ANDRE BARON, PhD, MPH Assistant Professor, Division of Hematology/Oncology, Department of Internal Medicine, University of Kentucky College of Medicine
and Markey Cancer Center; and Assistant Professor, Department of Epidemiology, College of Public Health, Lexington, Ky.
STEPHEN A. BRASSELL, MD Major, MC, Urology Service, Walter Reed Army Medical Center, Washington, DC.
LEE P. SHULMAN, MD Distinguished Physician, Northwestern Memorial Hospital; Professor, Department of Obstetrics and Gynecology, and Director,
Division of Reproductive Genetics, Northwestern University, Feinberg School of Medicine, Chicago, Ill; and Co-Director, National
Ovarian Cancer Early Detection Program.
For many cancers, earlier diagnosis and earlier detection of recurrence could have a profound impact on survival rates and
maximize positive outcomes. Concurrent with ongoing efforts to identify new, more effective diagnostic tools is an emphasis
on developing methods of diagnosing cancer that are minimally invasive, cost effective, easy to use, require little training
or technical skill, and are amenable to use in an office-based or clinical laboratory setting. Advances in imaging technology
and the development of sophisticated molecular and biochemical tools such as DNA and protein microarrays coupled with mass
spectroscopy and bioinformatics are driving the emergence of targeted, effective, and minimally invasive approaches to diagnosing
cancer in its earliest stages. Although these technologies may not yet be clinically available outside the research setting
and are certainly not yet part of the diagnostic armamentarium of primary care, they represent the future of cancer diagnosis
and may be only 5 to 10 years away.
EARLY DIAGNOSIS OF LUNG CANCER
The present Lung carcinoma kills more people worldwide than any other type of cancer.1 Treatment failure and high mortality rates are mainly due to late diagnosis resulting in unresectable tumors. A reliable
and cost-effective strategy for early detection could have a profound effect on survival in lung cancer. Even a small decrease
in lung cancer mortality would save thousands of lives each year.2
MRI scan showing a malignant breast tumor. (IMAGE: PHANIE/ PHOTO RESEARCHERS)
|
To date, however, no available lung cancer screening protocol has proven sufficiently robust, safe, and cost effective to
warrant a recommendation for population-based screening. The US Preventive Services Task Force, for example, in its updated
clinical guidelines, stated that although it found "fair evidence that screening with low-dose computerized tomography, chest
x-ray, or sputum cytology can detect lung cancer at an earlier stage" than it would be detected without screening, the group
also found "poor evidence that any screening strategy for lung cancer decreases mortality."3 Furthermore, the risks inherent in the high number of false-positive test results that may occur from the use of these screening
tools are cause for concern. These risks include the need for invasive diagnostic procedures to characterize suspicious nodules
as benign or malignant and the potential anxiety caused by a false-positive result. Thus, although low-dose spiral CT offers
a proven method for detecting small (less than 1 cm) lung tumors that are at an early, highly resectable stage, the challenge
lies in developing diagnostic algorithms that minimize the number of false-positive results and limit the number of patients
who undergo biopsy without missing treatable cancers.
The future Serial CT testing can be used to follow nodules detected on spiral CT screening over time to assess their growth and morphological
characteristics. A key drawback of this approach is that the lag between serial CT tests can delay the diagnosis of cancer
and initiation of treatment.
Figure 1: This color-enhanced coronal image, in a patient with lung cancer who is being screened for metastatic disease, was
obtained by combining the metabolic activity data from a positron emission tomography (PET) scan with the anatomic/spatial
data from a CT scan. (IMAGE: NEIL BORDEN/PHOTO RESEARCHERS)
|
The most promising noninvasive strategy for early diagnosis currently being evaluated combines spiral CT screening with positron
emission tomography (PET) scanning to assess suspicious nodules (see Figure 1). Additional studies are needed to determine
whether this test combination can result in reduced mortality and whether it will be feasible and cost effective on a population-wide
basis.1,4 Interim results show promise in an ongoing trial of combined spiral CT and PET using the glucose analog F-18 fluorodeoxyglucose
(FDG-PET) in current and former smokers aged 40 and older with no symptoms of lung cancer. These results have confirmed earlier
findings that low-dose spiral CT can contribute to early-stage diagnosis in a large proportion of cases and may increase the
chance for cure.5 Using spiral CT, a total of 973 nodules were detected on baseline evaluation; one or more nodules were observed in 440 of
the 911 individuals tested as part of the study. Lung cancer was detected in 14 of the 911 individuals; of these asymptomatic
lesions, 13 of 14 were diagnosed in stage I.
The investigators used FDG-PET to evaluate all noncalcified nodules 10 mm or greater and all smaller nodules that showed evidence
of growth. A lesion was considered positive for malignancy if FDG uptake was reported. Of the 11 nodules found to be positive
on FDG-PET, 9 were malignant, 1 was indeterminate, and 1 was benign (necrosis). Of the 14 negative nodules, 4 were malignant
and all of those were adenocarcinomas diagnosed in stage IA. The sensitivity and specificity of FDG-PET for the diagnosis
of malignancy were 69% and 91%, but the protocol included a 3-month follow-up CT for nodules with a negative FDG-PET, which
raised the sensitivity of the screening algorithm to 100%.
Another study using spiral CT to screen smokers tested the effectiveness of a diagnostic workup that relied on high resolution
CT to evaluate lesions larger than 5 mm and the subsequent selective use of PET to assess noncalcified lesions larger than
7 mm.1 Lesions smaller than 5 mm were followed with low-dose spiral CT at 12-month intervals. This diagnostic algorithm was associated
with complete tumor resection in 21 of the 22 lung cancers detected, with 17 of the 22 cancers being in stage I. These types
of studies demonstrate the promise of applying novel imaging techniques and combining technologies to create algorithms that
can safely detect and subsequently diagnose early-stage lung cancer.
REFINING DIAGNOSTIC STRATEGIES IN PROSTATE CANCER
The present A great deal of controversy continues to surround the use of prostate-specific antigen (PSA) levels in the diagnosis of
prostate cancer. The determination of highly specific and accurate PSA cut-off levels that are used to recommend a biopsy
continues to be a focus of research. A PSA value of more than 4 ng/mL is the generally accepted cutoff level for biopsy in
the general population. Alternatively, age-adjusted PSA cutoff values can be used: 2.5 to 3.5 ng/mL and over for 40- to 50-year-old
patients, 3.5 to 4.5 ng/mL and over for patients who are 50 to 60 years old, 4.5 to 5.5 ng/mL and over for those who are 60
to 70 years old, and 5.5 to 6.5 ng/mL for men in their 70s.6 For African American men, the diagnostic range is shifted downward.
Another measure of prostate health is the PSA velocity, which measures changes in PSA concentrations over time. A level of
0.75 ng/mL/y and over is an indication for biopsy. The percent free PSA represents another measurement that can help determine
cancer risk. A low value for the percent free PSA means that more of the circulating PSA is present in the bound form. This
indicates a greater likelihood of cancer, because most of the increased PSA present in prostate cancer is in the bound, not
unbound, form. The immune system recognizes this PSA as nonself, triggering an immune response that binds the circulating,
free PSA with immune components.
Ultimately, however, regardless of the PSA measurement, a diagnosis of prostate cancer can only be made on the basis of biopsy
and tissue histology. PSA levels only help guide the decision to perform a biopsy. Any one of 3 basic criteria can determine
the need for biopsy: PSA of 4 ng/mL or more, a palpable nodule on rectal examination regardless of the PSA level, or a PSA
velocity of more than 0.75 ng/mL/y. Even when decision-making is based on one of these criteria, only about 30% of individuals
who undergo biopsy will have prostate cancer.
Imaging technologies such as MRI and MRI/SPECT (single photon emission CT) have a role in staging of prostate cancer—determining
the presence of extracapsular extension—but they do not currently contribute to diagnosis. Studies are under way to evaluate
the utility of PET in prostate cancer diagnosis, but its role may be limited, since prostate cancer is not very metabolically
active compared with other cancers.
The future New biomarkers for prostate cancer, such as early prostate cancer antigen (EPCA), may prove useful for detecting early-stage
disease while yielding a low false-positive rate. Proteomics is being used to identify biomarkers in urine or blood that have
high specificity and sensitivity for prostate cancer and could be combined with PSA measurements to distinguish between benign
prostatic hypertrophy and prostate cancer (see "The promise of biomarkers". In a recent study, the authors identified characteristic
"protein profiles" in serum samples collected from 154 men with total serum PSA levels between 2.5 and 15 ng/mL who were recommended
to undergo prostate biopsies.7 The authors used computer algorithms to study and refine the pattern of proteins present in 63 of the 154 samples. These
protein profiles were then used to evaluate the remaining 91 serum samples (28 from men with biopsies positive for prostate
cancer and 63 from men with benign biopsies).
The results of this study demonstrate the potential power of proteomic profiling as a diagnostic tool for identifying patients
with elevated PSA levels who should undergo biopsies. When applied to the remaining 91 samples, the profile was able to discriminate
prostate cancer from benign prostatic disease with 100% sensitivity and 67% specificity. In other words, if the protein profile
had been used to determine the need for prostate biopsy in these 91 men, 67% of unnecessary biopsies (done in men with benign
disease) could have been avoided without missing any cancers. All 28 men with prostate cancer would have undergone biopsies.
The authors compared this result to those obtained using percent free PSA with a cutoff of 25% as the criterion for biopsy.
With percent free PSA testing, 7% of cancers would have been missed, while only 8% of unnecessary biopsies would have been
prevented.7
BREAST CANCER SCREENING
The present Standard, population-based protocols for breast cancer screening combine clinical breast examination and annual mammography
for women over 40 years of age. Newer imaging strategies such as digital mammography, MRI, and ultrasound are not likely to
replace mammography for screening the general population in the near future.8,9 These techniques are being evaluated for their advantages in screening specific patient populations to increase the chances
of detecting malignant lesions and for yielding additional diagnostic information following positive findings on mammographic
study to limit the number of women who undergo breast biopsy.
The future To date, study results comparing full-field digital mammography (FFDM) and conventional screen-film mammography have been
mixed, with some finding FFDM to be less sensitive than mammography, others claiming it to be more sensitive, and yet others
reporting similar cancer detection rates between the two techniques.8,9 FDMM has also been associated with both lower and higher recall rates, depending on the study.
FFDM has the advantage of enabling digital enhancement and manipulation of the breast image. It can be used with computer-aided
detection software, which may improve its diagnostic accuracy as radiologists gain experience and expertise with this evolving
technology.
MRI is being used as an adjunct to mammography and has found a particular role in screening high-risk populations. It is a
highly sensitive technique, more so than mammography. If a nodule does not demonstrate uptake of contrast agent, there is
a minimal chance that it is malignant.10 However, MRI tends to be less specific than mammography, and because of its relatively high false-positive rate, it cannot
be relied on as a sole indicator of the need for breast surgery.8,11 Its high cost also precludes its use for population-based screening. Whether it is a reliable tool for evaluating patients
with an abnormal finding on mammography or can help determine the need for a biopsy is not yet clear.12
MRI has advantages for screening women whose test results are positive for the breast cancer (BRCA) gene, since these women may begin a screening regimen at a younger age, when mammography may not be the optimal choice for
detecting tumors in denser breast tissue.8,11,13 For example, a recent prospective screening study in women who were 25 or older and had a genetic predisposition to breast
cancer compared mammography and MRI screening.14 Of the 4 cancers diagnosed in 367 women screened, MRI detected all 4, while mammography detected only 1.
Among another population of women with a strong family history of breast cancer, the Magnetic Resonance Imaging for Breast
Screening (MARIBS) study group reported a significantly higher sensitivity of contrast-enhanced MRI than of mammography for
detecting malignant lesions (77% versus 40%).15 The study went on to show that the difference in sensitivity was particularly evident in carriers of BRCA1 (92% versus 23%). In this study, the specificity of MRI was 81%, compared with 93% for mammography.
Ultrasound has shown emerging value for detecting cancers in women with dense breast tissue and for serial evaluation of benign
lesions.10 The use of ultrasound to image breast tissue requires significant expertise. In terms of its relevance for population-based
screening, it suffers from a lack of standardization, has variable interpretation criteria, and does not detect microcalcifications.8
One aspect of breast cancer diagnosis involves the identification of prognostic factors to help predict disease progression,
recurrence, and metastasis. In women with invasive breast cancer, the histologic status of the axillary lymph nodes serves
as a critical factor in prognosis, staging, and definition of the appropriate scope of clinical management. However, more
than 80% of women who undergo axillary lymph node dissection suffer at least one complication associated with the procedure.16
Sentinel lymph node biopsy is emerging as an alternative, minimally invasive technique for predicting axillary node status.
It carries a lower risk of complications than traditional axillary lymph node dissection and provides an accurate representation
of regional lymph node status.16,17 The procedure involves identifying the first node to receive lymphatic drainage from a tumor, using either a dye or radiolabeled
compound, or both, to trace the path of lymphatic drainage.17 Researchers are assessing the value of combining sentinel lymph node biopsy with other investigational, molecular techniques
aimed at probing the biology of a tumor and detecting micrometastatic disease.
Novel strategies in development to improve early diagnosis of breast cancer such as DNA microarrays and proteomic profiling
have shown promise but these tests are not likely to be available for clinical application for years to come. Gene expression
profiling using DNA microarray technology is being developed to predict metastasis of lymph-node-negative primary breast cancer,
as described in a recent article in the Lancet.18 The authors, using DNA microarrays to determine gene expression patterns in 115 breast tumors, identified a 76-gene "signature"
that they then used to evaluate tumors from 171 patients with lymph-node-negative breast cancer and predict the risk of metastasis.
The gene signature showed 93% sensitivity and 48% specificity and was strongly prognostic in identifying patients at risk
for developing distant metastases within 5 years.
Protein biomarkers may also prove valuable for diagnosing and evaluating breast cancer. At the American Association for Cancer
Research meeting earlier this year, researchers described a rapid, molecular diagnostic test capable of detecting early-stage
breast cancer.19 The test included 7 signature molecular markers found in breast cancer, including markers of inflammation, cell cycle control,
cell-cell contact, and tissue repair processes. The levels of those diverse markers, when used in combination, could differentiate
malignant from normal breast tissue.
Not only do these novel diagnostic strategies show promise for earlier detection of cancerous changes in tissues, but they
also offer hope for the development of less invasive methods of cancer detection. In the protein biomarker study, for example,
the researchers reported finding biomarkers of interest in immune cells circulating in the peripheral blood of patients with
breast tumors. The implication is that someday a simple blood test could help limit and better define the population of patients
who need to undergo a biopsy for more definitive diagnosis of a suspicious mass.
IS EARLY DETECTION OF OVARIAN CANCER POSSIBLE?
The present The potential benefits of earlier diagnosis of ovarian cancer are evident in current 5-year survival statistics:20- 80% to 90% for stage I tumors
- 65% to 70% survival with stage II disease
- 30% to 60% 5-year survival for tumors diagnosed in stage III
- 20% or less when diagnosed with stage IV ovarian cancer.
Unfortunately, at present, 75% to 80% of ovarian cancers are detected in stage III or stage IV, and the prognosis is poor.
Ovarian cancer is the fifth most common cause of cancer-related death in women, and it is the most lethal gynecologic malignancy.21 The lack of effective screening or early detection tests and the nonspecific nature of ovarian cancer symptoms hinder early
diagnosis. There is currently no effective method to screen for ovarian cancer. The cancer antigen-125 (CA-125) level should
not be used to screen for or diagnose an ovarian tumor outside the research setting.
The CA-125 value is elevated (more than 35 units/mL) in about 80% of women with advanced stage epithelial ovarian cancer.21 However, it is only elevated in 50% to 60% of women with stage I disease, and it has a positive predictive value of only
10%.21-22 Forty percent of patients with early-stage ovarian cancer will have a negative CA-125 test result. The only role for CA-125
testing is in monitoring disease progression and recurrence and in assessing the effects of treatment for ovarian cancer.
The unacceptably high rate of false-positive results with CA-125 screening generates more questions than answers and may lead
to unnecessary follow-up testing and invasive procedures. A false-positive result causes needless anxiety for healthy women.
At the same time, CA-125 screening will miss many cancers. Similarly, transvaginal ultrasound, although sometimes used for
screening or early detection, is not a reliable tool for diagnosing ovarian cancer. The bottom line is that there are no evidence-based
tests or diagnostic protocols available to detect ovarian cancer early in the natural course of the disease.
The future Early detection efforts in ovarian cancer are focused on developing laboratory and imaging tests that provide an objective
assessment of ovarian health. Imaging strategies in development include improved ultrasound techniques and the use of MRI
either to visualize ovarian tumors or detect changes in localized blood flow. Efforts are also under way to use proteomic
analysis to identify distinctive protein patterns linked to ovarian tumors.
Although tumor-derived and host response factors that are present as serum biomarkers show promise for early cancer detection,
a test targeting ovarian cancer does not appear imminent. Researchers are hopeful that a prototype assay will be available
for clinical use within 5 to 10 years. Part of the challenge lies in developing a reliable, reproducible, and easy-to-use
assay format that would be applicable in a traditional clinical laboratory setting.
To demonstrate the diagnostic potential of protein biomarkers, one group of investigators used a proteomic profiling approach
to establish a diagnostic pattern of protein markers. They developed a test comprising 5 candidate biomarkers that they used
successfully to distinguish serum samples derived from ovarian cancer patients from serum samples taken from healthy women.
The panel of biomarkers had an estimated 96.7% sensitivity and 96.7% specificity.23
OvaCheck (Correlogic Systems, Inc) is a product being marketed for ovarian cancer diagnosis. Reports of OvaCheck's 97% sensitivity
and 94% specificity have not been validated in peer-reviewed, published studies.24 An aggressive marketing and licensing strategy has generated publicity for the test, yet the scientific community's response
has overall been less than favorable, calling for proof of the test's effectiveness.5 To date, the FDA has not supported licensing of the product to commercial laboratories as a diagnostic test for ovarian cancer.24
CONCLUSIONS
For many cancers there are no good noninvasive and cost-effective methods of detecting and then diagnosing tumors at an early
stage. At present, a definitive cancer diagnosis requires direct visualization and histologic analysis of a biopsy specimen.
Much hope is riding on the sophisticated imaging and molecular-biochemical tools (and combinations of these techniques) that
are now under development.
In particular, a great deal of work is focused on identifying protein expression patterns in the blood and other body fluids
that can be used as biomarkers of cancer risk or new disease, or of cancer progression, recurrence, or metastasis. Although
these novel diagnostic tests appear to be at least several years away from clinical application, they offer the promise of
providing a window into the body and enabling early and definitive diagnosis of cancer with minimal risk of error.
Drs Baron, Brassell, and Shulman disclose that they have no financial relationship with any manufacturer in this area of medicine.
ARTICLE CONSULTANTS
REFERENCES
1. Pastorino U, Bellomi M, Landoni C, et al. Early lung-cancer detection with spiral CT and positron emission tomography in
heavy smokers: 2-year results. Lancet. 2003;362:593-597.
2. Humphrey LL, Teutsch S, Johnson M. Lung cancer screening with sputum cytologic examination, chest radiography, and computed
tomography: an update for the US Preventive Services Task Force. Ann Intern Med. 2004;140:738-739.
3. US Preventive Services Task Force. Lung cancer screening: recommendation statement. Ann Intern Med. 2004;140:738-739.
4. Gould MK, Maclean CC, Kuschner WG, et al. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and
mass lesions: a meta-analysis. JAMA. 2001;285:914-924.
5. Bastarrika G, Garcia-Velloso MJ, Lozano MD, et al. Early lung cancer detection using spiral computed tomography and positron
emission tomography. Am J Respir Crit Care Med. 2005;171:1378-1383.
6. National Cancer Institute. The Prostate-Specific Antigen (PSA) Test: Questions and Answers. Available at: http://cis.nci.nih.gov/fact/5_29.htm. Accessed July 26, 2005.
7. Ornstein DK, Rayford W, Fusaro VA, et al. Serum proteomic profiling can discriminate prostate cancer from benign prostates
in men with total prostate specific antigen levels between 2.5 and 15.0 ng/mL. J Urol. 2004;172:1302-1305.
8. Elmore JG, Armstrong K, Lehman CD, et al. Screening for breast cancer. JAMA. 2005;293:1245-1256.
9. Irwig L, Houssami N, van Vliet C. New technologies in screening for breast cancer: a systematic review of their accuracy.
Br J Cancer. 2004;90:2118-2122.
10. Smith AP, Hall PA, Marcello DM. Emerging technologies in breast cancer detection. Radiol Manage. 2004;26:16-24.
11. Veronesi U, Boyle P, Goldhirsch A, et al. Breast cancer. Lancet. 2005;365:1727-1741.
12. Morrow M, Magnetic resonance imaging in breast cancer: one step forward, two steps back? JAMA. 2004;292:2779-2780.
13. Kriege M, Brekelmans C, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial
or genetic predisposition. N Engl J Med. 2004;351:427-437.
14. Lehman CD, Blume JD, Weatherall P, et al. Screening women at high risk for breast cancer with mammography and magnetic
resonance imaging. Cancer. 2005;103(9):1898-1905.
15. MARIBS study group. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk
of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet. 2005;365:1769-1778.
16. Singh Ranger G, Mokbel K. The evolving role of sentinel lymph node biopsy for breast cancer. Eur J Surg Oncol. 2003;29:423-425.
17. Mahajna A, Hershko DD, Israelit S, et al. Sentinel lymph node biopsy in early breast cancer: the first 100 cases performed
in a teaching institute. Isr Med Assoc J. 2003;5:556-559.
18. Wang Y, Klijn J, Zhang Y, et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary
breast cancer. Lancet. 2005;365:671-679.
19. Khanna A, Walker A. Analysis of newer molecular signatures: promise of a diagnostic and management assay for breast cancer.
Proc Amer Assoc Cancer Res. 2005;46:3127.
20. American Cancer Society. Detailed Guide: Ovarian Cancer: How Is Ovarian Cancer Staged? Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_ovarian_cancer_staged_33.asp?sitearea=CRI&viewmode=print&. Accessed July 26, 2005.
21. Conrads TP, Fusaro VA, Ross S, et al. High-resolution serum proteomic features for ovarian cancer detection. Endocr Relat Cancer. 2004;11:163-178.
22. Baron AT, Boardman CH, Lafky JM, et al. Soluble epidermal growth factor receptor (SEG-FR) and cancer antigen 125 (CA125)
as screening and diagnostic tests for epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:306-318.
23. Yu K, Zheng S, Tang Y, Li L. An integrated approach utilizing proteomics and bioinformatics to detect ovarian cancer.
J Zhejiang Univ SCI. 2005;6B:227-231.
24. Conrads TP, Hood BL, Isaq HJ, et al. Proteomic patterns as a diagnostic tool for early-stage cancer. Mol Diagn. 2004;8:77-85
This article was written by Vicki Glaser based on individual interviews with Drs Baron, Brassell, and Shulman.
ON THE HORIZON
The promise of biomarkers
Much hope rests on the resurgence in interest in biomarkers for early cancer detection. The presence, absence, or increased
or decreased levels of these natural molecules in a tissue or tumor sample may signal the presence of a new cancerous lesion,
cancer recurrence, or metastatic disease. Ideally, though rarely, these markers are tumor-specific, yielding a highly sensitive
and specific tool for differentiating normal from cancerous tissue. More often they are proteins or other molecules present
at relatively low levels in normal tissue and at increased levels in cancer.
Most biomarkers can be measured on a continuum, and their presence or absence does not necessarily indicate disease. In fact,
investigators are just beginning to identify biomarkers whose levels are decreased in various cancers. Biomarkers may also
represent host response factors, compounds produced by the body in response to the presence of a tumor, or tumor-induced factors
such as growth factors, components of the immune system, or angiogenesis factors that are overproduced or under-produced to
support the growth or spread of the neoplasm. Research is focusing on 2 main types of biomarkers: genomic and proteomic.
DNA microarrays
Genomic biomarkers may include disease-related genes that are differentially expressed in normal versus cancerous tissues,
gene mutations, or single nucleotide polymorphisms. These last are variations in a particular nucleotide in a target gene
sequence that can serve as markers for cancer risk or for the development and progression of a neoplasm. DNA microarray technology
is a high-throughput technique for simultaneous analysis of the expression levels of thousands of genes.
Microarrays can contain tens of thousands of DNA sequences, each individually spotted in a grid onto a glass slide. Together
these spots may represent all the genes normally expressed by a particular tissue type, or a microarray might be designed
to represent only specific subsets of genes. A test protocol would involve labeling the DNA in a biopsy sample with a fluorescent
label and then allowing the labeled DNA to come into contact with the DNA bound to the surface of the microarray. Complementary
DNA strands would then hybridize, causing the hybridized DNA samples to emit a fluorescent signal. A detector would detect
and quantify the signal, yielding a measure of the level of expression of each gene represented in the biopsy sample. The
sample's gene expression pattern could then be compared with known gene expression profiles for various types of tumors for
the purpose of aiding diagnosis, classifying tumors, or describing subsets of disease that correlate with clinical outcomes.1
Proteomic profiling
Novel, robust technologies have been developed for separating complex samples into their individual protein components for
identification and analysis. The most widely used technique for creating protein fingerprints of biological samples and body
fluids is surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry.2 This technique can be used to compare the protein profiles of normal and cancerous tissue samples and to identify patterns
of proteins that can then be used to distinguish between healthy and diseased tissues. Computer algorithms can be created
to define and recognize specific protein profiles, and these smart software tools can then be used to evaluate protein patterns
in clinical samples—for example, to search for biomarkers of early-stage ovarian cancer in a blood sample.3
Researchers are experimenting with combinations of protein biomarkers to increase the sensitivity and specificity of predictive
tests. Selecting markers and designing test protocols that maximize both specificity and sensitivity pose formidable challenges.
Scientists are relying on neural networks, sophisticated mathematical algorithms, logistic regression, and other statistical
strategies to achieve these ends.
1. Macoska JA. The progressing clinical utility of DNA microarrays. CA Cancer J Clin. 2002;52:50-58.
2. Wulfkuhle JD, Paweletz CP, Steeg PS, et al. Proteomic approaches to the diagnosis, treatment, and monitoring of cancer.
Adv Exp Med Biol. 2003;532:59-68.
3. Conrads TP, Fusaro VA, Ross S, et al. High-resolution serum proteomic features for ovarian cancer detection. Endocr Relat Cancer. 2004;11:163-178.
We subscribe to the HONcode principles of the Health On the Net Foundation