Coffee drinking improves hepatitis C treatment response, study suggests

ScienceDaily (June 8, 2011) — Advanced hepatitis C patients with chronic liver disease may benefit from drinking coffee during treatment, according to a new study in Gastroenterology, the official journal of the American Gastroenterological Association (AGA) Institute. Patients who received peginterferon plus ribavirin treatment and who drank three or more cups of coffee per day were two times more likely to respond to treatment than non-drinkers.

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"Coffee intake has been associated with a lower level of liver enzymes, reduced progression of chronic liver disease and reduced incidence of liver cancer," said Neal Freedman, PhD, MPH, of the National Cancer Institute and lead author of this study. "Although we observed an independent association between coffee intake and virologic response to treatment, this association needs replication in other studies."

Among non-drinkers, 46 percent had an early virologic response; 26 percent had no detectable serum hepatitis C virus (HCV) ribonucleic acid at week 20; 22 percent had no detectable serum at week 48; and 11 percent had a sustained virologic response. In contrast, the corresponding proportions for those who drank three or more cups of coffee per day were 73 percent, 52 percent, 49 percent and 26 percent, respectively.

Approximately 70 to 80 percent of individuals exposed to HCV become chronically infected. Worldwide, these individuals are estimated to number between 130 and 170 million. Higher coffee consumption has been associated with slower progression of pre-existing liver disease and lower risk of liver cancer. However, the relationship with response to anti-HCV treatment had not been previously evaluated. Treatment with peginterferon and ribavirin resolves chronic hepatitis C in about half of patients. It is unknown whether coffee will improve response with the addition of new drugs that were recently approved for use in the U.S.

Because patients in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial also had previously failed interferon therapy, it is not clear whether the results can be generalized to other patient populations. Future studies among patients with less advanced disease, those who are treatment-naïve to prior therapy, or who are being treated with newer antiviral agents are needed.

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Genes that may help predict response to BRAF inhibitors for advanced melanoma identified

ScienceDaily (June 1, 2011) — Genetic analysis of the tumors from patients with advanced melanoma can clue researchers in to how well patients will respond to a therapy that targets the growth-promoting protein called BRAF, a researcher from the Perelman School of Medicine at the University of Pennsylvania will report on June 6 at the annual meeting of the American Society of Clinical Oncology. Looking outside of the BRAF gene, the researchers found loss of the tumor suppressor gene PTEN also appears to be associated with patient response to GSK436, which could help guide researchers to even more personalized approaches to melanoma therapy.

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The phase I clinical trial data highlight the role that genetic changes other than that in BRAF may play in a patient's resistance to BRAF inhibitors, a targeted therapy that has shown unprecedented efficacy among patients with metastatic disease.

"These findings are important because they suggest that performing genetic characterization of melanomas for genetic changes outside of BRAF could help predict the patients that may have worse responses to BRAF inhibitors," says Katherine Nathanson, MD, an associate professor of Medical Genetics in Penn's Abramson Cancer Center, who led the study. Armed with such information, a physician could prescribe a different drug or combination of drugs to target these advanced cancers. Guiding such decisions early can save time in the race to control metastatic melanomas, which commonly kill patients within a year after they're identified.

An estimated 40 to 60 percent of all melanomas carry a mutated BRAF gene. Although patients with advanced melanoma are often resistant to chemotherapy, drugs that go after the overactive BRAF protein -- which acts as a foot on a gas pedal promoting tumor growth -- have demonstrated promising results in Phase I and II trials. Research shows that as many as 80 percent of patients who take these drugs experience a clinical benefit. However, despite signs of initial success, months into receiving the therapy, the tumors of many patients receiving the BRAF inhibitor return and begin growing again.

"There has been a lot of focus on what happens with tumors as they develop resistance to BRAF inhibitors," Nathanson says. "We asked a different question: Are there mutations that help predict response to inhibitors before the patients begin drug treatment?"

Through a collaboration with GlaxoSmithKline, Nathanson's group obtained tumors from patients enrolled in a phase I trial of BRAF inhibitor GSK436. To date, the researchers have performed genomic profiling on the melanomas of 32 patients prior to beginning treatment with GSK436. "This unique sample set allowed us to systematically look at additional predictors for response to BRAF inhibitors," Nathanson says.

Her team found that patients with clear loss of PTEN genetically have a shorter period of progression free survival (4.2 months) on GSK436, as compared to those with normal PTEN (7.4 months). However, the numbers of patients are small and larger cohorts will be needed to confirm this preliminary finding. Mutations in several other genes believed to play a role in cancer, including MEK2 and CDK4, were also identified in two patients; however additional data are needed to clarify the predictive value of such mutations to BRAF inhibitors. Exploratory analysis also was done looking at the copy number of genes known to be important in melanoma. The presence of additional copies of CDKN2A, which is associated with tumor suppression, was significantly associated with an improvement in outcome.

"Because BRAF inhibitors will likely receive FDA approval soon, it's important to understand what additional factors will predict the patients who will be most helped by the drugs," Nathanson says. "Understanding what additional genetic changes are present in melanomas taken directly from patients paves the way for the development of combination therapies."

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Therapeutic melanoma vaccine improves response rate, progression-free survival, study finds

ScienceDaily (June 2, 2011) — A vaccine for one of the most lethal cancers, advanced melanoma, has improved response rate and progression-free survival for patients when combined with the immunotherapy drug Interleukin-2, according to research led by scientists from The University of Texas MD Anderson Cancer Center and Indiana University Health Goshen Center for Cancer Care.

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The findings, published in the June 2 New England Journal of Medicine, mark the first vaccine study in the disease -- and one of the first in cancer overall -- to show clinical benefit in a randomized Phase III clinical trial. It's also the first cancer vaccine to show an improved response rate in patients.

The research was first presented on the plenary session of 2009 American Society of Clinical Oncology.

According to the American Cancer Society, melanoma has one of the fastest growing incidence rates of all cancers. In 2010, more than 68,130 people in the U.S. were diagnosed with melanoma and 8,700 died from the disease. The five-year survival rates for those with regional and metastatic disease are 65 percent and 16 percent, respectively.

"Obviously, this is a disease, in its advanced setting, in need of better therapies for patients," said Patrick Hwu, M.D., professor and Chair of the Department of Melanoma Medical Oncology and the study's senior author. "This study serves as a proof-of-principle for the role of vaccines in melanoma and in cancer therapy overall. If we can use the body's own defense system to attack tumor cells, we provide a mechanism for ridding the body of cancer without destroying healthy tissue."

During their tenure at the National Cancer Institute NCI), Hwu and Douglas Schwartzentruber, M.D., the medical director of the Goshen Center for Cancer Care, were involved in the vaccine's development and early basic and clinical studies. The peptide vaccine, known as gp100:209-217 (200M), works by stimulating patients' T cells, known for controlling immune responses.

"This vaccine activates the body's cytotoxic T cells to recognize antigens on the surface of the tumor. The T cells then secrete enzymes that poke holes in the tumor cell's membrane, causing it to disintegrate," explained Schwartzentruber, the study's principal investigator and corresponding author.

After an NCI-led Phase II study combining the vaccine with Interleukin-2 (IL-2) showed response rates of 42 percent in metastatic melanoma patients, a Phase III randomized trial with the two agents opened more than a decade ago.

Conducting a large, multi-institutional trial with IL-2, however, had its own set of unique challenges, explained Hwu, as not all cancer centers and community hospitals are capable of administering the immunotherapy. A highly specialized therapy associated with such significant side effects as low blood pressure and capillary leak syndrome, which poses risks to the heart and lung, IL-2 is often delivered in intensive care units. MD Anderson is one of the few centers with a dedicated in-patient unit exclusively designed for the drug's delivery; before, the institution was offering the therapy in its ICU.

In the Phase III trial, 185 patients at 21 centers across the country were enrolled in the study. All had advanced metastatic melanoma and were stratified for cutaneous metastasis, a known indicator of response to IL-2. Patients were randomized to receive either high dose IL-2, or IL-2 and vaccine. In the IL-2 arm, 94 patients were enrolled and 93 were treated and evaluated for response; 91 were enrolled and 86 treated and 85 were evaluated for response in the IL-2 and vaccine arm. The primary endpoint of the study was clinical response; the secondary endpoints were toxic effects and progression-free survival.

The study found that those who received the vaccine had a response rate of 16 percent, and progression-free survival of 2.2 months, compared to 6 percent and 1.6 months respectively in those that did not. The study was not powered to look at overall survival, but for those receiving the vaccine, it trended positive, 17.8 months vs. 11.1 months.

"This is one of the first positive randomized vaccine trials in cancer and the findings represent a significant step forward for treatment of advanced melanoma," said Schwartzentruber. "However, the vaccine only can be given to half of those with melanoma because it has to match a patient's tissue type, or HLA. A major priority for us is to figure out ways to broaden our approach and use mixtures of peptides, for example, so that more patients are eligible."

The researchers would like to improve upon it by including other immune-stimulatory agents, such as newer vaccine adjuvants, other cytokines and antibodies that further activate immune cells.

"This is a very exciting time for the field of melanoma. During the last few years, the entire landscape has changed -- with the addition of targeted therapies such as those that target BRAF as well as those that stimulate the immune system. Still, these drugs work in a small number of patients, and/or resistance often develops," said Hwu. "Now, our focus will need to turn toward studying these novel therapies in combination and continue our quest for better vaccines, as well as researching ways to make the study inclusive of more metastatic melanoma patients."

The study was funded, in part, by the National Cancer Institute.

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No tie found between PTEN and response to breast cancer drug herceptin, according to new study

ScienceDaily (June 3, 2011) — Contrary to what many oncologists had thought, a tumor suppressor protein known as PTEN does not reduce the effectiveness of the breast cancer drug herceptin, according to a study by Mayo Clinic and North Central Cancer Research Group (NCCTG) investigators.

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The study, which looked at tumors from 1,802 patients enrolled in the NCCTG N9831 clinical trial, found that patients with HER2-positive breast cancer and had either a loss of PTEN functioning or normal PTEN activity did equally well when herceptin was added to chemotherapy to prevent breast cancer recurrence.

The researchers presented their findings during the American Society of Clinical Oncology Annual Meeting in Chicago.

"This is the largest study to date evaluating PTEN's presence or loss in the context of antiHER2 therapy, and we found no connection," says the study's lead investigator, oncologist Edith Perez, M.D., director of the Breast Clinic at Mayo Clinic in Jacksonville, Fla., and the Serene M. and Frances C. Durling Professor. "Our research team is very pleased to be able to test an important question in treatment of breast cancer and arrive at a definitive answer."

The researchers stained the samples for PTEN expression and linked that data with disease-free survival. They found that PTEN status did not impact disease-free survival significantly; there was only a slightly greater benefit of adding herceptin for patients with PTEN-tumors.

Preclinical studies and some small patient studies had suggested that tumors with loss of PTEN expression would not benefit from herceptin, Dr. Perez says. As a result, investigators were considering using PTEN biomarkers in clinical studies as a test of herceptin resistance, and patients who tested positive for PTEN loss might then be offered other therapies, or invited to participate in clinical trials.

"We have all been interested in biomarkers that predict for benefit to antiHER2 therapy," Dr. Perez says, "but PTEN is not one that we should pursue further, based on our rigorous analysis."

The tumor samples examined in the study came from NCCTG N9831, a phase III randomized, multicenter clinical trial that tested adjuvant herceptin given with, or following, chemotherapy with paclitaxel, compared with chemotherapy alone.

The study was funded by the National Cancer Institute, the National Institutes of Health and Genentech. The study includes 16 co-authors; nine are from the Mayo Clinic campuses in Florida, Minnesota, and Arizona.

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Plasticity of hormonal response permits rapid gene expression reprogramming: Gene expression reprogramming may allow cancer cell growth as well as normal differentiation