© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
The genomic revolution presents exciting opportunities to learn about the etiology of cancer and other complex diseases. In a commentary, Wacholder et al. (p. 434) argue that the practice of using the P value alone to declare a finding to be statistically significant is no longer appropriate for deciding which of the many reports of associations between genetic variants and common cancer sites are truly significant. They propose, instead, that investigators use the false-positive report probability (FPRP)—the probability of no true association between a genetic variant and a disease, given a statistically significant finding—to evaluate whether a finding is noteworthy. The authors show how to calculate FPRP and demonstrate how FPRP can be used in the design, analysis, and interpretation of molecular epidemiology studies. The authors conclude that the FPRP approach helps formalize what investigators have always been performing informally, that is, tempering enthusiasm for surprising findings with consideration of plausibility.
In an editorial, Thomas and Clayton (p. 421) discuss the issues around multiple comparisons and Bayesian paradigms for analysis of epidemiologic studies in the genomic era, and they highlight various aspects of the FPRP approach. They conclude that the fundamental issue of how associations between genetic variants and disease should be reported remains unclear.
Treatment Trends in Ductal Carcinoma In Situ of the Breast
An increased incidence of ductal carcinoma in situ (DCIS) of the breast has been documented. Baxter et al. (p. 443) used data from the Surveillance, Epidemiology, and End Results program to assess the treatment of patients with DCIS between 1992 and 1999. They found that, between 1992 and 1999, the incidence of DCIS dramatically increased with time from 2403 cases in 1992 to 4166 cases in 1999 and that the rate of mastectomy decreased from 43% in 1992 to 28% in 1999. However, because of the increased diagnosis of DCIS, the age-adjusted incidence of mastectomy for DCIS in the population did not change (7.8 per 100,000 women in 1992 and 1999). In addition, almost half of patients who had a lumpectomy did not undergo radiation therapy. The authors conclude that, although many patients were found to undergo aggressive therapy including mastectomy and axillary lymph node dissection, others appeared to be undertreated.
In an editorial, Morrow (p. 424) discusses certainties and uncertainties of DCIS. She states that the lack of understanding of the natural history of DCIS and the wide range of treatment options for DCIS have resulted in confusion among both women and their physicians regarding the selection of appropriate management strategies. She notes that the ability to predict how DCIS will progress in individual women will solve the treatment dilemma.
HPV, Oral Cells, and Risk of Head and Neck Cancer
Human papillomavirus (HPV) has been associated with the development of head and neck cancers. Smith et al. (p. 449) conducted a case–control study to determine the risk factors for head and neck cancer in relation to HPV infection. The authors detected oncogenic, or high-risk (HR), HPV types in oral cells from 22.9% of case patients and 10.8% of control subjects. Individuals with HPV-HR types, but not individuals with nononcogenic HPV types, had an increased risk of head and neck cancer compared with HPV-negative individuals. HPV-HR types detected in oral exfoliated cells were predictive of HPV-HR types in tumor tissue. The authors found a synergistic effect between detection of HPV-HR and heavy alcohol consumption, but an additive effect between detection of HPV-HR and tobacco use. The authors conclude that HPV testing of an oral rinse may provide an early biomarker for HPV-associated head and neck cancer.
Letrozole and Tamoxifen in a Mouse Breast Cancer Model
Clinical data from patients with estrogen receptor–positive breast cancer indicate that aromatase inhibitors, such as letrozole, are more effective and better tolerated than the antiestrogen tamoxifen. To investigate ways to optimize treatment using letrozole and tamoxifen, Long et al. (p. 456) treated a mouse xenograft breast cancer model with various combinations of these drugs. First-line treatment with letrozole was superior, in terms of time to tumor progression, to that with tamoxifen or with tamoxifen plus letrozole. Treatment with alternating courses of the two drugs was also not as effective as treatment with letrozole alone. Tumors progressing on tamoxifen were sensitive to second-line therapy with letrozole, but tumors progressing on letrozole were not sensitive to second-line therapy with tamoxifen or with fulvestrant, another antiestrogen. The authors note that further studies will be needed to determine the most effective second-line therapies for tumors that progress on letrozole.
Arsenic Exposure and Estrogen Signaling
Mice exposed to arsenic in utero develop a range of tumor types, including hepatocellular carcinoma, that are similar to those induced in adult mice by exposure to estrogenic compounds. To investigate the relationship between arsenic exposure in utero and estrogen signaling, Waalkes et al. (p. 466) analyzed the expression of the estrogen receptor-
(ER-) gene and several estrogen-responsive genes in the livers of adult male mice that developed hepatocellular carcinoma after arsenic exposure in utero. Liver expression of both the ER- and cyclin D genes was higher in arsenic-exposed mice than in control mice; in addition, several cytochrome P450 genes were expressed in a feminized pattern. Methylation of the ER- gene was much lower in exposed mice than in control mice. The authors suggest that overexpression of ER- in the liver, possibly as a result of reduced promoter methylation, may account for the development of hepatocellular carcinoma in mice exposed to arsenic in utero.
Melatonin and Breast Cancer
Experiments in animals have suggested that melatonin, a pineal hormone, has a protective role in the etiology of breast cancer, but results from several human studies have been inconsistent. Travis et al. (p. 475) conducted a prospective nested case–control study among British women to determine whether low levels of melatonin were associated with an increased risk for developing breast cancer. They found no evidence that the level of melatonin is associated with the risk for breast cancer. However, they note that other prospective studies are needed to further explore the relationship.
| ||||||||||||||||||||||||||||||||||||||||