National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
March 6, 2012 • Volume 9 / Number 5

Cancer Research Highlights

Vemurafenib Improves Survival for Patients with Metastatic Melanoma

Patients with metastatic melanoma whose tumors harbor a specific genetic mutation have improved overall survival with the targeted therapy vemurafenib (Zelboraf), according to longer-term follow-up data from a phase II clinical trial published in the February 23 issue of the New England Journal of Medicine. The mutation, the V600 mutation in the BRAF gene, is found in approximately half of patients diagnosed with melanoma.

After a median follow-up of almost 13 months, median overall survival was nearly 16 months in the trial of 132 patients whose cancer was no longer responding to standard treatments—a substantial improvement over the 6- to 10-month median survival traditionally seen in patients with metastatic melanoma. The median progression-free survival was 6.8 months.

Last year, based on the impressive early results of a large phase III trial, the Food and Drug Administration approved vemurafenib for the treatment of patients with metastatic disease whose tumors have this mutation.

In the current trial—funded by the drug’s manufacturer, Roche—a tumor response was observed in more than half of the patients, with 6 percent of patients experiencing a complete response. Most patients whose tumors responded to treatment saw their tumors shrink within 2 months.

Most patients taking the drug will ultimately develop resistance, said the study’s lead author, Dr. Jeffrey Sosman of Vanderbilt-Ingram Cancer Center in Tennessee. But a subset of patients, he noted, have shown no signs of progression even 2 years after beginning treatment.

The drug is generally well tolerated, the researchers reported. Nevertheless, 45 percent of patients had their dose of the drug reduced, and nearly two-thirds had to have their treatments temporarily stopped, because of side effects. Common side effects included rash, joint pain, and extreme sensitivity to light. And, as has been seen in other trials of vemurafenib, approximately one-quarter of patients developed cancerous or precancerous non-melanoma skin lesions.

In most of these patients, only one or two lesions were found, and in all cases they could be removed easily with surgery, Dr. Sosman said.

Less-Invasive Colorectal Screening Test May Detect Cancer as Effectively as Colonoscopy

Initial findings from a European clinical trial show that colonoscopy and fecal immunochemical testing (FIT), a type of stool test, detect a similar number of colorectal cancers. Investigators leading the COLONPREV trial are testing whether screening average-risk individuals only once with colonoscopy can reduce the number of deaths from colorectal cancer compared with biennial screening with FIT. The results from the trial’s first round of screening appeared February 23 in the New England Journal of Medicine.

More participants in the FIT group than the colonoscopy group complied with screening, 34.2 percent versus 24.6 percent. The two tests had similar cancer detection rates, and the stage of the cancers found did not differ between the groups. Colonoscopy, however, was better than FIT at detecting both advanced and, especially, nonadvanced adenomas. But the extent to which nonadvanced adenomas are likely to progress to more advanced disease is not yet known.

“Since the primary outcome of this trial is the reduction in the rate of death from colorectal cancer at 10 years, the relative benefits and risks of the two strategies will be assessed at the end of the trial,” explained the authors. Follow-up will continue through 2021.

These results hold promise, noted Dr. Barry Kramer, director of NCI’s Division of Cancer Prevention, because the less-invasive FIT—which had better screening participation—picked up the same number of cancers as colonoscopy during the initial period of the trial.

“The final proof will be mortality, but it’s certainly conceivable that, as the trial goes on, FIT will continue to pick up potentially lethal cancers that are missed by a one-time [colonoscopy],” he explained. In the COLONPREV design, patients assigned to colonoscopy get a single test, whereas patients assigned to FIT receive the stool test every 2 years over a 10-year period.

Chemotherapy Can Impair Cognition More than Two Decades Later

More than 20 years after treatment, breast cancer patients who received adjuvant chemotherapy exhibited cognitive deficits compared with women who were never diagnosed with cancer. The results, which appeared online February 27 in the Journal of Clinical Oncology, suggest that the phenomenon known as chemobrain can persist for decades after cancer treatment ends and may become more common as the number of cancer survivors grows.

To investigate chemotherapy’s long-term effects on cognition, Dr. Vincent Koppelmans of Erasmus MC University Medical Center in Rotterdam, the Netherlands, and his colleagues identified 196 eligible breast cancer patients from two Dutch hospital registries and invited them to participate in tests that measured learning, memory, information processing, and psychomotor abilities.

All of the patients had received six cycles of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) on average 21 years earlier and were between 50 and 80 years old when recruited to the trial. Women who had experienced a relapse, second primary tumor, or distant metastases, and those who used adjuvant endocrine therapy were excluded from the study.

The 1,509 women in the reference group were selected from the Rotterdam Study, a population-based study also being conducted in the Netherlands. These women had no history of cancer and were also between 50 and 80 years old when they were tested.

Although the researchers observed no difference between the two groups in a dementia screening test, the breast cancer survivors performed worse on some tests of delayed verbal memory, processing speed, and psychomotor speed. The survivors also had more memory complaints but fewer symptoms of depression.

This pattern of deficits is similar to those from other trials conducted closer to the time patients finished chemotherapy. But it is unclear whether the results of this study are representative of the long-term effects of other chemotherapy regimens.

Although newer regimens are now available for women with early-stage breast cancer, the authors noted, “[CMF] was the standard regimen up to the 1990s... [and] cyclophosphamide and fluorouracil continue to be incorporated into currently used regimens.”

“This work is an important reminder that it is not enough to focus on the cure and control of cancer,” commented Dr. Julia Rowland, director of NCI’s Office of Cancer Survivorship. “We must also attend to the impact of therapy on the long-term health and function of our growing population of survivors.”

See also: “Delving Into Possible Mechanisms for Chemobrain

Gene Mutation Implicated in Heightened Breast Cancer Risk in Some Families

An inherited mutation in the Abraxas gene, which encodes a protein that interacts with BRCA1 and other DNA-repair proteins, is associated with an increased risk of breast cancer in some families, new study results show. The findings were published February 22 in Science Translational Medicine.

Inherited mutations in BRCA1 and BRCA2 are the strongest known genetic risk factors for breast and ovarian cancer, but these mutations do not account for all familial breast cancers worldwide.

To determine whether mutations in Abraxas might influence breast cancer risk, a team of Finnish and U.S. researchers screened breast cancer patients from 125 Northern Finnish families with a history of breast cancer for hereditary mutations in the Abraxas gene. Several gene-sequence variants were found, one of which was likely to result in altered protein function.

Three of the families were found to carry this mutation, as did one additional woman from an unselected group of breast cancer patients who turned out to have a family history of the disease. In the two families in which this analysis could be performed, the mutation was found to occur together with breast cancer. The researchers did not find the Abraxas mutation in 868 healthy Northern Finnish women.

The Abraxas protein binds directly to the BRCA1 protein and is responsible for delivering BRCA1 to sites of DNA damage in the cell nucleus, explained Dr. Roger Greenberg of the University of Pennsylvania, a co-author of the study with Dr. Robert Winqvist of the University of Oulu in Finland. “The mutant protein still interacted with BRCA1 and other DNA-repair proteins but prevented them from getting to DNA damage sites,” Dr. Greenberg said.

Defects in the DNA repair process lead to changes in a cell’s genetic material that can increase the risk of breast cancer and other cancers. Indeed, the researchers found several cancer types besides breast cancer in two of the families with Abraxas mutations, suggesting that the gene may play a role in other cancers, as does the BRCA1 gene.

Because the study looked only at people in Northern Finland, “it will be important…to investigate Abraxas mutations in other populations,” Dr. Greenberg said. Eventually, he added, Abraxas could be one of several genes tested for mutations in families with a history of breast and ovarian cancer.

Furthermore, noted Dr. Richard Pelroy of NCI’s Division of Cancer Biology, the information gleaned on how Abraxas works in concert with BRCA1 could aid development of treatments that target BRCA1 defects.

Study Details Cancer-Promoting Activity of mTOR Protein

The mTOR protein, a regulator of protein translation that is overactive in many cancers, increases the production of a specific group of proteins that help cancer cells escape tumors and invade other tissues, according to a new study published online February 22 in Nature. The same study found that, in mouse models of metastatic prostate cancer, an investigational drug called INK128 that potently blocks mTOR’s activity shrank tumors and prevented metastasis more effectively than other mTOR inhibitors.

Because of its mechanism of action, INK128 and other drugs in development that target mTOR in a similar way may be particularly effective in treating metastatic disease, noted the study’s lead investigator, Dr. Davide Ruggero of the University of California, San Francisco.

Using a new technique called ribosome profiling that shows which messenger RNAs are being translated into proteins by the ribosomes in a cell, the research team pinpointed a group of four proteins—all of which cluster together in a signaling “node”—in advanced prostate cancer cell lines whose translation was altered by mTOR inhibition.

The technology, Dr. Ruggero explained, allows researchers to analyze what is happening at the functional level in cells, particularly the production of proteins, which are the primary drivers of cellular activity. “These four proteins were really most affected downstream [of mTOR] at the translational level,” he continued. “And we show, one by one, their functional role in making tumor cells more metastatic or more invasive.”

In the mouse models, “treatment with INK128 completely blocked the progression of invasive prostate cancer locally in the prostate gland, and profoundly inhibited the total number and size of distant metastases,” the study authors wrote.

Several study authors are from the California-based company Intellikine, which is developing INK128. The drug is being tested in several phase I trials.

Also in the News: Judge Rules against Graphic Warnings on Cigarette Packages

U.S. District Judge Richard Leon ruled last week that the Food and Drug Administration (FDA) regulation requiring cigarette packages and displays to carry graphic warnings of the consequences of smoking violated tobacco companies’ free speech rights under the First Amendment. The same judge temporarily blocked the regulation last fall. The government has appealed that decision and will have 60 days to appeal the new decision.

The FDA rule was scheduled to take effect this fall but is now on hold pending the outcomes of the government’s appeals. The Department of Health and Human Services, under which the FDA falls, released a brief statement that read: “This Administration is determined to do everything we can to warn young people about the dangers of smoking, which remains the leading cause of preventable death in America. …We are confident that efforts to stop these important warnings from going forward will ultimately fail.”

Also in the Journals: Questioning the Use of Progression-Free Survival as a Clinical Trial Endpoint

A comment paper published in the Journal of Clinical Oncology last week argues that the cancer research community should consider more carefully the use of progression-free survival (PFS) as an endpoint in clinical trials. Drs. Christopher Booth and Elizabeth Eisenhauer of the National Cancer Institute of Canada noted that growing numbers of trials are using PFS as an endpoint and that drugs are being approved based on the results of such trials.

Although PFS is easily measured, it is unclear whether an improvement in PFS signals improvement in overall survival or quality of life, the authors wrote, leading them to question whether using PFS merely lowers the bar for approving new drugs without real benefit for patients.

See also: “Progression-free Survival: Patient Benefit or Lower Standard?