FORT LAUDERDALE—Several innovative diagnostic and therapeutic advances were reported at the 7th Annual Eastern Cooperative Oncology Group (ECOG) Young Investigator Symposium, which was held at the ECOG Fall Meeting here in November. The program is intended to expose individuals early in their career to cooperative group research opportunities, and to provide them with a forum to present their research in a formal manner.
Senior members of ECOG also were given the opportunity to discuss the presentations, including Drs. Barbara Burtness of Fox Chase Cancer Center, Dr. Kapil Bhalla of Medical College of Georgia, Dr. Amit Verma of Albert Einstein College of Medicine, and Dr. Robert Gray of ECOG and Harvard School of Public Health.
Clinical Research Award to Rebecca Miksad
Two awards were presented for the most outstanding presentations in the clinical research category and the translational research category: The Clinical Research Award was presented to Rebecca Miksad, MD, MPH, an Instructor in Medicine at Beth Israel Deaconess Medical Center, Harvard Medical School, for her presentation entitled, “Evaluation of progression-free survival as a surrogate endpoint in advanced breast cancer.”
Progression-free survival is a potential surrogate endpoint for overall survival that is often evaluated in clinical trials of metastatic breast cancer. Dr. Miksad and her colleagues at the Department of Public Health at the University for Health Sciences, Medical Informatics and Technology, in Austria (Chair is Dr. Uwe Siebert) investigated the ability of progression-free survival to reliably and accurately predict the direction and the magnitude of the treatment benefit on overall survival, the gold standard endpoint in clinical oncology trials.
As a surrogate endpoint, progression-free survival has several potential advantages: Data may be more rapidly collected and, thereby, trials may be shorter, smaller, and cheaper; ineffective therapies may be weeded out sooner; and new treatments may be brought to patients more quickly.
Dr. Miksad and colleagues evaluated 31 trials evaluating chemotherapy for metastatic breast cancer in order to compare the trial-level treatment effect on progression-free survival (PFS) with the trial-level treatment effect on overall survival (OS) using meta-analytic regression analysis.
“Although trial-level treatment effect on PFS was significantly associated with the trial-level treatment effect on OS, predictions based on PFS were surrounded with uncertainty,” she said. “Although the findings were robust on cross-validation and sensitivity analyses, heterogeneity of the results could not be explained by the constant rate assumption, differences in PFS definition, year of last patient recruitment, or line of therapy. This uncertainty may limit interpretation of PFS data as a predictor of OS results.”
Dr. Miksad's findings suggest that surrogate endpoints such as PFS may have to be evaluated for each cancer type and for intervention type before they are used to make clinical and policy decisions.
Translational Research Award to Sanjay Goel
The Translational Research Award was presented to Sanjay Goel, MD, Assistant Professor of Medicine at Albert Einstein College of Medicine and Montefiore Medical Center in New York City, whose presentation was entitled, “PIK3CA/PTEN mutation status predicts response of colon cancer cells to the EGFR inhibitor cetuximab.”
Dr. Goel's work focused on determining potential mechanisms of resistance to cetuximab, a mononoclonal antibody directed at epidermal growth factor receptor (EGFR) that has been approved for the treatment of colorectal and head/neck cancer.
Dr. Goel screened a panel of 22 colon cancer cells and identified cetuximab-resistant and -sensitive cells. This differential sensitivity was confirmed in vivo using SCID mice xenograft models. Cetuximab induced G0/G1 arrest without induction of apoptosis. Cetuximab-sensitive cells were found to be sensitive to EGF-induced proliferation in serum-free conditions, while cetuximab-resistant cells were not, suggesting that cells dependent on ligand mediated canonical activation of this pathway were sensitive to cetuximab.
Neither EGFR protein/mRNA expression nor EGFR gene copy number (by FISH) correlated with cetuximab response. Examination of the mutation status of signaling components downstream of EGFR demonstrated that cell lines wild type for PIK3CA/PTEN were significantly more sensitive to cetuximab than were cells with activating PIK3CA mutations or loss of PTEN expression.
Consistently, PIK3CA wild-type isogenic HCT116 cells showed increased response to cetuximab compared with PIK3CA mutant controls. Cell lines mutant for K-Ras/BRAF also tended to be more resistant to cetuximab than wild type lines.
Lastly, cell lines mutant for both PIK3CA/PTEN and K-Ras/BRAF were highly resistant to cetuximab, indicating that mutations that constitutively and simultaneously activate the Ras and PIK3CA pathways confer maximal resistance to cetuximab.
Dr. Goel concluded: “Screening of colon tumors for PIK3CA/PTEN and K-Ras/BRAF mutation status could help identify patients likely to benefit from cetuximab therapy. Our findings merit further evaluation in clinical specimens in order to validate these observations. This project would not have been possible without Dr. Minaxi Jhawer, who was instrumental in performing the early experiments and Dr. John Mariadason in whose lab this project was carried out and was the principal investigator on this project.”
Next Symposium in November in Fort Lauderdale
The 8th Annual ECOG Young Investigator's Symposium will take place during the next fall ECOG meeting, in November. A call for abstracts will be issued in June, with an anticipated abstract deadline of early September. After review, individuals who have an abstract selected for presentation receive a travel grant to attend the ECOG fall meeting.
Additional information, including criteria for eligibility, is available on the ECOG Web site (www.ecog.org/general/yia.html). The program is made possible by an unrestricted educational grant from sanofi-aventis.