Today’s discoveries to tomorrow’s care: cancer biomarkers revisited

Cancer is one of the leading causes of death worldwide. It is estimated that approximately 7.4 million deaths per year, accounting for 13% of all deaths worldwide, are related to cancer. Despite extensive research into the field of oncology and some successful forays into prevention, screening and treatment, cancer remains a black box and deaths from cancer worldwide are projected to continue to rise to a staggering 9.2 million deaths in 2015 and 12 million deaths in 2030 [1]. A more concerted approach with evidence-based strategies as the nucleus of cancer prevention, early detection of cancer and management of patients is needed in order to reduce and control the morbidity and mortality associated with this devastating disease.

The hallmark of cancer is the growth of abnormal cells that divide uncontrollably, and possess the ability to infiltrate and destroy local and/or distant healthy tissue. The central feature in this cascade is the accumulation of abnormalities in the DNA of cells, which results in the transformation to a malignant phenotype. The genetic abnormalities may be inherited, or induced by carcinogens or infectious organisms through mechanisms that affect oncogenes or tumor suppressor genes [101]. Ongoing research has provided insight into the complex interplay between DNA, cellular components and the host that contribute to tumorigenesis and the development of progressive disease. Cellular damage or stress can clearly initiate undesirable events; however, perhaps equally important is the interplay between the tumor cell with the tumor microenvironment, as well as the host innate immune system [2]. Thus, in order to obtain a better understanding of the entire process of cancer progression, and to apply such knowledge to the reduction or prevention of disease, novel approaches must be explored.

One such novel approach is the concept of individualized or personalized medicine. Multiple genetic defects are most often responsible for the growth of malignant tumors. Furthermore, the multiplicity of tumors may vary considerably across patients, even when considering tumors originating from the same tissue type or organ. Until recently, standard medical practice was unable to tailor care to individual patients. However, with the advent of molecular profiling, via high-throughput technologies such as proteomics, genomics and metabolomics, it is now possible to identify unique differences within an individual tumor. Information about a patient’s unique tumor profile could be used to personalize medical care to that individual’s needs (i.e., ‘the right treatment for the right person at the right time’) [3].

The rising prevalence of cancer is one of the major factors stimulating research and development into the search for improved biomarkers. A biomarker is a measurable factor that may be used to shed light on a particular biologic state (i.e., biologic processes, pathologic process or response to a pharmacologic intervention) [4]. The demand for cancer-specific biomarkers is also driven by the concept of personalized medicine, where a unique molecular profile of a tumor is obtained and used to target specific gene products or pathways in hope of improving care by increasing efficacy and reducing treatment morbidity. As a result, the oncology biomarker commercial market possesses a high growth opportunity with numerous initiatives to encourage biomarker-based cancer prevention, early detection and treatment strategies. Accordingly, governmental agencies such as the US FDA and the National Cancer Institute have taken an active interest in the field of cancer biomarker development by encouraging and stimulating research into novel cancer biomarkers [102]. The increasing interest is also possibly caused by the declining success rate of oncology drugs in the market.

The clinical need to refine diagnosis, patient stratification and prognosis, as well as therapeutic monitoring, has further sparked the search for biomarkers as useful tools in patient evaluation and disease management. Despite a recent surge of novel biomarker entering clinical practice, critical appraisal of individual biomarkers and validation in large cohort studies are often lacking. Biomarkers in Medicine establishes a forum for commentary and debate on the identification of biomarkers, elucidation of their role and formalization, and approval of their application in modern medicine. Specifically, this issue with a special focus on using biomarkers to individualize and monitor cancer therapy offers a selection of recent reviews, reports and research highlights that provide an up-to-date insight into the development and use of cancer biomarkers.

Breast cancer is a prime example of a common tumor, with several successful biomarkers currently used in practice. The discovery of specific biomarkers for breast cancer has forever changed the management of women suffering from this disease. Monitoring of the expression of the estrogen receptor, progesterone receptor and oncoprotein Her-2 in breast tumor cells has proven invaluable in determining specific treatment regimens and overall prognosis for individual patients [5]. However, despite these advancements, significant room for clinical care improvement exists. Recently, analyses using high-throughput technologies of cancerous tissue and body fluids have yielded promising molecular signatures that enable breast cancer prognosis, prediction of treatment response and monitoring efficacy of therapy [6,7]. In this issue, Napieralski et al. provide an overview of several emerging biomarkers and how, along with integration of clinopathological data, they can continue to shape the future of breast cancer care. Validation of these biomarkers in large prospective studies is certainly needed but the strategy described in the review can serve as the blueprint for biomarker development and implementation in other organ sites [8].

Aggressive therapy, comprising surgery, radiation and chemotherapy, is the cornerstone for the treatment of head and neck tumors. However, such aggressive therapy does not guarantee a cure and is associated with significant morbidity [9]. Thus, identifying biomarkers and gene expression signatures that can complement, strengthen and increase the sensitivity of current clinicopathologic analyses would prove to be beneficial for both patient and healthcare system. Within this issue, Ziober et al. ask the question “is gene expression profiling of head and neck cancers ready for the clinic?” Their report gives a detailed account of the state of microarray analysis in the field [10]. In fact, data are provided illustrating how novel diagnostic signatures will be able to predict tumor behavior as well as patient outcome. With refinement, microarray analysis will be poised to take its place in the physicians’ armamentarium to fight cancer.

Despite advances in the management of many human cancers over the past few decades, improvements in survival are marginal, and the overall prognosis of the cancer patient often remains guarded. A question that often comes up in the clinical arena is: if we know that a certain therapy would not work, would we use it? The obvious answer is no; however, at times, we initiate therapy with a paucity of valid data and little confidence that it will be effective. Tailoring therapy to an individual patient is clearly the optimal approach for maximizing efficacy and minimizing drug toxicity. Wang et al. provide a review describing in detail how the right drug can (and must) be tailored to the right patient [11]. One such way to tailor therapy to an individual is to determine the molecular composition of each tumor and use these data to predict treatment response. Successful introduction of this strategy will not only substantially improve patient care but would also lead to a host of improvements in the delivery of healthcare. Jiang et al. present an article describing the status of k-ras gene mutations in colorectal and non-small-cell lung cancer, proposing that this can predict the response to targeted therapeutic agents such as cetuximab, erlotinib and gefitinib [12]. These observations have provoked an interest in utilizing the status of K-Ras as a biomarker, allowing clinicians to direct certain therapy to cancer patients. It will presumably be a matter of time before similar observations for other genes in other tumor types are discovered and developed towards clinical utility.

In addition to genetic alterations noted in tumor cells, numerous epigenetic aberrations have also been identified (e.g., DNA methylation, histone modification and nucleosome remodeling). These epigenetic modifications can result in the modification of individual gene expression directly, and, ultimately, affect the cellular phenotype through multiple downstream effects [13,14]. For example, epigenetic modification of the Rb gene may result in loss of gene function, which promotes a cell with unchecked proliferative ability. Maldonando et al. provide a review of current developments of epigenome research in ovarian cancer and how current research will shape the future of this disease [15].

This issue also takes a look at a development-stage company, Altor BioScience Corp. that is engaged in the discovery and development of targeted immunotherapeutic agents [16]. Altor understands that tumor-associated antigens are not usually expressed as integral membrane proteins and, thus, cannot be utilized as targets for antibody-based therapeutics. However, in order to expand the limited target range of antibodies, Altor has constructed a soluble single-chain T-cell receptor fusion protein (scTCR-STAR™ technology) specific for a peptide epitope of the human p53 tumor suppressor protein, which is overexpressed in a broad range of human malignancies. This fusion protein is capable of conjugating target and effector cells, and remains intact in the blood, substantially increasing the half-life of the target agent (e.g., IL-2) [17]. Encouraging Phase I data have been reported on the application of this fusion protein [18] and Phase II studies are underway. In addition to therapeutic applications, this scTCR STAR technology has enabled Altor to develop novel reagents for the development of disease-associated antigens derived from intracellular proteins as biomarkers.

In summary, advances in our understanding of the molecular composition of cancers have accelerated the introduction and implementation of biomarkers in the management of this disease. Identifying biomarkers that detect cancer early or determine the likelihood of cancer progression is crucial. Despite the complexity of tumors, we have identified several useful biomarkers that hold the potential to truly personalize medicine and improve the care of cancer patients. Further progress is likely to be accelerated by novel technology and by integration of novel biomarkers into the current clinicopathologic formula. This issue highlights past triumphs, present struggles and the future course of biomarker development. A continued focus on the identification, validation and translation of biomarkers to the clinic will, in time, provide more personalized care to the cancer patient.