MedicalResearch.com Interview with:
Jean-Bosco Tagne Ph.D.
Assistant Professor of Medicine
Boston University School of Medicine; Pulmonary Center
Boston, MA
Medical Research: What is the background for this study? What are the main findings?
Response: The lung transcription factor Nkx2-1 is an important gene regulating lung formation, and normal respiratory functions after birth. Alteration in the expression of this transcription factor can lead to lung interstitial disease, postnatal respiratory distress and lung cancer. MicroRNAs repress gene expression, also controlling lung cell differentiation. In this study, we characterized miRNAs regulated by Nkx2-1 in lung cells by genome-wide analysis and confirm the expression patterns of highly regulated miRNAs in normal lung and in lungs lacking functional Nkx2-1. By in vitro studies in lung cell lines we found that down-regulation of Nkx2-1 de-represses miR-200c. Increased miR-200c, in turn, reduces the expression of its predicted targets Nfib and Myb. These findings add new components to the gene regulatory network controlled by Nkx2-1 in lung epithelial cells that may have implications in the various roles of Nkx2-1 in development and disease particularly in this case lung cancer where the levels are seriously altered.
MedicalResearch.com Interview with:
Joao R. Inacio, MD
Cardiothoracic Radiologist Director Visiting Professor Program
Assistant Professor of Radiology, University of Ottawa
Medical Imaging, The Ottawa Hospital Ottawa, ON
Medical Research: What is the background for this study? What are the main findings?
Dr. Inacio: Lung cancer is the most common and most lethal cancer worldwide. Its prognosis remains poor with a 5-year survival rate of 6–18%. Adenocarcinoma has surpassed squamous cell carcinoma as the leading histologic type. The presence of metastases carries the worst prognosis in lung cancer and is the most important in determining staging and management. Hematogenous spread (i.e., carried by blood) is the most common mechanism of intrapulmonary metastasis. Cumulative evidence suggests that intrapulmonary aerogenous spread may exist and is under recognized.
Deriving from our clinical experience, we performed a literature review that supports the hypothesis that lung cancer, particularly adenocarcinoma, may spread through the airways. With aerogenous metastases, it has been postulated that cancer cells growing along the alveolar septa at the primary site detach from the basal membrane, spread through the airways and re-attach and grow along alveolar septa away from the primary focus.
Radiology-pathology correlation studies, using Chest Computed Tomography (CT), have documented the radiological evolution from focal adenocarcinoma to multifocal airspace disease and demonstrated cytologic and histologic findings supportive of aerogenous spread.
Dr. Puneeth Iyengar (left) and Dr. Robert Timmerman[/caption]
MedicalResearch.com Interview with:
Dr. Puneeth Iyengar, MD, PhD.
Assistant Professor Director of Clinical Research
Dept of Radiation Oncology Co-leader, Thoracic Disease Oriented Team Harold Simmons Cancer Center
UT Southwestern Medical Center Dallas, TX
Medical Research: What is the background for this study? What are the main findings?
Response: Stage IV Non-small cell lung cancer (NSCLC) remains a disease of limited survival, in the range of one year for a majority of patients who historically have gone on to receive systemic therapy only. Disease in this patient population most often recurs in the sites of original gross disease. With greater understanding of the biology and patterns of failure that occur in stage IV NSCLC, it is becomingly increasingly obvious that there are subsets of patients, those with limited sites of metastatic disease, who may benefit with more aggressive local therapy in addition to systemic agents to effectuate longer progression free survival (PFS) and potentially overall survival (OS). Since failures of treatment occur most commonly in original gross deposits, local non-invasive therapy in the form of stereotactic body radiation therapy (SBRT) may offer a means to curtail the recurrences, perhaps as a way to shift the time to and patterns of failure.
To address these concepts, a multi institutional single arm phase II study was conducted at UT Southwestern Medical Center in Dallas and University of Colorado Medical Center. Twenty-four patients with limited metastatic NSCLC (fewer than or equal to six sites of disease including the primary) who had progressed through at least one systemic therapy regimen were treated with SBRT to all sites of gross disease and the EGFR inhibitor erlotinib with progression free survival the primary end point. The results of the study were very significant, with a PFS in this study cohort of 14.7 months, compared to historical ranges of 2-4 months, and an OS of 20.4 months, compared to historical ranges of 6-9 months for this same patient population. The SBRT treatments were found to be very safe and efficacious – only 3 out of 47 measurable lesions irradiated recurred with a concomitant shift in failure patterns from local to distant sites. As importantly, EGFR status was evaluated in 13 patient tumors, with none harboring the most common mutations. One could, therefore, predict that with a mutation enriched population, the combination of EGFR inhibitor and SBRT may have offered even greater PFS and OS benefits. Our observations also suggest that the SBRT treatments probably contributed the most to the dramatic PFS and OS outcomes.
These findings were published in the Journal of Clinical Oncology in the December 1, 2014 print issue with an accompanying editorial.
MedicalResearch.com Interview with:
Dr. Martin C. Tammemägi
Professor (Epidemiology), Brock University
Department of Health Sciences
St. Catharines, Ontario, Canada L2S 3A1
Medical Research: What is the background for this study? What are the main findings?
Dr. Tammemägi: Lung cancer is the leading cause of cancer death in North America and the world. Lung cancer survival following diagnosis is generally poor, in the range of 10% to 15%, and has improved little over the last four decades. The biggest recent breakthrough for reducing lung cancer mortality came with the findings of the National Lung Screening Trial (NLST), a large, well-conducted randomized screening trial, which demonstrated that low dose computed tomography (LDCT) screening versus chest X-ray (CXR) screening can reduce lung cancer mortality by 20%. Currently, most guidelines for selecting screenees for lung screening use the NLST enrolment criteria of 30 or more pack-years smoked, former smokers must have quit smoking within 15 years and ages between 55 and 74, or use a variant of the NLST criteria. The US Preventive Services Task Force (USPSTF) essentially recommends using the NLST criteria but extended the inclusion age to 80 years.
The current study applied the PLCOm2012 lung cancer risk prediction model1 to NLST data and identified that the risk above which lung cancer mortality is consistently lower in the LDCT arm compared to the CXR arm, is ≥1.51% 6-year risk (65th percentile). The USPSTF and the PLCOm2012 risk ≥0.0151 criteria were then applied to the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO) intervention arm smokers (the PLCOm2012 was developed in PLCO controls) to determine who would be selected for lung cancer screening. Compared to USPSTF criteria, the PLCOm2012 risk ≥0.0151 threshold selected 8.8% fewer individuals, but identified 12.4% more lung cancers (sensitivity 80.1% vs. 71.2%), and had fewer false positives (specificity 66.2% vs. 62.7%). 26% of smokers who were USPSTF criteria positive had risks below the PLCOm2012 risk ≥0.0151 threshold. Of PLCO former smokers who quit more than 15 years ago, 8.5% had PLCOm2012 risk ≥0.0151, suggesting that they might benefit from screening (2.9% of them developed lung cancer in 6 year). None of 65,711 never-smokers in the PLCO had PLCOm2012 risk ≥0.0151, indicating that never-smokers should not be screened. Individuals age ≥65–80 years had significantly higher risks and more lung cancers than those 55-64 years.
MedicalResearch.com Interview with:
Marie-Christine Aubry, M.D.
Professor of Laboratory Medicine and Pathology
Consultant, Department of Laboratory Medicine and Pathology,
Mayo Clinic in Rochester, Minn.
Medical Research: What is the background for this study? What are the main findings?
Dr. Aubry: Up to 20% of patients will present with multifocal lung cancer or will develop a second lung cancer. The main clinical issue is distinguishing between independent primaries from true intrapulmonary metastases since this distinction will drive the therapy of the patient. Currently no ancillary studies allows for this distinction and the distinction is provider specific based on a combination of clinical, radiologic and pathologic assumptions. Based on our prior research using a method called mate pair sequencing , we observed that the probability of detecting identical chromosomal breakpoints in two unrelated tumors, from 2 different patients was basically zero. Similarly, when assessing different components within a single tumor, we always found identical chromosomal breakpoints between these components. We thus hypothesized that if two tumors within a patient were related, i.e. true metastasis, we should always find a number of identical chromosomal breakpoints between the tumors. And in contrast, if 2 tumors were truly independent primaries, we should not observe any chromosomal breakpoints in common.
We first studied a control group of patients that had
1- a primary lung cancer with a known distant metastasis (usually brain metastasis),
2- two lung cancers of different histologic subtype, adenocarcinoma and squamous cell carcinoma which are accepted as true independent primaries and
3- 1 tumor with different portions of the tumor being analyzed individually and compared as true relatedness.
There were thus a total of 11 pairs of tumors with predetermined status of independent primaries versus relatedness (ie metastasis or same tumor). The mate pair generated data showed a perfect concordance with this status. We then studied 11 pairs of lung tumors of similar histology (2 adenocarcinomas or 2 squamous cell carcinomas). The current gold standard for the distinction between independent primaries and intrapulmonary metastasis relies on a pathologist’s comparative morphologic assessment. In order to strengthen this gold standard, 2 pulmonary pathologists independently made this assessment. Interestingly, the pathologists agreed on the status of independent primaries and intrapulmonary metastasis in 9 (of 11) cases demonstrating the shortcomings of this gold standard. Furthermore, there were discordance between the pathologists’ prediction and the clinicians’ assessment in 3 of the 11 patients and the clinician could not come to a final assessment in 1 patient. The MP data was concordant with the pathology assessment in 8 of these 9 cases, and supported the pathologists’ prediction in 2 (of the 3) discordance with the clinical assumptions.
MedicalResearch.com Interview with:
William C. Black, MD
Professor of Radiology
Department of Radiology
Dartmouth-Hitchcock Medical Center
Lebanon, NH 03756
Medical Research: What is the background for this study? What are the main findings?
Dr. Black: Lung cancer is the leading cause of cancer related death in the U.S., killing more people than cancers of the colon, breast, and prostate combined. In 2011, the National Lung Screening Trial (NLST) demonstrated that screening for lung cancer with low-dose CT could reduce lung cancer mortality by 20% in adults at high risk for the disease. Since then, several medical organizations have recommended that eligible adults be offered screening. The U.S. Preventive Services Task Force (USPSTF) released a grade B recommendation for low-dose CT screening in December 2012, which means that private insurers must cover the cost of screening by January 1, 2015. The Centers for Medicare and Medicaid (CMS) is expected to issue a final decision on national coverage for CT screening in February 2015 and a preliminary decision for public comment on November 10, 2014.
MedicalResearch.com Interview with:
Peter J. Mazzone, MD, FCCP MPH
Director of the Lung Cancer Program for the Respiratory Institute
Cleveland Clinic
Medical Research: What are the main findings of this study?
Dr. Mazzone: There were 2 parts to this study. In the first part we looked at how the breath collection instrument and sensor were performing and made adjustments to both in order to optimize its performance.
In the second part we used the improved device and sensor to see if we could accurately separate a sensor signal of our patients with lung cancer from those without lung cancer. We found good separation of lung cancer from non-cancer breath signals, and very good separation of signals of one type of lung cancer from another.
We have concluded that a colorimetric sensor array based breath test is capable of separating those with lung cancer from those without.
MedicalResearch.com Interview wth:
Prof. dr. B.J. Slotman
VU University Medical Center Cancer Center
Amsterdam Netherlands
Medical Research: What are the main findings of this study?
Prof. Slotman: This randomized trial showed that the use of thoracic radiotherapy in patients with extensive stage small cell lung cancer reduces the risk of intrathoracic progression by about 50% and improves 2 years survival from 3 to 13%.
MedicalResearch.com Interview with:
Prof. Nir Peled MD PhD FCCP
Pulmonologist & Medical Oncologist
Thoracic Cancer Unit, Davidoff Cancer Center, RMC, Kaplan St, Petach Tiqwa, Israel
International Lung Cancer Association; Committee Chair; Prevention, Screening & Early Detection of Lung Cancer, IASLC.
MedicalResearch: What are the main findings of this study?
Dr. Peled: The study focuses on early detection of lung cancer through the exhale breath NaNose which was developed by Prof Hossam Haick (Israel). The study included 358 patients who were diagnosed or at risk for lung cancer. The multisite enrollments included UC Denver (Dr Fred Hirsch), Tel Aviv University (Dr Nir Peled), Jacksonville (Dr Stuart Millstone, Dr Douglas Johnson) and Liverpool (Dr John Field).
The NaNose was able to detect lung cancer with a very high accuracy (~90%) even when the lung nodule was tiny and hard to sample. It was even able to discriminate between sub histologies of cancer, which was unexpected.
MedicalResearch.com Interview with:
Daniel I. Sessler, M.D.
Michael Cudahy Professor and Chair, Department of Outcomes Research
Cleveland Clinic, Cleveland, OH
MedicalResearch.com: What are the main findings of the study?
Dr. Sessler: Free fatty acids, arachidonic acid and linoleic acid, and their metabolites hydroxyeicosatetraenoic acids (5-HETE, 11-HETE, 12-HETE, and 15-HETE) were 1.8 to 5.7-fold greater in 37 patients with adenocarcinoma versus 111 patients without cancer (all P<0.001). Areas under the receiver operating characteristics (ROC) curve were significantly greater than 0.50 discriminating lung cancer patients and controls for all biomarkers and phospholipids, and ranged between 0.69 and 0.82 (all P<0.001) for lung cancer patients versus controls. Arachidonic acid, linoleic acid, and 15-HETE showed sensitivity and specificity >0.70 at the best cutpoint. Concentrations of free fatty acids and their metabolites were similar in 18 squamous-cell carcinoma patients and 54 non-cancer controls.
MedicalResearch.com Interview with:
Renda Soylemez Wiener, MD, MPH
Assistant Professor of Medicine
The Pulmonary Center
Boston University School of Medicine
Center for Healthcare Organization & Implementation Research
Edith Nourse Rogers Memorial VA Hospital
MedicalResearch.com: What are the main findings of the study?
Dr. Soylemez Wiener: The main finding is that evaluation of pulmonary nodules to determine whether or not they are cancerous is inconsistent with clinical practice guideline recommendations in almost half of cases, suggesting there is room for improvement in clinical care of these patients. Patients with pulmonary nodules are sometimes evaluated more aggressively than they should be (18%), which can cause harms to patients from unnecessary invasive tests (biopsies or surgery) or unneeded radiation exposure from imaging studies. Still more patients (27%) are followed less aggressively than they should be, which in the worst case scenario could lead to delays in the diagnosis and treatment of cancer. It is particularly important to improve care of these patients now, because new guidelines from the US Preventive Services Task Force recommend CT screening for lung cancer screening, which often finds pulmonary nodules that require evaluation.
MedicalResearch.com Interview with:
Dr. Heather Wakalee MD
Associate Professor of Medicine (Oncology)
Stanford University Medical Center
MedicalResearch.com: What are the main findings of the study?
Dr. Wakalee: CO-1686, with the new hydrobromide formulation, has been active at multiple dose levels (500, 750 or 1000 mg orally twice daily). The response rate in patients with EGFR mutant (non-small-cell Lung Cancer) NSCLC that has progressed after therapy with EGFR TKI, and has centrally confirmed T790M, is 64% per RECIST. The majority of responses are ongoing at the time of this report. The drug has been overall very well tolerated.
MedicalResearch.com Interview with:
Dr. Azi Gazdar, MD
UT Southwestern Medical Center
W. Ray Wallace Distinguished Chair in Molecular Oncology Research
Hamon Center for Therapeutic Oncology, Pathology
MedicalResearch.com: What are the main findings of the study?
Dr. Gazdar: We describe the characteristics of lung cancers arising in subjects who inherited a germline mutation that predisposes to lung cancer. The mutation is rare in the general populations, and is inherited equally by both sexes. However it is a potent predisposing gene, and one third of the never smoking carriers will develop lung cancer. Thus, about 1% of patients who develop lung cancer carry the germline mutation. This figure may rise as awareness of the condition and its link to lung cancer is raised among doctors diagnosing lung cancer. However, lung cancers mainly develop in women who are lifetime never smokers. Lung cancer development is much less common among smokers and men, although accurate figures are not yet available. So the risk among carriers is somewhat similar to the BRCA genes predisposing to breast cancer, where a female carrier has about a 50% lifetime chance of developing breast cancer.
The specific germline mutation (known as T790M) occurs in a gene known as epidermal growth factor receptor (EGFR) gene. Sporadic mutations in this gene usually predict for effective responses to a class of drugs known as tyrosine kinase inhibitors (TKIs), which are widely used in the treatment of lung cancer. However, the T790M mutation, when it occurs in sporadic tumors not associated with germline inheritance are resistant to TKI therapy. Thus the prediction is that lung cancers arising in carriers with the germline mutation would also be resistant to TKI therapy.
MedicalResearch.com Interview with:
Mariam El-Zein, PhD.
Associée de recherche/ Research associate
Unité d'épidémiologie et biostatistique / Epidemiology & Biostatistics Unit
INRS-Institut Armand-Frappier
Université du Québec
MedicalResearch.com: What are the main findings of the study?
Answer: The overall indication is that a prior history of allergic diseases (asthma, eczema or hay fever) might decrease lung cancer risk. There was a 36% (odds ratio= 0.64, 95% confidence intervals: 0.44-0.93) reduction in lung cancer risk among subjects who reported a history of asthma. Hay fever was associated with a 67% (odds ratio= 0.33, 95% confidence intervals: 0.19-0.59) reduction in lung cancer risk. Smoking was accounted for using a comprehensive smoking index that takes into account multiple dimensions of smoking behaviour (i.e., smoking status, intensity, duration, and time since cessation). A lower risk of lung cancer (reduction by 37%; odds ratio= 0.63, 95% confidence intervals: 0.38-1.07) was found among those having had eczema, but was not statistically significant.
MedicalResearch.com Interview with:
Harry J de Koning, MD PhD
Professor of Public Health & Screening Evaluation
Rotterdam, The Netherlands.
MedicalResearch.com: What are the main findings of the study?
Dr. de Koning: Annual CT screening for lung cancer has a favorable benefit-to-harm ratio for individuals ages 55 through 80 years with 30 or more pack-years’ exposure to smoking. It would lead to 50% (model ranges, 45% to 54) of cases of cancer being detected at an early stage (stage I/II), 575 screenings examinations per lung cancer death averted, a 14% (range, 8.2% to 23.5%) reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5250 life-years gained per the 100 000-member (1950-) cohort. Harms would include 67 550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7% of all cases of lung cancer [model ranges, 1.4% to 8.3%]), again for a 100 000-member (1950-) cohort.
MedicalResearch.com Interview with: Dr. Peter Mazzone MD, MPH Pulmonary, Allergy and Critical Care Medicine Cleveland Clinic Main Campus Cleveland, OH 44195 MedicalResearch.com: What are the main findings of this study? Dr. Mazzone: There were 2 parts to this study: In the first part we looked at how the breath collection instrument and sensor were performing and made...
Dr. Atul Butte, MD, PhD
and
Julien Sage PhD
Departments of Pediatrics and Genetics
Department of Internal Medicine, University of California Davis Cancer Center
University of California Davis School of Medicine
Sacramento, California
MedicalResearch.com: What are the main findings of the study?
Answer: A major finding of the study is the identification of first-generation anti-depressants as possible drugs effective against a lethal subtype of lung cancer, small cell lung cancer.
A second important aspect of this work is the use of a bioinformatics-based drug repositioning pipeline developed by the Butte lab, which allowed us, when combined with advanced mouse models of lung cancer developed by the Sage lab, to identify a novel targeted therapy against SCLC and initiate a clinical trial in less than 2 years.
MedicalResearch.com Interview with:
Sandra Ryeom, PhD,
Assistant professor of Cancer Biology,
Perelman School of Medicine, University of Pennsylvania
MedicalResearch.com: What are the main findings of the study?
Answer: We identified an important pathway (calcineurin-NFAT-Angiopoeitin2) in the vasculature of early metastatic lung lesions that is critical for promoting lung metastases.
MedicalResearch.com: Were any of the findings unexpected?
Answer: Since there is limited understanding of regulation of tumor angiogenesis at metastatic sites, identification of the calcineurin pathway and a newly identified target of calcineurin-NFAT signaling was all unexpected.
MedicalResearch.com Interview with: Prasad Adusumilli MD, FACS
Associate Member, Thoracic Surgery
Memorial Sloan-Kettering Cancer Center
New York
MedicalResearch.com: What are the main findings of the study?
Answer: The current standard of care of for early-stage lung adenocarcinoma, the common form of lung cancer is curative-intent surgery either by limited resection, LR (removal of tumor with clear margins) or lobectomy, LO (removal of one-third to one-half of the lung harboring the tumor). Although lung-sparing LR is preferable, there is a reported incidence of 30-40% of recurrences within the same lung. The causative factor/s for these local recurrences is not known.
In our study, we analyzed recurrence patterns and pathological features in patients who underwent 476 LO and 258 LR performed at the Memorial Sloan-Kettering Cancer Center, New York. We investigated the morphological patterns in pathology specimens utilizing the recently proposed International Association for the Study of Lung Cancer / European Respiratory Society / American Thoracic Society (IASLC/ERS/ATS) classification. We noticed that presence of micropapillary morphology was associated with three times higher recurrences in patients undergoing LR compared to LO, these recurrences were lower when there is an adequate margin (2 cm) resected beyond the tumor. In patients undergoing LO, the recurrences were 75% less.
MedicalResearch.com Interview with: Ole Raaschou-Nielsen, MSc, PhD
Head of Research Group for Work, Environment & Cancer
Danish Cancer Society Research Center
Strandboulevarden 49
2100 Copenhagen Ø
MedicalResearch.com: What are the main findings of the study?
Answer: The study shows that people who live at locations with higher levels of particles in the air are at higher risk for development of lung cancer.
It seems that there is no threshold for air pollution with particles below which there is no risk; the results show that it is more like “the more air pollution the worse and the less pollution the better”.
The strongest association was seen for adenocarcinoma of the lung.