Large, Prospective Study Finds Long-Term Obesity Is Associated with Poorer Pancreatic Cancer Survival

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In this News Digest:

- Summary of a study being published online October 21, 2013 in the Journal of Clinical Oncology, reporting that patients with pancreatic cancer who were overweight or obese years before their diagnosis tend to have more advanced disease at diagnosis and shorter survival.

- The findings add to increasing evidence linking obesity with cancer, suggesting that maintaining a healthy body weight not only reduces the risk of developing certain cancers, but may also improve outcomes after a cancer diagnosis.

- Quote for attribution to Smitha Krishnamurthi, MD, American Society of Clinical Oncology Cancer Communications Committee member and gastrointestinal cancers expert

Newswise — New results from a prospective study published in the Journal of Clinical Oncology show that patients with a body mass index (BMI) in the obese range live on average two to three months less after a pancreatic cancer diagnosis, compared with healthy weight patients, even after adjusting for factors that are known to predict survival for patients with this disease, such as age and disease stage. This association was statistically strongest for people who were overweight two decades before their diagnosis.

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. Most patients with pancreatic adenocarcinoma, which accounts for more than 90% of new cases, survive less than a year after their diagnosis.

Obesity is a major public health problem in the United States and many other countries around the world. While it is well known that obesity is a risk factor for heart disease and diabetes, it is becoming increasingly clear that it is also associated with cancer risk and outcomes. In fact, scientists predict that obesity will become the leading preventable cause of cancer in the near future.

Several prior studies have shown that elevated BMI increases the risk of developing pancreatic cancer, but thus far there has been little research on whether BMI affects the aggressiveness of the disease or survival after diagnosis.

“This study adds to mounting evidence for the role of weight control in improving outcomes for patients with cancer. It also reinforces the importance of maintaining a healthy weight throughout your life, which may lead to better outcomes after diagnosis and help prevent pancreatic cancer from developing,” said senior study author Brian M. Wolpin, MD, MPH, an assistant professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA. “While our findings will not affect the way we treat patients today, they provide new leads for investigating the molecular pathways that may be responsible for the survival difference between obese and healthy-weight patients. Hopefully, in the future, that research will bring new approaches for treatment of pancreatic cancer.”

Researchers evaluated the association between patients’ BMI in 1986 and survival after diagnosis of pancreatic cancer among participants from two large prospective cohort studies – the Nurses’ Health Study and the Health Professionals Follow-Up Study. Participants of those studies were surveyed on medical history, health behaviors, and lifestyle choices. The present study assessed 902 cases of pancreatic adenocarcinoma that were diagnosed during a 24-year period.

Overall, the median length of survival after diagnosis for those patients was five months. According to Dr. Wolpin, on average, healthy weight patients (BMI less than 25 kg/m2) lived 2 to 3 months longer than obese patients (BMI greater than or equal to 35 kg/m2). The association between higher prediagnostic BMI and shorter survival persisted after adjusting for differences in age, gender, race/ethnicity, smoking status, and disease stage. Obese patients were also more likely to be diagnosed with advanced disease – 72% of obese patients had metastatic disease at diagnosis compared to 59% of healthy-weight patients.

The association between BMI and survival was even stronger among the 202 patients with high BMI assessed 18-20 years before diagnosis. Assuming that most people remain overweight once they gain weight, according to Dr. Wolpin, this finding suggests that being overweight for a prolonged period of time leads to worse outcomes. This study also suggests further avenues of research on the link between obesity and cancer. For example, it is not yet clear if the same changes that promote tumor development in obese people also affect the aggressiveness of the tumor. Several ongoing studies are already exploring metabolic (energy and nutrient processing) pathways and genomic changes in relation to obesity and cancer. This work might reveal whether tumors that develop in obese people are susceptible to different treatments than tumors that develop in healthy-weight people.

This research was funded in part by a 2009 Conquer Cancer Foundation of ASCO Career Development Award to Brian Wolpin.

ASCO Perspective:
Smitha Krishnamurthi, MD, ASCO Cancer Communications Committee member and gastrointestinal cancers expert
“While previous retrospective studies suggested a link between obesity and pancreatic cancer survival, the prospective nature of this study makes the findings more reliable. An interesting aspect of this study is that it suggests that obesity, particularly chronic obesity, increases the risk of death from pancreatic cancer. This study, however, could not distinguish if the increased risk of death was due to metabolic and inflammatory changes that accompany obesity or due to other health complications of obesity.”

The full study can be found online at the Journal of Clinical Oncology.

About the Journal of Clinical Oncology:
Journal of Clinical Oncology, the flagship journal of the American Society of Clinical Oncology, is a leader in reach, readership, impact, and influence. With a focus on significant clinical oncology research, Journal of Clinical Oncology publishes over 1,000 articles in 36 issues a year.

About ASCO:
Founded in 1964, the American Society of Clinical Oncology (ASCO) is the world's leading professional organization representing physicians who care for people with cancer. With more than 30,000 members, ASCO is committed to improving cancer care through scientific meetings, educational programs and peer-reviewed journals. ASCO is supported by its affiliate organization, the Conquer Cancer Foundation, which funds ground-breaking research and programs that make a tangible difference in the lives of people with cancer. For ASCO information and resources, visit www.asco.org. Patient-oriented cancer information is available at www.cancer.net.

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Cell Growth Discovery by UCSF Team Has Implications for Targeting Cancer

 to support growth, to repair damaged tissues, or simply to maintain our healthy adult functioning — is controlled in previously unsuspected ways UC San Francisco researchers have discovered. The findings, they said, may lead to new ways to fight cancer.

The steps leading a quiet cell to make and divvy up new parts to form daughter cells rely on some of the cell’s most complex molecular machines. Different machines play key roles at different stages of this cell cycle. Each of these cellular machines consists of many proteins assembled into a functioning whole. They carry out such tasks as repairing DNA in the newly replicated gene-bearing chromosomes, for instance, or helping pull the chromosomes apart so that they can be allocated to daughter cells. 

In a study published online on October 10, 2013 in the journal Molecular Cell, UCSF researchers led by molecular biologist Davide Ruggero, PhD, associate professor of urology, and computational biologist Barry Taylor, PhD, assistant professor of epidemiology and biostatistics, found that the production of entire sets of proteins that work together to perform such crucial tasks is ramped up together, all at once — not due to the transcription of genes into messenger RNA, a phenomenon scientists often study to sort out cellular controls — but at a later stage of gene expression that occurs within the cell’s protein-making factories, called ribosomes.

“We have found that these proteins are regulated specifically and exquisitely during the cell cycle,” Ruggero said. When this regulation falters, it wreaks havoc in the cell, he added. “Cell-cycle control is a process that is most often misregulated in human disease,” he said. 

More specifically, the researchers found that this coordinated timing of protein production during the cell cycle is largely governed at the tail end of gene expression, within the ribosome, where cellular machinery acts on messenger RNA to churn out the chains of amino acids that eventually fold into functional form as proteins.

In 2010 Ruggero reported key evidence suggesting that this stage of protein production, called “translation,” might be an often-neglected process in many tumors, ranging from lymphomas, multiple myeloma and prostate cancer.

In the new study, the researchers examined translation of messenger RNA into protein at the classic phases of the cell cycle, before the cell actually divides. These are the G1 phase, when cells grow and make lots of proteins before replicating their DNA; the S phase, when cells replicate their DNA; and the G2 phase, when cells make internal components known as organelles, which they divvy up along with the chromosomes when the cell actually divides during mitosis.

The scientists used a technique know as ribosome profiling, originally developed for yeast cells in the lab of Jonathan Weismann, PhD, Howard Hughes Investigator at UCSF and professor of cellular and molecular pharmacology, to figure out which messenger RNA was being translated into protein by the ribosome during human cell division. They then used computational techniques developed by Taylor’s lab team along with the lab team of Adam Olshen, PhD, professor of epidemiology and biostatistics, to better quantify which genes had been translated into proteins.

By conducting a genome-wide investigation of translation and interrogating the data with sophisticated computer algorithms, the researchers discovered that different groups of protein were made in abundance at a particular phase, only to be quieted during another phase of the cell cycle. Previous studies of translation of messenger RNA into protein focused on only one or just a few genes at a time, according to Ruggero and Taylor.

“We hope these methods will be helpful to others who study gene regulation at the translational stage in various diseases, and those who want to identify specific targets for drug development based on discoveries of aberrant translation,” Taylor said.

Ruggero has been a pioneer in probing the ability of tumor cells to make extraordinary amounts of protein to sustain their rapid growth and immortality. He also is exploring ways to therapeutically target this excess protein production in cancer.

One striking finding from this new UCSF study is the discovery that production of a protein called RICTOR is boosted due to increased translation during the S phase of the cell cycle. RICTOR serves as a signal to help the cell cycle run like finely tuned clockwork, but several studies suggest that RICTOR often is constitutively turned on in cancer, Ruggero said.

The biochemical signaling cascade within the cell that RICTOR is a part of is under extensive investigation for experimental cancer therapies, and these new findings may point to novel strategies for drug development Ruggero said. Ruggero and Craig Stumpf, PhD, a postdoctoral fellow with his lab and the first author of the Molecular Cell paper, now are tracking down the upstream trigger that coordinates timing of many of the other suites of proteins that are produced simultaneously during the different cell-cycle phases.

UCSF technician Melissa Moreno also worked on the study. The research was funded by grants from the National Institutes of Health.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital.