November 2012, Vol 1, No 5
Whole Genome Testing Moves Forward in Breast CancerUncategorized
Researchers presented the first large study to test the entire genome of individualized breast cancers to help personalize cancer at the 2012 ESMO Congress. They found that this approach is feasible and enables identification of genetic alterations that can be targeted by available drugs. They also saw early signs of clinical activity with this approach.
“Now that a number of drugs are available that target specific genetic alterations in cancers, genetic testing is usually performed. In most of these cases, these genetic testing approaches analyze only a limited number of genes,” said lead author of the study, Fabrice André, MD, Institut Gustav Roussy, Villejuif, France.
Theoretically, whole genome testing can identify both frequent and rare genetic alterations. “In addition, this approach allows us to quantify the level of genomic instability, and to detect whether driver mutations are associated with genomic alterations involved in resistance to specific targeted agents,” André explained.
Also, whole genome approaches could reduce expenditures related to genetic testing, because new bioassays would not need to be developed for each new targetable genetic alteration discovered in cancer. “An all-in-one assay could substitute for multiple tests,” explained Monica Arnedos, MD, one of the study coauthors.
The SAFIR01 trial analyzed the entire genome from a biopsy of a metastatic lesion prospectively. “We sought to identify molecular alterations and try to match these with a targeted therapy for each patient,” Arnedos said.
The investigators also wanted to determine the best technology for looking at the whole genome, and the best algorithm for identifying potential therapeutic targets. Most important, they plan to evaluate whether whole genome testing improves outcomes.
“First we did a pilot study in 108 patients where we performed whole genome analysis to determine feasibility. The techniques we used were array CGH and Sanger sequencing. Once feasibility was determined, we initiated the French national program, funded by French NCI and sponsored by UNICANCER,” Arnedos told listeners.
SAFIR01 was performed at 18 centers. As of September 23, 2012, biopsies were obtained from a metastatic lesion in 402 breast cancer patients, including 26 patients whose biopsies were under study. A genomic result was generated in 276 patients, including whole genome analysis in 251 patients. A targetable genomic alteration was identified in 172 (69%) of those patients. No patients had any evidence of disease progression while on treatment.
“Seventy-six genetic alterations were considered rare, low-frequency alterations. These alterations are unexpected, highlighting the need for whole genome approaches,” she said.
At the time of the ESMO Congress, 26 patients had received therapy targeted to their specific genetic alterations. Evidence of activity was observed in 8 of these patients. The data are still quite preliminary.
“In the next 3 years, we expect to have treated 80 patients with metastatic breast cancer using matched therapy selected from whole genome analysis,” Arnedos said.
The researchers plan to develop approaches to decrease biopsy failure and to improve access to targeted therapies.
Arnedos said these biopsies and tests are challenging. In 105 cases, the tumor sample was not sufficient for analysis, and in 19 cases the whole genome analysis was not interpretable.
The next trial, called SAFIR 2, will be a randomized trial comparing treatment based on whole genome testing versus treatment not driven by tumor biology.
“This approach is extremely important. It will identify patients who could benefit from a targeted drug not necessarily approved for that type of cancer. This approach will change the way we approve drugs. We have seen surprising compounds emerge that are effective. This will affect the regulatory process,” stated the press conference moderator, Christoph Zielinski, MD, Medical University of Vienna, Austria, who was not involved in these studies.
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