The expected growth of molecular techniques over the next 10 years will have a profound impact on clinical decision-making. Whereas clinical decision-making has been the domain solely of the clinician, the continued development of postgenomic platforms will increasingly blur the lines between diagnostic, prognostic, and therapeutic processes, necessitating the expertise of multidisciplinary clinical decision-making teams that include clinicians, pathologists, and laboratory technicians. This article will define the characteristics empowering molecular techniques, provide examples of high-impact molecular diagnostic and prognostic technologies leading the way, and address regulatory and implementation considerations for future application of molecular technologies.
Benefits of molecular testing and technologies
The utility of molecular technologies is credited to the advances in the identification of disease genes for a number of genetic diseases and susceptibilities, and the development of genetic targets for identification of disease-causing organisms. Molecular tests allow for rapid, simultaneous genetic profiling of multiple traits or mutations in a single diseased gene. Additionally, nucleic acid-based molecular diagnostics are able to identify infectious disease organisms from a variety of sample matrices. Table 1 lists six high-impact assays approved for diagnosis and treatment of infectious diseases and cancers.1,2 A searchable database of FDA-approved or FDA-cleared assays can be accessed at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm.
Table 1 - Molecular diagnostic platformsa
Molecular testing and infectious disease diagnosis
As more pathogen genomes are sequenced, multiple organisms can be detected and identified using a variety of molecular techniques. Since the first FDA-approved nucleic acid test—a DNA probe for the identification of Legionnaires’ disease from bacterial culture in 1986 (GenProbe Inc., San Diego, CA)—the field of molecular testing in infectious diseases has grown to represent about 70% of the global molecular testing market.3,4
Advantages of molecular infectious disease testing over conventional culture methods include rapid test results (1–5 hr), relatively small sample size, high clinical sensitivity and specificity in the presence of antimicrobial therapy, rapid identification of fastidious organisms, direct detection of resistant strains, and quantifiable results that may correlate to disease severity.
Targeted antimicrobial therapy within hours of suspected sepsis is likely to influence patient outcome, a time scale only accomplished by molecular diagnostic means.5 Despite the decreased therapeutic turnaround time allowable via molecular diagnostics, therapy often precedes diagnosis.6 Empirical antimicrobial treatment, for example, is routinely administered to a patient with suspected sepsis. Bacterial culture diagnosis will likely refine what therapeutic success had already confirmed. Molecular diagnosis from native sample types (i.e., blood, sputum, and urine) will preempt therapeutic results, but is unlikely to preempt therapy itself. Though inconclusive at this time, multiple studies investigate the possible correlation between early targeted antimicrobial treatment, facilitated by molecular infectious disease testing, and enhanced patient outcomes.7–9 In addition to decreased morbidity and mortality in patients with sepsis, targeted antimicrobial therapy may help to extend viability of our last remaining antibiotic defenses against resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA).
Sexually transmitted infections (STI) are the leading cause of reported disease in the United States each year, with an approximated 20 million new cases per year.10 Sexually transmitted infections, such as high-risk and low-risk subtypes of human papillomavirus (HPV), are increasingly diagnosed using molecular methods. In the case of human immunodeficiency virus (HIV), viral load assays are used to monitor HIV-infected individuals, predicting the progression of the disease, and titrating antiretroviral treatment.11 One issue exacerbating the ongoing public health problem of STI is the slow turnaround time (2–14 days) of current diagnostic platforms resulting in low patient return rates for STI results.12 Point-of-care molecular STI testing can facilitate rapid diagnosis for treatment and counseling within a single doctor’s appointment.13
Molecular testing in application of cancer prediction, prognosis, and diagnosis
All indicators (peer-reviewed papers published, grants, and patents) point to the future of molecular technologies in the application of cancer prediction, prognosis, and diagnosis.14 Modern molecular platforms provide clinicians with a tumor gene expression profile that allow clinicians to distinguish between different tumor subtypes, determine likelihood of recurrence after surgery, and predict tumor reaction to treatment.
While men are not immune, breast cancer affects more women globally than any other form of the disease, with 1.38 million new cancer cases diagnosed in 2008.15 The study of genotype changes found in adenocarcinomas, such as breast cancer, has identified the correlation between HER2/neu overexpression and poor prognosis. Molecular diagnostic tests using immunohistochemistry, fluorescence, chromogenic testing, and brightfield in situ hybridization have been developed to determine the HER2/neu tumor status. Standardization guidelines for performance and interpretation of HER2/neu testing in the United States were published jointly by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) in 2007.16
Companion diagnostics and personalized medicine
Companion diagnostics are tests that determine whether specific drugs should be administered based on a proven efficacy or risk in treating a specific patient population or disease. Companion diagnostics may also be used to monitor the response of a patient to a specific treatment for the purpose of optimizing safety or effectiveness.17 The paradigmatic companion diagnostic example is the diagnostic test for breast cancer tumors that overexpress HER2 genes and their predisposition to respond well to treatment with trastuzumab (Herceptin®, Genentech, San Francisco, CA). Regulatory action such as the requirement of HER2 testing prior to initiation of Herceptin therapy has prompted pharmaceutical companies to reconsider a one-drug approach for the treatment of all patients with a specific indication. Instead, biotechnology companies are increasingly shifting to prognostic and pharmacogenomics to determine the best treatment for individual patients. Market motivators for such a paradigm shift include:
- Companion diagnostics can increase the efficiency of clinical trials, thereby increasing the odds of success in a clinical development program
- When medicine has been proven safe and highly effective within a specific patient population, its price can increase to reflect the value to the patient
- As effective treatment of disease eliminates the need for additional medication or treatments, cost savings can be applied to diagnostic costs.
Table 2 - FDA-approved companion diagnostic tests manufacturers and theraputics
Table 2 lists examples of currently approved companion diagnostic tests and corresponding therapy. Companion diagnostics targeting metabolic diseases, such as diabetes and obesity, are likely to catch up to oncology and infectious disease over the next ten years.17,18
As nonclinical, laboratory-based results increasingly dictate clinical decisions, the clinical decision-making domain of the clinician is gradually encroached upon by the laboratory. For example, if clinicians are unable to determine the clinical significance of a result, or interpret a result based on their understanding of generally accepted information from the clinical community, then the evidence-based clinical judgment shifts away from the clinician to the test algorithm itself. Molecular technology-driven personalized medicine will further blur the lines between diagnostic, prognostic, and therapeutic categories and processes, creating anxieties among health-care practitioners over clinical jurisdictions.18
Though not clear to what extent, molecular technologies will surely play a significant role in the future of personalized medicine. There are many stakeholders (i.e., patients, clinicians, pathologists, laboratory technicians, pharmaceutical companies, and diagnostic test manufacturers), each with unique concerns and requirements regarding the changing application of molecular technologies. The FDA must facilitate an open discussion of these needs with fair representation from each stakeholder to determine a reasonable regulatory method for approval of novel genomic platforms. Clinical decision-making, regardless of how the application of molecular technologies may alter the originator, should optimize the patient standard of care regardless of historical precedent or technological conservatism.
- Buyse, M.; Loi, S. et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J. Natl. Cancer Inst. 2006, 98, 1183–92.
- DNA FISH Probe Assay. Summary of safety and effectiveness data (SSED); http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100027b.pdf. Accessed Oct 7, 2011.
- Edelstein, P.H. Evaluation of the Gen-Probe DNA probe for the detection of legionellae in culture. J. Clin. Microbiol. 1986, 23, 481–4.
- Renub Research: Global molecular diagnostic market: opportunities and future forecast. 8/2009, RE-1503. Accessed Oct 7, 2011.
- Dellinger, R.P.; Carlet, J.M. et al. Surviving sepsis campaign guidelines for management of severe sepsis. Crit. Care Med. 2004, 32, 858–73.
- Berg, M. The construction of medical disposals, medical sociology and medical problem solving in clinical practice. Sociol. Health Illn. 1992, 14, 151–80.
- Tran, N.K.; Wisner, D.H. et al. Multiplex polymerase chain reaction pathogen detection in patients with suspected septicemia after trauma, emergency, and burn surgery. Surgery 2011 [Epub ahead of print].
- Bravo, D.; Blanquer, J. et al. Diagnostic accuracy and potential clinical value of the LightCycler SeptiFast assay in the management of bloodstream infections occurring in neutropenic and critically ill patients. Int. J. Infect. Dis. 2011, 15, e326–31.
- Dowd, S.E.; Wolcott, R.D. et al. Molecular diagnostics and personalised medicine in wound care: assessment of outcomes. J. Wound Care 2011, 20, 232, 234–9.
- Centers for Disease Control and Prevention (2009). Sexually Transmitted Diseases in the United States, 2008—National Surveillance Data for Chlamydia, Gonorrhea, and Syphilis; http://www.cdc.gov/std/stats09/surv2009-Complete.pdf. Accessed Oct 7, 2011.
- Luft, L.M.; Gill, M.J. et al. HIV-1 viral diversity and its implications for viral load testing: review of current platforms. Int. J. Infect Dis. 2011, 15, e661–70.
- Schwebke, J.; Sadler, R. et al. Positive screening tests for gonorrhea and chlamydial infection fail to lead consistently to treatment of patients attending a sexually transmitted disease clinic. Sex. Transm. Dis. 1997, 24, 181–4.
- Swain, G.; McDonald, R. et al. Decision analysis: point-of-care Chlamydia testing vs. laboratory-based methods. Clin. Med. Res. 2004, 2, 29–35.
- Bourret, P.; Keating, P. et al. Regulating diagnosis in post-genomic medicine: re-aligning clinical judgment. J. Soc. Sci. Med. 2011, 73, 816–24.
- Cruver, A.M.; Portier, B.P. et al. Molecular pathology of breast cancer: the journey from traditional practice toward embracing the complexity of a molecular classification. Arch. Pathol. Lab. Med. 2011, 135, 544–57.
- Wolff, A.C.; Hammond, M.E. et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch. Pathol. Lab. Med. 2007, 131, 18–43.
- Naylor, S.; Cole, T. Overview of companion diagnostics in the pharmaceutical industry. Drug Discov. World. 2010; Spring Edition, 67–79.
- Hoggatt, J. Personalized medicine—trends in molecular diagnostics. inThought Alert 2011, 15, 53–5.
T. Keith Brock, BS is a Contributing Writer, American Laboratory/Labcompare; e-mail: firstname.lastname@example.org.