Posts Tagged ‘francisco’

Breast radiation trial provides more convenience, better compliance, lowered cost and patient outcomes on par with current treatment

These interim results of the 5-year Phase II clinical trial using the experimental regimen are being presented at the Breast Cancer Symposium 2014 in San Francisco by Anthony E. Dragun, M.D., vice chair and associate professor of radiation oncology at the University of Louisville.

Dragun, a radiation oncologist with University of Louisville Physicians, launched the trial three years ago at UofL’s James Graham Brown Cancer Center, a part of KentuckyOne Health and the only site offering the experimental regimen in the United States. A second KentuckyOne Health site is being planned, he said, and is expected to begin enrolling patients this autumn.

Reviewing data from Europe — the United Kingdom in particular — Dragun found an alternative to the currently standard daily radiation treatments prescribed to patients after a lumpectomy. Physicians in the U.K. and other European countries were reporting excellent results with a regimen of radiation administered once-weekly.

“Instead of daily treatments for 25-30 days, five to six treatments administered once each week were being used,” he said. “I thought this regimen would give our patients here in Kentucky a great deal of access and choice, so we developed the trial and launched it in 2011.”

Approximately 150 female patients have been enrolled in the trial thus far, he said. Patients undergoing a lumpectomy following diagnosis of breast cancer are given a choice of the current standard of daily radiation treatments or the option to enroll in the trial and receive treatment one time per week.

The radiation dosing has been calibrated to compensate for the change in how the treatments are administered, but no adverse effects have been seen, Dragun said. “The outcomes with once-weekly treatments are absolutely in line with what we see in daily breast irradiation,” he said. “The standard of care is maintained.”

Giving women the choice of how their treatment is administered means more women complete their treatment, he said. “Finding time for daily treatments for 6 weeks or more just isn’t possible for many women,” Dragun said. “Scheduling once-weekly treatments is much easier to fit into the busy lives our patients lead.

“We also see many patients who depend on public transportation or live in rural areas that are 30 miles or more from our center, and they have told us that they would not have been able to complete a traditional course of daily radiation treatment. Their only alternative would be a mastectomy,” he said.

Because radiation treatment is reimbursed on a per-treatment basis, Dragun said the overall cost is lowered. “We have reduced the number of treatments to about one-fourth to one-third of what the current daily treatment regimen is,” he said. “Medicare reimburses radiation costs on a per-treatment basis, and most private insurers do likewise.

“This means we’ve been able to reduce the cost by 50 to 60 percent without jeopardizing the quality of care.”

Dragun plans to enroll another 50 patients at the Louisville site and 30 at the future trial site. After the completion of this trial, he intends to expand into a multi-center Phase III trial at facilities in other states.

“We believe the once-weekly regimen such as this will become a standard option in the next decade,” he said.

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Powerful new system for classifying tumors revealed

“It’s only ten percent that were classified differently, but it matters a lot if you’re one of those patients,” said senior author Josh Stuart, a professor of biomolecular engineering at UC Santa Cruz.

Stuart helped organize the study as part of the Pan-Cancer Initiative of the Cancer Genome Atlas (TCGA) project. A large team of researchers from multiple institutions performed a comprehensive analysis of molecular data from thousands of patients representing 12 different types of cancer. This was the most comprehensive and diverse collection of tumors ever analyzed by systematic genomic methods. Each tumor type was characterized using six different “platforms” or methods of molecular analysis–mostly genomic platforms such as DNA and RNA sequencing, plus a protein expression analysis.

The research team used statistical analyses of the molecular data to divide the tumors into groups or “clusters,” first analyzing the data from each platform separately and then combining them in an integrated cross-platform analysis developed by co-first author Katherine Hoadley of the University of North Carolina. All six platforms as well as the integrated analysis converged on the same divisions of the cancers into 11 major subtypes. Five of those subtypes were nearly identical to their tissue-of-origin counterparts. But some tissue-of-origin categories split into several different molecular subtypes, and some subtypes encompass tumors with several different tissues of origin.

Bladder cancer was a particularly interesting group, because it split into seven different clusters, with most samples falling into one of three subtypes. One subtype was bladder cancer only, but some bladder cancers clustered with lung adenocarcinomas, and others with a subtype called ‘squamous-like’ that includes some lung cancers, some head-and-neck cancers, and some bladder cancers.

“If you look at survival rates, the bladder cancers that clustered with other tumor types had a worse prognosis. So this is not just an academic exercise,” Stuart said.

Other findings from the study reconfirmed cancer subtypes that were already recognized, such as the different subtypes of breast cancer based on well-characterized biomarkers. The findings provide a more refined, quantitative picture of the differences between breast cancer subtypes, Stuart said. For example, the results reinforce the idea that ‘basal-like’ breast cancers are a unique tumor type. “Basal-like breast cancers are as different from luminal breast cancers as they are from lung cancers,” he said.

The fact that all six platforms for molecular analysis identified the same set of subtypes, both individually and in multi-platform analyses, is an important result, Stuart noted. Not only does it give the researchers confidence in the subtypes they identified, it also means that different kinds of data can be used to classify a tumor.

“We can now say what the telltale signatures of the subtypes are, so you can classify a patient’s tumor just based on the gene expression data, or just based on mutation data, if that’s what you have,” Stuart said. “Having a molecular map like this could help get a patient into the right clinical trial.”

Although follow-up studies are needed to validate the findings, this new analysis lays the groundwork for classifying tumors into molecularly defined subtypes. The new classification scheme could be used to enroll patients in clinical trials and could lead to different treatment options based on molecular subtypes.

According to Stuart, the percentage of tumors that are reclassified based on molecular signatures is likely to grow as more samples and tumor types are included in the analysis (the next major Pan-Cancer analysis will include 21 tumor types). Coauthor Christopher Benz, an oncologist at the Buck Institute for Research on Aging and UC San Francisco, noted that the 10 percent reclassification rate in the current study is likely an underestimate due to the unequal representation of different tumors. “If our study had included as many bladder cancers as breast cancers, for example, we would have reclassified 30 percent,” Benz said.

The researchers reported that each molecular subtype may reflect tumors arising from distinct cell types. For example, the data showed a marked difference between cancers of epithelial and non-epithelial origins. “We think the subtypes reflect primarily the cell of origin. Another factor is the nature of the genomic lesion, and third is the microenvironment of the cell and how surrounding cells influence it,” Stuart said. “We are disentangling the signals from these different factors so we can gauge each one for its prognostic power.”

The study involved an enormous amount of molecular and clinical data, which was managed by data coordinator Kyle Ellrott, a software developer in Stuart’s lab at UC Santa Cruz. The data sets and results have been made available to other researchers through the Synapse web site ( Stuart worked with the bioinformatics company Sage Bionetworks to create Synapse as a data repository for the Pan-Cancer Initiative.

“It’s a huge amount of information, and all the data is available as programmable data sets that other researchers can use to do further analysis,” Stuart said. “The scale of this project is hard to imagine. All of the data that the TCGA project has been churning out got funneled into this paper, and it’s giving us an unbiased look at what the data have to tell us about cancer.”

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Key to aging immune system: Discovery of DNA replication problem

“We have found the cellular mechanism responsible for the inability of blood-forming cells to maintain blood production over time in an old organism, and have identified molecular defects that could be restored for rejuvenation therapies,” said Emmanuelle Passegué, PhD, a professor of medicine and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. Passegué, an expert on the stem cells that give rise to the blood and immune system, led a team that published the new findings online July 30, 2014 in the journal Nature.

Blood and immune cells are short-lived, and unlike most tissues, must be constantly replenished. The cells that must keep producing them throughout a lifetime are called “hematopoietic stem cells.” Through cycles of cell division these stem cells preserve their own numbers and generate the daughter cells that give rise to replacement blood and immune cells. But the hematopoietic stem cells falter with age, because they lose the ability to replicate their DNA accurately and efficiently during cell division, Passegué’s lab team determined.

Especially vulnerable to the breakdown, the researchers discovered in their new study of old mice, are transplanted, aging, blood-forming stem cells, which lack the ability to make B cells of the immune system. These B cells make antibodies to help us fight all sorts of microbial infections, including bacteria that cause pneumonia, a leading killer of the elderly.

In old blood-forming stem cells, the researchers found a scarcity of specific protein components needed to form a molecular machine called the mini-chromosome maintenance helicase, which unwinds double-stranded DNA so that the cell’s genetic material can be duplicated and allocated to daughter cells later in cell division. In their study the stem cells were stressed by the loss of activity of this machine and as a result were at heightened risk for DNA damage and death when forced to divide.

The researchers discovered that even after the stress associated with DNA replication, surviving, non-dividing, resting, old stem cells retained molecular tags on DNA-wrapping histone proteins, a feature often associated with DNA damage. However, the researchers determined that these old survivors could repair induced DNA damage as efficiently as young stem cells.

“Old stem cells are not just sitting there with damaged DNA ready to develop cancer, as it has long been postulated” Passegué said.

But not all was well in the old, surviving stem cells. The molecular tags accumulated on genes needed to make the cellular factories known as ribosomes. The ribosomes make all the cell’s proteins. Passegué will further explore the consequences of reduced protein production as part of her ongoing research.

“Everybody talks about healthier aging,” Passegué added. “The decline of stem-cell function is a big part of age-related problems. Achieving longer lives relies in part on achieving a better understanding of why stem cells are not able to maintain optimal functioning.”

Passegué hopes that it might be possible to prevent declining stem-cell populations by developing a drug to prevent the loss of the helicase components needed to faithfully unwind and replicate DNA, thereby avoiding immune-system failure.

Among the additional study authors are graduate student Johanna Flach and postdoctoral fellow Sietske Bakker, PhD, who performed the experiments in Passegué’s lab at the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. International collaborators included Juan Méndez, PhD, of the Spanish National Cancer Research Center, in Madrid, and Ciaran Morrison, PhD, of the National University of Ireland, in Galway.

The research was funding by the California Institute for Regenerative Medicine and the National Institutes of Health.

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