WAHINGTON, DC — A blood assay is much more successful than a traditional tissue biopsy for detecting key cancer mutations in patients with treatment-refractory gastrointestinal stromal tumors (GIST), new research shows.
This power of detection is important because new mutations evolve in patients with GIST and cause resistance to imatinib (Gleevec, Novartis) and sunitinib (Sutent, Pfizer), which are the standard therapies, said George D. Demetri, MD, from the Ludwig Center at the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.
He presented the data here at the American Association for Cancer Research 104th Annual Meeting.
"Detecting drug-resistant mutations...can help clinicians choose therapies with more precision for patients," Dr. Demetri said at a meeting press conference.
Traditionally, tumor tissue biopsies are performed to monitor mutations in cancer patients over time, including during treatment. But the approach is "problematic," said Dr. Demetri. In addition to being invasive, tissue biopsies are inherently incomplete because tumors are heterogenous and because only segments — and not the whole tumor — can be sampled.
"Liquid biopsies" could circumvent these limitations because tumor cells are constantly dying and leaking DNA into the blood stream, he explained.
In the study presented by Dr. Demetri, the BEAMing blood biopsy tool was used. It is a digital technology that has "exquisite sensitivity," he said. "It can detect 1 mutant bit of DNA among 10,000 normal alleles," he told reporters.
The approach was successful. "Our results show that it is possible to sum the total of all of the heterogeneity in a cancer and get a clear picture of the entire tumor burden using a simple blood sample," Dr. Demetri said in a press statement.
However, another oncologist, although impressed with the blood-based analysis, believes that it has not been proven that the blood tells the whole story of a cancer and its mutations. "What is happening with the blood may not tell you everything that is happening with the tumor," said press-conference moderator Giuseppe Giaconne, MD, PhD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, and the National Cancer Institute. He was not involved with the study.
However, Dr. Giaconne believes that blood biopsies can facilitate monitoring of cancer patients. "You could, in fact, easily monitor the patient without having to take multiple serial biopsies," he said.
Dr. Demetri noted that BEAMing technology, which is at least 5 years away from the clinic, can be used in multiple tumor types.
Four Times as Many Mutations Detected
The results presented by Dr. Demetri come from subanalysis data collected in the phase 3 GIST–Regorafenib in Progressive Disease (GRID) trial.
That trial demonstrated that the targeted therapy regorafenib (Stivarga, Bayer) significantly improved median progression-free survival, compared with placebo (4.8 vs 0.9 months; P < .0001), in patients with metastatic GIST who progressed on previous therapy with imatinib and sunitinib — the only other approved therapies for the disease. On the basis of the GRID study results, regorafenib was approved by the US Food and Drug Administration for use in GIST earlier this year.
Both imatinib and sunitinib have been wonderfully successful in the treatment of GIST, Dr. Demetri said. They were designed to inhibit a single gene mutation that causes an "uncontrollably active signaling kinase enzyme," he explained. The 2 targeted therapies have improved median overall survival in metastatic GIST from less than 6 months to nearly 5 years.
Because "secondary" mutations cause resistance to treatment, Dr. Demetri and colleagues retrospectively looked at the known resistance mutations to see if they could be detected in the blood with BEAMing.
The team used blood samples drawn at study entry, after the failure of both imatinib and sunitinib, and analyzed them for secondary KIT mutations, which appear after treatment with first-line targeted therapy.
They found 4 times as many secondary mutations in blood samples as in tissue samples (48% vs 12%).
In their blood analysis, the researchers also hoped to determine whether the investigational agent regorafenib is effective in patients with any of the secondary mutations that render imatinib and sunitinib ineffective. The usefulness of regorafenib depends, in part, on this, Dr. Demetri explained.
Regorafenib showed better disease control (improved progression-free survival) than placebo in all of the mutation subgroups, including the secondary mutations that arise from previous treatment with the other targeted therapies, he reported.
"With this technology, we hope to develop the most rational drug combinations and better tests to match patients with the most effective therapies going forward," Dr. Demetri said.
The subanalysis comparing blood and tissue biopsies also showed that BEAMing could detect the primary single gene mutation that causes GIST in the first place.
The study was supported by Bayer. Dr. Demetri reports financial ties with Bayer and multiple other pharmaceutical companies. Dr. Giaconne has disclosed no relevant financial relationships.
American Association for Cancer Research (AACR) 104th Annual Meeting: Abstract LB-295. Presented April 9, 2013.
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Cite this: 'Liquid Biopsy' More Precise in Detecting Cancer Mutations - Medscape - Apr 11, 2013.