Doctor Healthy: May 2015

Monday, May 25, 2015

NEW GENOMIC TEST INCREASES BRONCOSCOPY SENSITIVITY

A new genomic test may be able to improve the diagnostic performance of bronchoscopy and help avoid the need for more invasive procedures in patients with suspected lung cancer.

"This test can change clinical practice in pulmonary medicine," commented senior author Avrum Spira, MD, professor of medicine at Boston University School of Medicine, in Massachusetts, who is the coinventor of the test. "It allows physicians to confidently identify patients who are at low probability for having lung cancer following an indeterminate bronchoscopy result."

The Percepta Bronchial Genomic Classifier (Veracyte) is a bronchial-airway gene-expression classifier. Results of two large studies show that this genomic test can help pinpoint which patients with suspicious lung lesions may be able to safely avoid lung biopsies.

The results of both studies were presented at the American Thoracic Society 2015 International Conference, being held in Denver, Colorado, and were published concurrently online in the New England Journal of Medicine.

With the advent of the use of low-dose CT in the screening of patients at high risk for lung cancer, more suspicious lesions are being detected. The next step for these patients is a bronchoscopy. Following these two procedures, patients are then assessed as being at high, intermediate, or low risk for cancer. "The sweet spot for the test," Dr Spira told Medscape Medical News, "is the intermediate-risk group."

"While the test did well across all groups, the most difficult cases are where the physician is not sure what the next step is," he said.

Low-risk patients may just need to be followed closely and have repeat scans, whereas a biopsy would be indicated for high-risk patients. But for patients at intermediate risk, it is not as clear, Dr Spira explained. "And this is the group where the test had the biggest impact in clinical decision making. It had a negative predictive value of 91%, and these results provide an opportunity for patients to be monitored using CT scans instead of having to go undergo biopsy."

Accurate Diagnosis of Cancer

The test is a 23-gene molecular classifier that can detect molecular changes in the epithelial cells that line the respiratory tract. Cells are obtained from cytology brushings taken during bronchoscopy from the proximal airway.

Dr Spira and colleagues undertook the two studies to prospectively validate this classifier in patients undergoing bronchoscopy for suspected lung cancer and also to evaluate whether its use could change the diagnostic performance of bronchoscopy.

The cohort included current or former smokers who were undergoing bronchoscopy for suspected lung cancer at 28 different centers. A total of 639 patients in AEGIS-1 (298 patients) and AEGIS-2 (341 patients) met the criteria for inclusion. A genomic analysis was conducted in epithelial cells that were collected from the normal-appearing mainstem bronchus to assess the probability of lung cancer.

In AEGIS-1, the classifier accurately identified 194 of 220 patients with cancer (sensitivity, 88%; 95% confidence interval [CI], 83 to 92) and 37 of 78 patients without cancer (specificity, 47%; 95% CI, 37 to 58).

For the AEGIS-2 study, results were similar. The classifier correctly identified 237 of 267 patients with cancer (sensitivity, 89%; 95% CI, 84 to 92) and 35 of 74 patients without the disease.

In patients with a nondiagnostic bronchoscopic examination, the classifier accurately identified cancer in 49 of 57 patients in AEGIS-1 (sensitivity, 86%; 95% CI, 74 to 94) and in 58 of 63 patients in AEGIS-2 (sensitivity, 92%; 95% CI, 82 to 97).

False Negatives

Although the classifier achieved a high negative predictive value in patients with a nondiagnostic bronchoscopic examination, the authors note that 13 patients in this group had a false negative result. Although they had lung cancer, they had a negative classifier score. The majority of them (10 of 13) had a high (>60%) probability of cancer; three patients had an intermediate (10% to 60%) pretest probability of cancer.

There are going to be some false negatives, Dr Spira pointed out. "But the patients are followed and will have repeat scans."

The test is already on the market, but the initial release was limited to only about 30 centers through an early access program, he said. "It was a soft launch, and will soon be more readily available."

It can be performed in any facility in which bronchoscopies are performed. Samples are sent to a central laboratory to be analyzed.

The study is funded by Allegro Diagnostics and by grants from the National Institutes of Health, the Department of Defense, and the National Cancer Institute. Dr Spira is a coinventor of the genomic test; several of the authors have listed potential conflicts of interest, including relationships with Allegro.

STUDY FINDS LINK BETWEEN TESTICULAR CANCER AND GYM SUPPLEMENTS

Men who reported taking muscle-building supplements, such as pills and powders with creatine or androstenedione, reported a significantly higher likelihood of having developed testicular cancer than men who did not use such supplements, according to a study by Li et al in the British Journal of Cancer.

Moreover, said study senior author Tongzhang Zheng, DSc, the associated testicular germ cell cancer risk was especially high among men who started using supplements before age 25, those who used multiple supplements, and those who used them for years.

“The observed relationship was strong,” said Dr. Zheng, who led the study at Yale University School of Public Health, before joining the Brown University School of Public Health as Professor of Epidemiology. “If you used [supplements] at [an] earlier age, you had a higher risk. If you used them longer, you had a higher risk. If you used multiple types, you had a higher risk.”

Increasing Incidence of Testicular Cancer

Testicular cancer incidence rose to 5.9 cases per 100,000 men in 2011, from 3.7 cases in 100,000 in 1975, Dr. Zheng said. Researchers aren't sure why.

“Testicular cancer is a very mysterious cancer,” he said. “None of the factors we've suspected can explain the increase.”

The study is the first analytical epidemiologic study of the possible link between supplements and testicular cancer. Research was inspired by mounting evidence that at least some supplement ingredients may damage the testes.

“Our study found that supplement use was related to a higher risk of developing testicular cancer. These results are important, because there are few identified modifiable risk factors for testicular cancer,” said Russ Hauser, MD, MPH, ScD, Professor of Environmental Health Science at Harvard T.H. Chan School of Public Health.

Study Finds Significant Risk

Dr. Zheng's research team conducted detailed interviews of nearly 900 men from Massachusetts and Connecticut—356 of whom had been diagnosed with testicular germ cell cancer, and 513 who had not. In the interviews, researchers asked the men not only about their supplement use, but also about a wide variety of other possible factors, such as smoking, drinking, exercise habits, family history of testicular cancer, and prior injury to the testes or groin.

After tallying their data and accounting for all possible confounders, as well as age, race, and other demographics, the researchers found that men who used supplements had a 1.65 odds ratio (a 65% greater risk) of having developed testicular cancer compared to the men who did not use supplements.

The researchers defined “use” as consuming one or more supplements at least once a week for four consecutive weeks or more.

The odds ratios increased to 2.77 (a 177% greater risk) among men who used more than one kind of supplement, and to 2.56 among men who used supplements for 3 years or longer. Men who started using supplements at age 25 or younger also had an elevated associated odds ratio of 2.21, the researchers calculated.

“Considering the magnitude of the association and the observed dose-response trends, muscle-building supplement use may be an important and modifiable exposure that could have important scientific and clinical importance for preventing testicular germ cell cancer development, if this association is confirmed by future studies,” the study authors concluded.

Future large epidemiologic studies and laboratory experiments would be necessary to establish a causal link between supplements and testicular cancer.

Dr. Zheng is the corresponding author for the British Journal of Cancer article.

The study was supported by the National Institutes of Health, the National Natural Science Foundation of China, The Beijing Natural Science Foundation, and the Beijing Nova Program.

STATINS INCREASE DIABETES RISK

Statin therapy appears to increase the risk for type 2 diabetes by 46%, even after adjustment for confounding factors, a large new population-based study concludes.

This suggests a higher risk for diabetes with statins in the general population than has previously been reported, which has been in the region of a 10% to 22% increased risk, report the researchers, led by Henna Cederberg, MD, PhD, from the University of Eastern Finland and Kuopio University Hospital, and colleagues, who published their study online March 4 in Diabetologia.

The majority of people in this new study were taking atorvastatin and simvastatin, and the risk for diabetes was dose-dependent for these two agents, the researchers found.

Nevertheless, senior author Markku Laakso, MD, from the University of Eastern Finland and Kuopio University Hospital, told Medscape Medical News: "Even if statin treatment is increasing the risk of getting diabetes, statins are very effective in reducing cardiovascular risk.

"Therefore I wouldn't make a conclusion from my study that people should stop statin treatment, especially those patients who have a history of myocardial infarction or so on.

"But what I would say is that people who are at the higher risk, if they are obese, if they have diabetes in the family, etc, should try to lower their statin dose, if possible, because high-dose statin treatment increases the risk vs lower-dose statin treatment," he continued.

Asked to comment, Alvin C Powers, MD, from Vanderbilt University School of Medicine, Nashville, Tennessee, explained that there were limitations to the conclusions that could be drawn from this study.

Speaking as part of the Endocrine Society, he said: "The first thing is that this study did not examine the benefits of statin therapy, it examined only the risk of diabetes."

With every treatment, there are risks and benefits, and the benefits of statins have been clearly proven in certain situations. In those instances, "the benefit would outweigh the increased risk of diabetes for many people," Dr Powers told Medscape Medical News.

Statins Appear to Affect Insulin Secretion and Sensitivity

Dr Cederberg and colleagues explain that previous studies have suggested an increased risk of developing diabetes, of varying levels, associated with statin use. However, in many of these, study populations have been selective, especially in statin trials, which have included participants at high risk for cardiovascular disease.

Hence, the risk for diabetes in clinical trials is likely to differ from that in the general population. And very often, in previous studies the diagnosis of diabetes has been based on self-reported diabetes or fasting glucose measurement, leading to an underestimation of the actual numbers of incident diabetes cases.

In this new study, the authors investigated the effects of statin treatment on blood glucose control and the risk for type 2 diabetes in 8749 nondiabetic men age 45 to 73 years in a 6-year follow-up of the population-based Metabolic Syndrome in Men (METSIM) trial, based in Kuopio, Finland.

The authors also investigated the mechanisms of statin-induced diabetes by evaluating changes in insulin resistance and insulin secretion.

Diabetes was diagnosed via an oral glucose tolerance test (OGTT), HbA1c levels ≥ 6.5% (48 mmol/mol) or by having started glucose-lowering medication. During the follow-up, 625 of the participants were diagnosed with diabetes. OGTT-derived indices were used to assess insulin sensitivity and secretion.

Statins were taken by 2412 individuals. The drugs were associated with an increased risk for type 2 diabetes even after adjustment for age, body mass index, waist circumference, physical activity, smoking, alcohol intake, family history of diabetes, and beta-blocker and diuretic treatment, at a hazard ratio (HR) of 1.46.

The risk was found to be dose-dependent for simvastatin and atorvastatin, which were taken by 388 and 1409 participants, respectively. High-dose simvastatin was associated with a hazard ratio (HR) of 1.44 for diabetes vs 1.28 for low-dose therapy, while the HR for diabetes with high-dose atorvastatin was 1.37.

Statin therapy was also associated with a significant increase in 2-hour glucose (P = .001) and the glucose area under the curve at follow-up ( P < .001), as well as a nominally significant increase in fasting plasma glucose (P = .037).

Furthermore, individuals taking statins had a 24% decrease in insulin sensitivity and a 12% reduction in insulin secretion compared with those not receiving the drugs. These increases were again dose-dependent for atorvastatin and simvastatin.

Although pravastatin, fluvastatin, and lovastatin were found to be less diabetogenic than atorvastatin and simvastatin, the number of participants taking these agents was too small to reliably estimate their individual effects on the risk for diabetes, the research team notes.

Which Patients Should Take Statins?

Discussing the take-home message for prescribers seeking to balance the risk for diabetes with the benefits of statin therapy, Dr Laasko reiterated that individuals with a history of cardiovascular events and high LDL cholesterol "should definitely take statins."

However, he emphasized that the main aim of statins is to prevent a recurrent cardiovascular event, so individuals need to have had one event to start statin therapy.

"But in primary prevention, especially in women, who are at a lower risk of getting cardiovascular disease, maybe we should be more careful when we start statin treatment?" he ventured. "Statins are not meant to be a treatment for everybody."

Dr Powers observed that this new study doesn't provide any information about whether people who have diabetes who are on a statin should continue with the statin, "but there are clear benefits for statin therapy in people who have diabetes.

"People who have diabetes who are on a statin should continue with the statin.…This increased risk of diabetes, to me, is not relevant to their reason for taking the statin," he commented.

And in diabetes patients who have heart disease and are taking a statin, "the risk/benefit ratio would clearly be in the direction of benefit," Dr Powers observed.

In individuals who do not have diabetes and who are taking a statin, for example to reduce their risk for cardiovascular disease, "statin therapy has to be considered in the context of what's the benefit of the statin therapy in that group…especially in individuals who are genetically susceptible to type 2 diabetes or who have prediabetes," he continued.

"Those individuals will need to be monitored for the development of diabetes."

"People who are taking statins should keep taking statins, if there's an appropriate reason for them taking a statin. The risk/benefit ratio in most people is in favor of benefit; the risk is outweighed by that benefit," he concluded.

This work has been supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and a grant from Kuopio University Hospital. The authors have reported no relevant financial relationships.

NEW GENOMIC TEST INCREASES BRONCOSCOPY SENSITIVITY

A new genomic test may be able to improve the diagnostic performance of bronchoscopy and help avoid the need for more invasive procedures in patients with suspected lung cancer.

"While the test did well across all groups, the most difficult cases are where the physician is not sure what the next step is," he said.

Accurate Diagnosis of Cancer

For the AEGIS-2 study, results were similar. The classifier correctly identified 237 of 267 patients with cancer (sensitivity, 89%; 95% CI, 84 to 92) and 35 of 74 patients without the disease.

False Negatives

There are going to be some false negatives, Dr Spira pointed out. "But the patients are followed and will have repeat scans."

It can be performed in any facility in which bronchoscopies are performed. Samples are sent to a central laboratory to be analyzed.

CARDIAC MONITORING DURING TRASTUZUMAB TREATMENT

Breast cancer patients on adjuvant trastuzumab need cardiac monitoring, but most don't get it, new research suggests.

"We suspected that the rates of cardiac monitoring were going to be low, but we were surprised at how low the rates were, particularly in this high-risk group of patients. Of particular concern was that, even among patients with cardiac comorbidities, the rates of cardiac monitoring were not higher," lead author Dr. Mariana Chavez-MacGregor, assistant professor of Cancer Prevention at the University of Texas MD Anderson Cancer Center in Houston, told Reuters Health by email.

Physician characteristics may have greater influence than patient factors on the adequacy of cardiac monitoring, the authors wrote online May 11 in the Journal of Clinical Oncology.

Dr. Chavez-MacGregor and colleagues extracted Medicare-linked data from the Surveillance, Epidemiology, and End Results (SEER) database and the Texas Cancer Registry (TCR) to examine the patterns and adequacy of cardiac monitoring and to evaluate factors associated with adequate monitoring.

According to the authors, "Cardiac monitoring with echocardiogram or radionuclide ventriculography (multiple-gated acquisition scans) is part of the standard of care among patients receiving trastuzumab-based chemotherapy. The National Comprehensive Cancer Network guidelines recommend cardiac monitoring at baseline and at 3, 6, and 9 months after initiating trastuzumab therapy."

They identified 2,203 patients age 66 or older, with a median age of 72, who had full Medicare coverage and had been diagnosed with stage I to III breast cancer between 2005 and 2009 and treated with trastuzumab.

Only 793 (36.0%) of the patients were adequately monitored.

Patients who received optimal cardiac monitoring were more likely to have a more recent year of diagnosis (hazard ratio 1.83), a physician graduating after 1990 (HR, 1.66), a female prescribing physician (HR 1.37), and anthracycline use (HR 1.39).

Patients with cardiac comorbidities were not more likely to receive adequate cardiac monitoring.

Overall, 15.3% of the variance in the adequacy of cardiac monitoring was attributable to physician factors and 5.2% to patient factors.

"I think that our findings can create awareness among oncologists and hopefully impact the practice of oncologists by improving the rates of cardiac monitoring," Dr. Chavez-MacGregor wrote in an email.

Dr. Tracey O'Connor, associate professor of oncology at Roswell Park Cancer Institute in Buffalo, New York, told Reuters Health by email, "At 36%, the rates of optimal cardiac monitoring in this interesting study were surprisingly low, given the ready availability of guidelines to shape medical practice, and the knowledge that older patients are particularly likely to develop cardiac toxicity, making monitoring critical."

"Cardiac monitoring is especially important in elderly patients, who have more preceding cardiac history and are at higher risk for developing cardiac problems from trastuzumab," advised Dr. O'Connor, who was not involved in the study.

Dr. Susmita Parashar, director of the Winship at Emory Cardio-Oncology Program of Emory University in Atlanta, Georgia, said by phone, "These findings that only about one-third of these patients received adequate monitoring are alarming. It is disappointing that the quality of care is so low, but it does not surprise me because in a similar study, we found that only about one-third of lymphoma patients had adequate cardiac monitoring."

"Breast cancer patients taking trastuzumab may have decreased ejection fraction. If we don't follow up with these patients, they may have heart failure," cautioned Dr. Parashar, who was not involved in the study.

"Early detection and monitoring can prevent further progression. It's very important to monitor these patients so we can detect early subclinical heart disease and prevent heart failure," she added.

The authors acknowledged that they were limited by the retrospective nature of the data and the characteristics inherent in claims-based research.

Dr. Chavez-MacGregor called for further research "to determine what is the optimal/needed time interval to perform tests and whether any other tests (echocardiogram with strain for example) might be better to detect early cardiac dysfunction.

Dr. Chavez-MacGregor has received financial support from Roche, the parent company of Genentech, the maker of Herceptin (trastuzumab).