Cancer Research Highlights
Pancreatic Cancers May Develop Slowly Over Many Years
Pancreatic cancers may take more than a decade to progress to a lethal stage, according to an analysis of genetic changes in tumors from seven patients. The findings, which appeared October 28 in Nature, surprised even the researchers themselves by indicating that there is a long lag time between the first cancer-causing genetic change in a pancreatic lesion and the development of life-threatening metastatic disease. This lag time represents a window of opportunity for detecting the cancer in its early stages, the researchers noted.
The study, by researchers at Johns Hopkins’ Sol Goldman Pancreatic Cancer Research Center, contradicts a widely held view that the disease is so deadly because it spreads rapidly. Pancreatic cancer is frequently diagnosed only after the disease has spread to other tissues, and many patients do not survive beyond a year.
The research builds on a genomic analysis of 24 pancreatic cancer genomes that was reported in 2008 by the Hopkins researchers. In the current study, the researchers carried out a genetic analysis of multiple different regions within a single patient’s primary pancreatic tumor. After identifying cancer-related mutations in regions of the primary tumor and in metastatic tumors of seven of the original patients, the researchers used mathematical models to estimate the timeline of pancreatic cancer progression.
On average, the researchers estimated, 11.7 years had passed between the initiating mutation in the tumor cell and the development of the first cancer cell that gave rise to the “parental clone,” which contains all of the mutations known to drive pancreatic cancer development. Another 6.8 years passed before at least one subclone had gained the genetic potential to spread. From that point, another 2.7 years, on average, passed before the patients’ deaths.
“We were all surprised by how slow the natural history of pancreatic cancer seems to be,” said lead researcher Dr. Christine Iacobuzio-Donahue. “This disease seems to be so lethal, and the feeling among many people has been that you can’t do anything about pancreatic cancer. But we now know that it takes years for metastases to develop. So we finally have an idea of what we need to do in terms of early detection and when we need to do it.”
In an accompanying study published in Nature, researchers at the Wellcome Trust Sanger Institute profiled genomic rearrangements—chromosomal alterations that result when DNA has been broken and shuffled in some way—in primary and metastatic pancreatic tumors from 13 patients. Most of the rearrangements were found to occur early in the disease. The ability “to identify and understand these early mutations provides a route to the discovery of drug targets,” the study authors concluded.
Cetuximab May Benefit Some Patients with KRAS Gene Mutations
European researchers have found evidence that colorectal cancer patients with a specific mutation in the KRAS gene may benefit from the targeted drug cetuximab. Previous studies had indicated that patients with mutant KRAS derive no benefit from cetuximab, and the American Society of Clinical Oncology has recommended that patients with mutated forms of KRAS not receive the drug. This new retrospective analysis of data from 579 patients with chemotherapy-resistant colorectal cancer was published October 27 in JAMA.
Researchers led by Dr. Wendy De Roock from the University of Leuven in Belgium analyzed data from patients with advanced colorectal cancer who had received cetuximab, with or without chemotherapy, in six clinical trials or who had received cetuximab outside of a clinical trial. They compared survival of patients with the normal KRAS gene, patients with the most common mutation in a part of the KRAS gene called codon 13, and patients with all other KRAS mutations.
Patients with the mutation in codon 13 (called p.G13D) survived for longer than patients with other KRAS mutations who received cetuximab (medians of 7.6 months versus 5.7 months). In addition, overall survival was similar between patients with the p.G13D mutation and patients with a normal KRAS gene.
In a corresponding set of experiments in cell lines, the researchers found that cetuximab inhibited the growth of colorectal cells containing the normal KRAS gene and cells containing the p.G13D mutation, but not cells with other KRAS mutations. The researchers observed the same pattern when cetuximab was given to mice implanted with colorectal cancer cells.
Because the new analysis of patient data “is a retrospective observational study that relies largely on nonrandomized or cross-trial comparisons…it can therefore only suggest an association between p.G13D mutation status and survival benefit after cetuximab-based treatment,” stated the authors. They concluded that prospective randomized trials in patients with the p.G13D mutation are needed “before conclusions about potential beneficial effects of cetuximab…should be inferred.”
Protein Found on Tumor Blood Vessels Might Be Cancer Target
A cell-surface protein called the follicle-stimulating hormone (FSH) receptor, which was previously thought to exist only in specialized areas of the ovaries and testes, has been found on the surface of blood vessels in 11 different tumor types but not in the surrounding normal tissue. The results of the study, published October 21 in the New England Journal of Medicine, raise the possibility that the receptor could potentially be exploited for cancer imaging and targeted treatments.
Researchers led by Dr. Aurelian Radu from Mount Sinai School of Medicine examined tumor samples taken from 1,336 cancer patients who had not received chemotherapy or hormone therapy before surgery. Blood vessels that had the FSH receptor were found at the periphery of every tumor sample taken from 773 men with prostate cancer.
In a follow-up set of samples from 563 patients with 10 different tumor types, the FSH receptor was also found in each sample, regardless of tumor type or stage. The researchers also examined normal tissue samples and noncancerous tissue samples taken from inflammatory, regenerative, or proliferative diseases or conditions, and did not find FSH receptors.
With the exception of those in the kidney cancer samples, the blood vessels that had FSH receptors were restricted to the periphery of the tumors, in a layer approximately 10 mm thick. An imaging agent that could specifically target the FSH receptor could be used to define the boundary between normal and tumor tissue for surgery or radiation therapy, the authors hypothesized.
In an in situ test, the researchers perfused euthanized mice carrying prostate tumor xenografts with a solution of antibodies that attach to the FSH receptor, bound to a molecular imaging agent. The antibodies selectively bound to the outside of tumor blood vessels, and the imaging agent was taken up by the blood vessel cells. However, the researchers cautioned that because of the way the experiments were carried out, their results “cannot be considered to be a proof-of-principle demonstration that the FSH receptor expressed on tumor-associated blood vessels can be exploited clinically.” But since the FSH receptor may play an important biological role in tumor blood vessel formation, they hypothesized that blocking FSH-receptor signaling could be a new strategy against tumors.
More Evidence Suggests Aspirin May Prevent Colorectal Cancer
While previous results have shown that aspirin and celecoxib (a selective COX-2 inhibitor) reduce the risk of colorectal adenomas and precancerous polyps in people at high risk, a new meta-analysis showed that both colorectal cancer and deaths from the disease may be reduced by long-term daily use of aspirin. The results were published online October 21 in The Lancet.
Dr. Peter Rothwell of the University of Oxford and his colleagues calculated 20-year risk estimates by pooling data from more than 14,000 patients enrolled in five randomized trials conducted in the United Kingdom, Sweden, and the Netherlands. The trials were designed to study the effect of aspirin on the risk of heart attack and stroke, but cancer data were collected as well. The researchers found that patients who took at least 75 mg of aspirin daily for about 5 years had a 24 percent lower risk of colorectal cancer and a 35 percent lower risk of dying from the disease.
For those trials where data were available for sites within the colon, the preventive benefit of aspirin appeared to be confined primarily to the proximal colon, with a reduction in incidence of about 55 percent. Cancer incidence in the distal colon was not reduced. This distinction is important because colorectal cancer screening with sigmoidoscopy, the screening approach more commonly used in Europe, does not detect cancer in the proximal colon. (Although colonoscopy, the approach more commonly used in the United States, surveys the entire colon, its benefits may be limited mainly to the more distal part of the colon.)
The authors acknowledged a number of limitations to the study. They noted, for example, that they “did not model the effect of the reduction in deaths due to colorectal cancer on the overall balance of risk and benefit of long-term use of aspirin,” which can cause nausea, heartburn, and irritation and bleeding in the intestines, bowel, and stomach. In addition, they noted, the five trials included in the study “predated endoscopic screening for adenomas, which also reduces colorectal cancer incidence and mortality, and might therefore reduce the absolute benefit of aspirin.”
“These findings represent some of the longest follow-up data following 5 years of treatment,” said Dr. Ernest Hawk of the University of Texas M. D. Anderson Cancer Center. “They also answer a long-standing question: what dose is required for a protective benefit? This study suggests that 75 mg is adequate.”
Also in the News: Experimental DNA Test May Detect Colorectal Polyps and Cancer
An investigational screening test for colorectal cancer that detects DNA mutations or methylations in stool samples shows promise in detecting both precancerous adenomas and cancers, researchers from the Mayo Clinic and Exact Sciences reported last week. The findings, from the first clinical validation study of the next-generation test, were presented at the American Association for Cancer Research special conference, Colorectal Cancer: Biology to Therapy, in Philadelphia.
The test, which detects genetic changes known as methylation to several genes and mutations in the KRAS gene, identified nearly 64 percent of adenomas greater than 1 cm in size and 85 percent of cancers, based on known findings in the patients from whom the samples were taken. The test picked up adenomas and cancers regardless of their location in the colon, explained lead investigator Dr. David Ahlquist of the Mayo Clinic. The detection figures were based on a test designed to have 90 percent specificity, meaning it would be expected to have a false-positive rate of 10 percent, Dr. Ahlquist said.
The researchers used stored stool samples from patients from four different centers, but there was no standardized system for sample collection or storage, Dr. Ahlquist noted. Prospective studies of the test are expected to begin next year. Mayo stands to receive royalty and other payments from Exact Sciences under a licensing agreement with the company, Dr. Ahlquist said.