Cancer Research Highlights
Low-Dose Radioactive Iodine Destroys Thyroid Tissue Left after Surgery
A low dose of radioactive iodine given after surgery for thyroid cancer destroyed (ablated) residual thyroid tissue as effectively as a higher dose, with fewer side effects and less exposure to radiation, according to two European randomized controlled trials published May 3 in the New England Journal of Medicine. Both trials also showed that either administering thyrotropin alfa or withdrawing thyroid hormones before administering radioactive iodine was effective for thyroid ablation at both radioactive iodine dose levels.
Researchers from France and the United Kingdom enrolled 752 and 438 patients with low-risk thyroid cancer, respectively, in their trials (here and here). Both studies randomly assigned patients to receive either low-dose radioactive iodine (1.1 GBq) or high-dose radioactive iodine (3.7 GBq) several months after surgery.
For radioactive iodine treatment to work, thyroid-stimulating hormone (thyrotropin) levels must be elevated. The researchers therefore randomly assigned study participants in both dose groups to either withdrawal of the replacement thyroid hormones given after surgery (to allow the body’s own thyrotropin level to rise) or administration of recombinant thyrotropin (thyrotropin alfa). Although thyrotropin alfa causes less discomfort than the withdrawal of replacement thyroid hormones, there was some concern that the drug might interfere with the effectiveness of radioactive iodine treatment.
Low-dose and high-dose radioactive iodine resulted in similar numbers of successful ablations in both trials: about 95 percent of patients in the French trial and 85 percent of patients in the U.K. trial, which enrolled patients with larger tumors than the French trial. In both trials, at both dose levels, rates of successful ablation did not differ significantly between patients receiving thyrotropin alfa or those undergoing replacement thyroid hormone withdrawal.
Ablation of residual thyroid tissue with radioactive iodine makes it easier to monitor patients with low-risk disease for local or distant recurrence, and its use has been rising in the United States. One recent study found that the use of ablation in younger patients with low-risk thyroid cancer rose from about 3 percent in 1973 to about 40 percent in 2007.
But whether radioactive iodine improves survival for low-risk patients remains unknown. “That benefit is much harder to prove in low-risk individuals because their survival from this disease is so good to begin with,” explained Dr. Erik Alexander of Harvard Medical School, who co-authored an editorial accompanying the two trials. A trial testing whether radioactive iodine improves disease-free survival in low-risk patients was recently launched in the United Kingdom.
Sequencing Study Identifies Gene that May Contribute to Melanoma
Also in the News: Sunburn and Indoor Tanning Still Common
Two new reports show that young adults in the United States are engaging in behaviors that increase their risk of skin cancer. Although more people are using sunscreen, staying in the shade, and wearing long clothing down to the ankles to protect themselves from the sun, sunburn remains common, according to the first study; half of all adults 18 to 29 years old reported at least one sunburn in the past year.
A second study found that roughly 30 percent of non-Hispanic white women 18 to 25 years old use indoor tanning devices, greatly increasing their risk of skin cancer.
Both reports appeared in the May 11 Morbidity and Mortality Weekly Report.
A whole-genome sequencing study of metastatic melanoma tumor samples has identified a gene, PREX2, that appears to be commonly mutated in melanoma and may play a role in driving the cancer’s growth and spread. Published online May 9 in Nature, the findings also indicate that rearrangements in chromosomes may contribute to melanoma’s progression and resistance to treatment, the authors wrote.
To conduct the study, Dr. Levi Garraway of Dana-Farber Cancer Institute and Harvard Medical School, and his colleagues from a number of U.S. and European institutions, performed whole-genome sequencing of 25 metastatic melanoma tumor samples and matched healthy tissue from the same patients.
They found that the number of mutated genes varied by the tumor’s location on the body. Tumors in areas that receive little sun exposure had the fewest genetic mutations, whereas those taken from areas that typically receive greater sun exposure had substantially more mutations. A tumor sample taken from a patient with a history of chronic sun exposure had the largest number of mutations.
Chromosomal rearrangements (also called translocations), within the same chromosome and between chromosomes, were common, the authors reported. Given the complexity and location of some of these rearrangements, they “may contribute importantly to melanoma genesis or progression,” the authors wrote.
Chromosomal rearrangements were frequently found near the gene PREX2. Although the most commonly mutated genes were BRAF and RAS, both of which have been linked to melanoma, PREX2 was also commonly mutated. An analysis of an additional 107 melanoma tumor samples confirmed the finding, with approximately 14 percent of the tumors harboring PREX2 mutations.
The researchers also showed that tumor growth was accelerated far more in mice implanted with melanocytes—the pigment-producing cells in which melanoma first develops—with PREX2 mutations than in mice implanted with melanocytes without such mutations.
PREX2 doesn’t appear to fit neatly into the mold of genes typically associated with cancer, they reported. “The pattern of mutations here looks a lot more like a tumor-suppressor gene, but from the functional experiments, it behaved more like an oncogene,” said study co-author Dr. Michael Berger of Memorial Sloan-Kettering Cancer Center in a news release.
Experimental Gene Therapy Protects Normal Cells from Toxic Effects of Chemotherapy
In a proof-of-concept study, a gene therapy technique designed to protect normal blood stem cells from the toxic effects of chemotherapy allowed three patients with glioblastoma to tolerate high doses of an experimental drug. All three patients survived longer than the median time for patients with this type of brain cancer, which has a poor prognosis. One patient remained alive without the disease progressing for more than 2 years after diagnosis. Dr. Hans-Peter Kiem of Fred Hutchinson Cancer Research Center and his colleagues published the findings May 9 in Science Translational Medicine.
The three patients had tumors that overexpressed a gene called MGMT. An experimental drug called O6-benzylguanine (O6-BG) inhibits the protein produced by MGMT and makes tumors more sensitive to anticancer drugs such as temozolomide, but it also increases the toxicity of chemotherapy to normal blood cells, including blood-forming stem cells. To make treatment with O6-BG tolerable, the researchers inserted a mutant MGMT gene called P140K, which makes cells resistant to O6-BG, into the patients’ blood stem cells.
The patients first underwent surgery to remove as much of their tumor as possible, followed by radiation therapy. Then stem cells were collected from their blood. The researchers cultured the stem cells in the lab and used a virus to deliver the mutant gene to the cells, in a process known as transduction. Next, the patients received the chemotherapy drug carmustine. Finally, the researchers infused the transduced stem cells into the patients, and the patients then received additional chemotherapy with O6-BG and temozolomide.
Each patient tolerated at least three cycles of combined drug treatment, and one patient received nine cycles. Normal blood cells containing the mutant MGMT gene were detected in the patients up to 14 months after stem cell transplantation. The researchers did not see any changes in the bone marrow indicative of leukemia during the study, although they plan to monitor the transduced stem cells in the remaining patient during follow-up. (One concern with gene therapy is that the foreign genes might insert themselves into the normal genome at a location that triggers a second cancer.)
The lack of toxicity seen in these patients and their relatively good survival “suggests that this approach will allow for administration of multiple cycles of this chemotherapy, possibly at higher, more-effective doses, potentially leading to better treatment outcomes,” concluded the authors.