Multiple biomarkers in molecular oncology

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Multiple biomarkers in molecular oncology ‘…a prevailing hypothesis is that a panel of biomarkers would cumulatively possess a higher specificity and sensitivity than any single biomarker.’ Expert Rev. Mol. Diagn. 7(3), 223–225 (2007)

Donald J Johann Jr and Timothy D Veenstra† † Author for correspondence SAIC-Frederick, Inc., Laboratory of Proteomics & Analytical Technologies, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA Tel.: +1 301 846 7286 [email protected]

10.1586/14737159.7.3.223

Several years ago the Director of the National antiemetics and hematologic growth factors. Cancer Institute, Andrew von Eschenbach, These advances have transformed the practice put forth the goal of eliminating the suffering of oncology from the hospital to an outand death that results from cancer by as early patient/community setting. Over the past as 2015. This goal did not explicitly state that 20 years, biomedical science has transformed a cure for cancer would be found, only that HIV/AIDS from a killer with defined cersuffering and death resulting from this condi- tainty, to a chronic disease that can be effection would be eliminated. That goal may best tively managed. An argument can be made be accomplished by intervening at a number that improved outcomes in coronary heart disof phases of the disease. The most obvious ease and HIV/AIDS are due to effective phase, which probably has the greatest impact biomarkers that enable adequate tailoring of on a cancer patient’s quality of life, is early care on a patient-by-patient basis. Biomarker use in clinical cardiology is now detection. Early detection is a key determinant in the survival rate of cancer patients, incorporated into guidelines. These mandate affords the greatest number of treatment the use of a variety of biomarkers and biooptions for the oncologist and, in general, the marker panels for both risk assessment and best outcomes for patients. Treatment repre- management. For example, cholesterol panels sents another aspect of intervention that can are used for both risk assessment and coronary impact a patient’s survival. The most appro- disease management. Risk assessment affords pre-emption, allowing the priate treatment given at ‘Biomarker use in clinical patient and physician to the proper time is also a cardiology is now discuss strategies, such as major factor on the patient’s survival and qual- incorporated into guidelines.’ lifestyle changes and begin ity of life. Unfortunately, there is no universal medication, if indicated. Troponin is a very treatment for cancer and, too often, the treat- sensitive and specific marker of cardiac necroment assignment for an individual patient is sis and is central to the management of myocardial infarctions. Other routine measures categorically determined. Why has progress for improved patient out- used in a biomarker context include blood comes significantly lagged in oncology versus pressure and inflammatory markers (i.e., heart disease and HIV/AIDS? Since 1950, the C-reactive protein). These quantitative measures death rates due to coronary heart disease for enable cardiologists to effectively personalize patients aged 40–60 years have improved dra- care to patients. Biomarker use in HIV/AIDS is also central matically. In contrast, there has been minimal improvement in patient outcomes for cancer. to clinical practice. Patients with HIV/AIDS Significant progress in oncology has revolved now have their immune systems reconstituted around supportive care measures; specifically, routinely. HIV and infectious disease specialregimens focused on improved pain control, ists customize complex antiviral regimens to

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patients with the aid of biomarkers, such as viral load, CD4 as determine which course of treatment would most effectively counts and, in some cases, viral genotypes. Viral loads and work for an individual patient. Increasing the rate at which CD4 counts are routinely measured and tracked over time early-stage cancers are diagnosed would minimally require the and are vital to guide sophisticated medical therapies. Thus, discovery of a biomarker that could be measured from a routhe incorporation of biomarkers into HIV/AIDS clinical prac- tinely drawn biospecimen acquired during a routine physical. tice enables a disease state molecular feedback, and helps Unfortunately, past experience suggests that a single biomarker avoid the threats of opportunistic disease, life-threatening will not suffice. Testing for prostate-specific antigen, for instance, will miss a percentage of men with prostate cancer sickness and death. Compared with cardiology and HIV/AIDS, biomarker use (false negative), and incorrectly identify some who prove not to in clinical oncology is quite limited. This is not due to a lack have cancer (false positive). This lack of sensitivity and specifiof time or effort, but rather a more complex disease process. city is not surprising given the degree of heterogeneity present Interestingly, a few of the true successes in oncology involve in both solid tumors and the human population at large. Thus, the routine clinical use of biomarkers. For example, germ cell a prevailing hypothesis is that a panel of biomarkers would tumors have an approximate 95% 5-year survival, and rela- cumulatively possess a higher specificity and sensitivity than tively high success rate for cure, especially when detected at an any single biomarker. Efforts to identify panels of biomarkers for diseases such as early stage of disease. Diagnosis, treatment response and relapse monitoring all involve biomarker (e.g., α-fetoprotein, cancer have been and continue to be pursued. In one of the β-human chorionic gonadotropin) assessment. Today, breast earliest and most famous studies, Emanuel Petricoin and cancer survival can be extended. Breast cancer treatment Lance Liotta compared serum obtained from women with choices are dictated by biomarker analysis, specifically, the neoplastic and non-neoplastic disease within the ovary. They estrogen receptor and ERBB2 (also known as HER2). These found that a simple pattern of peaks within a mass spectrum biomarkers are integral in therapy selection and also for could correctly classify cancer-affected from noncancer, with a enhancing quality of life by avoiding toxic treatments of sensitivity and specificity of 100 and 95%, respectively [1]. unlikely benefit. Most recently, cKIT receptor mutational Subsequent to this study, a number of others were able to demanalysis from gastrointestinal stromal ‘The new wealth of molecular onstrate similar diagnostic capabilities tumors (GIST) is now used for predicting with biospecimen taken from patients with methods, scientific tools and response to tyrosine kinase inhibitors other types of cancer. The Petricoin and resulting data streams has Liotta study was subsequently cited and (TKIs) and likelihood of resistance. Just a few years ago GIST was a certain death transformed biomedicine into criticized for reproducibility issues; howan information science.’ sentence. Today, the use of upfront diagever, it was quite disruptive through the nostic testing coupled to TKI therapy has transformed GIST scientific community and served to establish the entire concept to a disease of prolonged survival with a minimal degree of of MS-based clinical proteomics for biomarker discovery [2]. toxicity for a myriad of patients, many of whom possess Key concepts utilizing mass spectral patterns to identify grossly metastatic disease. regions of interest, combat dynamic range problems and hunt The new wealth of molecular methods, scientific tools and for biomarkers continue to evolve [3]. resulting data streams has transformed biomedicine into an New biomarker discovery technologies are sorely needed to information science. This phenomenon is certainly true for advance patient outcomes in cancer treatment. The Strategic oncology. Cancer is a complex multifactorial disease. When a Consensus Conference on Biomarker Research in Breast Cancell escapes its normal process of replication and division, there cer was a recent groundbreaking meeting of prominent breast are a plethora of changes at the gene, transcript, protein and cancer scientists and clinicians to discuss strategies to metabolite level that accompany this evasion. While science improve biomarker research. A priority-based timeframe for used to be limited in the numbers of molecular changes that the implementation of both focal and broad recommendacould be studied, present technologies have enabled entire tions over the next three years was established [4]. At the genomes, transcriptomes, proteomes and now metabolomes to recent American Association for Cancer research (AACR) be analyzed within single experiments. These new techniques special conference on Advances in Proteomics in Cancer also bring much hope and promise to advance all of clinical Research (February 27 – March 2, 2007), biomarker disoncology, from clinical practices based on categorical treatment covery methods were extensively discussed. In general, there assignments to more rational therapies based on an individual’s was scientific consensus that MS serum biomarker discovery tumor characteristics. The rapidly evolving fields of mass is best approached employing a method of tissue or proximal spectroscopy (MS) and clinical proteomics have demonstrated fluid analysis, and then using that information to map into significant promise for exploiting the complex information the more complex serum proteomic space. content contained in tumors to provide necessary scientific Clinical proteomics is a young science and MS methods coninsights for clinical advances. tinue to rapidly evolve. Modern molecular analyses of tumor A major thrust area in proteomics is to find novel biomarkers tissue result in data streams of enormous size and complexity. that can be used to diagnose cancer at its earliest stages, as well The heterogeneity, intricate nature and aberrant pathways of

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Multiple biomarkers in molecular oncology

tumors are only beginning to be understood. These challenges coupled to a heterogeneous human population make robust biomarker discovery a daunting task, especially assays based on solitary proteins. Therefore, assay technologies composed of multiple biomarkers are a logical choice for advancing molecular oncology. The discovery phase of the diagnostic assay and biomarker pipeline is well suited for MS, given its sensitivity and flexibility. References 1

Petricoin EF, Ardekani AM, Hitt BA et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 359, 572–577 (2002).

2

Ransohoff D. Lessons From controversy: ovarian cancer screening and serum proteomics. JNCI 97, 315–318 (2005).

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As demonstrated in cardiology and HIV/AIDS, the discovery and development of reliable biomarkers enables rapid clinical progress. The continued transformation of medical oncology from categorical treatment designations to rational treatment assignments as a function of individual tumor or serum analyses will very likely help alleviate the suffering and death from cancer. Additionally, it may enable new forms of molecular-based cancer risk assessments, allowing for preemptive strategies and prophylaxis.

Jaffe J, Mani DR, Leptos K, Church G, Gillette M, Carr S. PEPPeR, a Platform for Experimental Proteomic Pattern Recognition. Mol. Cell. Proteomics 5, 1927–1941 (2006).

Affiliations •

Donald J Johann Jr, MD, PhD National Cancer Institute at Frederick, Laboratory of Proteomics & Analytical Technologies, Frederick, MD 21702-1201, USA

Hinestrosa MC, Dickersin K, Klein P et al.. Shaping the future of biomarker research in breast cancer to ensure clinical relevance. Nat. Rev. Cancer 7, 309–315 (2007).

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Timothy D Veenstra, PhD Director, SAIC-Frederick, Inc., Laboratory of Proteomics & Analytical Technologies, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA Tel.: +1 301 846 7286 [email protected]

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