© Oxford University Press 2006.
IN THIS ISSUE
Independent Evaluation of the Gail ModelThe Gail model, which predicts the absolute risk of invasive breast cancer, has been used to counsel at-risk women and design intervention studies. This model has been validated in U.S. populations, but its performance in other populations is uncertain because of variations in breast cancer rates. Decarli et al. (p. 1686) used Italian data from a case–control study and cancer registries to develop a new risk prediction model that uses the same risk factors as the Gail model. They tested the predictive accuracy of the two models using independent data. Both models had equivalent discriminatory accuracy for populations but only modest discriminatory accuracy for individuals.
In an editorial, Elmore and Fletcher (p. 1673) discuss why models such as the Gail and Italian models cannot accurately assess an individual woman's risk of breast cancer. They note that much work is needed in the field of cancer risk prediction.
Cellular Telephone Use and the Risk of Cancer
Increasing cellular telephone use has raised concerns about potential health risks. Schüz et al. (p. 1707) compared cancer incidence among 420,000 cellular telephone subscribers in Denmark with that expected nationwide during 1982–2002. Cellular telephone use was not associated with risk of brain tumors, even among subscribers of 10 years or more. Cellular telephone use was associated with a lower risk of smoking-related cancers among men but with a higher risk among women. The authors conclude that overall, there was no association between tumor risk and short-term or long-term cellular telephone use.
BRCA1, BRCA2 Frequency and Cancer Penetrance
BRCA1 and BRCA2 mutations in the general population have not been well characterized. Risch et al. (p. 1694) studied 1,171 unselected patients with ovarian cancer to determine whether they carried these mutations. They also obtained the cancer histories of 8,680 first-degree relatives. Risks were increased for cancers of the breast (in both females and males), ovary, pancreas, liver, testis, and others among mutation carriers. The authors said that approximately 1% of the general population carries BRCA1 or BRCA2 mutations, a greater frequency than previously thought.
In an editorial, Offit (p. 1675) points out that mutation frequency estimates in this population were derived from the frequencies in case patients and not measured directly in control subjects. The population also included subjects from groups known to carry founder mutations. He recommends that these frequencies be confirmed because they will impact penetrance estimates in other study designs.
Predicting Drug Exposure for a Class of Anticancer Drugs
Cancer drugs may fail because the concentration required to ameliorate the cancer is not attained. Gefitinib, an epidermal growth factor tyrosine kinase inhibitor, has shown variability among patients in the plasma concentrations achieved. Li et al. (p. 1714) gave the drug midazolam, which is rapidly cleared by enzymes (CYP3A) that eliminate toxic drugs, to cancer patients and measured its clearance from the plasma. They then gave the patients gefitinib and monitored its concentration over 4 weeks. Using modeling, the authors found that the speed with which midazolam was cleared from the plasma predicted the gefitinib levels in the patient. They conclude that a test for CYP3A activity could allow clinicians to better tailor the gefitinib dose.
The ABCG2 Polymorphism and Gefitinib Toxicities
Gefinitib has activity against advanced non–small-cell lung cancer, but it also has serious side effects (diarrhea and skin toxicity). The efflux transporter protein ABCG2, which is expressed in the intestines and liver, is believed to transport gefitinib across the cell membrane. Cusatis et al. (p. 1739) investigated the association between ABCG2 variants and toxic effects in gefitinib-treated patients. Patients with at least one copy of a particular variant (the Q141K allele) had a much higher rate of diarrhea than those lacking it. The variant was not associated with skin toxicity. ABCG2 transports other oral drugs, and the authors note that investigating the effects of specific polymorphisms may assist in individualizing treatment.
p27Kip1, Cyclin E Expression, and Breast Cancer Survival
Abnormal expression of the cell cycle regulatory proteins p27Kip1 and cyclin E may be associated with breast cancer survival and relapse. Porter et al. (p. 1723) investigated these markers in patients with breast cancer. Lower p27Kip1 expression was associated with worse overall and disease-free survival among all women treated with adriamycin and cyclophosphamide and a subset with hormone receptor–positive cancer. Cyclin E expression was not associated with survival. The authors conclude that low p27Kip1 expression may be associated with poor breast cancer prognosis, especially in women with receptor-positive tumors.
Smoking, CIMP, and BRAF Mutations in Colon Cancer
Cigarette smoking has been associated with microsatellite instability in colon cancer. Most colon cancers with microsatellite instability have wide-spread methlyation of GC-rich genome sequences, called CpG islands (i.e., the CpG island methylator phenotype [CIMP]), and many harbor a specific BRAF mutation. Samowitz et al. (p. 1731) investigated whether the association between smoking and colon cancer could be explained through smoking-induced CIMP and/or BRAF mutations. Heavy smoking was associated with an increased risk of CIMP-high colon cancer and BRAF mutations. The association was related to the amount smoked but was independent of microsatellite instability. Moreover, it was limited to CIMP-high tumors with either wild-type or mutated BRAF genes. They conclude that the link between smoking and colon cancer may be explained by the association between smoking and CIMP and BRAF mutations.
Cognitive Function and Breast Cancer Chemotherapy
Some breast cancer patients experience a cognitive decline after chemotherapy. Schagen et al. (p. 1742) performed a prospective study to compare changes in cognitive performance among high-risk breast cancer patients who received high-dose or standard-dose chemotherapy, stage I patients who received no systemic chemotherapy, and healthy control subjects. More high-dose chemotherapy patients experienced deterioration in cognitive performance than control subjects. No difference was observed for the standard-dose or the no-chemotherapy groups. The authors conclude that some breast cancer treatment affects cognition in a subset of women.
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