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Tuesday, May 23, 2017

A new study shows that so-called “light” cigarettes have no health benefits to smokers and have likely contributed to the rise of a certain form of lung cancer that occurs deep in the lungs.

For this new study, researchers at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James) and five other universities/cancer centers examined why the most common type of lung cancer, called adenocarcinoma, has increased over the past 50 years, rather than decreasing as smokers have been able to quit. Other types of lung cancer have been decreasing in relationship to fewer people smoking, but not lung adenocarcinoma. Because of this, lung adenocarcinoma is now the most common type of lung cancer.

 

Results confirm what tobacco-control researchers have suspected for years: There is no health benefit to high-ventilation (light) cigarettes–long marketed by the tobacco industry as a “healthier” option–and these cigarettes have actually caused more harm. Holes in cigarette filters were introduced 50 years ago and were critical to claims for low-tar cigarettes.

 

“This was done to fool smokers and the public health community into thinking that they actually were safer,” said Peter Shields, MD, Deputy Director of the OSUCCC–James and a lung medical oncologist. “Our data suggests a clear relationship between the addition of ventilation holes to cigarettes and increasing rates of lung adenocarcinoma seen over the past 20 years. What is especially concerning is that these holes are still added to virtually all cigarettes that are smoked today.”

 

The FDA was given the authority to regulate the manufacture, distribution, and marketing of tobacco products through the Family Smoking Prevention and Tobacco Control Act in 2009. Current regulations ban tobacco companies from labeling and marketing cigarettes as “low tar” or "light." Study authors, however, say that given this new data, the FDA should take immediate action to regulate the use of the ventilation holes, up to and including a complete ban of the holes.

 

“The FDA has a public health obligation to take immediate regulatory action to eliminate the use of ventilation holes on cigarettes,” added Shields. “It is a somewhat complicated process to enact such regulations, but there is more than enough data to start the process. We believe that such an action would drive down the use and toxicity of conventional cigarettes, and drive smokers to either quit or use less harmful products. There are some open questions about unintended consequences for enacting a ban, which provides for an important research agenda.”

 

A team made up of lung oncology, public health, and tobacco regulation researchers conducted a comprehensive, multi-faceted analysis of existing literature that included chemistry and toxicology studies, human clinical trials and epidemiological studies of both smoking behavior and cancer risk. They studied scientific publications in the peer-reviewed literature and internal tobacco company documents.

 

Researchers hypothesized that the higher incidence rates of lung adenocarcinoma were attributable to the filter ventilation holes, which allow smokers to inhale more smoke that also has higher levels of carcinogens, mutagens and other toxins.

 

“The filter ventilation holes change how the tobacco is burned, producing more carcinogens, which then also allows the smoke to reach the deeper parts of the lung where adenocarcinomas more frequently occur,” explained Shields.

 

To date, all the scientific evidence involves the adverse impact of adding ventilation, but not removing it. Additional research is needed to confirm that the addictiveness of the cigarette or toxic exposures from cigarettes would not increase with elimination of the ventilation holes. The OSUCCC–James and researchers at the University of Minnesota, Roswell Park Cancer Institute, Virginia Tech, Harvard University and Medical University of South Carolina are conducting additional research to reconcile human biomarkers studies and smoke distribution/exposure in the lung.


Tuesday, May 23, 2017

Cells are constantly turning proteins on and off via molecular switches—phosphate molecules—that have become common drug targets.

"All the drugs we currently have to treat our cancer patients target what we call kinases, which attach phosphate molecules to proteins. But equally important to this are the enzymes that take the phosphate off," said Goutham Narla, MD, PhD, Pardee-Gerstacker Professor in Cancer Research, Associate Professor at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Center in Cleveland, Ohio.

One enzyme—PP2A—can "turn off" tumor proteins by removing phosphate molecules attached to them. But according to Narla, "This tumor suppressor is turned off in pretty much every major cancer. Its inactivation is essential for a normal cell to become a cancer cell."

"There are some 2,000 plus papers on the role of PP2A in cancer. Breast cancer, prostate cancer, lung cancer, brain cancer, childhood cancers, ovarian cancer, endometrial cancer, every major cancer involves the inactivation of this protein," he continued. "Molecules that allow us to turn it back on, like the one in our study, have the potential to work in a broad range of cancer patients."

Narla and his team decided to take an unconventional approach to cancer drug development by seeking molecules that directly target PP2A, in an effort to reactivate its tumor suppressor properties (J Clin Invest 2017; doi:10.1172/JCI89548).​

Study Methodology, Results

Forty-five researchers, including eight students from the Young Scientist Foundation and Mark R. Chance, PhD, Vice Dean for Research at Case Western Reserve School of Medicine, collaborated to screen a series of drug-like molecules for their ability to reactivate PP2A in lung cancer cells and prevent lung cancer tumors in mice. The prototype drug molecules were created from FDA-approved medications by Michael Ohlmeyer, PhD, Associate Professor at Icahn School of Medicine at Mount Sinai, New York City.

The team found one particular prototype drug can attach to a subunit of the PP2A protein, effectively activating the enzyme. As Narla explained, the study is the first to use a small molecule to directly activate an enzyme that removes phosphate molecules. "There are indirect ways that have been shown to get at these kinds of enzymes, but this is the first example of a direct activation of one. Our drug actually binds to and turns on PP2A."

The prototype drug also prevented lung cancer cells from proliferating in laboratory models, including mouse models. Mice injected with the drug had fewer lung cancer tumors and did not experience weight loss or behavioral abnormalities associated with other cancer medications. In the mouse models, the drug was comparably effective to currently available combination therapies used to slow lung cancer progression.

To confirm exactly where the drug attaches to PP2A, the researchers also developed lung cancer cells with specific mutations at the putative drug binding site. Mice with tumors created from the mutated cancer cells did not benefit from the prototype drug, as the drug could not attach to and reactivate PP2A. The results confirmed the prototype drug attaches to PP2A at two specific amino acids within a subunit of the enzyme, information that could help inform other drug developers.

"This is the first example ever of a cancer drug that directly binds to and activates an enzyme that removes phosphate molecules. Therefore, our findings could have broad applicability to the treatment of a large number of human cancers, including lung cancer as we demonstrated in this paper," Narla said.

"We are continuing to test our drug in a large series of animal models. If things continue to go well, we hope to start clinical trials next year with this drug. Our initial clinical trials would be quite broad and would include a number of diverse cancer patients, including patients with lung cancer," he concluded.


Tuesday, May 23, 2017

Lung adenocarcinoma, which accounts for about 40 percent of U.S. lung cancer cases, is believed to arise from benign tumors known as adenomas.

MIT biologists have now identified a major switch that occurs as adenomas transition to adenocarcinomas in a mouse model of lung cancer. They've also discovered that blocking this switch prevents the tumors from becoming more aggressive. Drugs that interfere with this switch may thus be useful in treating early-stage lung cancers, according to researchers (Nature 2017; doi:10.1038/nature22334).

"Understanding the molecular pathways that get activated as a tumor transitions from a benign state to a malignant one has important implications for treatment. These findings also suggest methods to prevent or interfere with the onset of advanced disease," said Tyler Jacks, PhD, Director of MIT's Koch Institute for Integrative Cancer Research, Cambridge, Mass., and the study's senior author.

The switch occurs when a small percentage of cells in the tumor begin acting like stem cells, allowing them to give rise to unlimited populations of new cancer cells.

"It seems that the stem cells are the engine of tumor growth. They're endowed with very robust proliferative potential, and they give rise to other cancer cells and also to more stem-like cells," said Tuomas Tammela, MD, PhD, a postdoc at the Koch Institute and lead author of the paper.

In this study, the researchers focused on the role of the cell signaling pathway, Wnt. This pathway is usually turned on only during embryonic development, but it is also active in small populations of adult stem cells that can regenerate specific tissues such as the lining of the intestine.

One of the Wnt pathway's major roles is maintaining cells in a stem-cell-like state, so the MIT team suspected that Wnt might be involved in the rapid proliferation that occurs when early-stage tumors become adenocarcinomas.

The researchers explored this question in mice that are genetically programmed to develop lung adenomas that usually progress to adenocarcinoma. In these mice, they found that Wnt signaling is not active in adenomas, but during the transition, about 5-10 percent of the tumor cells turn on the Wnt pathway. These cells then act as an endless pool of new cancer cells.

In addition, about 30-40 percent of the tumor cells begin to produce chemical signals that create a "niche," a local environment that is necessary to maintain cells in a stem-cell-like state.

"If you take a stem cell out of that microenvironment, it rapidly loses its properties of stem-ness," Tammela said. "You have one cell type that forms the niche, and then you have another cell type that's receiving the niche cues and behaves like a stem cell."

While Wnt has been found to drive tumor formation in some other cancers, including colon cancer, this study points to a new kind of role for it in lung cancer and possibly other cancers such as pancreatic cancer.

"What's new about this finding is that the pathway is not a driver, but it modifies the characteristics of the cancer cells. It qualitatively changes the way cancer cells behave," Tammela explained.

When the researchers gave the mice a drug that interferes with Wnt proteins, they found the tumors stopped growing and the mice lived 50 percent longer. Furthermore, when these treated tumor cells were implanted into another animal, they failed to generate new tumors.

The researchers also analyzed human lung adenocarcinoma samples and found that 70 percent of the tumors showed Wnt activation and 80 percent had niche cells that stimulate Wnt activity. These findings suggest it could be worthwhile to test Wnt inhibitors in early-stage lung cancer patients, the researchers noted.

They are also working on ways to deliver Wnt inhibitors in a more targeted fashion to avoid some of the side effects caused by the drugs. Another possible way to avoid side effects may be to develop more specific inhibitors that target only the Wnt proteins that are active in lung adenocarcinomas. The Wnt inhibitor that the researchers used in this study, which is now in clinical trials to treat other types of cancer, targets all 19 of the Wnt proteins. ​


Tuesday, May 23, 2017

Lung cancer screening using a low-dose CT scan can be a lifesaving test for high-risk patients. While it offers clear benefits, incidental findings and radiation exposure mean there are some potential risks associated with yearly screening. Most patients do not fully understand the benefits or potential harms of a screening program, nor are they clear on exactly who should undergo testing.

A new study in CHEST determined that a structured prescreening counseling and shared decision-making visit with health care professionals leads to a better understanding of the benefits and risks, as well as the eligibility criteria (2017; doi:10.1016/j.chest.2016.10.027).

Lung cancer screening is recommended for anyone over the age of 55 who has smoked for more than the equivalent of 30 pack-years. Pack-years are calculated by multiplying the packs per day smoked by the number of years someone has been a smoker. Current evidence suggests the benefits of lung cancer screening for this population outweigh the risks, but practitioners also recognize there is a balance, and much of the success of screening programs is tied to their implementation.

"Screening presents a unique challenge to this balance as a minority of patients screened will experience the benefit while all have the potential to be harmed," explained lead investigator Peter J. Mazzone, MD, MPH, FCCP, Director of the Lung Cancer Program for the Respiratory Institute and the Lung Cancer Screening Program, Cleveland Clinic. "All patients are presumably healthy at the time of screening. In addition, the fulcrum of this balance shifts based on how an individual patient values each side of the balance."

During this study, investigators designed a program that involved a counseling and shared decision-making visit for patients prior to starting lung cancer screening. These visits were divided into different educational components focusing on eligibility requirements, the benefits and harms of lung cancer screening, and the personalized benefit and risk for each participant. Patients were encouraged to ask questions during sessions.

After analyzing pre- and post-visit surveys, investigators found participants initially had a very modest understanding of the eligibility criteria, benefits, and harms of screening. After viewing educational materials and participating in the shared decision-making process with the practitioner, follow-up surveys showed patients had a better grasp on the nuances of screening.

"We found a generally poor level of understanding of the eligibility criteria, benefits, and harms of screening upon entry into the program," stated Mazzone. "This understanding improved substantially after the visit at the time of the decision about whether or not to proceed with screening. Patients generally felt the messages were delivered at an appropriate level and felt more comfortable about their decision after the visit."

The study showed that people started with a better understanding of the benefits of lung cancer screening than the harms or eligibility criteria. Researchers theorize this is because health care providers are more comfortable discussing the benefits of screening than trying to convey the complexities of potential harm. Patients with a lower level of education were also less likely to understand the concepts pre- and post-visit but did show benefit from the counseling sessions, leading investigators to recommend exploring strategies to enhance the teaching tools used for people with the lowest education levels.

Medicare and Medicaid already require a counseling and shared decision-making visit before lung cancer screening, but the impact and effectiveness of these sessions are not fully understood. "This is the first study to show that this visit can improve a patient's understanding of lung cancer screening, allowing them to make a decision about participation that fits their values," noted Mazzone. "The Centers for Medicare and Medicaid Services' (CMS) mandate for a counseling and shared decision-making visit has been present for just the past 2 years. As programs are being developed, it is important that they understand the value of this visit. Also, since CMS pays for this visit, it is important to prove that there is value."

The findings demonstrated that knowledge gained during the visit wanes over time, suggesting additional value to a shared decision-making visit prior to each annual screen. "This would also provide an opportunity to reconfirm eligibility, deliver additional smoking cessation counseling when needed, and build a stronger patient/provider relationship. Information about personalized risk has been shown to help patients make more informed choices about participation in screening for other cancers. This portion of our visit may have contributed to the increased level of comfort with the decision to pursue lung cancer screening expressed by our patients," concluded Mazzone.​


Thursday, May 18, 2017

A new study shows that the number of women in the U.S. living with distant metastatic breast cancer (MBC) is growing. This is likely due to the aging of the U.S. population and improvements in treatment. Researchers came to this finding by estimating the number of U.S. women living with MBC including women who were initially diagnosed with metastatic disease, and those who developed MBC after an initial diagnosis at an earlier stage.

The researchers also found that median and 5-year relative survival for women initially diagnosed with MBC is improving, especially among younger women.

 

The study was led by Angela Mariotto, PhD, Chief of the Data Analytics Branch of the Division of Cancer Control and Population Sciences at the NCI, with coauthors from NCI, the Metastatic Breast Cancer Alliance, and the Fred Hutchinson Cancer Research Center (Cancer Epidemiology Biomarkers Prev 2017; DOI:10.1158/1055-9965.EPI-16-0889).

 

In documenting the prevalence of MBC, the findings point to the need for more research into how to address the health care needs of women who live with this condition. "Even though this group of patients with MBC is increasing in size, our findings are favorable," said Mariotto. "This is because, over time, these women are living longer with MBC. Longer survival with MBC means increased needs for services and research. Our study helps to document this need."

 

Although researchers have been able to estimate the number of women initially diagnosed with MBC, data on the number of women whose cancers spread to a distant organ site, either as a progression or a recurrence after being first diagnosed with an earlier stage of breast cancer, has been lacking because U.S. registries do not routinely collect or report data on recurrence. To develop a more accurate estimate of the total number of women living with MBC, researchers used data from NCI's Surveillance, Epidemiology, and End Results (SEER) Program to include women who developed MBC after diagnosis. The researchers estimated that, as of Jan. 1, 2017, more than 150,000 women in this country were living with MBC, and that three in four of them had initially been diagnosed with an earlier stage of breast cancer.

 

The study also shows that, despite the poor prognosis of MBC, survival of women initially diagnosed with MBC has been increasing, especially among women diagnosed at younger ages. The researchers estimated that between 1992-1994 and 2005-2012, 5-year relative survival among women initially diagnosed with MBC at ages 15-49 years doubled from 18 percent to 36 percent. Median relative survival time between 1992-1994 and 2005-2012 increased from 22.3 months to 38.7 months for women diagnosed between ages 15-49, and from 19.1 months to 29.7 months for women diagnosed between ages 50-64. The researchers also reported that a small but meaningful number of women live many years after an initial diagnosis of MBC. More than 11 percent of women diagnosed between 2000-2004 under the age of 64 survived 10 years or more.

 

Based on their calculations, the researchers estimated that the number of women living with MBC increased by 4 percent from 1990 to 2000 and by 17 percent from 2000 to 2010, and they project the number will increase by 31 percent from 2010 to 2020. Although the largest group of women with MBC consists of women who have been living with metastatic disease for 2 years or less (40 percent), one-third (34 percent) of women with MBC have lived for 5 years or more with the disease.

To estimate the number of U.S. women living with MBC, the researchers applied a back-calculation method to breast cancer mortality and survival data from the SEER Program. The method they used assumes a breast cancer death is preceded by MBC that was either found at diagnosis or after a recurrence with metastatic disease.

 

Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations. To help implement the comprehensive and accurate collection of these data, NCI is funding pilot studies aimed at identifying ways to leverage existing data and informatics methods to efficiently capture information on recurrent disease.

 

By including women with recurrence, this study provides a more accurate number of women in the U.S. currently living with MBC. This estimation can help with health care planning and the ultimate goal of better serving these women.

 

"These findings make clear that the majority of MBC patients, those who are diagnosed with non-metastatic cancer but progress to distant disease, have never been properly documented," said Mariotto. "This study emphasizes the importance of collecting data on recurrence at the individual level in order to foster more research into the prevention of recurrence and the specific needs of this growing population."