PARIS (EGMN) – Alterations in the expression of a well-known cancer gene called Myc may explain why some patients with non–small cell lung cancer are resistant to the effects of platinum-based chemotherapy.

The first results of a gene expression profiling analysis of NSCLC samples, taken prospectively from patients during the BATTLE trial, were presented at the Worldwide Innovative Networking in Personalized Cancer Medicine Symposium.

“Myc is downregulated in treatment-refractory non–small cell lung cancer and may be an important factor in chemoresistance,” said Dr. Pierre Saintigny, a clinical research fellow at the University of Texas M.D. Anderson Cancer Center in Houston.

“This observation has been validated in vitro in cell lines selected for cisplatin resistance, and consistent with this observation Myc protein levels correlate with sensitivity to platinum-based agents in NSCLC cell lines,” he added.

The clinical results of the phase II BATTLE (Biomarker-Based Approaches of Targeted Therapy for Lung Cancer Elimination) trial were reported recently at the American Association for Cancer Research meeting in April. These showed that selecting treatment based on a patient’s individual tumor characteristics was not only feasible, but also improved patient outcomes.

“This is a new kind of trial,” Dr. Saintigny explained, “it is biopsy driven and patients had to have a mandatory biopsy with analysis of 10-15 biomarkers before inclusion in one of the four treatment arms.”

The BATTLE trial involved 255 patients who were randomized to molecularly targeted treatment with erlotinib alone or in combination with bexarotene, sorafenib, or vandetanib, an experimental drug. All of the patients included in the trial had stage III/IV tumors, and had been heavily pretreated with a variety of chemotherapeutic and molecularly targeted agents.

Core biopsy samples obtained from the patients were frozen and made available for further analysis of gene expression. A total of 32 of these samples were assessed by Dr. Saintigny and associates, and compared with a control group of 45 lung samples taken from patients with stage III/IV tumors that had not previously been treated.

Gene expression profiling was generated using the U133 Plus 2.0 Array platform. Pathway and gene set analyses were used to identify networks and pathways associated with chemoresistance. Validation of the findings was performed in an independent set of cisplatin-sensitive cell lines using reverse phase protein array technology.

“The first study we did was to try to find some biologic features associated with chemorefractory NSCLC,” Dr. Saintigny said. A total of 3,963 probe sets were found to be differentially expressed between the BATTLE and untreated NSCLC samples.

Additional analyses showed that the expression of certain DNA repair genes was upregulated in the BATTLE samples compared with the control samples, and that the expression of Myc, and of many of the genes it regulates, was downregulated.

Furthermore, Myc expression was associated with sensitivity to cisplatin.

These data suggest that the role of anticancer agents that specifically target Myc may need to be reevaluated, Dr. Saintigny suggested, and that the mechanisms behind the downregulation ofthe oncogene should be further explored.

“Probably the most important message is that oncogenic drivers, of which Myc is one, may be modified by systemic therapies,” Dr. Saintigny observed. He proposed that these findings highlight the importance of taking biopsies from patients before they enter clinical trials to try to understand how such oncogenic drivers are altered by treatment.

Further analysis of the BATTLE samples will be undertaken, including testing of available gene expression signatures in relation to the primary end point of the study (8-week disease control) and the duration of progression-free survival in the four treatment arms.

“People talk a lot about personalized medicine, but this is the first time in a prospective clinical trial that a biopsy was mandated, analyzed for biomarkers, and then treatment was assigned based on the molecular defects,” said Dr. Waun Ki Hong, professor of medicine and head of the division of cancer medicine at the M.D. Anderson Cancer Center, Houston.

“We used to treat lung cancer patients empirically with chemotherapy, but it is clear that the biologic behavior of each tumor can be different,” Dr. Hong said. “The BATTLE data show that it is possible to target therapy according to the underlying genetic abnormality and thus represents the first real step in advancing personalized medicine.”

Dr. Saintigny reported no conflicts of interest. Dr. Hong is the principal investigator of the BATTLE program project, which is supported by the U. S. Department of Defense.

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