Multiple myeloma study uncovers genetic diversity within tumors

The most comprehensive genetic study to date of the blood cancer multiple myeloma has revealed that the genetic landscape of the disease may be more complicated than previously thought. Researchers have shown that an individual patient's tumor can harbor populations of cancer cells equipped with different mutations. These findings could have therapeutic implications for patients in the future.

"What this new work shows us is that when we treat an individual patient with multiple myeloma, it's possible that we're not just looking at one disease, but at many—in the same person, there could be cancer cells with different genetic make-ups," said co-senior author Todd Golub, MD, of the Broad Institute of the Massachusetts Institute of Technology and Harvard University, in Boston. "These findings indicate a need to identify the extent of genetic diversity within a tumor as we move toward precision cancer medicine and genome-based diagnostics."

In a detailed study of samples from more than 200 multiple myeloma patients, the researchers identified frequent mutations in several key genes known to play an important role in cancer including KRAS, NRAS, and BRAF. But they found that many of these telltale mutations were not present in all cancer cells within a tumor—instead, they were often found in only a smaller fraction of cells, known as a subclonal population. The study was published in Cancer Cell (2014; 25[1]:91-101).

Many promising cancer therapies used in treatment today target a specific genetic mutation. This new work suggests that such targeted therapies may have limitations in patients whose tumors are made up of these subclonal populations.

The research team performed follow-up experiments in the lab to explore some of the therapeutic implications, looking specifically at BRAF, a cancer gene for which several inhibitors, or drugs, exist. Previous studies indicated that around 4% of multiple myeloma patients may have mutations in this gene, and a recent report on a single multiple myeloma patient treated with drugs targeting BRAF showed promising results. In the lab, however, the research team found evidence that treating a tumor harboring subclonal BRAF mutations with one of these targeted drugs may at best kill a fraction of the cells, and at worst, stimulate another cancer cell subpopulation to grow.

"There's clearly potential for these drugs in some patients with multiple myeloma, but we show that there are also potential problems for others," said co-senior author Jens Lohr, MD, PhD, also of the Broad Institute. "If a patient has a BRAF mutation in less than 100% of his cells, or if he has mutations in KRAS or NRAS at the same time may influence the response to an inhibitor."

Resistance—or the ability for tumors to shrink and then grow back—has become a major hurdle in treating patients with targeted therapies such as BRAF inhibitors. The new research suggests that subclonal populations could be one of the potential reasons many patients suffer relapse after treatment.

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