage breast cancer may result in cognitive impairment. Five published studies have investigated cognitive function in this setting, and the consistent results of all five studies suggest an adverse effect of adjuvant chemotherapy. These studies are reviewed with particular attention to their methodologic limitations. For example, all five studies used cross-sectional designs, none controlled for possible confounding hormonal factors, and three examined patients who had not received a uniform chemotherapy regimen. The potential roles of chemotherapy-induced menopause and of adjuvant hormonal therapy in cognitive impairment are also discussed. Priorities for future research include confirmation of an effect of adjuvant chemotherapy in a study with a longitudinal design, closer examination of the potential contribution of hormonal factors, and similar studies on the effect of adjuvant therapy on cognitive function in other cancer types. If an effect of systemic adjuvant therapy on cognitive function is confirmed, such an effect will have implications for informed consent. It may also result in incorporation of objective measures of cognition in clinical trials of adjuvant therapy and in the investigation of preventive interventions that might minimize the impact of cognitive dysfunction after cancer treatment.     

Ongoing US cooperative group trials using taxanes in the adjuvant setting

The use of systemic adjuvant therapy in women with early-stage breast cancer has been demonstrated to have a profound impact on survival. The role of paclitaxel and docetaxel in the adjuvant setting has attracted a great deal of attention. Both of these agents are highly active in patients with advanced breast cancer. In addition, they can be utilized in combination with anthracyclines, which have been shown to provide a slightly better outcome in patients with early-stage breast cancer compared to non-anthracycline-containing regimens. Randomized trials have demonstrated a potential role for paclitaxel in adjuvant chemotherapy. In the Cancer and Leukemia Group B 9344 trial, which explored the use of doxorubicin and cyclophosphamide with or without paclitaxel, the initial analysis demonstrated a 22% reduction in the relative risk of relapse and a 26% reduction in the relative risk of death in the paclitaxel group. However, a clear role for the use of paclitaxel in adjuvant therapy remains to be defined. The Breast Cancer International Research Group trial 001 compared the combination of docetaxel/doxorubicin/cyclophosphamide to 5-fluorouracil/doxorubicin/cyclophosphamide. This trial demonstrated a promising reduction in the relative risk of recurrence of 32% for the docetaxel/doxorubicin/cyclophosphamide group. Ongoing trials will help to further define the role of taxanes in the adjuvant setting for patients with operable breast cancer.     

Prognostic significance of S100A4-expression and subcellular localization in early-stage breast cancer

Purpose

Prognostic factors are useful in order to identify early-stage breast cancer patients who might benefit from adjuvant treatment. The metastasis-promoting protein S100A4 has previously been associated with poor prognosis in breast cancer patients. The protein is expressed in diverse subcellular compartments, including the cytoplasm, extracellular space, and nucleus. Nuclear expression is an independent predictor of poor outcome in several cancer types, but the significance of subcellular expression has not yet been assessed in breast cancer.

Methods

Nuclear and cytoplasmic expression of S100A4 was assessed by immunohistochemistry in prospectively collected tumor samples from early-stage breast cancer patients using tissue microarrays.

Results

In patients not receiving adjuvant systemic therapy, nuclear or cytoplasmic expression was found in 44/291 tumors (15%). Expression of either nuclear or cytoplasmic S100A4 was associated with histological grade III, triple-negative subtype, and Ki-67-expression. Patients with S100A4-positive tumors had inferior metastasis-free and overall survival compared to S100A4-negative. When expression was analyzed separately, nuclear S100A4 was a significant predictor of outcome, while cytoplasmic was not. In patients who received adjuvant treatment 23/300 tumors (8%) were S100A4-positive, but no tumors displayed nuclear staining alone. S100A4-expression was strongly associated with histological grade III and triple-negative subtype. Although not significant, metastasis-free and overall survival was numerically reduced in patients with S100A4-positive tumors.

Conclusion

S100A4-expression was associated with poor outcome in early-stage breast cancer, but the low percentage of positive tumors and the modest survival differences imply that the clinical utility in selection of patients for adjuvant treatment is limited.

     

Medical management of early-stage breast cancer

With improved screening and education, a greater proportion of breast cancer is detected at an early stage. Although the prognosis for many of these patients is excellent following definitive local therapy alone, some subsets of node-negative patients have a 30% chance of eventually developing metastatic disease that will be incurable with current therapy. Thus, an increasing proportion of early-stage patients are being offered some form of adjuvant therapy, with the expectation of improved relapse-free survival, and possibly improved overall survival. Efforts have been made to base the selection of patients for adjuvant therapy on specific prognostic factors. Meanwhile, the scope and complexity of putative prognostic factors continues to widen, and now includes such items as the presence of occult microscopic metastases, DNA ploidy and proliferative fraction, cytogenetic abnormalities, oncogene expression, growth factor receptors, and expression of hormonally regulated proteins. In addition, there is now a considerable range of options with regard to the composition, dose intensity, and sequence of multimodality therapy. Data regarding the classification, significance, and interpretation of prognostic factors is reviewed together with the development, current status, and recommendations regarding adjuvant therapy for patients with early-stage breast cancer. For 1991, the National Cancer Institute (NCI) has estimated that 175,000 new cases of breast cancer will be diagnosed in American women. It is also estimated that 44,500 women will die of breast cancer. Unfortunately, the age-adjusted death rate from breast cancer has shown no overall change from 1930 through 1987. However, effective screening techniques continue to identify an increasing percentage of early-stage tumors, which should exceed 50% of all new tumors in 1991. Ultimately, our understanding of environmental and genetic risk factors may identify new ways to reduce the impact of this disease. In the interim, development and application of effective systemic adjuvant chemotherapy and hormonal therapy has become increasingly important. There is no question that a greater proportion of patients with less extensive disease are now being offered some form of adjuvant therapy. Meanwhile, selection of patients for adjuvant therapy, and choice among specific adjuvant regimens, has remained controversial. Analysis of multiple prognostic factors is performed not only in the context of cooperative investigational trials, but more often in the offices of individual physicians caring for individual patients. Tumor biopsies can now be routinely sent to specialized laboratories for performance of complex assays with potential prognostic information, although interpretation of these results with reference to a specific patient is often uncertain.(ABSTRACT TRUNCATED AT 400 WORDS)     

New tools in adjuvant breast cancer radiotherapy

During the last century management of breast cancer became increasingly less aggressive for small tumors. Randomized trials demonstrated similar overall survival between mastectomy and breast-conservative surgery (BCS) followed by adjuvant radiation therapy (RT). BCS plus adjuvant RT +/- systemic therapy has become the standard of care for women with early breast cancer. Advances in modern RT technology allowed significant increase in high precision of target definition. Intensity modulated radiation therapy (IMRT) and gating, under investigation in miscellaneous cancers, are also in development for breast-cancer patients. These techniques decrease radiation toxicities and could be useful in the setting of concurrent use of RT and new systemic therapies such as trastuzumab. Another advance in RT is the development of accelerated partial breast irradiation (APBI) as a new concept in the adjuvant setting for early-stage breast cancer. Intraoperative RT (IORT), immediate postoperative RT (interstitial brachytherapy or Mammosite device implantation) and delayed postoperative RT (external beam of photons or protons with 3D conformation) are under investigation. In this review, the role of modern whole breast irradiation is discussed, the rational of partial breast irradiation is argued and the different techniques are detailed.     

New period of systemic treatment for breast cancer

The systemic adjuvant treatment for breast cancer is showing remarkable progress with targeted therapy, such as Trastuzumab, in addition to cytotoxic chemotherapy. The timing of adjuvant chemotherapy is also shifting from post surgery to pre surgery. In terms of adjuvant endocrine therapy for hormonal receptor positive breast cancer, Aromatase inhibitor now is established as a standard treatment for postmenopausal patients. LH-RH analog is also standard for premenopausal patients with Tamoxifen. Further, longer survival might be expected with the new combination of cytotoxic chemotherapy and Trastuzumab for locally advanced or metastatic breast cancer patients. Because the trend of systemic treatment for breast cancer patients is to focus on maintaining patients' quality of life, targeted therapy with Trastuzumab and/or new upcoming drugs(e. g., Bevacizumab, Lapatinib, Sunitinib), might be the mainstream systemic therapy. In this section, we discuss standard and new systemic therapy for primary, locally advanced, and metastatic breast cancer patients.     

Status of Accelerated Partial Breast Irradiation

Breast-conserving therapy is accepted as a standard of care option for patients with early-stage breast cancer. However, studies examining patterns of failure after treatment suggest that a lengthy course of adjuvant whole breast irradiation delivered as a component of breast-conserving therapy may not always be necessary; indeed, in appropriately selected patients, radiation therapy delivered only to the tumor bed may be acceptable. Several modalities of delivering accelerated partial breast irradiation (APBI) have been developed, the most prevalent being multi-catheter interstitial brachytherapy, the MammoSite breast brachytherapy catheter (Hologic Corporation, Bedford, MA) and three-dimensional conformal external-beam radiation therapy. The purpose of this article is to review the published experiences on the most common modalities of delivering APBI and to outline the current open national phase 3 trial. To date, phase 1/2 studies have demonstrated excellent local control and cosmetic outcomes in early-stage breast cancer patients treated with APBI. As increasing knowledge is accumulated regarding the efficacy and safety of APBI, a consensus will emerge regarding its potential replacement of whole breast irradiation in selected early-stage breast cancer patients.     

Adjuvant aromatase inhibitors following tamoxifen for early-stage breast cancer in postmenopausal women: what do we really know?

Adjuvant hormonal therapy in the treatment of women with early-stage, hormone receptor (HR)-positive breast cancer is now considered the standard of care. Adjuvant tamoxifen decreases the risk of breast cancer recurrence and death in women with early-stage breast cancer when taken for 5 years. The benefits of tamoxifen are counterbalanced by toxicities including an increased risk of endometrial cancer and thromboembolic events. The selective aromatase inhibitors (AIs)--including anastrozole, letrozole, and exemestane--are challenging the role of tamoxifen as the adjuvant hormonal therapy of choice in postmenopausal women. Results of the Arimidex and Tamoxifen Alone or in Combination trial favor the use of anastrozole over tamoxifen as initial adjuvant hormonal therapy, with improvement in disease-free survival (DFS) and a favorable toxicity profile. The results of 2 large adjuvant trials using AIs sequentially with tamoxifen in postmenopausal women with early-stage, HR-positive breast cancer have been reported. The MA-17 study randomized women to placebo or letrozole for 5 years after completion of 4.5-6 years of initial tamoxifen. The Intergroup Exemestane Study (IES) randomized women following 2-3 years of adjuvant tamoxifen to continue to receive tamoxifen or switch to exemestane for a total of 5 years of adjuvant hormonal therapy. The MA-17 and IES trials demonstrated superior DFS with the AI and corroborated the smaller GROCTA-4B and Italian Tamoxifen Arimidex trials, which studied sequential therapy with aminoglutethamide or anastrozole. There is now substantial medical evidence supporting the use of AIs in postmenopausal women with early-stage, HR-positive breast cancer.     

Ovarian ablation for premenopausal early-stage breast cancer: an update

Ovarian ablation is the oldest form of systemic treatment of breast cancer and consists of removal of the main source of estrogen biosynthesis in premenopausal women: Over the last century several different means of stopping ovarian function have been studied: surgical oophorectomy, ovarian irradiation, and more recently, chemical castration by gonadotropin-releasing hormone analog therapy. In unselected patients the response rate to ovarian ablation is of about 35% but the likelihood of response is considerably higher for patients with hormonal receptor-positive tumors, the therapy being most effective in women who are actively menstruating. In spite of this evidence, the role of ovarian ablation in the management of early-stage breast cancer still remains controversial. Here we review current evidence supporting the value of this ablative procedure as an adjuvant and update ongoing clinical research to refine our knowledge about its use.     

Cardiac effects of adjuvant therapy for early breast cancer

Adjuvant chemotherapy is an established standard of care for most patients diagnosed with early breast cancer, and its popularity is gaining worldwide. The systemic armamentarium presently includes anthracyclines and taxanes, alkylating agents, fluoropyrimidines, and antimetabolites; in the future, it may include platinum compounds and the recombinant humanized anti-HER2 monoclonal antibody, trastuzumab, as well. Anti-estrogens continue to play an important role in the adjuvant setting for hormone-sensitive primary breast cancer. Adjuvant radiotherapy is common in the setting of early-stage disease as breast conservation gains popularity, and radiation is often employed in the postmastectomy setting as well. As treatment guidelines continue to evolve with newer data, the relative benefits of treatment in many situations continues to grow. Refinement of the optimal identification of patients at risk for local and distant relapse is a continued challenge facing the treating clinician. Parallel to this effort, and of equal importance, is the ability to shield patients that will gain little, if any, benefit from treatment and to identify those who may be at greater risk to suffer from potential toxicities. Until these factors are better defined, the recognition by clinicians of long-term side effects associated with adjuvant therapy is obligatory. Acute toxicities from treatment are often reversible, but late onset adverse effects of therapy can increase morbidity and mortality in long-term survivors, and continue to be of concern. One of the most serious side effects of adjuvant therapy of early breast cancer is cardiac toxicity. This article will provide an overview of the cardiac effects of adjuvant therapy in the treatment of early breast cancer.     

Anastrozole as adjuvant therapy for early-stage breast cancer: implications of the ATAC trial

Tamoxifen has been the gold standard adjuvant therapeutic agent for postmenopausal women with hormone-sensitive breast cancer for > 25 years. Although it continues to play an important role in treating premenopausal women, tamoxifen's association with some serious safety and tolerability issues, including increased incidence of endometrial cancer and thromboembolic events, may be cause to limit its use in postmenopausal women. Anastrozole was the first drug to show improved efficacy and safety compared with standard therapies for first- and second-line therapy of hormone-sensitive advanced breast cancer in postmenopausal women. This article provides a review of the results of the first major analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) early-stage breast cancer trial, initiated in 1996, and discusses the implications for the use of anastrozole in the adjuvant setting. This randomized, double-blind, multicenter trial compared tamoxifen (20 mg once daily) with anastrozole (1 mg) alone and in combination with tamoxifen, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, early-stage breast cancer. The results of the ATAC trial show anastrozole to be more effective and better tolerated than tamoxifen in this group of patients, and an updated follow-up suggests the therapeutic index for anastrozole will continue to remain superior to that of tamoxifen. Anastrozole is now emerging as a new standard for the adjuvant treatment of postmenopausal women with hormone-sensitive early-stage breast cancer. New adjuvant trials are currently using anastrozole in the control arm.     

A stochastic simulation model of U.S. breast cancer mortality trends from 1975 to 2000

BACKGROUND: We present a simulation model that predicts U.S. breast cancer mortality trends from 1975 to 2000 and quantifies the impact of screening mammography and adjuvant therapy on these trends. This model was developed within the Cancer Intervention and Surveillance Network (CISNET) consortium. METHOD: A Monte Carlo simulation is developed to generate the life history of individual breast cancer patients by using CISNET base case inputs that describe the secular trend in breast cancer risk, dissemination patterns for screening mammography and adjuvant treatment, and death from causes other than breast cancer. The model generates the patient's age, tumor size and stage at detection, mode of detection, age at death, and cause of death (breast cancer versus other) based in part on assumptions on the natural history of breast cancer. Outcomes from multiple birth cohorts are summarized in terms of breast cancer mortality rates by calendar year. RESULT: Predicted breast cancer mortality rates follow the general shape of U.S. breast cancer mortality rates from 1975 to 1995 but level off after 1995 as opposed to following an observed decline. Sensitivity analysis revealed that the impact adjuvant treatment may be underestimated given the lack of data on temporal variation in treatment efficacy. CONCLUSION: We developed a simulation model that uses CISNET base case inputs and closely, but not exactly, reproduces U.S. breast cancer mortality rates. Screening mammography and adjuvant therapy are shown to have both contributed to a decline in U.S. breast cancer mortality.