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© Oxford University Press 2008.
IN THIS ISSUE
Antioxidant Supplementation During Cytotoxic TherapyDespite extensive research, questions remain about the efficacy and safety of the use of dietary antioxidant supplementation during conventional chemotherapy and radiation therapy. Several randomized clinical trials have demonstrated that the concurrent administration of antioxidants with chemotherapy or radiation therapy reduces treatment-related side effects. However, some data indicate that antioxidants may protect tumor cells as well as healthy cells from oxidative damage from radiation or chemotherapy, although, other data suggest that antioxidants can protect normal tissues without decreasing tumor control. Lawenda et al. (p. 773) review data from preclinical studies, observational studies, and published randomized clinical trials regarding the putative benefits and potential risks of antioxidant supplementation concurrent with cytotoxic therapy. They conclude that the use of supplemental antioxidants during chemotherapy and radiation therapy should be discouraged because of the possibility of tumor protection and reduced survival.
The Role of Overlapping Tumor Supressors in Melanoma
The CDKN2A/INK4A locus includes two tumor suppressor genes, p14ARF (ARF) and p16INK4a (p16), whose coding sequences overlap. There has been strong evidence that inactivation of p16 is a critical event in the development of melanomas in humans, but evidence from mouse models has suggested an important role for ARF. Using a variety of techniques, Freedberg et al. (p. 784) analyzed mutations and DNA methylation at the CDKN2A/INK4A locus in 60 melanoma metastases and found that inactivation of ARF in the presence of an intact p16 gene occurred frequently. The authors raise the possibility that alterations in ARF, p16, or both could translate into particular tumor characteristics.
In an editorial, Peters (p. 757) reviews the evidence implicating ARF, p16, and an additional tumor supressor at the same locus, p15INK4b, in oncogene-induced senescence and susceptibility to cancer. He suggests the need for caution in concluding that ARF is inactivated in the absence of confirmatory expression data.
Serum Vitamin D Level and Risk of Prostate Cancer
Vitamin D has been found to suppress proliferation and differentiation of human prostate cancer cells in vitro, raising the possibility that higher serum levels of vitamin D might be associated with reduced risk of or mortality from prostate cancer. However, results of epidemiological studies of the association between vitamin D levels and risk of prostate cancer have been mixed. Ahn et al. (p. 796) investigated this association in a nested case–control study of men participating in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The risk of prostate cancer overall and of nonaggressive disease did not differ according to serum vitamin D level. However, men with vitamin D levels above the lowest quintile had an increased risk of aggressive disease, although no clear dose–response association was evident.
In an editorial, Mucci and Spiegelman (p. 759) note that the authors have provided an excellent example for other researchers to follow in examining aggressive disease as a separate stratum. They note that a randomized trial would provide the best evidence of the relationship between vitamin D and prostate cancer and suggest that prostate cancer incidence could be analyzed in trials of vitamin D supplementation designed to examine other endpoints.
Trial of FEC Alone or Followed by Paclitaxel for Early Breast Cancer
Taxanes are among the most active drugs for the treatment of metastatic breast cancer. Martín et al. (p. 805) investigated taxanes in the adjuvant setting in a phase III randomized trial among women with lymph node–positive breast cancer. They compared fluorouracil, epirubicin, and cyclophosphamide (FEC) treatment with FEC treatment followed by weekly paclitaxel (FEC-P). FEC-P treatment was associated with a statistically significant 23% reduction in the risk of relapse compared with FEC treatment and a non–statistically significant 22% reduction in the risk of death. There was no evidence for an interaction between either HER2 or hormone receptor status and effect of paclitaxel treatment. The authors conclude that addition of taxanes to FEC adjuvant chemotherapy reduces the risk of relapse for patients with lymph node–positive breast cancer irrespective of HER2 or hormone receptor status.
In an editorial, Hudis and Dang (p. 761) emphasize that there is a risk when results of unplanned subset analyses, such as the earlier analyses suggesting that hormone receptor and HER2 status could predict benefit from paclitaxel, guide clinical practice. Hypothesis-generating subset analyses should not change practice until they are confirmed prospectively. The prospective study by Martín et al. joins a growing list of studies that do not support the hypothesis that hormone receptor and HER2 status predicts which patients will benefit from adding taxanes to chemotherapy.
ER-Dependent Signaling in an Aggressive Prostate Cancer
Prostate cancers that have a translocation that causes the 5'-untranslated region of the transmembrane protease serine 2 to be fused to the coding region of the ERG transcription factor (TMPRSS2-ERG) are more aggressive than prostate cancers without this gene fusion. To determine the pathways involved in TMPRSS2-ERG function in these cancers, Setlur et al. (p. 815) used gene expression profiling of more than 6000 prostate cancers in men in the Swedish Watchful Waiting and the Physicians Health Study cohorts. From the resulting unique 87-gene signature, they used computational modeling to determine the molecular pathway through which the TMPRSS2-ERG gene fusion acts. The modeling suggested that the estrogen receptor (ER) was involved in the pathway. The authors then tested the effects of ER agonists on cell viability and TMPRSS2-ERG expression using prostate cancer cell lines. Viability of an androgen receptor–negative prostate cancer cell line was sustained and TMPRSS2-ERG expression increased with ER
agonist treatment; both decreased with ERβ agonist treatment. The authors conclude that TMPRSS2-ERG fusion prostate cancer is a unique molecular subclass of prostate cancer and that TMPRSS2-ERG expression is ER dependent.
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Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 773-783.
J Natl Cancer Inst 2008 100: 815-825.
J Natl Cancer Inst 2008 100: 805-814.
J Natl Cancer Inst 2008 100: 796-804.
J Natl Cancer Inst 2008 100: 761-763.
J Natl Cancer Inst 2008 100: 757-759.
J Natl Cancer Inst 2008 100: 784-795.
J Natl Cancer Inst 2008 100: 759-761.
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