Several lung and pulmonary cancer studies presented at the 102nd Annual Meeting of the American Association for Cancer Research (AACR), held April 2 through April 6, 2011 in Orlando, Florida, highlighted new findings that may help scientists combat the nation's leading cancer killer. Fadlo Khuri, MD, editor of Cancer's chest/lung disease section and chair of the department of hematology and medical oncology at Emory University in Atlanta, Georgia, commented on some of the lung cancer studies from the meeting.
Protein Test May Detect Early Stage, Asbestos-Related Pulmonary Cancer
Researchers believe a new biomarker may be the most accurate yet in detecting proteins that are secreted from tumors caused by asbestos exposure. The proteomic assay was able to detect 15 of 19 cases of malignant pleural mesothelioma in stages I or II, making the test approximately 80% sensitive. The specificity was 100%, with no false-positive results. The blinded test was performed under the auspices of the National Cancer Institute's Early Detection Research Network Biomarker Discovery Lab and led by Harvey I. Pass, MD, director of thoracic surgery and thoracic oncology at New York University Langone Medical Center in NewYork City.
Malignant pleural mesothelioma is an asbestos-related cancer that is likely to peak in incidence in 20 years because of a latency period of 20 to 40 years after asbestos exposure. The disease is usually fatal because it is generally diagnosed at an advanced stage. The goal of the test would be to diagnose it at an earlier stage.
Dr. Pass and colleagues examined 170 blood samples from 90 patients diagnosed with malignant mesothelioma and 80 patients who had been exposed to asbestos. Approximately 75% of the samples were used to derive 19 specific biomarkers for mesothelioma whereas the other 25% were used in the blinded test.
Called the Multiplex SOMAmer Assay, the test uses SOMAmers (chemically modified DNA molecules that bind specifically to target proteins) to identify and quantify proteins in a broad range of concentrations. Researchers are refining the test and validating the results in other patient blood samples, Dr. Pass notes.
Dr. Khuri: “I thought this was a promising and interesting approach and the best abstract at AACR because of the potential to catch the disease early where the patient can benefit. We need further validation, but this is what I consider a very nice start”
Lung Cancer Risk Increases in Presence of HPV Antibodies
Lung cancer patients were significantly more likely to have several high-risk forms of human papfflomavirus (HPV) antibodies compared with people who did not have lung cancer, according to research from the International Agency for Research on Cancer (IARC). The results were consistent among current smokers, former smokers, and those who had never smoked.
Devasena Anantharaman, PhD, a postdoctoral fellow at the IARC in Lyon, France, and colleagues used serological tests to identify several high-risk and low-risk types of HPV in 1633 lung cancer patients and 2729 matched controls from 6 central European countries. Low amounts of antibodies to all types of HPV were found in the control group; however, in the lung cancer group, antibodies to proteins in 8 types of high-risk HPV were significantly increased.
High-risk HPV-16 and HPV-18 account for approximately 70% of cervical cancers and 40% to 60% of head and neck cancers. Lower risk HPV-6 and HPV-1 1, which cause genital warts, have been observed in respiratory papillomatosis, a benign lung condition.
Dr. Khuri: “This study is very provocative. For a while there has been evidence that HPV may be indicated in lung tumorigenesis. This is the first study showing an association, but we have no real hypothesis so far with regard to the causal relationship. We need to confirm the association and then try to understand the mechanism, much the way we understand it in cervical cancer and are starting to understand it in head and neck cancer. We need other larger population studies and case-control studies, preferably in different populations, not just central European. Then we need to correlate the findings with age at presentation and metastatic or early stage disease. These are some of the early questions that need to be asked.”
BATTLE Researchers Identify New Biomarkers for EGFR Inhibition
Scientists presented new findings from the ongoing Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, noting that they have identified new biomarkers that predict response to the epidermal growth factor receptor (EGFR) inhibitor erlotinib.
“We have limited ability to match the right drug with the right patient, and the best case we can do is with the EGFR mutation and EGFR inhibitors,”notes John Heymach, MD, PhD, associate professor of head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston. “Patients without these mutations can also benefit from erlotinib … but we can't predict who will and won't benefit.”
Approximately 10% to 15% of patients with non-small cell lung cancer (NSCLC) have EGFR mutations; BATTLE researchers are trying to determine mutations for the remainder of patients who do not. They performed gene expression profiling and core needle biopsies on 101 patients and found that the presence of an epithelial-tomesenchymal (EM'T) signature as well as the presence of a novel 5-gene signature including lipocalin-2 (LCN2) were predictive of response to erlotinib, including in patients with wild-type EGFR. Response was measured by disease control and progression-free survival.
Patients with the EMT genotype had a disease control rate of 64%, whereas the controls had a response rate of 10%. In addition, patients with the 5-gene signature had a response rate of 84%, whereas the controls had a response rate of 0%.
The new markers have been tested retrospectively, but the upcoming BATTLE 2 trial will prospectively test the predictive ability of these gene signatures, Dr. Heymach says.
Dr. Khuri: “If you can show which patients without EGFR mutations are likely to benefit from erlotinib, then that is helpful because not many of them do that well with it. The really rich thing about this study is that they showed they can get serial core biopsies through patients and use them to develop exploratory biomarkers that they can validate in subsequent trials. They are identifying new signatures that will predict benefit in patients who don't have clear signature driver mutations. The best is yet to come from this group.”
Target for Lung Cancer Chemoprevention Identified
Endobronchial dysplasia could predict how well a chemoprevention agent is working, according to Paul Bunn, MD, executive director of the International Association for the Study of Lung Cancer. “About half of lung cancer cases are in former smokers,” Dr. Bunn says. “The question is, what can we do to help former smokers lower their risk of lung cancer?”
Dr. Bunn presented updated results from a study that tested the effect of oral iloprost (used to treat primary pulmonary hypertension) on the improvement of endobronchial dysplasia in 152 current or former smokers. He and his colleagues analyzed the effect of iloprost on former smokers who had endobronchial dysplasia at the time of enrollment and found a significant improvement in prevalence of the dysplasia. “The changes were as big as or bigger than the changes we've seen between current and former smokers,” Dr. Bunn says.
The finding indicates that scientists can test agents such as iloprost and use their effect on endobronchial dysplasia as an Outcome.
Dr. Khuri: “We have a long history of running prevention trials in lung and head and neck cancer based on epidemiological data, and initial results were encouraging. But we learned that in active smokers, the interventions, such as beta carotene, were not very effective and can actually cause harm. It was a sobering experience. We couldn't show that intervening with natural compounds was effective.
This is a well-conducted study by an outstanding group that shows you can get buy-in from more than a dozen institutions to carry out this type of research. This study is very interesting. Not surprisingly, there wasn't much effect in active smokers, but iloprost was very effective in reversing dysplasia in former smokers. Endobronchial dysplasia is a very good endpoint, and we need to start thinking about designing trials in former smokers and probably including patients who do not have any endothelial abnormalities in their airways because we don't know how to judge improvement in them.
Other chemoprevention studies have looked at the use of celecoxib in current and former smokers and demonstrated effectiveness. One study showed celecoxib was effective in former smokers, but when it was stopped after 6 months, any improvements in premalignancies were reversed.”.1