Expert Point of View: Michael Seiden, MD

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“We are approaching the 15th year of exploring molecularly targeted therapies in ovarian cancer,” said Michael Seiden, MD, of Fox Chase Cancer Center, Philadelphia, and formal discussant of the papers presented during an oral abstract session on gynecologic cancer at the 2012 ASCO Annual Meeting.

He said that there have been some successes with molecularly targeted therapy, most notably targeting chronic myelogenous leukemia with imatinib (Gleevec). But he doubted that this approach would improve survival in serous ovarian cancer, a disease with tremendous genomic instability.

Both the olaparib trial in platinum-sensitive patients and the bevacizumab (Avastin) trial in platinum-resistant patients showed improved progression-free survival. The bevacizumab trial was hailed as the first randomized trial to show improved progression-free survival in platinum-resistant patients. Yet Dr. Seiden believes both trials will ultimately fail to improve survival.

Activation of Many Factors

By way of explanation, he said, “Cancer is a concert of activation of many factors, including amplifications, translocations, and mutations. Therapeutic ‘home runs’ have all been associated with targeting activated oncogenes, such as HER2/neu in breast cancer, ALK in lung cancer, and BRAF in melanoma. Targeting pathways that are activated secondary to the loss of tumor-suppressor genes have been dramatically less effective,” he stated.

“In order to make inroads in improving survival in serous ovarian cancer, we will need to change the natural history of the disease. This cancer has had extreme genomic disruption—an unparalleled amount of deletions in chromosomes that look dramatically different from other cancers. In addition to genomic instability, there are somatic mutations within a gene,” Dr. Seiden continued.

He believes that conventional phase III trials are not the answer and that new trial designs are needed that will incorporate genomic data to address the genomic complexity of this disease. Also, a powerful predictive biomarker will be needed. “We don’t even have a moderately good biomarker in ovarian cancer,” he stated.

He suggested that it might be reasonable to stop all ovarian cancer trials of molecularly targeted agents. Perhaps there are small or medium-sized groups of genomically similar patients who could be studied, but this would take “deep” genomic sequencing of about 10,000 patients. The cost of genomic sequencing is going down, and it might be reasonable that trials of molecularly targeted agents be required to submit the full genome for all patients in clinical trials, he said. ■

Disclosure: Dr. Seiden reported no potential conflicts of interest.

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