MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.
"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.
"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.
Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.
The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).
Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).
Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.
Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.
Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.
Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
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