Dramatic response and resistance to cancer drug traced to unsuspected mutations

The DNA of a woman whose lethal thyroid cancer unexpectedly melted away for 18 months has revealed new mechanisms of cancer response and resistance to the drug everolimus, said researchers.

The investigators, from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard in Boston, Massachusetts, discovered two previously unknown mutations in the cancer's DNA. One made the woman's cancer extraordinarily sensitive to everolimus, accounting for the remarkably long-lasting response. The second mutation was found in the DNA of her tumor after it had evolved resistance to the drug 18 months after treatment started, according to the study, published in the New England Journal of Medicine (2014; doi:10.1056/NEJMoa1403352).

The single case study illustrates how repeatedly sequencing a patient's cancer DNA, which can be done first prior to treatment and again when the tumor shows signs of resistance, can identify unsuspected response and resistance mutations that may help guide treatment of other patients.

"This is personalized, precision medicine at its best," said senior author Jochen Lorch, MD, a thyroid cancer specialist at the Head and Neck Treatment Center at Dana-Farber.

Having identified the mutation, which occurred in a gene called TSC2, that caused the patient's dramatic response to everolimus, researchers at Dana-Farber have opened a clinical trial to test the drug's effectiveness in other patients with TSC2 mutations. This type of trial, sometimes called a basket trial, is becoming more common as studies of patients who are exceptional responders are revealing previously unknown response mutations to a variety of drugs. A basket trial pools patients with a particular response mutation, regardless of the type of cancer they have.

"The study of patients with extraordinary responses can yield critically important insights," said first author Nikhil Wagle, MD, of Dana-Farber. "These studies could help us develop methods for matching patients to drugs, highlight effective uses for otherwise 'failed' therapies, and design new therapeutic strategies to fight cancer."

Everolimus (Afinitor) is approved to treat tumors associated with tuberous sclerosis complex (TSC), a rare genetic disorder caused by mutations in TSC1and TSC2 genes. It is also approved for use in brain tumors, pancreatic cancer, kidney cancer, and advanced breast cancer. Everolimus targets the protein kinase mTOR, which regulates important cell functions including growth and proliferation, and is overactive in some cancers.

The patient whose stunning response to the drug prompted the hunt for mutations was a 56-year-old woman whose anaplastic thyroid cancer was diagnosed in 2010. This form of thyroid cancer is almost always fatal within a few months. "No treatment has ever worked," said Lorch. The tumor spread to her lungs despite surgery, radiation, and chemotherapy.

Lorch, who was leading a clinical trial of everolimus for a more treatable type of thyroid cancer, decided to include the woman and a handful of other anaplastic patients. To his surprise, after a few months the tumor shrank to a very small size. It remained that way for an unheard-of 18 months until it began to grow again. Using whole-exome DNA sequencing, which scans the protein-coding regions of the genome, the investigators discovered a mutation in the TSC2 gene.

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