© Oxford University Press 2006.
IN THIS ISSUE
Surrogate Endpoint for Prostate Cancer OutcomeClinical trials of new drugs could be speeded up if researchers could measure surrogate endpoints (e.g., biomarkers) that completely capture the true outcomes of interest (e.g., survival). Several statistical criteria have been developed that can be used to validate a candidate surrogate endpoint. In this issue, Petrylak et al. (p. 516) report a retrospective analysis of data on survival and serum prostate-specific antigen (PSA) levels from a clinical trial in men with metastatic androgen-independent prostate cancer, which showed that several specific changes in PSA level met these criteria. The optimal surrogate endpoint was a decline in serum PSA level of at least 30% over the first 3 months of treatment. This decline was achieved by 77% of men in the superior treatment arm and only 40% of men in the inferior arm, and men with this decline had a more than 50% reduction in the risk of death. The authors note that, because the PSA surrogates were identified through a data-driven approach, they must be validated in independent prospective trials.
In an editorial, Baker (p. 502) notes that the analysis of data from a single trial limits the conclusions that can be drawn from the analysis. He points out that a more reliable approach is to use meta-analytic validation measures—i.e., measures that use data from multiple trials with the same surrogate and true endpoints.
Functional Limitations in Elderly Cancer Survivors
The number of elderly cancer survivors is increasing, and their quality of life has not been fully studied. Sweeney et al. (p. 521) calculated the prevalence of functional limitations among 25,719 women who were enrolled in a population-based cohort study in 1986 and reported on limitations at follow-up in 1997. Women who were cancer survivors for less than 2 years reported the most limitations. Even women who had survived for 5 or more years were more likely than those who had not had cancer to report that they were unable to do heavy household work, walk a half mile, and walk up and down stairs. The authors suggest that interventions to maintain or regain physical function be considered for elderly cancer survivors.
In an editorial (p. 504), Rowland and Yancik stress the importance of considering long-term quality of life when making treatment choices and designing treatment strategies.
Assessing Prostate Cancer Risk
Prostate-specific antigen (PSA) testing is the primary method for diagnosing prostate cancer in the United States. To integrate other risk factors into individualized risk prediction, Thompson et al. (p. 529) used data from 5519 men in the placebo arm of the Prostate Cancer Prevention Trial to develop a predictive model of prostate cancer. The men underwent prostate biopsy and had at least one PSA measurement and a digital rectal examination (DRE) performed during the year before the biopsy and at least two PSA measurements performed during the 3 years before the biopsy. Higher PSA level, positive family history of prostate cancer, and abnormal DRE result were associated with an increased risk of prostate cancer, whereas a previous negative prostate biopsy was associated with reduced risk. Higher PSA level, abnormal DRE result, older age at biopsy, and African American race were associated with increased risk of high-grade disease, whereas a previous negative prostate biopsy was associated with reduced risk. Neither age at biopsy nor PSA velocity was associated with prostate cancer risk.
In an editorial, Carter (p. 506) discusses why the risk assessment tool described by the authors may not be relevant to the detection of life-threatening prostate cancers. He also discusses the study's implications for the choice of a threshold for prostate biopsy and for the overdiagnosis of prostate cancer.
Breast Implants and Cancer
Although there is no consistent evidence for increased risk of cancer among women with cosmetic implants, few studies have measured risk beyond 15 years. To examine such long-term cancer risks, McLaughlin et al. (p. 557) used data from the Swedish Cancer Registry to determine cancer risk through 2002 among 3486 Swedish women who underwent cosmetic breast implantation between 1965 and 1993. Except for a two- to threefold increase in lung cancer and a reduced risk of breast cancer, the authors found no associations between cosmetic implants and risk of cancer overall or risk of any cancer type. The authors conclude that the observed increased risk of lung cancer was expected due to the high prevalence of smoking among Swedish women with implants in the study.
Reproductive Factors, BRCA1/2, and Breast Cancer
Multiparity, young age at first childbirth, and breast feeding are associated with a reduced risk of breast cancer in the general population. Andrieu et al. (p. 535) performed a retrospective cohort study of 1601 women who carried a mutation in BRCA1 or BRCA2 to examine whether reproductive factors influence breast cancer risk differently in mutation carriers and noncarriers. Among parous women older than 40 years, an increasing number of full-term pregnancies was associated with a decreased breast cancer risk, regardless of whether they carried BRCA1 or BRCA2 mutations. In BRCA2 mutation carriers, first childbirth at age 20 years or older was associated with an increased risk of breast cancer compared with first childbirth before age 20 years; in BRCA1 mutation carriers, first childbirth at age 30 years or later was associated with a reduced risk of breast cancer compared with first childbirth before age 20 years. Neither history of induced abortion or miscarriage nor of breast-feeding was associated with breast cancer risk.
Antitumor Activity of Novel PI3K Inhibitor
Yaguchi et al. (p. 545) identified the molecular target of ZSTK474 (a novel s-triazine derivative), investigated its effects on cellular signaling pathways, and examined its antitumor efficacy and toxicity in vivo. They found that phosphatidylinositol 3-kinase (PI3K) was the molecular target for ZSTK474 and that ZSTK474 directly inhibited PI3K activity, apparently by binding to the ATP binding site of PI3K, and did so more effectively than another PI3K inhibitor LY294002. It also inhibited the phosphorylation of signaling components downstream of PI3K, such as protein kinase Akt. When orally administered to mice, ZSTK474 has strong antitumor activity against human cancer xenografts and reduced the phosphorylation of Akt, without toxic effects in critical organs. The authors conclude that ZSTK474 is a new PI3k inhibitor with strong antitumor activity that merits further investigation as an anticancer agent.
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