scope:

Preface

We are living amidst a sea-change in our treatment of breast cancer. As Shakespeare imagined the sailor under the sea, so this medical transformation is both rich and strange. It was this richness, and a desire to make it less strange, that prompted this book, Breast Cancer: Translational Therapeutic Strategies.

While the processes of the ocean are timeless, it is worth asking why the seachange in breast cancer medicine is happening now. There are several major contributors to this transformation. The first has been the recent availability of novel targeted drugs. Breast cancer medicine had for decades depended on two systemic treatment options-chemotherapy and endocrine therapy; the latter representing the earliest successful effort to target therapies based on an improved understanding of tumor biology and biomarker testing. The emergence of anti-HER2 targeted therapy with the humanized monoclonal antibody trastuzumab in the 1990s heralded a major new class of therapeutic modalities. Laboratory and clinical evidence indicated that trastuzumab would be effective only in tumors that were markedly HER2 overexpressing. This created a pressing need for diagnostic tests for HER2 overexpression so that tumors, and thus patients, could be appropriately selected for therapy. The impact of trastuzumab on HER2-positive metastatic breast cancer revised treatment algorithms such that therapy depended entirely on tumor HER2 status. In 2005, reports from several major adjuvant trials of trastuzumab demonstrated that this therapeutic impact extended into early stage breast cancer management as well.

In addition to the apparent clinical benefits of targeted therapy, the focus on HER2 testing and targeted treatment fueled research into the second major transforming event in breast cancer medicine-the characterization of clinical subsets of breast cancer. It became obvious that not all breast cancers were the same. Indeed, several major clinical types of breast cancer could be characterized by marker analysis: estrogen receptor and/or progesterone receptor positive, HER2 positive, and "triple negative" (lacking estrogen receptor and/or progesterone receptor and HER2 expression) subsets. These subsets had immediate practical clinical implications in terms of selecting therapy for both early- and late-stage breast cancers.

Biotechnology advances that facilitated the development of new therapeutics like trastuzumab were accompanied by a further explosion of interest in the large-scale study of gene expression patterns. When genomic tools were applied to breast cancer, the tumor subsets defined by treatment options (hormone receptor subsets, HER2 subsets) were immediately rediscovered, as these tumors all possessed strikingly different patterns of gene expression for one another. In fact, the use of gene expression profiling to characterize breast cancers further deepened the appreciation of breast cancer subsets, as it was found that differences between tumors are not merely "skin deep" and limited to small numbers of growth factors. Rather, the differences between subsets were profound and affected expression of literally hundreds of genes throughout the tumor cell genome. With these observations, the field quickly shifted from the question, "Are there important subsets of breast cancer?" to the questions, "Since there are important subsets, how much pathobiological information do we need to characterize these subsets, and how best should such characterization be done?"

The final major contribution to the transformation of breast cancer treatment has not been a technical or pharmacological revolution, but rather a transformation in the way we think about the disease and its treatment. Namely, clinical researchers and clinicians have become increasingly willing to accept the scientific observations on breast cancer heterogeneity and novel breast cancer therapeutics, and clearly show a willingness to incorporate this new understanding into day-to-day clinical practice. This final step may yet prove to be the most critical. Paradigms of breast cancer treatment that developed from the 1960s through the 1990s were more or less premised on the concepts that all breast tumors were fundamentally similar and should be treated with similar techniques. Thus, seminal trials of breast cancer surgery, radiation therapy, and chemotherapy accrued patients irrespective of tumor biology. As a result, treatment principles learned in these trials were held as true for all types of breast cancer. Lacking better tools to characterize breast cancer variation, investigators did the best they could.

The tools to describe this heterogeneity among breast cancers, however, now exist. Fortunately, the clinical community has been receptive to using these tools both to describe and explain, and ultimately to treat, breast cancers in different and individually tailored fashions based on the biology of the underlying tumor. In fact, few recent trends in oncology better highlight that oft-cited cliche´ of "bench to bedside" than the evolution in breast cancer treatment in recent years. Truly, this is the exemplar par excellence of translational therapy, where research discoveries in the lab and the clinic have become integrated into ordinary medical care. The rapid incorporation of new discoveries into standard practice is one of the marvels of both the scientific enterprise and clinical care.

This book, assembled with the help of some of the finest clinical investigators in breast cancer medicine today, is designed to highlight the sea-change in breast cancer treatment that has and continues to occur. The book is divided into three major sections. The first section addresses methodological issues for translational medicine and research in oncology. Despite exciting new diagnostic and treatment tools, traditional challenges persist. These include the proper design and analysis of clinical trials, probably nowhere better illustrated than in studies involving high throughput microarrays, which are all the more critical when coping with myriad clinical subsets of tumors, and the limitless quantity of bioinformation entering databases make proper analyses essential. There is a need to explore novel treatment approaches in the geriatric patient population, a demographic group that comprises the largest number of breast cancer patients but which continues to be underrepresented in clinical and scientific studies of breast cancer. Finally, there is a discussion of neoadjuvant breast cancer treatment, a strategy that is increasingly being looked to for early insights into tumor biology and treatment effects.

The second section of the book explores the molecular and cellular heterogeneity of breast cancer. New techniques have emerged to characterize breast cancers into pathobiological subtypes and to detect microscopic foci of cancer. The clinical implications of these new technologies are rapidly emerging and promise to redefine the fundamental nature of our understanding of breast tumors, the traditional methods of determining breast cancer prognosis and selection of therapy, and the monitoring of treatment efficacy.

Finally, the volume closes with a section on novel treatments for breast cancer. This portion of the book includes updates on important tailored therapies, including new endocrine options for ER-positive breast cancer. There are chapters discussing the state of the art for targeted treatments for HER2-positive breast cancer, which are already entering the "next generation" of trials, and other targeted small molecule growth factor inhibitors. In addition, this section highlights the development of new antiangiogenic agents as breast cancer treatments, an entire new avenue of targeted therapy now entering clinical practice. Finally, there is an update on emerging chemotherapeutics, which retain a critical role in breast cancer treatment. It is interesting to note that despite the understandable excitement and enthusiasm for novel targeted drugs, chemotherapy continues to be the backbone upon which most of these treatments have proven their worth. In fact, the ability of chemotherapy to potentiate the effects of newer biological agents means that chemotherapy advances are more relevant to clinical practice than ever.

We believe strongly that Breast Cancer: Translational Therapeutic Strategies is arriving at a most timely moment. The confluence of science, technology, and clinical thinking is reshaping the discourse of breast cancer care just as it promises to improve results for breast cancer patients. We hope that this volume continues the transformation of our approaches to breast cancer into future progress that is even richer, and undoubtedly no less strange.