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The genomic era has allowed enormous strides in our understanding of the molecular changes that underlie malignant transformation. Mutations have been discovered that are critical drivers of large cross-sections of human cancers. These discoveries have allowed us to find drugs that target these drivers and make important strides in treatment. Genomics and high-throughput technologies have illuminated the complexity of cancer and the facility with which cancers adapt during their natural history. The field is evolving rapidly with new discoveries and new drugs reported monthly. This book is a timely foundation for understanding in context the origins of molecular oncology and its future directions. The content reviews available technologies for the analysis of cancer tissues and genes; summaries of key oncogenic pathways from a molecular perspective; the technologies, pathways and targeted therapies of a wide range of human malignancies; and new pharmacologic therapies that have a common mechanistic target.
The advent of high-throughput technologies in the 1990s generated great anticipation that patterns of gene expression or of other molecular characteristics of tissues or tumors would allow refinements in diagnosis, prognosis, and treatment selection to revolutionize the treatment of cancer. A voluminous literature was generated. Companies were formed. New statistical methods were developed to analyze the thousands of data elements that were analyzed in scores of samples. A large number of important discoveries have come from the ability to perform wholesale analyses of gene expression, gene methylation, and DNA alterations. However, application of high-throughput technologies to clinical practice and to decision-making that affects patient care has been slow to evolve from these findings. Thus early anticipation that macromolecular profiles of cancers would replace conventional diagnostics and provide prognostic insight has largely been unfulfilled. There are some important instances where the management of some cancers has incorporated information that was originally gleaned from high-throughput analyses. This chapter will summarize different approaches to high-throughput analysis and enumerate the instances where results from these approaches have impacted patient care.
The importance of biomarkers
Cancer treatment is characterized by the application of morbid and toxic therapies to all patients with a particular stage of a cancer to benefit a subset of those patients. We have long sought to discriminate between those patients who will benefit from a therapy and those who will not. In the age of molecular oncology, clinical discriminators have been sought among biomarkers. A “biomarker” is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a[n]…intervention” (1). For example, the serum cholesterol level is a biomarker that indicates risk for cardiac disease and indicates the use of cholesterol-lowering drug therapy. Similarly, biomarkers in cancer treatment include expression of estrogen receptor (ER) to indicate the need for hormonal therapy of breast cancer. Other examples of useful biomarkers in cancer therapy are α-fetoprotein and β-human chorionic gonadotrophin, indicators of active and recurrent germ-cell tumor. In clinical oncology there are a limited number of individual biomarkers that are useful for diagnostic, prognostic, or predictive purposes.
This book was conceived more than five years before its publication date. It was intended to provide a resource that summarized technology, biochemistry, molecular pathophysiology, and targeted therapeutics. As contributors were being recruited and chapters written the field that was being described changed at an accelerating pace. It is a tribute to scientific progress that volumes like this are out-of-date as they are published, but books like this are not meant to contain the most current laboratory discovery or report the most recent FDA approval.
While this book was being written there have been major advances in molecular oncology. The Cancer Genome Atlas (cancergenome.nih.gov) has demonstrated the broad spectrum of mutations in an expanding list of cancers. DNA sequence analysis alone has demonstrated that as cancers grow, metastasize, and develop treatment resistance, individual tumor sites within a single patient evolve differently and demonstrate increasingly complex spectra of driver and passenger mutations. These findings alone strongly support the Darwinian view of tumor progression. The complexities of cellular dysregulation in cancer may arise from DNA sequence changes, but extend to other levels of gene regulation. During the writing of this book the role of micro-RNAs (miRNAs) in cancer was elucidated. Aberrations in epigenetics such as DNA methylation and histone acetylation were demonstrated. Cancer drug development has also proceeded at increasing rates. In the period 2008–2012 there were 51 approvals of new drugs for cancer treatment by the US Food and Drug Administration. Many of these approvals resulted from impressive data in Phase II trials that clearly demonstrated efficacy where no agents have worked before.