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ASCO Update: Genetic Sequencing May Shape Future of Clinical

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Genetic Sequencing May Shape Future of Clinical Trials, Cancer Therapy

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Improved understanding of cancer genetics continues to play a key role in individualizing treatment. Recent discoveries have set the stage for new clinical trials to differentiate likely responders and identify biologic pathways that could be targeted by emerging agents.

The Education Session “Genomics in Gynecologic Cancers: Important Findings from the Cancer Genome Atlas and Beyond” will highlight the advances in molecular technology for gynecologic cancers, as well as the findings of the Cancer Genome Atlas (TCGA) project, and offer some perspective on their potential, said Session Chair Douglas A. Levine, MD, head of the Gynecology Research Laboratory at Memorial Sloan- Kettering Cancer Center. The session will be held today, 9:45 AM-11:00 AM, S406.

“These are basic research findings that need to be translated into the clinical arena,” Dr. Levine told ASCO Daily News. “They are actionable and they should help shape clinical trials that will enable us to offer better outcomes for our patients.”

Some of the most challenging questions about managing cancer focus on why some patients respond to a given treatment better than others. Increased understanding of the genetic makeup of responders, and nonresponders, may enable oncologists to stratify patients and target therapies to those more likely to benefit.

“These discoveries take us beyond the traditional and histologic classifi cations, allow us to stratify tumors in a more intelligent manner, and help us move toward individualization of care,” Dr. Levine said.

Widespread use of these techniques would even allow researchers to glean information from negative trials, Dr. Levine said. A trial that achieved only a 5% response rate would be considered a failure, but if genetic testing revealed something unique and specific about the responders, subsequent trials that targeted similar patients might achieve a much higher response rate. Conversely, even therapies that have much higher response rates still have substantial subsets of patients who do not respond. Identifying these patients before initiating treatment would minimize the application of ineffective therapies that carry significant toxicities.

As an example of how advanced genetic sequencing techniques could affect future trials, Dr. Levine cited the poly(ADPribose) polymerase (PARP) inhibitors, which have been shown to provide increased benefi t to patients with inherited BRCA mutations. However, it was unknown whether PARP inhibitors would be benefi cial for patients with somatic BRCA mutations. This subset of patients was believed to be too small to warrant additional testing, but next-generation genetic sequencing indicated that approximately 20% of patients had a somatic mutation.

The TCGA also determined that either BRCA1 methylation or mutation—but not both—will be present in a single tumor, suggesting that this is an important pathway that might be a target for treatment, Dr. Levine said. This distinction can assist in testing because the methylation assay, which is simpler and less expensive, can be performed first. Then, only if it is negative, would it be necessary to consider sequencing to detect a mutation.

The necessary tools for this level of genetic mapping are becoming available, but implementation requires the right scientists asking the right questions in appropriately designed trials with the right collaborators and suffi cient funding, Dr. Levine said.

“There are clinical trials being conducted that are utilizing genetic sequencing, but they are not being done as much as they should,” Dr. Levine said. “Resources are not unlimited, and many clinical trials are generally negative, but if we could learn something from every clinical trial, we could make better use of our fi nancial and patient resources.”

Findings from TCGA

The TCGA was a joint venture sponsored by the National Cancer Institute and the National Human Genome Research Institute. It targeted ovarian cancer—the fifth-leading cause of death among women in the United States with a 5-year survival rate of only 31%—with a goal of identifying new therapeutic avenues, thereby moving the field of ovarian cancer forward, said Session Speaker Paul Spellman, PhD, associate professor at the Oregon Health & Science University and member of the TCGA.

Researchers expected to fi nd a signifi cant number of point mutations that were oncogenic or had tumorsuppressing capabilities and would have represented the primary molecular causes of high-grade serous ovarian cancer, Dr. Spellman said. Instead, they found that 96% of all tumors they examined had a mutation of the TP53 gene, and follow-up investigation revealed that this mutation occurred very early in tumor development.

A number of other genes were found to have cancer-causing mutations, but they were not recurrent, which led researchers to hypothesize that the imprint mutation itself was not the most significant finding. Analysis of the DNA copy number for these tumors identifi ed 113 significant focal copy number aberrations, showing that high-grade ovarian cancer is a genome structure disease, rather than a disease of small point mutations in specifi c genes, he said.

By showing ovarian cancer as a wider structural disease, rather than the result of a mutation of a few genes, this research should direct future efforts to develop therapies and diagnostic tools that target these focal copy number aberrations, Dr. Spellman said.

The TCGA also identified a very robust predictor of clinical response. Although not useful as a diagnostic criteria because it does not specify odds of survival (and even in the patients who respond, the 5-year survival rate was only 40%), it does suggest there is a biologic difference between the tumors that may prove to be a target for treatment, Dr. Spellman said.

The next target for the TCGA is endometrial cancer, and new, unpublished fi ndings are expected to be presented in this session. In ovarian cancer, where the disease carries a high frequency of mortality and all patients must be treated aggressively, the researchers’ questions focus on fi nding the best treatment. In the genetic sequencing of endometrial cancer, research will focus on identifying the small subset of patients who are more likely to have terminal disease and must be treated aggressively, while sparing a majority of patients from unnecessary treatment, Dr. Levine said. Early results are encouraging that genomic approaches will identify subsets of patients independent of previous fi ndings using histologic and pathologic techniques.

Paul J. Goodfellow, PhD, will also discuss genomics in endometrial cancer in this session.

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