Genetic Signature Associated with Breast Cancer Relapse

Scientists have identified a genetic "signature" associated with breast tumors that recur years after treatment. The signature is based on the activity of 76 genes and could potentially be a diagnostic tool for identifying patients at risk for relapse before they are treated, according to a study in the February 19 issue of Lancet.

Dr. John Foekens of Erasmus MC, Rotterdam, Netherlands, and his colleagues profiled gene activity in 286 tumors from patients with lymph-node-negative breast cancer who had not received hormone or chemotherapy after their initial treatment. Using DNA microarrays, they tracked nearly 18,000 genes, eventually pinpointing 76 that strongly correlated with the risk of recurrence. The researchers tested the signatures of those genes in 171 patients and accurately identified 93 percent of those who had relapsed within 5 years of treatment.

The ability to use genetic signatures to recognize tumors that are likely to recur after treatment could allow doctors to tailor treatment plans accordingly, sparing patients with good prognoses unnecessary therapy. Currently, there are no reliable diagnostic tools to predict which patients are likely to relapse.

Several recent studies have generated candidate signatures for breast tumors, but the authors of an editorial accompanying the new study observe that there is a "complete lack of agreement" among the lists of suspect genes. "Much larger numbers of observations" are needed to develop reliable consensus signatures, write Dr. Tor-Kristian Jenssen of PubGene AS, Vinderen, Norway, and Dr. Eivind Hovig of Norwegian Radium Hospital, Montebello, Norway.

Chronic Myeloid Leukemia Vaccine May Boost Remission Rate

A multicenter, observational study of 16 patients with chronic myeloid leukemia (CML) identified a vaccine that holds promise as an adjuvant therapy to imatinib (Gleevec) and interferon, the current treatments of choice for CML, according to a report in the February 19 issue of Lancet.

The study's authors, led by Dr. Monica Bocchia from Siena University in Italy, emphasized that the vaccine treatment was designed to further reduce any residual disease - after remission effects from one of the other drugs had leveled off - as well as to increase the number of patients able to reach complete cytogenic remission. The vaccine - known as CMLVAX100 - is a multipeptide compound. It targets malfunctions at the p210 fusion point by generating peptide-specific CD8 and CD4 cells.

The study patients had all experienced varying degrees of remission while on chemotherapy with either imatinib or interferon; however, all had some residual disease at the molecular level. Their disease conditions had also stabilized for a median of between 10 months (imatinib) and 17 months (interferon), as indicated by bone marrow assessment for Philadelphia chromosome-positive cells, the marker traditionally used to measure CML at the cellular level.

After 6 vaccinations in 3 months, 15 of the 16 patients experienced further reductions of their disease, with 7 progressing to complete cytogenic remission. In addition, some of those who did progress to complete remission showed no detectable transcripts of the BCR-ABL gene, which encodes the p210 protein.

In an accompanying editorial, researchers at the Beckman Research Institute, City of Hope National Medical Center, noted that while imatinib had "revolutionized the therapy of CML," drug resistance and other factors would make a vaccine a welcome addition to the treatment arsenal.

New Biomarker May Improve Early Detection of Liver Cancer

Patients who have liver cirrhosis, an antecedent to liver cancer, can undergo frequent screening to catch cancer early, if it develops. But the current screening procedures for liver cancer, including ultrasound and blood tests (one of which detects alpha fetoprotein, or AFP), are not very reliable. However, researchers have identified a blood protein - des-gamma-carboxyprothrombin (DCP) - that may solve this problem, and NCI has launched a new clinical trial, led by Dr. Jorge Marerro of the University of Michigan and coordinated by Dr. Paul Wagner of NCI's Cancer Biomarkers Research Group, to determine whether an assay that detects DCP will improve the accuracy and sensitivity of liver cancer screening over the methods currently available.

DCP, a precursor to the protein prothrombin, is produced by the liver to help blood clot. DCP levels start to rise in patients with liver cancer, and this trend can be monitored through a blood test. The test kit, which was developed by Eisai Company and is being supplied to the study free of charge by this company, has shown 90 percent accuracy in detecting DCP.

Now the validity of that test will be measured through the EDRN-established phase II clinical validation trial conducted at six centers across the United States: University of Michigan; Mount Sinai Hospital in New York City; University of Pennsylvania; Mayo Clinic; St. Louis University; and Stanford University. Over the course of 2 years, researchers will monitor 450 patients who have liver cancer, 170 of whom are early stage, and a control group of 450 patients who have cirrhosis but not cancer. Data are expected in early 2007. "If DCP is proven as an early biomarker alone or as an adjunct to AFP," says Dr. Sudhir Srivastava, chief of NCI's Cancer Biomarkers Research Group, "it will trigger early intervention leading to a much needed effective clinical management of the disease."

NCI Researchers Improve Efficacy of Anti-Cancer Immunotoxin

NCI researchers have improved the anticancer immunotoxin HA22 by simply changing one amino acid in this protein. The researchers, led by Dr. Ira Pastan, increased HA22's toxicity to cancer cells over two-fold without producing any additional harmful side effects in mice. These results appear in the February 15 Clinical Cancer Research and demonstrate that genetic engineering can be used to increase the efficacy of immunotoxins and other drugs, allowing researchers to create the most effective drugs before clinical testing.

Immunotoxins, which are emerging as promising cancer treatment agents, are hybrid proteins comprising an antibody portion that selectively bind targets on the surface of cancer cells and a toxin that kills the cancer cell once it is internalized. The immunotoxin HA22's antibody component targets the surface protein CD22, which is expressed on many B-cell lymphomas and leukemias. Dr. Pastan and colleagues mutated the toxin's arginine 490 residue to an alanine, hypothesizing that altering this exposed portion of HA22 might increase its half-life in the blood and make it more resistant to degradation.

Interestingly, the engineered HA22 (R490A) did not have an increased half-life, but was still more effective than HA22. HA22 (R490A) was two to three times more toxic to several different B cell lymphoma cell lines and was also about twice as effective in reducing tumors in mouse models. At therapeutic doses, HA22 (R490A) was well tolerated in mice, causing some weight loss but no other adverse effects.

Higher PSA Yields More Biopsies, Early PLCO Data Show

Rates of biopsy among men with abnormal prostate-specific antigen (PSA) and digital rectal exam (DRE) tests show wide variance, according to some early data from the prostate cancer screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. Published in the March issue of the Journal of Urology, the study shows that at 3 years, of the 2,717 men who had a baseline positive PSA (greater than 4 nanograms per milliliter based on results from a central laboratory) at study entry, 41 percent had a biopsy within 1 year and 64 percent had a biopsy within 3 years. PSA scores of 7 ng/ml or higher were associated with significantly higher biopsy rates. Biopsy rates were lower among men who had positive DRE results but negative PSA results, with 27 percent of the 4,449 men in this category obtaining a biopsy within 3 years.

Diagnostic follow-up of PLCO participants was not included in the trial design, meaning that after screening, the decision for participants to undergo a biopsy or not was left to the discretion of treating physicians. Given the "large, geographically diverse sample of American men" participating in PLCO, said study lead author Dr. Paul F. Pinsky from NCI's Division of Cancer Prevention, "these results suggest that the experience of PLCO men in terms of follow-up biopsy is generally representative of current practice patterns in the United States."

A related commentary in the journal criticized the PLCO design for not requiring that participants undergo "effective therapy if cancer is found." In the study authors' published response, they explained that the design was necessary because "study investigators…work within a medical system of physician patient/autonomy, particularly those regarding the choice of diagnostic follow-up procedures or therapies." In addition, they argued, the study data "indicate that the medical community at large does not view immediate biopsy as the standard of care for all men with positive prostate cancer screens" and "clearly show that physicians are using clinical judgment in determining who should be biopsied."