October 2015, Vol. 4, No. 5
Molecular Biomarkers Are Getting Attention in Early Detection of Cancer
Biomarkers have a promising role in the early detection and risk stratification of colonic neoplasia, lung cancer, and breast cancer said presenters at PMO Live 2015.
Molecular Biomarkers: Colorectal Cancer
The vast majority of screening colonoscopies are negative for significant lesions of advanced adenomas or carcinoma in average-risk and even high-risk persons, pointing to the need for personalized screening. The solution may lie in prescreening to identify patients likely to benefit from colonoscopy, said Hemant K. Roy, MD.
There are a myriad of blood, stool, and tissue biomarkers in various stages of development for this purpose.
Methylated SEPT9 from blood has a sensitivity of 51% for detection of colonic neoplasia, but for advanced adenomas it was only about 10%, “so this represents a small step forward, but it is available,” said Roy, Chief, Section of Gastroenterology, Boston Medical Center, MA.
MicroRNAs (miRNAs) are small noncoding RNAs that are 18 to 25 nucleotides long. At least 2500 miRNAs are dysregulated during carcinogenesis. Given their relative resistance to degradation, miRNAs have been used as biomarkers in blood and stool.
miR-21 expression levels in serum samples had an area under the curve of 0.927 for colorectal cancer and 0.803 for adenomas (J Natl Cancer Inst. 2013;105:849-859). Many serum biomarkers “have better traction for prognosis” than for early detection, he said. These include carcinoembryonic antigen, carbohydrate antigen 19-9, and vascular endothelial growth factor.
A multitarget stool DNA test had a sensitivity for colorectal cancer of 92.3%, compared with 73.8% for fecal immunochemical test (FIT), and a specificity for all nonadvanced adenomas of 86.6%, compared with 94.9% for FIT (N Engl J Med. 2014;370:1287-1297).
For advanced adenomas, the sensitivity of fecal DNA is only 42.2%. “If this is our real target, it represents a problem, especially since the fecal DNA test, while quite good, is still expensive at about $500 a test,” he said.
Field carcinogenesis has potential, said Roy. Markers in the endoscopically normal rectal mucosa are cellular markers (decreased apoptosis and increased proliferation), protein expression markers (tumor necrosis factor-alpha and MSH2/hMLH1), and molecular markers (proteomic, methylation, and microarray).
“You can look at the tissue specimen of the tumor itself, do microsatellite instability testing…followed by BRAF testing,” he said.
Genetic variants appear to differentiate individuals who benefit from aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) as a chemopreventive from those who may be harmed; NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype but with a higher risk among those with rare TA or AA genotypes (JAMA. 2015;313:1133-1142). Also, persons who had high expression of 15-PDGH in normal colonic mucosa were found to derive particular benefit from aspirin as a chemopreventive (Sci Transl Med. 2014;6:233re2).
Airway Gene Expression: Lung Cancer
Bronchial airway gene expression can serve as an early diagnostic biomarker for lung cancer, said Avrum Spira, MD, MSc.
“This test now has been launched clinically,” he said. “It’s the first of what I believe are many molecular biomarkers that are going to be emerging in the clinical space for the early detection of lung cancer.”
Identifying smokers at highest risk for lung cancer is the goal behind identification and use of airway gene expression, explained Spira, Founding Chief, Division of Computational Biomedicine, Department of Medicine, Boston University Medical Center, MA.
Smoking alters epithelial cell gene expression throughout the respiratory tract, but the airway epithelial cell genomic response to, and damage from, smoking is variable.
Bronchial airway gene expression reflects molecular alterations observed in the tumor itself and in the adjacent “local field.” Among smokers with a CT scan of the chest that is suspicious for lung cancer, an endoscopic brush of cytologically normal airway epithelial cells in the mainstem bronchus is profiled for gene expression activity. An 80-gene biomarker applied had a sensitivity of 80% and a specificity of 84% in 2 independent cohorts in distinguishing smokers with and without lung cancer. Sensitivity improved to 95%, and the negative predictive value (NPV) was 95% when combined with cytology obtained at bronchoscopy (Nat Med. 2007;13:361-366).
In a prospective multicenter study of smokers undergoing bronchoscopy for suspected lung cancer, a genome biomarker, when used in combination with bronchoscopy, had a sensitivity of 97%, compared with 75% for bronchoscopy alone (N Engl J Med. 2015;373:243-251). The genomic classifier has high sensitivity for detecting lung cancer across all cell types and stages of disease, and had high sensitivity and high NPV among intermediate-risk patients, in whom physicians are most uncertain about cancer status, said Spira.
A Clinical Laboratory Improvement Amendments test was launched in April 2015 to improve the preoperative diagnosis of lung cancer by reducing unnecessary invasive procedures.
The nasal epithelium may serve as a surrogate for the airway gene expression response to tobacco smoke exposure, which could result in a less invasive screening tool for population-based studies. “Genes associated with cancer in the nasal epithelium are similarly upregulated and downregulated in the bronchial epithelium,” he said.
The State of Biomarkers for Breast Cancer
Biomarkers for early detection of breast cancer are lacking but are in the works, said Susan L. Neuhausen, PhD, Professor in Cancer Etiology and Outcomes Research, Beckman Research Institute of City of Hope, Duarte, CA. These biomarkers may augment mammographic screening for detection.
“The current best biomarker is a genetic biomarker,” she said, referring to BRCA1 and BRCA2 mutations. “Timely BRCA1/2 testing is integral to clinical practice because it informs management options.” But BRCA1 and BRCA2 account for only about 3% to 5% of all breast cancers, and in a much higher proportion in women diagnosed at a younger age.
The strategies that work to prevent cancer in BRCA1/2 carriers, however, are the same as the ones used for other high-risk genes. Multigene clinical panels for breast cancer have been developed.
The Breast Cancer Association Consortium has identified about 100 loci that are associated with an increased risk of developing breast cancer. “On an individual level, these don’t really account for much risk. However, if you combine them, they actually do account for risk,” she said.
A polygenic risk score, in which odds ratios were combined across single nucleotide polymorphisms, of those women in the lowest quintile had a 5.2% lifetime risk of developing breast cancer, compared with 16.6% among those in the highest quintile. “So there was clear discrimination, but what you really want to know is, does it give you better prediction than current models?” she said.
The polygenic risk score improved the accuracy of risk prediction, from a receiver operating characteristic area under the curve of 0.66 to 0.69.
Using the polygenic risk score on top of the Breast Cancer Surveillance Consortium risk score reclassified a small proportion of women but, importantly, it classified another 3% of all women as being at a higher than 3% risk of developing breast cancer over the 5 years for which prevention strategies may be appropriate.
In terms of early detection models, potential plasma and serum biomarkers are cell-free circulating plasma DNA, cell-free miRNA, serum proteomics, salivary-free amino acid profile, and plasma infrared spectroscopy patterns.
Potential assays from cell-free DNA and miRNA include an 8-gene panel, including CST6, somatic mutations, copy number, and miRNAs. Challenges to their use are the heterogeneity of mutation profiles, precluding the use of a single marker; the instability of DNA in the plasma, so it needs to be extracted shortly after the blood draw; and normalization of miRNA levels.
Challenges to the use of assays from serum proteomics are their ability to meet the bar for high sensitivity and high specificity.
Increasingly, genomic alterations are being recognized and targeted for clinical trials. Improving clinical trial accrual in this environment may require multiple histology basket trials that increase the percentage of patients with “actionable” alterations, said Funda Meric-Bernstam, MD, at PMO Live 2015. The implications for the use of predictive markers for [ Read More ]
Each year, the Bonnie J. Addario Lung Cancer Foundation (ALCF) recognizes luminaries in the quest to cure lung cancer with the Addario Lectureship Award. This year, Fred R. Hirsch, MD, PhD, Professor of Medicine and Pathology, University of Colorado School of Medicine, Denver, delivered his keynote lecture on the many [ Read More ]