Cancer Research Highlights
Adjuvant Chemotherapy May Benefit Older Patients with Colorectal Cancer
A new analysis of results from a large clinical trial indicates that some patients with colorectal cancer who are age 70 or older may have improved outcomes with post-surgical chemotherapy that includes newer agents. The finding, presented at the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium, runs counter to the results of a data analysis from another clinical trial, published last year, that found no such benefit.
In the nearly 1,900-patient clinical trial, participants with stage III colorectal cancer who received capecitabine and oxaliplatin, a regimen called XELOX, lived longer after surgery without their tumors progressing than those who received an older regimen, the drugs 5-fluorouracil (5-FU) and leucovorin. Overall survival data aren’t yet available from the trial, explained the study leader, Dr. Daniel Haller, of the University of Pennsylvania’s Abramson Cancer Center, during a press briefing.
Disease-free survival after 3 years of follow up was 71 percent among patients who received XELOX compared with 67 percent among patients who received 5-FU and leucovorin. When disease-free survival was analyzed by age group (younger than 70 and 70 or older), XELOX led to improved disease-free survival for patients in both age groups, although the improvement was statistically significant only in patients younger than 70. The lack of statistical significance among those 70 or older, Dr. Haller said, was likely due to the smaller number of trial participants who fell into that age group—approximately 400 patients.
The finding that patients over age 70 may benefit from this adjuvant regimen is clinically important, Dr. Haller argued. Based on the recently published MOSAIC trial results and an analysis of six clinical trials of adjuvant therapy for colorectal cancer, which showed no benefit with the addition of oxaliplatin to adjuvant therapy in patients age 70 and older, some oncologists are not including such newer drugs as part of adjuvant chemotherapy offered to patients in this age group, regardless of their health status, he said.
The findings should help clinicians make more informed choices about adjuvant therapy with their patients who are older than age 70, said Dr. Jack Welch of NCI’s Division of Cancer Treatment and Diagnosis. The data show that some patients over age 70 can tolerate the XELOX regimen, he continued. “And capecitabine is an oral drug, which might make treatment more accessible for elderly patients with limited transportation options,” so the convenience of the regimen could contribute to patient compliance, he said.
Brain Cancer, Like Other Cancers, Has Distinct Subtypes
A survey of genomic changes in several hundred brain tumors revealed two new molecular subtypes of the disease and confirmed two previously known subtypes. The findings, from The Cancer Genome Atlas (TCGA) Research Network, indicate that glioblastoma, the most common malignant brain tumor in adults, includes at least four distinct forms that are recognizable by their genetic signatures. In additional work, the researchers found that the response to aggressive therapies for glioblastoma varied by subtype, according to their report in the January 19 Cancer Cell.
The ability to detect subtypes establishes a framework for future research and holds promise for matching patients with the most appropriate therapies. The findings could also lead to therapies directed at the molecular changes underlying each subtype, as has happened in some types of breast and other cancers. Similarly, experimental models could be developed for each subtype. The results may also help investigators identify the cells of origin for these cancers, which would have implications for treatment.
The work builds on a recent report by TCGA authors describing a core set of molecular pathways that are commonly deregulated in glioblastoma. In the current study, Dr. Neil Hayes of the Lineberger Comprehensive Cancer Center at the University of North Carolina and his TCGA colleagues integrated various types of genomic information for 200 tumors, including changes in the number of copies of genes and DNA mutations.
The four subtypes were characterized by alterations involving the genes PDGFRA, IDH1, EGFR, and NF1. In each tumor subtype, a series of molecular events occurred, often leading to changes in the activity of thousands of genes. This observation was validated in a second set of 260 tumors.
“This work is a powerful example of how data from TCGA can be used by research teams to better understand and treat complex diseases such as glioblastoma,” said NCI Deputy Director Dr. Anna Barker.
Dr. Hayes added, “These results give us a clear direction for how we’d like to proceed in this disease. Based on the patterns, we can divide patients up in a logical manner and eventually tailor therapies for more individualized care.” Noting that TCGA investigators will be analyzing a number of tumor types in the coming year, he continued, “This paper is a model for how we’d like to proceed. And it’s good to have a model, because we have a lot of data coming our way.”
Strategy May Enhance Umbilical Cord Blood Transplants
A new study offers a potential way to help restore blood cells and the immune systems of patients who have had treatments, such as chemotherapy, that deplete normal cells along with tumor cells. The method increases the numbers of hematopoietic stem cells that can be obtained from umbilical cord blood by stimulating the Notch signaling pathway of cord blood stem/progenitor cells in the laboratory (ex vivo). These cells can then be transplanted into patients, where they give rise to new blood cells, including the white blood cells of the immune system.
A team from the Fred Hutchinson Cancer Research Center (FHCRC) tested the method in a phase I trial of patients with acute leukemias. The modified transplanted cells repopulated certain immune cell types faster than normal umbilical cord blood did, in some cases by more than a week, the researchers reported online in Nature Medicine on January 17. The results, while preliminary, suggest that this method reduces the time it takes for the patient’s immune system to recover after a transplant. Speeding this recovery is important because the lack of an immune system leaves patients vulnerable to life-threatening infections.
The Notch signaling pathway is an important regulator of development. A decade ago, Dr. Irwin D. Bernstein of FHCRC and his colleagues discovered that increased activity of the Notch1 gene was associated with expanded populations of hematopoietic stem/progenitor cells. Since then, he and others have been developing ways to translate this discovery into the clinic without having to alter the gene itself. Instead, their technique stimulates Notch signaling through molecules that interact with proteins in the pathway.
“This study demonstrates in principle that a well-known regulator of development can be used to self-renew a population of cells for therapeutic purposes without altering the genetic makeup of the cells,” said Dr. Bernstein. He collaborated on the trial with Dr. Colleen Delaney, who coordinates the cord blood transplant program at FHCRC. It is not yet known whether the strategy will improve the outcomes of patients, but the researchers plan to address that question in ongoing studies.
Acupuncture Reduces Joint Pain in Some Women with Breast Cancer
In a small randomized clinical trial, breast cancer patients experiencing joint pain and stiffness from aromatase inhibitor (AI) treatment reported an improvement in pain from acupuncture. Eighty percent of women receiving acupuncture reported at least a 2-point improvement on a 10-point pain scale, compared with 22 percent of women who received a sham treatment. These results were published January 25 in the Journal of Clinical Oncology.
Researchers led by Dr. Katherine D. Crew of Columbia University enrolled 51 women in the trial, 43 of who were randomly assigned and 38 of who completed the treatment. Scheduling difficulties accounted for most of the women who enrolled but did not begin or finish treatment.
All of the women were blinded to their treatment assignment, which consisted of either 12 acupuncture sessions or 12 sham treatments (in which needles were lightly inserted into the body at points thought to have no effect on pain) over the course of 6 weeks. The researchers used three different scales to measure changes in joint pain, stiffness, and knee and hand function.
At the beginning of the study, women in the acupuncture group reported a mean worst pain score of 6.7 (on a scale from 1 to 10), compared with a mean score of 5.6 in women in the sham group. After treatment, women in the acupuncture group reported a mean worst pain score of 3.0, compared to 5.5 in women in the sham group. These numbers corresponded to a 50 percent improvement in pain scores for the acupuncture group.
“To our knowledge,” concluded the authors, “this report is the first randomized, placebo-controlled trial establishing the use of an intervention to control AI-related joint symptoms, which should be confirmed in a larger randomized trial.”
Genome Scans for Pancreatic Cancer Yield Clues to Risk
A genome-wide association study for pancreatic cancer has, for the first time, identified regions on three chromosomes that may harbor risk factors for the disease. Researchers now have new leads for investigating genetic factors involved in this deadly disease. One of the regions, on chromosome 5, has been associated with multiple diseases and may have a role in various cancers, the study authors reported online in Nature Genetics on January 24.
“This is really the first large, comprehensive effort that has identified novel genomic regions associated with an increased risk of pancreatic cancer,” said lead author Dr. Gloria M. Petersen of the Mayo Clinic. The genetics of pancreatic cancer are challenging to study, she noted, because the disease is relatively rare and many patients do not live more than a year after diagnosis.
In the team’s initial analysis reported last year, the researchers found that a variant in the gene ABO, which determines blood type, is associated with the risk of pancreatic cancer. For the current analysis, the team expanded their efforts and collected DNA from nearly 4,000 patients in 13 different studies around the world. They then tested 550,000 DNA markers (single-nucleotide polymorphisms) in both the patients and a comparison group. The top hits included segments on chromosomes 1, 13, and 5.
“The three regions are unequivocally associated with the risk of pancreatic cancer, and they point to biologically new and interesting places in the genome,” said senior author Dr. Stephen Chanock of NCI’s Division of Cancer Epidemiology and Genetics. The region on chromosome 5 appears to play a role in multiple cancers and in this respect may be comparable to a region on chromosome 8, known as 8q24, which is associated with at least five different cancers, he added.
Previous studies have linked the segment on chromosome 5 to cancers of the brain, lung, and bladder, as well as to melanoma, leukemia, and pulmonary fibrosis. This region includes two genes associated with cancer, including TERT, which is essential for maintaining the ends of chromosomes, called telomeres. Changes in the activity of this gene can cause cells to live longer and may lead to cancerous changes, the researchers noted.