NCI Cancer Bulletin: A Trusted Source for Cancer Research NewsNCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 9, 2007 • Volume 4 / Number 2 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Cancer Research HighlightsCancer Research Highlights

Soft-Tissue Sarcoma Risk Increased in Retinoblastoma Survivors

Patients with the hereditary form of retinoblastoma, an extremely rare form of pediatric cancer caused by a germline mutation in the RB1 gene, are at significantly increased risk of developing soft-tissue sarcomas. Researchers in NCI’s Division of Cancer Epidemiology and Genetics (DCEG) estimated the risk for individual histologic subtypes of soft-tissue sarcoma for the first time in these patients. Study results were published in the January 3 JNCI.

The study evaluated 963 patients with hereditary retinoblastoma who were diagnosed between 1914 and 1984 and lived at least 1 year after diagnosis. "Because this cohort has been followed longer than most other groups of childhood cancer survivors, we were able to determine risks for several subtypes of soft-tissue sarcoma, especially types that occur later in adulthood," said lead author Ruth Kleinerman.

Researchers found that for these survivors, the risk of leiomyosarcoma, a tumor of the smooth muscle cells, was the highest among all subtypes - up to 400 times higher than the general population - and remained high for decades. Forty-five percent of all soft-tissue sarcomas were diagnosed 30 or more years after the retinoblastoma diagnosis. 

Radiotherapy was associated with an increased risk of all subtypes of soft-tissue sarcoma evaluated in the study.

"This is important to understand because patients with hereditary retinoblastoma have excellent long-term survival rates," stated senior author and DCEG Director, Dr. Joseph F. Fraumeni, Jr. But he cautioned, "The risks seen in this study reflect treatments commonly used decades ago but no longer used in modern practice."

The authors stressed the importance of continuing surveillance throughout adulthood for survivors of hereditary retinoblastoma and the need to evaluate current treatment regimens that have been designed to have less long-term toxicity.

Molecular Signatures for Lung Cancer Outcomes Identified

The search for molecular signatures that allow more reliable prediction of the risks for recurrence and shortened survival times for lung cancer patients has yielded additional gene-expression profiles for the disease, according to results from two recently published studies. The two described gene signatures, which are different, may prove helpful in identifying patients with early-stage lung cancer who are at increased risk of recurrence and shorter survival times and who might benefit from aggressive postsurgical therapy.

A study from Taiwan, published January 4 in the New England Journal of Medicine (NEJM), identified 16 genes from 125 patients with non-small-cell lung cancer (NSCLC) who had undergone surgery to treat stage I-III disease. This 16-gene set was further narrowed to a 5-gene signature that was closely associated with relapse-free and overall survival rates among the patients, according to researchers led by Dr. Hsuan-Yu Chen of the National Taiwan University College of Public Health. Using a scoring method, they identified 59 patients with high-risk and 42 patients with low-risk gene signatures. Median overall survival was only 20 months for the high-risk individuals, compared with 40 months for the low-risk patients. The 5-gene signature’s predictive accuracy was confirmed with data from other NSCLC patients and published data.

A second study, published on the Public Library of Science (PLoS) Medicine Web site, involved a meta-analysis of data from seven gene-profile studies of patients with stage I NSCLC. The researchers identified a 64-gene signature that was also accurate in identifying high-risk versus low-risk patients with more than 85 percent accuracy.

In an editorial accompanying the NEJM article, M.D. Anderson researchers Drs. Roy Herbst and Scott Lippman commented that the Taiwan study "reflects the maturation of the first phase of lung-cancer genomics, which has been based on stored tissue and clinical charts. The field is now poised to begin its next phase - conducting prospective trials of adjuvant chemotherapy in patients with early lung cancer who are selected because they have a high risk of relapse or metastasis according to the molecular signature identified by Chen et al or others."

ASCO/CAP Publish Guidelines on HER2 Testing in Breast Cancer

An expert panel convened by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) has released new guideline recommendations on testing for human epidermal growth factor receptor 2 (HER2) in women with breast cancer.

HER2 status has important implications for prognosis, response to therapy, and selection of therapy, the panel wrote in the January 1 Journal of Clinical Oncology. This includes the use of the targeted therapy trastuzumab (Herceptin), which has proven in randomized clinical trials to improve response rates, time to progression, and survival in women with early-stage and metastatic breast cancer whose tumors overexpress HER2.

Yet, the available evidence suggests that a significant portion of HER2 testing results may be wrong, the panel explained. They highlighted, for instance, two prospective substudies of randomized clinical trials investigating the adjuvant use of trastuzumab which found that "20 percent of HER2 assays performed in the field … were incorrect when the same specimen was re-evaluated in a high-volume, central laboratory. Such a disorganized practice and high rate of inaccuracy, for such an important test that dictates a critically effective yet potentially life-threatening and expensive treatment, is not acceptable."

The recommendations, based on a systematic and thorough review of the available literature, lay out an optimal algorithm for HER2 testing, as well as requirements for the two primary techniques by which such testing is performed, fluorescent in situ hybridization, or FISH, and immunohistochemistry, or IHC. It also includes recommendations on optimal tissue handling, internal validation and quality assurance procedures, external proficiency assessment, and laboratory accreditation.

Study Shows How Arsenic Treatment Kills Rare Leukemia Cells

A new study from researchers at Dartmouth Medical School has shown how arsenic treatment for acute promyelocytic leukemia (APL), a rare form of myelocytic leukemia, destabilizes lysosomes in APL cells.  It also induces the degradation of an oncogenic protein resulting from the fusion of the promyelocytic leukemia (PLM) protein and the retinoic acid receptor α (RAR-α), which can lead to apoptosis of APL cells, according to results published in the January 3 JNCI.

Dr. Sutisak Kitareewan and colleagues treated three APL cell lines with sodium arsenite to induce lysosomal destabilization. The researchers detected and measured activity of lysosomal protease cathepsin L and conducted in vitro degradation assays of PML/RAR-α in cell lysates with and without protease inhibitors.

The study found that arsenite treatment destabilized lysosomes in APL cells. These arsenite-treated APL cells showed an increase in lysosomal cathepsin L activity, and the lysates from the treated cells induced PML/RAR-α degradation, leading to cell death, or apoptosis.

The researchers concluded, "Future studies should be directed toward elucidating the mechanism of arsenite-induced release of lysosomal enzymes and determining whether arsenite treatment of nonhematopoietic tumor cells as well as other hematopoietic tumor cells act through a similar mechanism."