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Pak1 Expression and Tamoxifen Resistance
Phosphorylation and activation of estrogen receptor 
(ER) by p21-activated kinase 1 (Pak1) could limit the effectiveness of antiestrogen treatment in breast cancer. Holm et al. (p. 671) evaluated Pak1 protein expression and subcellular localization in primary breast tumors from premenopausal patients who had been randomly assigned to receive 2 years of adjuvant tamoxifen or no treatment and compared tamoxifen response in relation to Pak1 and ER expression. Among patients with ER–positive tumors with low Pak1 expression, those treated with tamoxifen had better recurrence-free survival than those who received no treatment; for patients whose tumors had high cytoplasmic or any nuclear Pak1 expression, recurrence-free survival did not differ between treatment groups. Overexpression of wild-type Pak1, but not of Pak1 lacking functional nuclear localization signals, in human MCF-7 breast cancer cells compromised tamoxifen response. The authors conclude that Pak1, particularly nuclear Pak1, may have a role in ER signaling and in tamoxifen resistance.
In an editorial, Jordan (p. 657) discusses several factors that might have confounded interpretation of the response rates in the trial in which the patients participated and integrates the findings into a general model of intrinsic tamoxifen resistance.
Radiation Therapy and Older Patients with Breast Cancer
Although recent trials have questioned the necessity of breast radiation therapy for older patients with breast cancer, the effectiveness of radiation therapy for older patients in the community setting has not been addressed. Smith et al. (p. 681) used the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database from 1992 through 1999 to identify patients aged 70 years or older who were treated with conservative surgery for small, lymph node–negative, estrogen receptor–positive breast cancer. Radiation therapy was associated with a lower risk of a second ipsilateral breast cancer or subsequent mastectomy. The absolute risk reduction associated with radiation therapy was, at 5 years, 4.0 events per 100 women and, at 8 years, 5.7 events per 100 women. The authors conclude, moreover, that readily identifiable characteristics, such as histology and comorbidity, can determine which patients are most likely to benefit from radiation therapy.
In an editorial, Hillner and Mandelblatt (p. 660) point out that Smith et al. have shown that a well-designed observational study can reproduce estimates of the impact of treatment seen in the trial setting and, given its larger size, can also provide insights on subgroups. They conclude that because clinical trial enrollment by older women is unlikely to increase soon, high-quality observational studies can provide important information for clinical and policy decision-making.
Lung Cancer Mortality in Never Smokers
To determine the age-, sex-, and race-specific risks of lung cancer incidence and mortality among never tobacco smokers, Thun et al. (p. 691) measured rates of death from lung cancer among more than 94,000 adults who reported never smoking at enrollment in the Cancer Prevention Study (CPS) I and CPS II during 1959–1972 and 1982–2000, respectively. The age-standardized lung cancer death rates among men and women never smokers in CPS II were 17.1 and 14.7 per 100,000 person-years, respectively. Age-standardized rates of lung cancer mortality among never smokers were higher in men than women in both studies and in African American women than white women in CPS II. The authors conclude that, in contrast to the current perception, lung cancer death rates are not higher among female than male never smokers, and that the finding that lung cancer mortality was higher among African American than white women never smokers should be confirmed in other studies.
Statin Use and Breast Cancer Risk
The widely used and highly effective cholesterol-lowering drugs known as statins are pleiotropic agents. Both observational and preclinical data have suggested that these molecules, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A, have anticancer activity. However, studies of the association between statin use and breast cancer have yielded conflicting results. Cauley et al. (p. 700) investigated the association between statin use and breast cancer in a prospective study of nearly 160,000 postmenopausal women who were enrolled in the Women's Health Initiative. After 6.7 years of follow-up, statin users had essentially the same risk of breast cancer as non-users. Moreover, there was no trend in risk by duration of statin use, and statin potency was not associated with risk. Users of hydrophobic statins experienced a statistically significant although modest reduction in risk, however, raising the possibility of within-class differences.
Recombinant Human Erythropoietins and Cancer Patients
Bohlius et al. (p. 708) present an updated systematic review of 57 trials and 9353 cancer patients from publications of randomized controlled trials between January 1, 1985, and April 30, 2005, comparing the effects of epoetin and darbepoetin plus red blood cell transfusion with transfusion alone for prophylaxis or treatment of anemia in cancer patients with and without antineoplastic therapy. They found that treatment with epoetin and darbepoetin statistically significantly reduced the risk for red blood cell transfusion and improved hematologic response but that it also increased the risk of thrombo-embolic events. The authors conclude that caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients at high risk for thrombo-embolic events.
Prostate Cancer Recurrence after Radical Prostatectomy
To extend predictions of the probability of prostate cancer recurrence to 10 years after radical prostatectomy, Kattan et al. (p. 715) updated the previous preoperative nomogram that predicted recurrence at 5 years. The new nomogram uses clinical stage, serum prostate specific antigen level, biopsy Gleason grade—all factors used in the previous nomogram—as well as prognostic information of systematic biopsy results and year of surgery. The authors validated the new nomogram on an independent cohort of 1545 prostate cancer patients and found the new nomogram to be more accurate than the previous one. The authors conclude that the new preoperative nomogram provides robust predictions of prostate cancer recurrence up to 10 years after radical prostatectomy.
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