Late-Breaking Science and Clinical Trials
Embargo expired: 4/19/2009 5:00 PM EDT
Source Newsroom: American Association for Cancer Research (AACR)
Newswise — As part of its efforts to showcase the latest breakthroughs in cancer science, the American Association for Cancer Research will host a press conference highlighting the newest research and clinical trial results from the AACR 100th Annual Meeting 2009.
The press conference will take place in room 108 of the Colorado Convention Center on Sunday, April 19, 2009, at 3:00 p.m. MST. Those reporters who cannot attend in person can dial in using the following information:
"¢ U.S./Canada Dial-In: (888) 282-7404
"¢ International Dial-In: (763) 488-9184
"¢ Access Code: 88610627
Michael Caligiuri, M.D., program chairperson for the AACR 100th Annual Meeting 2009 and the director and CEO of the Comprehensive Cancer Center " James Cancer Hospital at The Ohio State University, will moderate the press conference. Caligiuri said that the abstracts presented are an example of the conference's theme, "Science, Synergy and Success."
"For science to be successful it must be team science and these team efforts provide the synergies that will one day lead to success in the fight against cancer," he said.
LB-259. A Pilot Study Utilizing Molecular Profiling of Patients' Tumors to Find Potential Targets and Select Treatments for Refractory Cancers
Patients with advanced cancers, which had progressed on standard therapies and who had their tumors undergo molecular profiling, were able to be placed on chemotherapy regimens that had demonstrated effects on tumor size and progression-free survival.
Daniel Von Hoff, M.D., senior investigator and physician-in-chief at TGen, a non-profit research institute in Arizona, and chief scientific officer of Scottsdale Healthcare and U.S. Oncology Research, said this trial demonstrates the efficacy of personalized medicine.
"These patients had their tumors evaluated using immunohistochemistry and microarray profiling, used in a rigorous clinical setting," he said.
Von Hoff and colleagues applied these techniques to 66 patients at nine centers and selected their treatment regimens according to what they learned.
"This trial was unique because patients acted as their own control. We compared progression-free survival after the patients progressed on their prior treatment regimen with what had occurred before molecular profiling," said Von Hoff. "This allowed us to control issues that confound other trials like tumor subtypes and differences in biology."
Of the patients who were studied, 8 percent had ovarian cancer, 17 percent had colorectal cancer, 27 percent had breast cancer and 48 percent had cancers that were classified as miscellaneous. All these patients had progression of the tumor on prior chemotherapy regimens.
After molecular profiling identified a precise target, a new treatment was suggested and there were noted improvements in progression-free survival for some patients. Among patients with ovarian cancer, the improvement in progression-free survival was 20 percent; for colorectal, the improvement was 36 percent; for breast, the improvement was 44 percent; and for miscellaneous cancers the improvement was 16 percent. Von Hoff said beyond progression-free survival, there were improvements in tumor size that will be presented at the Annual Meeting.
"With this trial, we are showing the power of personalized medicine using the tools we already have available to us. As these tools become more precise and more effective, the value of personalized medicine will increase," said Von Hoff.
LB-93. BRAF, PIK3CA and KRAS Mutations and Loss of PTEN Expression Impair Response to EGFR-targeted Therapies in Metastatic Colorectal Cancer
New research shows that in patients with metastatic colorectal cancer, certain gene mutations may be associated with resistance to cetuximab and panitumumab " two monoclonal antibodies that target the epidermal growth factor receptor (EGFR).
Findings from previous studies have shown that the KRAS gene is a major predictive biomarker of resistance to EGFR-targeted therapies in these patients; however gene mutations only account for about 40 to 50 percent of those who are resistant.
"This study evaluates, for the first time, the relative contribution of all these molecular alterations. We performed a comprehensive analysis of KRAS, BRAF, PIK3CA gene mutations and loss of PTEN expression in patients with metastatic colorectal cancer treated with cetuximab and panitumumab," said Federica Di Nicolantonio, Pharm.D., Ph.D., research fellow in the Laboratory of Molecular Genetics at The Institute for Cancer Research and Treatment of the University of Turin Medical School, Turin, Italy.
"While KRAS and BRAF mutations never occur at the same time within the same sample, PTEN and/or PIK3CA genetic alterations can present concomitantly with either KRAS or BRAF mutations," she added.
Di Nicolantonio and colleagues conducted univariate and multivariate analysis of these four biomarkers. They retrospectively reviewed gene mutations in tumor samples of 132 patients with metastatic colorectal cancer. Patients were treated with EGFR-targeted monoclonal antibody regimens.
A significant fraction (23/55) of patients with no molecular alterations received some clinical benefit from the treatment, compared to 5 percent (3/56) among patients with one alteration and 0 percent (0/24) for patients with at least two alterations. Notably, none of the responders displayed PIK3CA or BRAF mutations.
"If you consider alterations in all four genes, then more than 70 percent of colorectal cancer patients unlikely to respond to EGFR-targeted therapies can be identified," Di Nicolantonio said. "This work has major potential clinical implications. Once prospectively validated, our results could immediately turn into molecular tests to be used in clinical practice."
LB-94. A "Vascular Normalization Index" as a Mechanistic Biomarker to Predict Survival After a Single Dose of Cediranib in Recurrent Glioblastoma Patients: Insights from a Phase II Study
Researchers at Massachusetts General Hospital have found a biomarker that may be useful in identifying patients with recurrent glioblastoma, or brain tumors, who would respond better to anti-vascular endothelial growth factor (VEGF) therapy, specifically cediranib.
"Vascular normalization is an important mechanism of how these drugs work in cancer patients," said Rakesh K. Jain, Ph.D., Andrew Werk Cook professor of tumor biology at Harvard Medical School and director of the Edwin L. Steele Laboratory for Tumor Biology in the Department of Radiation Oncology at Massachusetts General Hospital Cancer Center, Boston.
Cediranib is a highly potent inhibitor of VEGF receptor tyrosine kinases. It is an oral agent administered once daily. Preclinical studies in mice treated with cediranib have shown that it controls edema, which is primarily responsible for increased survival, according to Jain.
The aim of this study was to find potential biomarkers that could be used to select the patients up front who would respond better to treatment with cediranib. Jain and colleagues measured vascular normalization prior to and one day after patients received cediranib using advanced magnetic resonance imaging technique. They also performed blood analysis, and then examined correlations between vascular parameters and treatment response after a single dose of cediranib in 31 patients with recurrent glioblastoma.
The correlative analysis in this single arm phase II study showed that those patients whose extent of vascular normalization was higher, had a longer duration of overall survival as well as progression-free survival.
"Our study suggests that just one day after starting treatment, imaging and blood biomarkers together can identify patients who best are responding to treatment," said Jain. "If this approach is validated in larger studies, we could use these tools to keep patients on therapies that their tumors respond to, and shift non-responders to other therapies much earlier."
LB-95. Identification of the EGFRvIII Mutation in Glioblastoma by Magnetic Resonance Perfusion-Weighted Imaging (MR-PWI) and VEGF Expression
Magnetic resonance perfusion-weighted imaging (MR-PWI) may be a useful tool to help make rational treatment decisions based on its ability to accurately identify genetic mutations in malignant brain tumors, according to researchers from the University of Pennsylvania.
"To my knowledge this is the first demonstration that an MRI technique, or any imaging technique, can predict with very high specificity and positive predictive value the mutational status of a human tumor," said Donald M. O'Rourke, M.D., associate professor of neurosurgery at the University of Pennsylvania, Philadelphia.
The aim of this study was to determine the accuracy of relative cerebral blood volume (rCBV) and vascular endothelial growth factor (VEGF) measurements in an effort to identify the frequent genetic alterations of the epidermal growth factor receptor (EGFR) in patients with gliobastoma; the most prevalent EGFR genetic alteration is known as EGFRvIII. MR-PWI is a method of assessing blood flow to discriminate between higher grade gliomas, including glioblastomas, and less malignant forms.
O'Rourke and colleagues analyzed tissue samples from 97 participants and used real-time polymerase chain reaction to evaluate VEGF expression. Findings showed higher rCBV values using MR-PWI in patients with EGFRvIII compared to those who did not have the genetic mutation.
"We were not so surprised the cerebral blood volume correlated with this particular EGFR mutation because the cerebral blood volume value has been previously shown by our group to correlate with high-grade versus low-grade tumors, and EGFRvIII tumors are the most malignant type of glioblastomas," O'Rourke said. "We were somewhat surprised that VEGF was not the only variable to explain the elevation in cerebral blood volume. I didn't expect there to be such robust data behind it."
Advanced imaging modalities, such as MR-PWI, may provide non-invasive surrogate markers for EGFRvIII and, ultimately, other glioblastoma mutations, and potentially aid in the facilitation of treatment selection for patients, according to O'Rourke.
"If we are able to substantiate these findings and see the perfusion value changing while we are treating the patient, then we will know if we should continue with treatments directed against EGFRvIII or switch to alternative treatment strategies for our patients with malignant gliomas," he said. "These findings are potentially powerful, but provocative; MRI could serve as a non-invasive way to predict glioblastoma subtypes, select the best therapy for the patient and monitor its success over time."
LB-96. Phase III Validation of Ovarian Cancer Biomarkers in Pre-Diagnostic Specimens from the PLCO Screening Trial
Panels of screening biomarkers may not work much better than CA 125 alone in ovarian cancer screening.
A collaboration of researchers nationwide identified the current best biomarkers for ovarian cancer in specimens taken at the time of diagnosis (phase II) and compared them in specimens taken months or years prior to diagnosis (phase III). Speaking for the group, Daniel W. Cramer, M.D., Sc.D., professor of obstetrics and gynecology at the Brigham and Women's Hospital, Harvard Medical School, said that CA 125 remains the undisputed best single biomarker for this cancer, but additional markers can add a small benefit in sensitivity and specificity.
Cramer and colleagues first focused on blood samples taken at the time of diagnosis from 160 cases of ovarian cancer, 160 benign disease controls and 480 general population controls. They evaluated performance of more than 50 markers. Results showed the most accurate biomarkers to be: CA 125, HE4, CA 72.4, Transthyretin, HK6, B7H4, MMP7 and CA 15.3.
The researchers then compared these markers along with recently proposed "panels" in specimens that had been drawn months or years prior to a diagnosis of ovarian cancer from women who had participated in the Prostate, Lung, Colon and Ovarian Cancer (PLCO) screening trial. This trial enrolled men and women in various screening arms including one testing CA 125 and ultrasound for ovarian cancer between 1993 and 2001.
"It was disappointing that several of the panels performed no better than CA 125 alone," said Cramer. "However, several markers do seem to add value including HE4, CA 72.4, and MMP7 and measuring markers over time might also improve performance. General population screening for ovarian cancer cannot currently be recommended but the foundations for it are becoming clearer."
The study was sponsored by the National Cancer Institute's Early Detection Research Network and Specialized Program of Research Excellence.
LB-91. Inherited DICERI Mutations in Familial Pleuropulmonary Blastoma
Children who inherit a mutated copy of the DICER1 gene may be predisposed to pleuropulmonary blastoma, a rare form of lung cancer.
Dana Ashley Hill, M.D., chief of anatomic pathology at Children's National Medical Center in Washington, D.C., said pediatric cases of pleuropulmonary blastoma are extremely rare, with only about 25 to 35 cases reported each year in the United States.
Hill said this was the first time scientists have identified a genetic mutation in one cell type that drives cancer formation in a different cell type.
"This study is an example of the advances that can be made in the study of a rare disease, and it will help physicians who are very likely encountering their first case of pleuropulmonary blastoma," she said. "It helps not only those families with the disease, but sheds light on important biological mechanisms."
Pleuropulmonary blastoma arises during fetal development, and the majority of patients who have the disease are diagnosed before 6 years old. More than 25 percent of children who have this disease report a family history. For the current study, Hill and colleagues analyzed four families that included 14 clinically affected members.
Researchers identified 10 sequence defects in the DICER1 gene that all appeared to be loss of function mutations. All family members had these mutations in common.
Hill said in a normal genetic make-up, DICER1 would contribute to the development of lung tissue. Its loss of function leads to the malignancy characterized by pleuropulmonary blastoma.
"These cells that lose DICER1 are deregulated in such a manner that they now direct adjacent cells to proliferate uncontrollably and that predisposes these adjacent cells to develop additional genetic abnormalities and become cancerous," said Hill.
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and nearly 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. The AACR publishes six major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.