For many years, researchers have recognized the promise that biomarkers hold for advancing the way we think about and treat cancer. Biomarkers are molecules found in biological specimens (eg, blood, bodily fluids, or tissues) that can serve as indicators of normal biological processes, pathogenic processes, or response to medical therapy.

 Clinical applications of biomarkers in oncology are expected to improve diagnosis, prognosis, prediction of response or recurrence, and disease monitoring. Biomarker discovery and development is moving forward through novel uses of complex technologies.

An educational session at the 2011 San Antonio Breast Cancer Symposium focused on 3 important technologies used in biomarker research: metabolomics, proteomics, and epigenetics. The first speaker was Arun Sreekumar, PhD, Baylor College of Medicine, who talked about metabolomics as a vehicle for biomarker identification and development. Gordon Mills, MD, PhD, University of Texas MD Anderson Cancer Center, followed with a discussion of proteomics. The final speaker, Stephen Baylin, MD, of Johns Hopkins University, provided an overview of epigenetics.

The American Association of Cancer Research, Food and Drug Administration, and National Cancer Institute (AACRFDA- NCI) Cancer Biomarkers Collaborative defines biomarker discovery and development as a pipeline of linked processes: hypothesis generation, research study design, sample collection, data collection, data analysis, assay development, assay validation, clinical qualification, regulatory approval, and clinical use.

 Collectively, the speakers touched upon many of these processes. While each speaker concentrated on a particular approach toward biomarker discovery and evaluation, they all adhered to a central theme: the successful application of biomarkers toward the design of combined rational therapy will require integrative efforts that exploit the information provided by these and other technologies.

 Dr Mills summarized the overarching goal of this type of research: “The key goal as we move forward is to have a sufficient understanding of what is happening in our patients’ tumors to develop rational combinatorial therapy and link biomarkers of patients who are likely to benefit to the best targeted therapy.”

The availability of high-throughput technologies has vastly broadened the potential for untargeted biomarker discovery, making it possible to scan hundreds of molecules at once. All 3 speakers emphasized the importance of establishing validity and maintaining quality control throughout each phase of biomarker discovery and development.

Metabolomics is the study of metabolites and the metabolome (sidebar). In his talk, Dr Sreekumar defined it as “the comprehensive and simultaneous systematic determination of metabolite levels in the metabolome and their changes over time as a consequence of stimuli, for example, disease, environmental changes, and drugs.” He explained that metabolites, as the end products of protein action, serve as cellular physiology indicators.

Dr Sreekumar began his talk by putting genomic, transcriptomic, proteomic, and metabolomic technologies into context with one another. The metabolome comprises about 3000 metabolites, making it less complex than the other “—omic” approaches. 

 According to Dr Sreekumar, they are also more approachable: “Metabolites are much more stable than genes or proteins and can be easily identified in biofluids.” Cancer-focused metabolic research is ongoing to identify metabolic markers of disease and tumor-specific biochemical pathways that can serve as druggable targets. During an interview conducted after his presentation, Dr Sreekumar remarked, “There are metabolic tests already available, like in the case of diabetes, you can look at glucose. Testing of metabolites is clinically done for metabolic syndrome, diabetes, and so on, but similar tests in the field of cancer have not come about yet. Our goal is to see whether we can provide such a test.”

Proteomics refers to studies of the proteome— the proteins of an organism or cellular system along with any modifications to those proteins&mdash;to understand cellular biology. In general, targeted therapies exploit a specific protein product within a perturbed cellular signaling pathway. The benefits of targeted therapies are often short-lived because cells are capable of adaptively responding after exposure to these drugs. These adaptive responses are revealed at the protein level through changes in homeostatic networks, feedbacks, and crosstalks. It is hoped that the identification of the mechanisms behind adaptive responses will inform the design of rational combined therapies. Dr Mills spoke about why it is important to move beyond RNA and DNA studies. “Although we have some incredible targeted therapeutics, as we look at what is going on with patients, most of the time only a subpopulation of patients respond. We obviously do not know why certain subpopulations respond and, in most of the cases, those responses are short-lived.”

Protein biomarkers can be assayed using relatively inexpensive standard assays, such as fluorescent in situ hybridization (FISH), enzyme-linked immunosorbent assay (ELISA), and Western blot, already in practice in CLIA-certified laboratories. While protein biomarkers are ripe with potential, their identification has been hampered by the inherent complexities of protein biology and the limitations that current technologies present. Dr Mills reviewed the efforts of the National Cancer Institute’s Clinical Proteomic Technologies Tumor Analysis Consortium, established to advance proteomics research.

 It is hoped that information gained from this program’s integrative approaches will produce a deeper understanding of cancer biology, with high-quality data sets, reagents, and analytically validated quantitative assays to be made publicly available.

DNA is subject to a number of modifications that do not involve a change in the actual DNA sequence, for example, methylation of DNA (the addition of a methyl group to a DNA strand) and histone deacetylation (removal of an acetyl group from a histone protein). Epigenetics is the study of functionally relevant changes of this nature (Figure 1).

Dr Baylin focused most of his talk on the deregulation of DNA methylation, just 1 type of epigenetic abnormality (Figure 2).

 It is becoming apparent that methylation losses and gains happen simultaneously across the cancer genome in a nonrandom manner. In effect, what happens is that some epigenetic changes turn off (repress) critical tumor suppressor genes while other changes maintain genes that drive the cancer in an active configuration.

Next-generation sequencing projects such as the Cancer Genome Atlas Project have revealed that mutations in epigenome- modifying proteins occur at high frequency in cancer cells.

What these mutations actually mean to the phenotype of the epigenome is not clearly understood. According to Dr Baylin, “This is going to be a big exercise that you are going to see, I predict, over the next few years—linking the change in the hard drive (DNA) to what happens to make the change in packaging of the DNA. I think this is going to be extremely instructive not only in providing targets of therapy all built on this growing understanding but also in our understanding of these genetic and epigenetic linkages.”

Earlier in the session, Dr Sreekumar presented published data from a metabolomic analysis of bladder cancer that affirmed the notion that a true understanding of cancer biology is going to come from studies that link all of these fields together. The data demonstrated that deregulation of an important enzyme pathway is linked to epigenetic modifications in the form of methylation.

Therapeutics that target epigenetic aberrations may be able to reverse the changes that shut down tumor suppressors. This differs from the mechanism of many anticancer interventions that aim to kill cancerous cells. In fact, in an ongoing study presented by Dr Baylin, researchers are taking old drugs like the demethylating agent azacitidine and the histone deacetylation inhibitor entinostat and using them at nanogram doses that are much lower than historical cell-killing doses. Early results from a small study involving patients with recurrent non-small-cell lung cancer are promising. Preclinical studies of low dose azacitidine for the treatment of breast cancer are also ongoing, with encouraging preliminary results.

Cancer treatment decisions are based, for the most part, on cancer type and stage, and not molecular characteristics of the cancer cells. The hope is that biomarkers will enable physicians to base treatment selection on the molecular profile of each patient’s cancer.

Most biomarkers identified to date have been stalled in the research setting and have not been carried over to clinical use. Clearing the hurdles that are preventing crossover will require a collaborative effort that brings together scientists and policy makers from a variety of disciplines and who represent academic, private, and public settings.

Dr Mills emphasized this in his introductory statements by saying, “As we move forward to helping patients and translating our observations to patients we have to learn how to work with industry.…Many of the things we are doing are moving forward and we are working with industry in a way that is going to help our patients.”

The author (KF) reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Concept and design (KF); drafting of the manuscript (KF); and critical revision of the manuscript for important intellectual content (KF).1. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89-95.

2. Khleif SN, Doroshow JH, Hait WN; for the AACRFDA-NCI Cancer Biomarkers Collaborative. AACR-FDANCI Cancer Biomarkers Collaborative Consensus Report: advancing the use of biomarkers in cancer drug development. Clin Cancer Res. 2010;16:3299-3318.

3. Mills G. Proteomics. 34th Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2011; San Antonio, TX.

4. Nass SJ, Moses HL, eds. Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment. Washington, DC: National Academies Press; 2006.

5. Beecher C. The human metabolome. In: Harrigan GG, Goodacre R, eds. Metabolic Profiling: Its Role in Biomarker Discovery and Gene Function Analysis. Boston, MA: Kluwer Academic Publishers; 2003.

6. Clinical Proteomic Tumor Analysis Consortium. Office of Cancer Clinical Proteomics Research Web site. http://proteomics.cancer.gov/programs/cptacnetwork. Accessed December 19, 2011.

7. Baylin SB, Schuebel KE. Genomic biology: the epigenomic era opens. Nature. 2007;448:548-549.

8. Baylin SB, Jones PA. A decade of exploring the cancer epigenome-biological and translational implications. Nat Rev Cancer. 2011;11:726-734.

9. The Cancer Genome Atlas. http://cancergenome.nih.gov/. Accessed December 19, 2011.

10. Putluri N, Shojaie A, Vasu VT, et al. Metabolic profiling reveals potential markers and bioprocesses altered in bladder cancer progression [published online ahead of print October 11, 2011]. Cancer Res. 2011;71:7376-7386.

Articles

Evidence-Based Oncology

Metabolomics, Proteomics, and Epigenetics

Technologies Behind Biomarker Discovery and Development

It’s hardly shocking that physicians have generally resisted moving over to electronic health records (EHRs). Cost concerns and well-founded wariness over the lack of standards-based interoperability among many EHR systems has prevented many a doctor from making the leap.

The problem is that healthcare information technology isn’t going away. In fact, much like an aggressive disease, it’s only going to grow stronger. Health reform and its ever-evolving changes are quickly transforming the EHR conversation from one of “I’ll stick with paper” to “I’d best do this if I want my practice to be fully efficient.”

The value gained from carefully researching and employing an EHR system is worth the investment, especially for oncologists, who are managing a gravely sick patient population.

The US Oncology Network is one of many oncology-based organizations that advocate for the use of healthcare information technology, encouraging physicians to embrace the array of benefits that lead to fewer errors, better targeted care and improved outcomes, access to vital life-saving treatments, and the latest research.

The Oncology Electronic Health Record Field Guide

 a publication of the American Society of Clinical Oncology (ASCO), encourages oncologists to adopt an oncologyspecific EHR rather than a generic one. For economic reasons, however, some oncology practices have opted for generic EHRs that have been tailored to their needs. But going this route carries the risk of not having the full menu of critical features that oncologists need. Plus, it’s still likely that even oncology-specific EHRs will need to be customized within the subspecialties. For example, surgeons may not have much use for an EHR with a prescription-writing function because they typically prescribe only a handful of formulary medications for a limited amount of time, as opposed to medical oncologists whose chronically ill patients need multiple drugs. Each oncologist should pick and choose the functionalities they need, as laid out by ASCO:

• Tumor staging—Tumor-Node-Metastases (TNM) nomenclature and others

• Multidisciplinary and data-intensive work flow—pathology, lab, imaging

• Chemotherapy dosing and administration

• Clinical trial and protocol management

Yet another benefit to employing an EHR is the fact that payers are giving closer attention to pay for performance (P4P). Knowing this, oncologists should be further encouraged to adopt the technology to ensure the efficient incorporation of consensus measures of quality and the use of best practice tools.

Some EHRs include a patient portal application, enabling the physician to gather a patient’s medical history before the first visit. With the portal, an individual’s medical data can be directly uploaded into the EHR and become part of the permanent record.

Additionally, with some systems, patients can establish and manage a separate personal health record (PHR), either as part of the EHR or as a separate Webbased tool. PHRs can store treatment history, making it simple for other medical facilities to capture and use the information.

From a physician-to-physician standpoint, The US Oncology Network offers a Web-based community called “The Oncology Portal,” which allows its member physicians to collaborate in real time.

The following summary is from Navigating Cancer, Inc, an oncology-specific, HITECH- certified patient portal

Hematology Oncology Consultants, PA, is an established practice with 6 oncologists and 2 locations in the Orlando, Florida, region. They had not yet adopted an EHR and were looking for a solution that could help them achieve 3 goals:

• Offer their patients electronic access to their medical records and solve additional criteria to help them qualify for the federal HITECH Act Meaningful Use incentives.

• Begin capturing patient information in a structured database that had the flexibility to integrate with any future EHR vendor they selected.

• Find a cost-effective solution that would improve their new patient registration process while providing them with hard cost savings.

After implementing the patient engagement portal, the practice realized the following results:

• New patients register online from home, where they have access to their medical history, resulting in more complete and legible forms.

• Patient information now captured in a structured database, and once integrated with an EHR, will provide patients with access to their medical records online, both requirements to qualify for the Meaningful Use incentives.

• Patient education materials now delivered electronically, another requirement to qualify for the Meaningful Use incentives. Eliminated the need for paper materials, freeing up storage space in the clinic.

• Eliminated hard costs for printing and mailing new patient registration materials, saving $100 per doctor per month.

• High patient satisfaction, with 90% of patients agreeing or strongly agreeing that the online registration process was better than filling out paper forms.

Connect With Other Healthcare Organizations

Oncology reimbursement is changing as health reform continues to take shape. Bundled payments, episode-of-care payments, and, potentially, full capitation,

are in the offing. To meet federal meaningful- use incentive targets, satisfy the data demands of health plan P4Ps, and participate in accountable care organizations (ACOs), it’s important for oncologists to collaborate with other providers, hospitals, and insurers so that no one loses momentum during the transition.

To expedite the process, oncologists should choose an EHR that’s interoperable with other EHRs in their network. Talk to peers, physician referrers, and nearby hospitals to find out which EHRs they use. Also make sure that the EHR has interfaces to connect with those systems. If they don’t, contact the vendor to find out how much the development costs will be. Connectivity between EHRs is the future and should be considered when deciding which one to choose.

The Oncology EHR Field Guide: Selecting and Implementing an EHR is a comprehensive, oncology-specific handbook developed to help practitioners select and implement current and future EHRs. Developed with input from volunteer oncologists, the 64-page book costs $76 for members and $95 for non-members. The following chapters are included:

Why Oncologists Must Tailor Clinical Features to Their Needs

The Truth About Electronic Health Records 

In recent years, the sequencing of the human genome and advances in supercomputer technology have helped drive hopes that a deeper understanding of the biology of cancer would yield the markers needed to truly usher in the long-awaited era of personalized medicine. While that optimism remains and there have been bright points of success, notable problems have slowed progress and led to criticism.

Biomarkers offer great potential for improving management of cancer at every point from screening and detection to diagnosis, staging, prognosis, and the assessment of treatment response. Striking advances have been made in several fields, particularly breast cancer, and fresh research suggests significant steps forward in lung cancer.

Currently, the Biomarkers Consortium, a public-private partnership founded by the Food and Drug Administration (FDA), the National Institutes of Health, and the pharmaceutical industry, is working on 9 projects, 2 of which are related to cancer. The Consortium is executing research into outcome measures for lung cancer and lymphoma, as well as a trial to “accelerate the pace of identifying effective novel agents for breast cancer.”

Biomarkers are a large part of the personalized medicine movement. They are a tool to help doctors choose the right drug for the right patient. The use of biomarkers in studies can make it easier to determine whether or not an established treatment will work for specific patients with certain types of cancers.

If personalized medicine leads to a disease being detected at an earlier stage, the disease can be treated more effectively. But the use of biomarkers also means that doctors can reduce adverse drug reactions and shorten treatment by removing much of the uncertainty of trial and error. Furthermore, the use of biomarkers in personalized medicine can better aid preventative care by making it possible for doctors to predict who can get specific diseases by monitoring patients.

In clinical trials, biomarkers increase the efficiency of a drug trial by making it easier to eliminate potentially unsuccessful candidates early in the process. The ability of biomarkers to detect and monitor the progression of a disease can reduce the time span of drug discovery by as much as a decade, the FDA reported. According to the FDA, if a pharmaceutical company can increase its but later on they fail,” Srivastava said. “The public gets so excited about it that they demand we must succeed as soon as possible. But the fact of the matter is, the hype usually does not translate into clinical studies.” At the same time, Srivastava said, the scientific community is getting organized and gaining momentum. “The infrastructure is in place to move forward in the right direction. More breakthroughs are a matter of time,” he said. Notable Shortcomings Analyzed Many researchers who have reviewed the progress made on biomarkers thus far have found much to criticize. In 2010, Eleftherios P. Diamandis, MD, PhD, professor and head of the Division of Clinical Biochemistry, University of Toronto, Canada, and associate scientist at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, reviewed cancer biomarkers initially hailed as breakthroughs and their subsequent failings.4 These included nuclear magnetic resonance of serum for cancer diagnosis; lysophosphatidic acid for ovarian cancer; 4- and 6-parameter diagnostic panels for ovarian cancer; osteopontin for ovarian cancer; early prostate cancer antigen-2 (EPCA- 2) for prostate cancer detection; proteomic profiling of serum by mass spectrometry for ovarian cancer diagnosis; and peptidomic patterns for cancer diagnosis.4 Diamandis found problems ranging from inappropriate statistical analysis to biases in patient and control subject selection. Problems with EPCA- 2, for example, included reporting values that were beyond the detection limit of the assay and using inappropriate agents to test EPCA-2. Duke University recently gained the successful prediction of failure by even 10 percent, it could save easily $100 million. Yet progress has been slow on the vast, ever-changing, and controversial frontier of biomarker research, with fewer than 2 dozen cancer biomarkers approved so far by the FDA among the thousands researchers have explored.

In August, the FDA approved 3 targeted therapies: an anaplastic lymphoma kinase inhibitor, an inhibitor of a mutation found in 40% to 60% of patients with cutaneous melanomas, and a drug for Hodgkin lymphoma patients who are CD30-positive.

Experts have advanced a brew of reasons for the gap between potential and performance, in a complex field that requires the coordination of a diverse team of pathologists, molecular biologists, and biostatisticians.

Last year, the AACR-FDA-NCI Cancer Biomarkers Collaborative described a “growing imperative” to modernize the drug development process, and made 27 recommendations in 8 different areas for doing so.

Meanwhile, the pharmaceutical industry is exploring ways to improve biomarker development, with some industry analysts seeing regulatory issues as a significant sticking point in economically feasible biomarker development (

 Industry Testing New Models for Developing Biomarkers). 

Sudhir Srivastava, PhD, MPH, the founding chief of the Cancer Biomarkers Research Group at the National Cancer Institute (NCI), said that one of the challenges in biomarker research is the unrealistic expectations promoted by many study investigators.

“With almost every paper, even if there is a remote chance of success, you see a press release hyping a discovery, but later on they fail,” Srivastava said. “The public gets so excited about it that they demand we must succeed as soon as possible. But the fact of the matter is, the hype usually does not translate into clinical studies.” At the same time, Srivastava said, the scientific community is getting organized and gaining momentum. “The infrastructure is in place to move forward in the right direction. More breakthroughs are a matter of time,” he said.

Many researchers who have reviewed the progress made on biomarkers thus far have found much to criticize.

In 2010, Eleftherios P. Diamandis, MD, PhD, professor and head of the Division of Clinical Biochemistry, University of Toronto, Canada, and associate scientist at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, reviewed cancer biomarkers initially hailed as breakthroughs and their subsequent failings.

 These included nuclear magnetic resonance of serum for cancer diagnosis; lysophosphatidic acid for ovarian cancer; 4- and 6-parameter diagnostic panels for ovarian cancer; osteopontin for ovarian cancer; early prostate cancer antigen-2 (EPCA- 2) for prostate cancer detection; proteomic profiling of serum by mass spectrometry for ovarian cancer diagnosis; and peptidomic patterns for cancer diagnosis.

 Diamandis found problems ranging from inappropriate statistical analysis to biases in patient and control subject selection. Problems with EPCA- 2, for example, included reporting values that were beyond the detection limit of the assay and using inappropriate agents to test EPCA-2.

Duke University recently gained the national spotlight in one of the most widely publicized biomarker failings. A research team had devised genetic tests to assess tumor cells by looking for gene patterns that would determine which drugs would best attack a particular cancer. The tests turned out to be worthless, though they were once hailed as a breakthrough that was seen as the first fruit of the new genomics. The fact that the research relied on publicly available data sets and algorithms made it possible to determine it to be flawed. Keith A. Baggerly, PhD, and Kevin R. Coombes, PhD, statisticians at MD Anderson Cancer Center in Houston, Texas, spent 2000 hours finding all of the errors in the research and found even simple errors, such as row or column offsets.

And at the NCI, the Cancer Biomarkers Research Group recently did its own random review of 1000 papers detailing biomarker discoveries. “In almost 90 percent of the papers, there was a lot of hype,” Srivastava said.

Of course, there have been successes in the cancer biomarker field, one of the more significant biomarkers being the protein HER2. First discovered in the early 1980s, HER2 can be found in 20 to 25 percent of breast cancers, and an excess of this protein is found in some ovarian, stomach, lung, and uterine cancers. The excess production of HER2 causes tumors to grow faster and recur more frequently. The breast cancer drug trastuzumab (Herceptin) targets HER2, reduces its production, and even stimulates the body to attack cancers directly.

Another example is the Philadelphia chromosome, a marker for chronic myeloid leukemia, which results from the movement of DNA from one site on the human genome to another.

At the American Society of Clinical Oncology (ASCO) conference in June, featured research included a prospective study by the 14-member Lung Cancer Mutation Consortium that identified at least 1 of 10 “driver” mutations in tumors of nearly two-thirds of patients with advanced lung cancer.

In a phase I trial, researchers from MD Anderson demonstrated that the ability to match individual patients with targeted cancer therapies based on the molecular profile of their tumors resulted in dramatically superior clinical outcomes, a finding that may improve patient selection for clinical trials at early stages and thus help speed drug development.

In addition, researchers at Indiana University Melvin and Bren Simon Cancer Center in Indianapolis discovered the first predictive biomarker for taxane-induced peripheral neuropathy, single nucleotide polymorphisms in the RWDD3 gene, through a genetic analysis of more than 2000 breast cancer patients.

The Cancer Biomarkers Research Group, which operates the Early Detection Research Network (EDRN), a collaborative effort of nearly 40 institutions, has a goal of accelerating the translation of biomarker information into clinical applications and evaluating new ways of testing tumors for predictive markers. “But we see our role as not just to be the accelerator of biomarker findings, but also to put the brake on bad findings,” Srivastava said of the EDRN.

Srivastava highlighted 3 key hurdles that have historically held back biomarker progress: a lack of foundational studies, a lack of sustained funding, and a lack of quality biological samples for testing. “The most important players in industry and the federal government are not investing enough, yet expectations are very high,” he said. “If you look at the funding level for early detection and diagnosis, it is not as high as one would like to see as you do in drugs.”

His budget is between $20 million and $26 million a year, spread out over about 40 institutions, which boils down to about $600,000 per institution. “It’s not enough to do the discovery,” he said, noting that investment in biomarkers may not be as appealing to investors because it is a long-term effort, while investors want to see short-term gains.

A lack of acceptable biological samples also has been a big obstacle, Srivastava and other scientists said. Many programs do not use quality samples, or there is not much information about the stage at which samples were collected.

Dean E. Brenner, MD, of the University of Michigan Medical Center, tackled this question during an ASCO presentation titled “An Update on Biomarkers for the Early Detection of Cancer, Prediction of Prognosis, and as Surrogate Endpoints for Cancer Prevention. “Garbage in, garbage out,” he said, noting that biosamples can be unstable and difficult to analyze. “You need good quality.”

Martin J. van den Bent, MD, PhD, Erasmus University Medical Center, The Netherlands, in a presentation on “Molecular Biomarkers in Neuro-oncology: Ready for Clinical Practice?” at the ASCO annual meeting, stressed the need for the adequate analytical performance of biomarkers, clinical performance, and independent validation. He cautioned that the biomarker research is still in need of development: “We need to think twice before we topple the old regime…. We could be looking at something so young and immature, the ugly ducklings that need to mature over time.”

None of the hurdles or the comparatively slow pace of progress mean it is time to give up hope, Srivastava said.

He said the most promising areas of cancer biomarker research over the next 5 years are prostate, ovarian, and colon cancers, and scientists are focusing more and more not just on single biomarkers, but on panels of biomarkers as successful diagnostic tools.

ASCO and other professional organizations are developing guidelines to help clinicians sort data regarding the usefulness of biomarkers in treating patients. Timothy D. Gilligan, MD, an oncologist in the Solid Tumor Oncology department at the Cleveland Clinic in Ohio, was part of an ASCO panel that developed guidelines on the appropriate uses for serum markers of germ cell tumors (GCTs).

 The panel did an exhaustive search of published material, reviewing hundreds of papers to identify relevant studies, and developed consensus guidelines based on data from 81 reports.

Gilligan noted that GCTs are unique in that they are largely curable, even when they are very advanced, and that biomarkers have been used for a long time to measure tumor progression, with a fair amount of evidence supporting their use. “In almost all cases, when the marker goes up, it is a sign of the tumors progressing, and when the marker goes down, they are responding to treatment,” he said. “There is a lot at stake in doing it right, though, so you don’t overtreat people.”

Like many other clinicians, Gilligan sees not only accuracy and reliability as big challenges with biomarkers, but also raises the question of utility. “Just because you can measure something doesn’t mean it is helpful to measure,” he said. “There are plenty of tumor markers that are often elevated if cancer is present, but knowing whether the marker is going up or down does not necessarily mean better care for the person.”

Promise and Pitfalls Along the Path to Personalized Care

The Great Biomarker Chase 

For more than 75 years, the cancer programs of Duke University Medical Center in Durham, North Carolina, have been at the forefront of research and patient care, with more than 800 researchers, physicians, and clinical staff serving nearly 6000 new patients each year from the United States and abroad. In 1972, Duke’s cancer program was designated as one of the nation’s 8 original comprehensive cancer centers by the National Cancer Institute (NCI), and is today one of only 40 such centers nationwide. Ranked as one of the top cancer hospitals in the United States for nearly 20 years by US News & World Report, Duke attracts the best cancer clinicians and scientists from across the country and around the world, and maintains clinical and research partnerships throughout the United States, as well as in India, China, and Singapore.

Those familiar with Duke’s stellar reputation are well aware of the accolades, honors, and achievements credited to its cancer researchers, clinicians, and academicians, but few milestones have inspired the kind of excitement being generated by the November 2010 formation of the new Duke Cancer Institute (DCI). The DCI brings together clinicians, researchers, and educators from across Duke’s hospital, medical school, and health system under a single administrative umbrella. This, in turn, intimately links patient care, research, and medical training in a unified pursuit. A new cancer center building is scheduled to open in February 2012, and a new leader, Michael B. Kastan, MD, PhD, was named to the Institute’s helm in May.

Already, DCI promises to have a profound impact on both cancer research and patient care. By providing unprecedented and unique opportunities for teamwork between Duke’s scientists and caregivers, the reorganization aims to more quickly translate novel therapies from bench to bedside and to optimize all aspectsof patient care. The most important of its goals is to provide patients with a less tangible but equally critical tool in the battle against their cancers: hope. The Preston Robert Tisch Brain Tumor Center and the Duke Prostate Center (DPC) serve as 2 prime examples.

The Preston Robert Tisch Brain Tumor Center

Using the words “brain cancer” and “hope” in the same sentence may seem counterintuitive, but neurooncologist Henry S. Friedman, MD, co-director of the Preston Robert Tisch Brain Tumor Center, does so routinely and unabashedly.

“Everything we do for our patients is doomed to fail unless we’re able to offer them hope,” he said, “and the formation of the new Institute is helping to translate ‘hope’ from nebulous concept to concrete reality.”

Established in 1937 as one of the nation’s first brain tumor research and clinical programs, the Duke program was renamed the Preston Robert Tisch Brain Tumor Center in 2005 in recognition of a $10 million gift from the Tisch family. Today, the Center is one of the world’s leading adult and pediatric neuro-oncology centers, and has received the NCI’s highest rating of “outstanding” for each of the last 10 years.

The Center’s 250-plus scientists, physicians, nurses, and other staff have at their disposal the resources of a leading research hub at the cutting edge of translational medicine, providing them with the means to offer patients the latest treatment advances, as well as access to a range of clinical trials, including those examining the efficacy of stem cell therapy and cancer vaccines. Equally important is the Center’s reputation for providing the compassionate support needed by patients and their families living with brain and spinal cancers.

“The philosophy of hope has always formed the foundation for the care we provide at the Center,” said Friedman, who considers brain and spinal cancers curable until proved otherwise. “This is a guiding principle that necessarily comes from the top down, and is continually nourished and sustained among veteran staff and new hires.” He went on to note that, even for patients living with these most feared of all malignancies, the brain tumor center’s integral role in the DCI fosters hope with an exchange of ideas and research findings that will speed the pace of discovery.

Friedman cited glioblastoma, the most common malignant brain tumor in adults, as an example. “While most people would tend to use the word ‘hopeless’ when referring to this diagnosis, patients with glioblastoma don’t necessarily die, and many are living longer than ever before,” he said. This point is borne out by NCI data showing that, compared with 1985, when fewer than 25% of patients lived 5 years with brain cancer, the 5-year survival rate now hovers at 35%, and more patients are surviving 10 and even 15 years past their initial diagnosis. (See http://seer.cancer.gov/faststats/selections.php?#Output.)

“Even those who ultimately succumb to their disease reap the benefits of enhanced quality of life,” Friedman said. “Hope is self-sustaining.” Friedman is, however, careful to differentiate between false hope and the hope given to patients at the Tisch Center. “We’re not talking about some abstract concept based on hand-holding and words of encouragement,” he stressed. “Real hope requires that we deliver substance.”

According to Friedman, “substantive hope” is one of the “4 pillars” that form the foundation for the care provided to the 900 to 1000 newly diagnosed patients seen each year at the Tisch Center. The other 3 core missions are basic research, clinical research, and exemplary patient care.

While the evaluation of a variety of therapeutic approaches is nothing new in the field of neuro-oncology, the care teams at the Tisch Center take this approach a step further by assessing the feasibility of multiple treatment strategies attempted not in sequence but all at once. “Rather than trying one treatment and then another when the first fails, we look at a comprehensive approach to treatment for each patient that may involve the use of multiple therapies from the onset,” he explained. Such an approach might involve approved therapies, along with those under investigation through clinical trials, including vaccines and targeted therapies involving monoclonal antibodies and anti-angiogenesis agents. The Center’s researchers also are involved in comprehensive genetic analyses aimed at identifying tumor aberrations for targeting by these novel agents. “What the DCI does is foster a venue for the free flow of information among our scientists and clinicians,” Friedman said. “There’s little doubt that our patients will be the primary beneficiaries.”

Also receiving a new infusion of hope by virtue of DCI’s reorganization are the patients of Duke’s genitourinary cancer program, which has long been a leader among the specialties of Duke’s cancer program.

Each year, Duke clinicians treat 700 to 800 newly diagnosed prostate cancer patients from around the world, and the number of those seeking treatment and/or second opinions at the DPC continues to grow. One favorable “side effect” of this growth is the recent influx of more than a dozen top medical oncologists, urologists, and radiation oncologists into the Duke program.

From the beginning, patients have had the opportunity to interact with a variety of specialists at the prostate cancer center, including urologists, medical oncologists, radiation oncologists, and support staff. But with the Center’s scheduled move into the new clinical building in February, patients will have access to all prostate specialists under one roof in a facility that also will house many of the Center’s scientists.

Urologist and medical oncologist Daniel J. George, MD, has been the director of the section of genitourinary medical oncology at Duke University Medical Center since 2003, and was recently appointed Duke’s medical director of cancer clinical research.

“Our genitourinary cancer program serves as an excellent example of late stage, the disease still appears to be testosterone-dependent. “This relatively new understanding has moved the field toward targeted therapies even in castrate-resistant disease,” he explained, noting that ongoing research in areas such as upregulation of androgen and the use of copper-dependent agents to create conditional lethality is especially exciting. Echoing George’s enthusiasm is Stephen J. Freedland, MD, Duke’s vice chief of urology research and associate director of genitourinary cancer clinical research. Freedland views the reorganization provided by the new Institute as a natural next step in the evolution of cancer care and research. “The reorganization removes some significant barriers and allows us to take full advantage of our colleagues’ areas of strength and expertise,” he said. Freedland noted, for example, that clinical trials have historically tended to be a strength of medical oncologists, while urologists tended to excel at creating databases. The shared expertise made possible by the DCI will give Freedland access to the best of both worlds in his planned clinical trials to examine the effects of diet and lifestyle modifications on the progression of prostate cancer. He noted that it also will prove beneficial in his ongoing trial of the use of hormonal therapy in prostate cancer and a low-sugar diet for resultant diabetes. Some clinics have already been how and why the DCI will set Duke apart from other cancer centers,” said George. “As successful as our cancer programs have been, the separation between research and clinical care has been somewhat limiting, and the new Institute is providing the means and venue for true continuity with respect to both research and patient care.”

In what he described as a paradigm shift, George explained that the historically department based faculty has now become program based, with all resources pooled under the DCI umbrella. Also unique is the geographic proximity of the undergraduate campus to the medical center, facilitating collaboration between medical oncology, radiation oncology, pharmacology, and those from departments such as chemical engineering.

“It’s an exciting time for genitourinary cancer researchers,” said George, whose own research includes trials of drugs that inhibit blood flow to tumors and whose areas of interest include the study of blood flow in renal cell carcinoma and growth factors as prognostic markers and molecular targets in prostate cancer.

“We’re now making very real strides in our understanding of the biology of these cancers, which, in turn, allows us to make some very meaningful progress,” he said. George cited endstage metastatic prostate cancer as a prime example, noting that, even in this late stage, the disease still appears to be testosterone-dependent. “This relatively new understanding has moved the field toward targeted therapies even in castrate-resistant disease,” he explained, noting that ongoing research in areas such as upregulation of androgen and the use of copper-dependent agents to create conditional lethality is especially  exciting.

Echoing George’s enthusiasm is Stephen J. Freedland, MD, Duke’s vice chief of urology research and associate director of genitourinary cancer clinical research. Freedland views the reorganization provided by the new Institute as a natural next step in the evolution of cancer care and research.

“The reorganization removes some significant barriers and allows us to take full advantage of our colleagues’ areas of strength and expertise,” he said. Freedland noted, for example, that clinical trials have historically tended to be a strength of medical oncologists, while urologists tended to excel at creating databases. The shared expertise made possible by the DCI will give Freedland access to the best of both worlds in his planned clinical trials to examine the effects of diet and lifestyle modifications on the progression of prostate cancer. He noted that it also will prove beneficial in his ongoing trial of the use of hormonal therapy in prostate cancer and a low-sugar diet for resultant diabetes.

Some clinics have already been integrated, and Freedland noted that clinicians have begun to meet monthly to discuss patient care. “Everyone will have an equal voice and an equal stake in patient outcomes,” he said, adding that even physician compensation will be determined by group productivity.

“We’re all in this together,” he said.

“While many in the profession tend to give lip service to the terms ‘teamwork’ and ‘multidisciplinary,’ it’s hard to imagine patient care, research, and even compensation being more intimately tied than here at Duke.”

George agreed, citing the DCI as an example of the commitment to “break down barriers, pool resources, and live and die by the program’s success.”

George said that commitment is truly put to the test when patients are feeling especially desperate.

“It’s especially inspiring to me when I see patients come from elsewhere with exhausted options and we’re able to give those patients and their families a very real and concrete sense of hope,” George said.

The rapid emergence of new therapies for both prostate and brain cancers has placed a renewed focus on the need for exemplary patient education and advocacy. “If we don’t adequately explain the potential benefits and side effects of these new treatments, we run the risk of patients becoming noncompliant or simply giving up on treatment,” said George. “And for those living with cancer as a chronic condition, patient education becomes a lifelong necessity,” he added, acknowledging that nurses are often better than physicians at helping patients cope with the nuts and bolts of living with their cancer and the effects of therapy.

Tracy K. Gosselin, RN, Duke University Medical Center’s associate chief nursing officer, noted that the new structure brought about by the DCI has shined a light on the need to examine the roles of nursing in a changing environment. “Many would describe nurses as the glue that ties together all the aspects of care for our patients,” she said. Not surprisingly, education, advocacy, and symptom management are areas of critical importance. “To us, creating a weekly calendar of scheduled appointments or helping to translate the jargon of a consent form may seem routine, but to patients such things can actually make the difference between quitting and remaining on treatment,” Gosselin said.

The 4 Pillars: Foundation for Care

Nab-paclitaxel (Abraxane) is an alternative form of the drug where paclitaxel is bound to albumin nanoparticles.

It is an antimicrotubule agent. These work to inhibit the microtubule structures, a part of the cell’s machinery for replicating itself. Inhibition of these structures ultimately results in cell death.

Paclitaxel usually requires solvents to dissolve it before the medication can be administered. When bound to albumin, it dissolves more readily, negating the need for irritating solvents. This means that the medication can be injected more quickly than the non-bound version. There are also indications that the nab-paclitaxel version may preferentially enter the cell.

Nab-paclitaxel is indicated for use in the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

The economic impact of nab-paclitaxel has been mixed. Dranitsaris and colleagues looked at clinical and safety data comparing it with docetaxel and noted that nab-paclitaxel had the lowest incidence of grade 3-4 toxicity and lower overall costs of managing the toxic effects. When they used the median number of cycles given and the cost effects of the toxicity, overall cost for nab-paclitaxel was $15,105 compared with $15,268 for docetaxel and $3357 for paclitaxel. However, the incremental cost per quality-adjusted life-year (QALY) gained was more favorable for nab-paclitaxel than docetaxel ($56,800 vs $739,600).

Another study by the same group compared nab-paclitaxel weekly or every 3 weeks with a standard regimen of docetaxel. Patients getting nab-paclitaxel 100 mg/m2 weekly and 300 mg/m2 every 3 weeks had average costs comparable to the docetaxel arm. Those administered nab-paclitaxel 150 mg/m2 weekly had significantly higher overall costs, but also had a significant improvement in progression-free survival. Relative to docetaxel, the incremental costs per progression-free year were £5660, £31,800, and £9900 for the 100 mg/m2 weekly, 150 mg/m2 weekly, and 300 mg/m2 every 3 weeks dosing, respectively.

Lenalidomide (Revlimid) in combination with dexamethasone is indicated for the treatment of multiple myeloma (MM) patients who have received at least 1 prior therapy.

How lenalidomide works is not well understood. Experiments have demonstrated that lenalidomide inhibits the growth of cells derived from patients with multiple myeloma in vitro. It has been shown to inhibit the secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha. Lenalidomide also inhibited the expression of cycoloxygenase-2 (COX-2) but not COX-1 in vitro.

A study by Fullerton et al assessed resource utilization in MM associated with 4 approved therapies. They included single-agent bortezomib, bortezomib with pegylated liposomal doxorubicin, thalidomide plus dexamethasone, and lenalidomide plus dexamethasone in their models.

The costs in all models were primarily driven by the direct expenditures for the drugs. The $64,806 cost for lenalidomide with dexamethasone was a 1.7-fold increase over the combination including thalidomide, and a 1.9-fold increase over drug costs for the bortezomib/ doxorubicin combination.

Adding associated medical costs to the model, lenalidomide/dexamethasone represented a cost savings compared with the other regimens. The total cost, including prophylaxis for deep vein thrombosis and pulmonary embolism, was 1½ times that seen in either the thalidomide/dexamethasone or the bortezomib/doxorubicin combination.

A discrete event simulation model was used to estimate long-term health and cost results of lenalidomide plus dexamethasone versus dexamethasone alone in patients with MM who had received either 1 or 2 or more prior rounds of therapy.

In those with just 1 prior therapy, lenalidomide with dexamethasone was associated with improvements in both survival and QALYs when compared with dexamethasone alone. They equated this to £20,617 per life-year gained and £28,943 in QALYs gained in those patients who received lenalidomide.

When the group with 2 or more previous therapies was assessed, similar results were seen. The incremental cost of the combination was £19,218 per life-year gained and £28,184 per incremental QALY gained.

Ipilimumab (Yervoy) is indicated for use in melanoma that has metastized or cannot be removed by surgery. It is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).

Blockade of CTLA-4 augments T-cell activation and proliferation. The mechanism of action of ipilimumab in patients with melanoma is indirect, possibly through a T-cell mediated anti-tumor immune response.

Because of its relative newness, having been approved by the FDA in March 2011, the economic impact of ipilimumab is not yet well defined. A Medline search using the drug’s name and the MESH terms “cost-benefit analysis” and “drug cost/statistics and numerical data” found no studies. A more general search using Google was similarly unproductive, returning only a draft report by England’s National Institute for Clinical Excellence (NICE) and a similar one from Ireland’s National Centre for Pharmacoeconomics (NCPE).

NICE tentatively recommended against adding ipilimumab to the National Health System’s coverage. This does not mean that the medication will be banned, just that the governmental program will not pay for treatment.

The Committee concluded that the most plausible cost per year of improved health would fall between £54,000 and £70,000 per QALY gained. They did note that a lack of data on longer-term benefits could result in a significantly higher true incremental cost-effectiveness ratio (ICER).

The NCPE also completed an economic evaluation of the medication. The Centre looked at a Markov decision analysis indicating a baseline incremental cost per QALY gained with ipilimumab versus best supportive care as €147,899. The incremental cost per life-year gained was €92,443.

A probabilistic sensitivity analysis indicated that the probability of ipilimumab being cost-effective over a willingness to pay range between €20,000 per QALY to €45,000 per QALY was 0%.

The budget impact assessment, based on a cost per dose above €20,000 and an average cost of treatment over 4 cycles, exceeded €85,000. Differing scenarios put the gross budget impact of using the medication between €4.8 million and €7.4 million in 2012. This would have increased between €500,000 and €1.8 million by 2016.

This led the Centre to conclude that there had been a failure “to demonstrate the costeffectiveness of ipilimumab for the treatment of advanced melanoma in adult patients who received prior therapy.”

Because of that, the Centre could not recommend reimbursement at the submitted price.

1. Desai N, Trien V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, AB-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12:1317-1324.

2. Anon. How Abraxane may help. http://www.abraxane.com/dtc/how-abraxane-may-help.aspx. Accessed November 13, 2011.

3. Abraxis Bioscience. Abraxane Package Insert Revised. http://www.abraxane.com/docs/Abraxane_ PrescribingInformation.pdf. Accessed November 13, 2011.

4. Dranitsaris G, Cottrel W, Spirovski B, et al. Economic analysis of albumin-bound paclitaxel for the treatment of metastatic breast cancer [published online ahead of print November 26, 2008]. J Oncol Pharm Pract. 2009;15(2):67-78.

5. Dranitsaris G, Coleman R, Gradishar W. Nab-paclitaxel weekly or every 3 weeks compared to standard docetaxel as first-line therapy in patients with metastatic breast cancer: an economic analysis of a prospective randomized trial [published online ahead of print June 3, 2009]. Breast Cancer Res Treat. 2010;119(3):717-724.

6. Anon. Revlimid prescribing information. http://www.drugs.com/pro/revlimid.html. Accessed November 13, 2011.

7. Fullerton DSP, Trautman H, Huang H, et al. A budget impact model comparing resource utilization of four approved therapies for multiple myeloma (MM) in the U.S. [abstract]. Blood. 2007;110:3324.

To help oncology providers better understand drug mechanisms of action, and the economic implications of their use. 

Drug Profiles

Where Are We Spending the Most Money in Metastatic Lung Cancer?

Metastatic lung cancer is frequently diagnosed and extremely difficult to treat; a great deal of resources are expended on therapies and health services for patients with metastatic lung cancer once they undergo chemotherapy. In 2004, lung cancer treatment expenditures were one-fifth of Medicare’s entire spending on cancer. The benefits of lung cancer treatment are limited, and therefore therapy costs must be weighed against outcomes. This is particularly true today, as there is increased scrutiny on the costs of care—even cancer care.

Researchers from Amgen, Kaiser Permanente, and the health economic consultant Policy Analysis Inc studied the health claims of 4068 patients (mean age, 65 years) who began chemotherapy between 2000 and 2006 until their deaths or the end of the study period to determine cumulative healthcare resource utilization and expenditures. The information was collected from a large, private, multi-payer health insurance claims database. Patients’ inpatient and outpatient service claims and medication claims were followed for a median of 334 days.

Over a mean 500-day follow-up period, the cumulative healthcare expenditures averaged $125,849 per patient. Total healthcare costs included 34% for outpatient care, such as emergency department and/or physician office visits, hospital outpatient/home health/hospice/skilled nursing services, and 20% for acute hospital inpatient care. Outpatient chemotherapy and other medication costs were estimated at 22% and 24%, respectively (Figure). For patients whose total costs were above $200,000, chemotherapy and other medication costs accounted for more than 50% of the total, percentages similar to those with far lower total costs.

The majority of costs for patients with metastatic lung cancer receiving chemotherapy are associated with outpatient and not inpatient care, the researchers pointed out. This may be important, they added, when allocating overall healthcare resources, identifying possible cost savings from disease prevention, and assessing the cost-effectiveness of new medical interventions. Cost-effectiveness evaluations of new strategies for preventing, screening, and treating early stage and metastatic lung cancer can be useful when regulatory and reimbursement decisions must be made, according to the researchers.

Vera-Llonch M, Weycker D, Glass A, et al. Healthcare costs in patients with metastatic lung cancer receiving chemotherapy. BMC Health Services Research. 2011;11:305.

Treatment Response and Survival in Patients With Epithelial Ovarian Cancer

Interest in the use of biomarkers has grown to help determine which patients have a greater likelihood of receiving optimal benefit from oncologic treatments. This concept of optimizing the value of treatment is now being applied to another aspect of cancer care. Investigators from the University of Minnesota used mathematical modeling to help determine whether global gene expression data of tumor tissue attained during surgery and before the beginning of chemotherapy treatment in 54 patients with advanced stage epithelial ovarian cancer (EOC) can help predict which patients would mostly likely suffer a recurrence.

The researchers developed 3 prognostic biomarker models (termed F1, F2, and F3) based on the existence of tumor gene combinations (from a total of 12 genes) that were very accurate (overall sensitivity: 96%—100% and overall specificity: 96%–100%) in identifying both the patients who responded (long-term survivors [LTS]) and the non-responders (short-term survivors [STS]) to platinum/taxol chemotherapy. From a total population of 54 individuals, the researchers randomly selected 34 patients (14 LTS, 20 STS) in order to develop and test the F1, F2, and F3 prognostic biomarker models. This discovery study phase was the first step in assessing a prognostic (or a diagnostic) test, resulting in extremely high sensitivity and specificity. In the validation study, information from the tumors of 20 patients (not included in the discovery phase) were used to test the 3 prognostic biomarker models. In this phase, all 3 models gave a correct prognosis for the 20 unknown subjects with regard to treatment response and survival.

When the discovery study and validation study results were then combined, the F1 and F3 models had a treatment response sensitivity of 100% (24/24 LTS subjects) and a specificity of 97% (29/30 STS subjects). The F2 model demonstrated a sensitivity of 96% (23/24 LTS subjects) and a specificity of 1.000 (30/30 STS subjects). In terms of survival, both the F1 and F3 models demonstrated a sensitivity of 97% (29/30 STS subjects) and a specificity of 100% (24/24 subjects), whereas the F2 model had perfect sensitivity (30/30 STS subjects) and a specificity of 96% (23/24 subjects).

The 12 tumor genes tested were categorized into 3 general groups: (1) genes that regulate cytostructural protein expression, (2) genes for cell proliferation regulation, and (3) metabolism regulation genes.

By using these prognostic biomarker tests to develop new, more effective pharmacological regimens, the researchers noted, considerably more successful treatments and a significant increase in survival rates for all patients with advanced stage EOC are possible.

Nikas JB, Boylan KLM, Skubitz APM, Low WC. Mathematical prognostic biomarker models for treatment response and survival in epithelial ovarian cancer. Cancer Informatics. 2011:10;233-247.

A “Poster Child” for Targeted Cancer Therapy?

Multiple myeloma (MM) exhibits considerable biologic and clinical variation—it is not surprising, then, that a single, uniform therapeutic approach for patients with MM fails more often than it succeeds, said commentators from the University of Texas MD Anderson Cancer Center, Houston, and Changzheng Hospital, Shanghai, China.

Much work had gone into developing a 70-gene and 15-gene model, created by the University of Arkansas for Medical Sciences (UAMS) and the Intergroupe Francophone du Myelome, respectively, to identify patient populations who are at risk of poor outcomes as determinedby their tumor gene expression profiles (GEPs). Effective as well as distinct treatments for different MM subtype patients that improved response rate, progression-free survival, and overall survival with low toxicity and rational cost-effectiveness was the ultimate aim of the stratification.

Total therapy 4 (TT4) by UAMS and Mayo Stratification of Myeloma Risk-Adapted Therapy consensus guidelines from the Mayo Clinic are 2 typical examples of targeted therapy, based on the GEP stratifications. A 2-year complete response will be the primary clinical end point of ongoing research to determine the validity of guidelines. Mayo Clinic researchers categorized patients into standard-risk, intermediate-risk, and high-risk groups depending on mutations and abnormalities discovered through multiple methods. Sixty percent were standard risk, and 20% of patients were determined to be in the high- and low-risk groups. Personalized therapy recommendations included regimens that could result in a high overall response rate with minimal early toxicity for a standard-risk patient. Those in the intermediate- risk group could follow a bortezomib- based induction regimen (high-dose melphalan) with or without consolidation before lenalidomide maintenance. The authors pointed out that in the high-risk subjects, new drugs and novel approaches may be best, and a “total therapy 3 like” approach may be most appropriate for patients exhibiting p53 deletion.

Although there are now over 40 novel pharmacologic targets presently undergoing clinical trials, the authors acknowledged that it is still not clear which will play a critical role for any subgroup of patients with multiple myeloma. Strengthening the insights on patient stratifications according to molecular heterogeneity and making rationally cost-effective treatment available for different subsets of patients should be the goal, they noted, and can be achieved by optimizing the current therapeutic strategies. A particular emphasis should be placed on immunomodulatory therapies, the authors concluded, because of their potential to eliminate remaining myeloma cells that will enhance the efficacy after a bonemarrow transplant.

Jiang H, Yi Q, Hou J. Strategic consideration on treatment of multiple myeloma (editorial). Chin Med J. 2011;124:2965-2968.

Developments in Treatment Approaches to Patients With HER-2+ Breast Cancer Refractory to Trastuzumab

Before the introduction of trastuzumab in the 1990s, women with breast tumors overexpressing the human epidermal growth factor receptor (HER)-2 gene had significantly shorter survival than patients found to be negative for HER-2 overexpression. The advent of targeted therapy with trastuzumab was touted as one of the first successes in matching molecular biomarkers with effective pharmacologic treatment. Overall survival in patients receiving this monoclonal antibody in addition to chemotherapy had an overall survival that was 5 months longer than those who did not receive the combination as first-line therapy. However, more than 50% of women with advanced breast cancer exhibit resistance to trastuzumab, and disease progression and/or recurrence is common in those who originally respond to therapy. Oncologists from China and the United Kingdom sought to review the mechanisms of resistance and find new ways of classifying molecular pathways that would identify biomarkers, enabling additional methods for effectively stratifying patients who will benefit more fully from trastuzumab treatment.

They categorized the possible causes for resistance to trastuzumab as follows:

 Expression of p95HER-2, an abbreviated form of HER-2 that does not possess the binding receptor to which trastuzumab attaches

 Activation of the PI3K-AKT pathway (in a small retrospective study, patients demonstrating activation of this pathway had poor response to treatment)

 Abnormal signaling of other receptors, such as HER-3, insulin-like growth factor 1 receptor, and EGFR

Other miscellaneous mechanisms, such as expression of glycoprotein mucin 4 and autocrine production of transforming growth factor-beta

Much work is ongoing to find medications that are useful in patients with trastuzumab resistance, which work against 1 or more of these pathways. For example, lapatinib’s response rates as monotherapy are very low (up to around 5%). Response rates in combination with other chemotherapy does exhibit differences in time to disease progression of about 2 months. Multi-HER tyrosine-kinase inhibitors are currently in clinical trials that show some promise in trastuzumabresistant patients, helping about one-fourth of patients in a phase 2 trial.

The authors also pointed out that more research is needed to clarify the molecular mechanisms differentiating trastuzumab-resistant and —refractory breast cancer. It may also be that this intensive research reveals that resistance may be less frequent with another monoclonal antibody related to trastuzumab, like neratinib, and that this should be used eventually as first-line therapy.

Review of the most recent evidence-based literature discussing breast, colorectal, lung, and ovarian cancers, in addition to melanoma and multiple myeloma. 

February

Technologies Behind Biomarker Discovery and Development

The Truth About Electronic Health Records

The Great Biomarker Chase

The 4 Pillars: Foundation for Care

Drug Profiles

Latest in Literature

The Economics of Cancer Care in the United States

Putting Value Into Practice

Trying Something New: Episode Payments for Cancer Therapy

Payer Management of Oncology Gets Serious

Unraveling the Complexity of Drug Shortages

Are We Winning the War on Cancer?

Targeted Products Yield Most Promising Results