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

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Abstract

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.

Introduction

Most women with newly diagnosed breast cancer present with early-stage or locally advanced disease, with only a minority found to have overt metastatic disease at diagnosis.1 Nevertheless, breast cancer is the second most common cause of cancer death in women in the United States. Fortunately, we continue to make steady progress in the treatment of this disease, with a reduction in breast cancer mortality from 1975 to 2005.1 This change is likely multifactorial but attributable, at least in part, to advances in systemic therapy as well as to the development of better risk stratification tools over the past decade.

Our understanding of breast cancer has evolved to recognize that it appears to be a systemic disease with micrometastatic involvement at diagnosis in many patients. Today, adjuvant systemic therapy is 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 agents, such as the taxanes, new antihormonal agents, such as the aromatase inhibitors (AIs), and the development of targeted therapies, including trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA). Numerous studies have also taught us that the dosing and schedule of administration of systemic therapies are as equally important factors as the agents themselves in improving outcomes. However, increasing understanding of the biology and genomics of breast cancer continues to demonstrate that it is a heterogeneous disease, with some patients requiring more aggressive adjuvant systemic therapy than others. The decision to administer adjuvant systemic therapy is a complex one, based on the risk of recurrence and death of breast cancer balanced against medical and psychologic risk factors that might predispose to adverse events. Fortunately, the past decade has also witnessed the development of improved risk stratification tools that have helped individualize the decision to recommend adjuvant systemic therapy.

Herein, we review salient developments over the past decade that have helped shape the adjuvant systemic therapy of today. However, in order to understand where we are, we must first review where we have been by highlighting key historical milestones in the evolution of adjuvant breast cancer care.

Section snippets

Chemotherapy Pre-2000s: Where It All Began

Adjuvant trials of chemotherapy were initially launched in the 1960s based on the premise that breast cancer metastases were caused by the surgical manipulation of the tumor.1 These early studies focused on patients with axillary nodal metastases who had a high risk of recurrence. Initial adjuvant treatment consisted of single agents but later evolved into combination chemotherapy. Numerous combinations were evaluated, with the most common being cyclophosphamide, methotrexate, and

Chemotherapy Over the Past Decade: Advances

The unique mechanism of action of taxanes, their partial lack of cross-resistance with anthracyclines, and their activity in the metastatic setting provided a rationale for evaluating these agents in the adjuvant setting. The two taxanes used most commonly in the adjuvant setting are paclitaxel and docetaxel, which have similar antitumor activity because of their high-affinity binding to β-tubulin with subsequent blockade of cell division. Altogether, results are available from 21 clinical

Endocrine Therapy for Early-Stage Breast Cancer

The knowledge that breast cancer cells are estrogen-dependent comes from Beatson's observation, over 100 years ago, that metastatic breast cancer regresses with excision of the ovaries.22 Based on that concept, adjuvant endocrine therapy in early-stage breast cancer is designed to prevent breast cancer cells from receiving endogenous estrogen stimulation, thus eradicating clinically occult micrometastases and decreasing the rate of relapse. Tamoxifen, a serum ER modulator, has been the

Predictive and Prognostic Molecular Markers in Early-Stage Breast Cancer

It is well known that ER and PgR expression is an important prognostic marker in early-stage breast cancer, and the ASCO 2007 guidelines recommend that ER and PgR status be tested in all primary breast cancers.49 In addition, ER and PgR status has been well established as a predictor of response to adjuvant endocrine therapy. The past decade has further established the importance of testing for the expression of HER2 in all primary breast cancers. As with the expression of ER and PgR, HER2

Adjuvant Targeted Therapy in Early-Stage Breast Cancer

Earlier in this review we highlighted the advances made in adjuvant chemotherapy over the past decade. However, despite this progress, a significant number of patients still relapse after initial therapy. Further advances will require a more profound understanding of breast cancer biology, which will in turn lead to new therapeutic strategies that will enhance the efficacy of our current adjuvant chemotherapy. Below is a discussion of targeted/biologic agents that have had a profound impact on

The New Era of Genomics

Historically, prognostic estimates were derived only from information on tumor size, extent of lymph node involvement, and histologic grade. Treatment decision algorithms in breast cancer have become complicated, as more patients present with lymph node–negative, early-stage disease and as a growing number of new therapies are becoming available. Prognostic profiling has also become more sophisticated with the increase in our understanding of the biology of the disease. Quantitative computer

Conclusion

The past decade has seen the development of many new agents in the realms of conventional chemotherapy, targeted therapy, and endocrine therapy. These new therapies have immensely contributed to improvement in patient outcomes, but despite a bigger armamentarium, the optimal adjuvant systemic therapy for early-stage breast cancer remains a work in progress.

In this new era, anthracyclines remain active agents in the treatment of women with early-stage breast cancer, but taxanes have emerged as

Disclosures

The authors report no relevant conflicts of interest.

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