Showing papers in "Journal of the National Cancer Institute in 2006"

Gene Expression Profiling in Breast Cancer: Understanding the Molecular Basis of Histologic Grade To Improve Prognosis

Abstract: Background: Histologic grade in breast cancer provides clinically important prognostic information. However, 30% – 60% of tumors are classifi ed as histologic grade 2. This grade is associated with an intermediate risk of recurrence and is thus not informative for clinical decision making. We examined whether histologic grade was associated with gene expression profi les of breast cancers and whether such profi les could be used to improve histologic grading. Methods: We analyzed microarray data from 189 invasive breast carcinomas and from three published gene expression datasets from breast carcinomas. We identifi ed differentially expressed genes in a training set of 64 estrogen receptor (ER) – positive tumor samples by comparing expression profi les between histologic grade 3 tumors and histologic grade 1 tumors and used the expression of these genes to defi ne the gene expression grade index. Data from 597 independent tumors were used to evaluate the association between relapse-free survival and the gene expression grade index in a Kaplan – Meier analysis. All statistical tests were two-sided. Results: We identifi ed 97 genes in our training set that were associated with histologic grade; most of these genes were involved in cell cycle regulation and proliferation. In validation datasets, the gene expression grade index was strongly associated with histologic grade 1 and 3 status; however, among histologic grade 2 tumors, the index spanned the values for histologic grade 1 – 3 tumors. Among patients with histologic grade 2 tumors, a high gene expression grade index was associated with a higher risk of recurrence than a low gene expression grade index (hazard ratio = 3.61, 95% confi dence interval = 2.25 to 5.78; P <.001, log-rank test). Conclusions: Gene expression grade index appeared to reclassify patients with histologic grade 2 tumors into two groups with high versus low risks of recurrence. This approach may improve the accuracy of tumor grading and thus its prognostic value. [J Natl Cancer Inst 2006;98:262 – 72]

Randomized Multicenter Trial of Sentinel Node Biopsy Versus Standard Axillary Treatment in Operable Breast Cancer: The ALMANAC Trial

Abstract: BACKGROUND: Sentinel lymph node biopsy in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized trials on morbidity and mortality outcomes. We conducted a multicenter randomized trial to compare quality-of-life outcomes between patients with clinically node-negative invasive breast cancer who received sentinel lymph node biopsy and patients who received standard axillary treatment. METHODS: The primary outcome measures were arm and shoulder morbidity and quality of life. From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516). Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution). Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented. All statistical tests were two-sided. RESULTS: The relative risks of any lymphedema and sensory loss for the sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval [CI] = 0.23 to 0.60; absolute rates: 5% versus 13%) and 0.37 (95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%), respectively. Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P .05). CONCLUSION: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes.

The Response of CD24 −/low /CD44 + Breast Cancer–Initiating Cells to Radiation

Abstract: Background: If cancer arises and is maintained by a small population of cancer-initiating cells within every tumor, understanding how these cells react to cancer treatment will facilitate improvement of cancer treatment in the future. Cancer-initiating cells can now be prospectively isolated from breast cancer cell lines and tumor samples and propagated as mammospheres in vitro under serum-free conditions. Methods: CD24 − /low /CD44 + cancer-initiating cells were isolated from MCF-7 and MDA-MB-231 breast cancer monolayer cultures and propagated as mammospheres. Their response to radiation was investigated by assaying clonogenic survival and by measuring reactive oxygen species (ROS) levels, phosphorylation of the replacement histone H2AX, CD44 levels, CD24 levels, and Notch-1 activation using fl ow cytometry. All statistical tests were two-sided. Results: Cancer-initiating cells were more resistant to radiation than cells grown as monolayer cultures (MCF-7: monolayer cultures, mean surviving fraction at 2 Gy [SF 2Gy ] = 0.2, versus mammospheres, mean SF 2Gy = 0.46, difference = 0.26, 95% confi dence interval [CI] = 0.05 to 0.47; P = .026; MDA-MB-231: monolayer cultures, mean SF 2Gy = 0.5, versus mammospheres, mean SF 2Gy = 0.69, difference = 0.19, 95% CI = − 0.07 to 0.45; P = .09). Levels of ROS increased in both mammospheres and monolayer cultures after irradiation with a single dose of 10 Gy but were lower in mammospheres than in monolayer cultures (MCF-7 monolayer cultures: 0 Gy, mean = 1.0, versus 10 Gy, mean = 3.32, difference = 2.32, 95% CI = 0.67 to 3.98; P = .026; mammospheres: 0 Gy, mean = 0.58, versus 10 Gy, mean = 1.46, difference = 0.88, 95% CI = 0.20 to 1.56; P = .031); phosphorylation of H2AX increased in irradiated monolayer cultures, but no change was observed in mammospheres. Fractionated doses of irradiation increased activation of Notch-1 (untreated, mean = 10.7, versus treated, mean = 15.1, difference = 4.4, 95% CI = 2.7 to 6.1, P = .002) and the percentage of the cancer stem/initiating cells in the nonadherent cell population of MCF-7 monolayer cultures (untreated, mean = 3.52%, versus treated, mean = 7.5%, difference = 3.98%, 95% CI = 1.67% to 6.25%, P = .009). Conclusions: Breast cancer – initiating cells are a relatively radioresistant subpopulation of breast cancer cells and increase in numbers after short courses of fractionated irradiation. These fi ndings offer a possible mechanism for the accelerated repopulation of tumor cells observed during gaps in radiotherapy. [J Natl Cancer Inst 2006;98: 1777 – 85 ]

Validation and Clinical Utility of a 70-Gene Prognostic Signature for Women With Node-Negative Breast Cancer

Abstract: Background: A 70-gene signature was previously shown to have prognostic value in patients with node-negative breast cancer. Our goal was to validate the signature in an independent group of patients. Methods: Patients (n = 307, with 137 events after a median follow-up of 13.6 years) from fi ve European centers were divided into high- and low-risk groups based on the gene signature classifi cation and on clinical risk classifi cations. Patients were assigned to the gene signature low-risk group if their 5-year distant metastasis – free survival probability as estimated by the gene signature was greater than 90%. Patients were assigned to the clinicopathologic low-risk group if their 10-year survival probability, as estimated by Adjuvant! software, was greater than 88% (for estrogen receptor [ER] – positive patients) or 92% (for ERnegative patients). Hazard ratios (HRs) were estimated to compare time to distant metastases, disease-free survival, and overall survival in high- versus low-risk groups. Results: The 70-gene signature outperformed the clinicopathologic risk assessment in predicting all endpoints. For time to distant metastases, the gene signature yielded HR = 2.32 (95% confi dence interval [CI] = 1.35 to 4.00) without adjustment for clinical risk and hazard ratios ranging from 2.13 to 2.15 after adjustment for various estimates of clinical risk; clinicopathologic risk using Adjuvant! software yielded an unadjusted HR = 1.68 (95% CI = 0.92 to 3.07). For overall survival, the gene signature yielded an unadjusted HR = 2.79 (95% CI = 1.60 to 4.87) and adjusted hazard ratios ranging from 2.63 to 2.89; clinicopathologic risk yielded an unadjusted HR = 1.67 (95% CI = 0.93 to 2.98). For patients in the gene signature high-risk group, 10-year overall survival was 0.69 for patients in both the low – and high – clinical risk groups; for patients in the gene signature low-risk group, the 10-year survival rates were 0.88 and 0.89, respectively. Conclusions: The 70-gene signature adds independent prognostic information to clinicopathologic risk assessment for patients with early breast cancer. [J Natl Cancer Inst 2006;98: 1183 – 92 ]

Prospective Study of Predictors of Vitamin D Status and Cancer Incidence and Mortality in Men

Abstract: use of a multiple linear regression model. We used results from the model to compute a predicted 25(OH)D level for each of 47 800 men in the cohort based on these charac teristics. We then prospectively examined this variable in relation to cancer risk with multivariable Cox proportional hazards models. Results: From 1986 through January 31, 2000, we documented 4286 incident cancers (excluding organ-confi ned prostate cancer and nonmelanoma skin cancer) and 2025 deaths from cancer. From multivariable models, an increment of 25 nmol/L in predicted 25(OH)D level was associated with a 17% reduction in total cancer incidence (multivariable relative risk [RR] = 0.83, 95% confi dence interval [CI] = 0.74 to 0.92), a 29% reduction in total cancer mortality (RR = 0.71, 95% CI = 0.60 to 0.83), and a 45% reduction in digestive-system cancer mortality (RR = 0.55, 95% CI = 0.41 to 0.74). The absolute annual rate of total cancer was 758 per 100 000 men in the bottom decile of predicted 25(OH)D and 674 per 100 000 men for the top decile; these respective rates were 326 per 100 000 and 277 per 100 000 for total cancer mortality and 128 per 100 000 and 78 per 100 000 for digestive-system cancer mortality. Results were similar when we controlled further for body mass index or physical activity level. Conclusions: Low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestivesystem cancers. The vitamin D supplementation necessary to achieve a 25(OH)D increment of 25 nmol/L may be at least 1500 IU/day. [J Natl Cancer Inst 2006;98:451 – 9]

Rising Incidence of Small Renal Masses: A Need to Reassess Treatment Effect

Abstract: The incidence of kidney cancer has been rising over the last two decades, especially in cases where the disease is localized. Although rates of renal surgery parallel this trend, mortality rates have continued to rise. To investigate the basis of this "treatment disconnect" (i.e., increased rates of treatment accompanied by increased mortality rates), we analyzed patient data from nine registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. We assembled a cohort of 34503 kidney cancer patients and derived incidence, treatment, and mortality trends for kidney cancer, overall and as a function of tumor size. From 1983 to 2002, the overall age-adjusted incidence rate for kidney cancer rose from 7.1 to 10.8 cases per 100000 US population; tumors ≤4 cm in size accounted for most of the increase. Adjusted rates of renal surgery increased concurrently, most notably for tumors 7 cm. Our results demonstrate that the rising incidence of kidney cancer is largely attributable to an increase in small renal masses that are presumably curable. The fact that increased detection and treatment of small tumors is not reducing mortality argues for a reassessment of the current treatment paradigm.

Assessing Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial

Abstract: Background: Prostate-specifi c antigen (PSA) testing is the primary method used to diagnose prostate cancer in the United States. Methods to integrate other risk factors associated with prostate cancer into individualized risk prediction are needed. We used prostate biopsy data from men who par ticipated in the Prostate Cancer Prevention Trial (PCPT) to develop a predictive model of prostate cancer. Methods: We included 5519 men from the placebo group of the PCPT who underwent prostate biopsy, had at least one PSA measurement and a digital rectal examination (DRE) performed during the year before the biopsy, and had at least two PSA measurements performed during the 3 years before the prostate biopsy. Logistic regression was used to model the risk of prostate cancer and high-grade disease associated with age at biopsy, race, family history of prostate cancer, PSA level, PSA velocity, DRE result, and previous prostate biopsy. Risk equations were created from the estimated logistic regression models. All statistical tests were two-sided. Results: A total of 1211 (21.9%) men were diagnosed with prostate cancer by prostate biopsy. Variables that predicted prostate cancer included higher PSA level, positive family history of prostate cancer, and abnormal DRE result, whereas a previous negative prostate biopsy was associated with reduced risk. Neither age at biopsy nor PSA velocity contributed independent prognostic information. Higher PSA level, abnormal DRE result, older age at biopsy, and African American race were predictive for high-grade disease (Gleason score ≥ 7) whereas a previous negative prostate biopsy reduced this risk. Conclusions: This predictive model allows an individualized assessment of prostate cancer risk and risk of high-grade disease for men who undergo a prostate biopsy. [J Natl Cancer Inst 2006;98:529 – 34]

Tumor Vascular Permeability, Accumulation, and Penetration of Macromolecular Drug Carriers

Abstract: BACKGROUND Delivery of anticancer therapeutic agents to solid tumors is problematic. Macromolecular drug carriers are an attractive alternative drug delivery method because they appear to target tumors and have limited toxicity in normal tissues. We investigated how molecular weight influences the accumulation of a model macromolecular drug carrier, dextran covalently linked to a fluorophore, in tumors. METHODS We used dextrans with molecular weights from 3.3 kDa to 2 MDa. Vascular permeability, accumulation, and three-dimensional penetration of these dextrans were simultaneously measured in solid tumors via a dorsal skin fold window chamber, intravital laser-scanning confocal microscopy, and custom image analysis. RESULTS Increasing the molecular weight of dextran statistically significantly reduced its vascular permeability by approximately two orders of magnitude (i.e., from 154 x 10(-7) cm/s, 95% confidence interval [CI] = 134 to 174 x 10(-7) cm/s, for 3.3-kDa dextran to 1.7 x 10(-7) cm/s, 95% CI = 0.7 to 2.6 x 10(-7) cm/s for 2-MDa dextran; P < .001, two-sided Kruskal-Wallis test) but increased its plasma half-life, which provided ample time for extravasation (i.e., to enter tumor tissue from the vasculature). Tumor accumulation was maximal for dextrans with molecular weights between 40 and 70 kDa. Dextrans of 3.3 and 10 kDa penetrated deeply (greater than 35 microm) and homogeneously into tumor tissue from the vessel wall. After a 30-minute period, a high concentration was observed only approximately 15 microm from the vessel wall for 40- to 70-kDa dextrans and only 5 microm for 2-MDa dextrans. CONCLUSIONS Increasing the molecular weight of dextran statistically significantly reduced its tumor vascular permeability. Dextrans of 40 and 70 kDa had the highest accumulation in solid tumors but were largely concentrated near the vascular surface.

Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Abstract: Background: Preclinical and observational studies suggest a relationship between dietary fat intake and breast cancer, but the association remains controversial. We carried out a randomized, prospective, multicenter clinical trial to test the effect of a dietary intervention designed to reduce fat intake in women with resected, early-stage breast cancer receiving conventional cancer management. Methods: A total of 2437 women were randomly assigned between February 1994 and January 2001 in a ratio of 40 : 60 to dietary intervention (n = 975) or control (n = 1462) groups. An interim analysis was performed after a median follow-up of 60 months when funding for the intervention ceased. Mean differences between dietary intervention and control groups in nutrient intakes and anthropometric variables were compared with t tests. Relapse-free survival was examined using Kaplan-Meier analysis, stratified log-rank tests, and Cox proportional hazards models. Statistical tests were two-sided. Results: Dietary fat intake was lower in the intervention than in the control group (fat grams/day at 12 months, 33.3 [95% confidence interval {CI} = 32.2 to 34.5] versus 51.3 [95% CI = 50.0 to 52.7], respectively; P<.001), corresponding to a statistically significant (P =.005), 6-pound lower mean body weight in the intervention group. A total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) have been reported in 96 of 975 (9.8%) women in the dietary group and 181 of 1462 (12.4%) women in the control group. The hazard ratio of relapse events in the intervention group compared with the control group was 0.76 (95% CI = 0.60 to 0.98, P =.077 for stratified log rank and P =.034 for adjusted Cox model analysis). Exploratory analyses suggested a differential effect of the dietary intervention based on hormonal receptor status. Conclusions: A lifestyle intervention reducing dietary fat intake, with modest influence on body weight, may improve relapse-free survival of breast cancer patients receiving conventional cancer management. Longer, ongoing nonintervention follow-up will address original protocol design plans, which called for 3 years of follow-up after completion of recruitment.

Population BRCA1 and BRCA2 Mutation Frequencies and Cancer Penetrances: A Kin–Cohort Study in Ontario, Canada

Abstract: Background: BRCA1 and BRCA2 mutations in general populations and in various types of cancers have not been well characterized. We investigated the presence of these mutations in unselected patients with newly diagnosed incident ovarian cancer in Ontario, Canada, with respect to cancers reported among their relatives. Methods: A population series of 1171 unselected patients with incident ovarian cancer diagnosed between January 1, 1995, and December 31, 1999, in Ontario, Canada, was screened for germline mutations throughout the BRCA1 and BRCA2 genes. Screening involved testing for common variants, then protein truncation testing of long exons, and then denaturing gradient gel electrophoresis or denaturing high-performance liquid chromatography for the remainder of BRCA1 and BRCA2, respectively. Cox regression analysis was used to examine cancer outcomes reported by the case probands for their 8680 fi rst-degree relatives. Population allele frequencies and relative risks (RRs) were de rived from the regression results by an extension of Saunders – Begg methods. Age-specifi c Ontario cancer incidence rates were used to estimate cumulative incidence of cancer to age 80 years by mutation status. Results: Among 977 patients with invasive ovarian cancer, 75 had BRCA1 mutations and 54 had BRCA2 mutations, for a total mutation frequency of 13.2% (95% confi dence interval [CI] = 11.2% to 15.5%). Higher risks for various cancer types in the general Ontario population were associated with BRCA1 mutation carriage than with noncarriage, including ovarian (RR = 21, 95% CI = 12 to 36), female breast (RR = 11, 95% CI = 7.5 to 15), and testis (RR = 17, 95% CI = 1.3 to 230) cancers. Higher risks were also associated with BRCA2 mutation carriage than with noncarriage, particularly for ovarian (RR = 7.0, 95% CI = 3.1 to 16), female and male breast (RR = 4.6, 95% CI = 2.7 to 7.8, and RR = 102, 95% CI = 9.9 to 1050, respectively), and pancreatic (RR = 6.6, 95% CI = 1.9 to 23) cancers. Cancer risks differed according to the mutation’s position in the gene. Estimated cumulative incidence to age 80 years among women carrying BRCA1 mutations was 24% for ovarian cancer and 90% for breast cancer and among women carrying BRCA2 mutations was 8.4% for ovarian cancer and 41% for breast cancer. For the general Ontario population, estimated carrier frequencies of BRCA1 and BRCA2 mutations, respectively, were 0.32% (95% CI = 0.23% to 0.45%) and 0.69% (95% CI = 0.43% to 1.10%). Conclusions: BRCA1 and BRCA2 mutations may be more frequent in general populations than previously thought and may be associated with various types of cancers. [J Natl Cancer Inst 2006;98: 1694 – 706 ]

Worldwide Human Papillomavirus Etiology of Cervical Adenocarcinoma and Its Cofactors: Implications for Screening and Prevention

Abstract: Background Most cancers of the uterine cervix are squamous cell carcinomas. Although the incidence of such carcinomas of the uterine cervix has declined over time, that of cervical adenocarcinoma has risen in recent years. The extent to which human papillomavirus (HPV) infection and cofactors may explain this differential trend is unclear. Methods We pooled data from eight case-control studies of cervical cancer that were conducted on three continents. A total of 167 case patients with invasive cervical adenocarcinoma (112 with adenocarcinoma and 55 with adenosquamous carcinoma) and 1881 hospital-based control subjects were included. HPV DNA was analyzed in cervical specimens with the GP5+/6+ general primer system followed by type-specific hybridization for 33 HPV genotypes. Blood samples were analyzed for chlamydial and herpes simplex virus 2 (HSV-2) serology. Multivariable unconditional logistic regression modeling was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). All tests of statistical significance were two-sided. Results The adjusted overall odds ratio for cervical adenocarcinoma in HPV-positive women compared with HPV-negative women was 81.3 (95% CI = 42.0 to 157.1). HPV 16 and HPV 18 were the two most commonly detected HPV types in case patients and control subjects. These two types were present in 82% of the patients. Cofactors that showed clear statistically significant positive associations with cervical adenocarcinoma overall and among HPV-positive women included never schooling, poor hygiene, sexual behavior-related variables, long-term use of hormonal contraception, high parity, and HSV-2 seropositivity. Parity had a weaker association with adenocarcinoma and only among HPV-positive women. Use of an intrauterine device (IUD) had a statistically significant inverse association with risk of adenocarcinoma (for ever use of an IUD compared with never use, OR = .41 [95% CI = 0.18 to 0.93]). Smoking and chlamydial seropositivity were not associated with disease. Conclusions HPV appears to be the key risk factor for cervical adenocarcinoma. HPV testing in primary screening using current mixtures of HPV types and HPV vaccination against main HPV types should reduce the incidence of this cancer worldwide.

Preoperative Nomogram Predicting the 10-Year Probability of Prostate Cancer Recurrence After Radical Prostatectomy

Abstract: An existing preoperative nomogram predicts the probability of prostate cancer recurrence, defined by prostate-specific antigen (PSA), at 5 years after radical prostatectomy based on clinical stage, serum PSA, and biopsy Gleason grade. In an updated and enhanced nomogram, we have extended the predictions to 10 years, added the prognostic information of systematic biopsy results, and enabled the predictions to be adjusted for the year of surgery. Cox regression analysis was used to model the clinical information for 1978 patients treated by two high-volume surgeons from our institution. The nomogram was externally validated on an independent cohort of 1545 patients with a concordance index of 0.79 and was well calibrated with respect to observed outcome. The inclusion of the number of positive and negative biopsy cores enhanced the predictive accuracy of the model. Thus, a new preoperative nomogram provides robust predictions of prostate cancer recurrence up to 10 years after radical prostatectomy.

Recombinant Human Erythropoietins and Cancer Patients: Updated Meta-Analysis of 57 Studies Including 9353 Patients

Abstract: This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005, on the effects of epoetin alfa and beta (i.e., epoetin) and darbepoetin alfa (i.e., darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.

Body Size and Risk of Colon and Rectal Cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC)

Abstract: Background: Body weight and body mass index (BMI) are positively related to risk of colon cancer in men, whereas weak or no associations exist in women. This discrepancy may be related to differences in fat distribution between sexes or to the use of hormone replacement therapy (HRT) in women. Methods: We used multivariable adjusted Cox proportional hazards models to examine the association between anthropometric measures and risks of colon and rectal cancer among 368 277 men and women who were free of cancer at baseline from nine countries of the European Prospective Investigation Into Cancer and Nutrition. All statistical tests were two-sided. Results: During 6.1 years of follow-up, we identified 984 and 586 patients with colon and rectal cancer, respectively. Body weight and BMI were statistically significantly associated with colon cancer risk in men (highest versus lowest quintile of BMI, relative risk [RR] = 1.55, 95% confidence interval [CI] = 1.12 to 2.15; P-trend =.006) but not in women. In contrast, comparisons of the highest to the lowest quintile showed that several anthropometric measures, including waist circumference (men, RR = 1.39,95% CI = 1.01 to 1.93; P-trend = .001; women, RR = 1.48, 95% CI = 1.08 to 2.03; P-trend =.008), waist-to-hip ratio (WHR; men, RR = 1.51, 95% CI = 1.06 to 2.15; P-trend =.006; women, RR = 1.52, 95% CI = 1.12 to 2.05; P-trend =.002), and height (men, RR = 1.40, 95% CI = 0.99 to 1.98; P-trend =.04; women, RR = 1.79, 95% CI = 1.30 to 2.46; P-trend <.001) were related to colon cancer risk in both sexes. The estimated absolute risk of developing colon cancer within 5 years was 203 and 131 cases per 100 000 men and 129 and 86 cases per 100000 women in the highest and lowest quintiles of WHR, respectively. Upon further stratification, no association of waist circumference and WHR with risk of colon cancer was observed among postmenopausal women who used HRT. None of the anthropometric measures was statistically significantly related to rectal cancer. Conclusions: Waist circumference and WHR, indicators of abdominal obesity, were strongly associated with colon cancer risk in men and women in this population. The association of abdominal obesity with colon cancer risk may vary depending on HRT use in postmenopausal women; however, these findings require confirmation in future studies.

New Primary Neoplasms of the Central Nervous System in Survivors of Childhood Cancer: a Report From the Childhood Cancer Survivor Study

Abstract: Background: Subsequent primary neoplasms of the central nervous system (CNS) have frequently been described as late events following childhood leukemia and brain tumors. However, the details of the dose – response relationships, the expression of excess risk over time, and the modifying effects of other host and treatment factors have not been well defi ned. Methods: Subsequent primary neoplasms of the CNS occurring within a cohort of 14 361 5-year survivors of childhood cancers were ascertained. Each patient was matched with four control subjects by age, sex, and time since original cancer diagnosis. Tumor site – specifi c radiation dosimetry was performed, and chemotherapy information was abstracted from medical records. Conditional logistic regression was used to estimate odds ratios (ORs), to calculate 95% confi dence intervals (CIs), and to model the excess relative risk (ERR) as a function of radiation dose and host factors. For subsequent gliomas, standardized incidence ratios (SIRs) and excess absolute risks (EARs) were calculated based on Surveillance, Epidemiology, and End Results data. Results: Subsequent CNS primary neoplasms were identifi ed in 116 individuals. Gliomas (n = 40) occurred a median of 9 years from original diagnosis; for meningiomas (n = 66), it was 17 years. Radiation exposure was associated with increased risk of subsequent glioma (OR = 6.78, 95% CI = 1.54 to 29.7) and meningioma (OR = 9.94, 95% CI = 2.17 to 45.6). The dose response for the excess relative risk was linear (for glioma, slope = 0.33 [95% CI = 0.07 to 1.71] per Gy, and for meningioma, slope = 1.06 [95% CI = 0.21 to 8.15] per Gy). For glioma, the ERR/Gy was highest among children exposed at less than 5 years of age. After adjustment for radiation dose, neither original cancer diagnosis nor chemotherapy was associated with risk. The overall SIR for glioma was 8.7, and the EAR was 19.3 per 10 000 person-years. Conclusions: Exposure to radiation therapy is the most important risk factor for the development of a new CNS tumor in survivors of childhood cancers. The higher risk of subsequent glioma in children irradiated at a very young age may refl ect greater susceptibility of the developing brain to radiation. [J Natl Cancer Inst 2006;98: 1528 – 37 ]

Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study.

Abstract: Background: Childhood cancer survivors who retain ovarian function after completing cancer treatment are at increased risk of developing premature menopause, defi ned as cessation of menses before age 40 years. However, published data pertaining to the risk and frequency of premature menopause are limited. Methods: We assessed the incidence of and risk factors for premature menopause in 2819 survivors of childhood cancer who were older than 18 years and were participants in the multicenter Childhood Cancer Survivor Study (CCSS). The comparison group was 1065 female siblings of participants in the CCSS. A multiple Poisson regression model was constructed to determine risk factors for nonsurgical premature menopause. All statistical tests were twosided. Results: A total of 126 childhood cancer survivors and 33 control siblings developed premature menopause. Of these women, 61 survivors (48%) and 31 siblings (94%) had surgically induced menopause (rate ratio [RR] = 0.8, 95% confi dence interval [CI] = 0.52 to 1.23). However, the cumulative incidence of nonsurgical premature menopause was higher for survivors than for siblings (8% versus 0.8%; RR = 13.21, 95% CI = 3.26 to 53.51; P <.001). A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score (based on number of alkylating agents and cumulative dose), and a diagnosis of Hodgkin lymphoma. For survivors who were treated with alkylating agents plus abdominopelvic radiation, the cumulative incidence of nonsurgical premature menopause approached 30%. Conclusions: The results of this study will facilitate counseling current survivors about their future risk of premature menopause and aid in designing new regimens that seek to diminish late ovarian toxicity. [J Natl Cancer Inst 2006;98: 890 – 6 ]

Gene Expression Profiling of Primary Cutaneous Melanoma and Clinical Outcome

Abstract: Background Gene expression profiling data for human primary cutaneous melanomas are scarce because of the lack of retrospective collections of frozen tumors. To identify differentially expressed genes that may be involved in melanoma progression and prognosis, we investigated the relationship between gene expression profiles and clinical outcome in a cohort of patients with primary melanoma. Methods Labeled complementary RNA (cRNA) from each tissue sample was hybridized to a pangenomic 44K 60-mer oligonucleotide microarray. Class comparison and class prediction analyses were performed to identify genes whose expression in primary melanomas was associated with 4-year distant metastasis-free survival among 58 patients with at least 4 years of follow-up, distant metastasis, or death. Results were validated immunohistochemically at the protein level in 176 independent primary melanomas from patients with a median clinical follow-up of 8.5 years. Survival was analyzed with a Cox multivariable model and stratified log-rank test. All statistical tests were two-sided. Results We identified 254 genes that were associated with distant metastasis-free survival of patients with primary melanoma. These 254 genes include genes involved in activating DNA replication origins, such as minichromosome maintenance genes and geminin. Twenty-three of these genes were studied at the protein level; expression of five (MCM4, P = .002; MCM3, P = .030; MCM6, P = .004; KPNA2, P = .021; and geminin, P = .004) was statistically significantly associated with overall survival in the validation set. In a multivariable Cox model adjusted for tumor thickness, ulceration, age, and sex, expression of MCM4 (hazard ratio [HR] of death = 4.04, 95% confidence interval [CI] = 1.39 to 11.76; P = .010) and MCM6 (HR of death = 7.42, 95% CI = 1.99 to 27.64; P = .003) proteins was still statistically significantly associated with overall survival. Conclusion We identified 254 genes whose expression was associated with metastatic dissemination of cutaneous melanomas. These genes may shed light on the molecular mechanisms underlying poor prognosis in melanoma patients.

BAY 43-9006 Inhibition of Oncogenic RET Mutants

Abstract: Background : Medullary and papillary thyroid carcinomas are often associated with oncogenic activation of the RET tyrosine kinase. We evaluated whether the biaryl urea BAY 43-9006, which is known to inhibit several other tyrosine kinases, blocks RET kinase function and oncogenic activity. Methods : We examined BAY 43-9006 activity against oncogenic RET in vitro and in cellular RET signaling in oncogenic RET-transfected NIH3T3 fi broblasts by using immunocomplex kinase assays and immunoblotting with phospho-specifi c antibodies. The effects of BAY 43-9006 on proliferation of human TPC1 and TT thyroid carcinoma cells, which harbor spontaneous oncogenic RET alleles, and on RAT1 fi broblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and fl ow cytometry. Growth of TT cell – derived xenograft tumors in athymic mice treated orally with BAY 43-9006 or with vehicle was measured. All statistical tests were two-sided. Results : BAY 43-9006 inhibited oncogenic RET kinase activity at half-maximal inhibitory concentrations (IC 50 s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fi broblasts transformed by oncogenic RET and of thyroid carcinoma cells that harbor spontaneous oncogenic RET alleles. Moreover, BAY 43-9006 inhibited the growth of cells carrying RET V804L (IC 50 = 110 nM, 95% confi dence interval [CI] = 88 to 133 nM) or RET V804M (IC 50 = 147 nM, 95% CI = 123 nM to 170 nM), both mutants that are resistant to anilinoquinazolines and pyrazolopyrimidines. After 3 weeks of oral treatment with BAY 43-9006 (60 mg/kg/day), the volume of TT cell xenografts ( n = 7) was reduced from 72.5 to 44 mm 3 (difference = 28.5 mm 3 , 95% CI = 7 mm 3 to 50 mm 3 ), whereas in vehicle-treated mice ( n = 7), mean tumor volume increased to 408 mm 3 (difference = 320 mm 3 , 95% CI = 180 mm 3 to 460 mm 3 ; untreated versus treated, P =.02). This inhibition paralleled a decrease in RET phosphorylation. Conclusions : BAY 43-9006 is a powerful inhibitor of the RET kinase. Its potential as a therapeutic tool for RET-positive thyroid tumors, including those expressing V804 mutations merits study. [J Natl Cancer Inst 2006;98:326 – 34]

Cyclooxygenase-2 (COX-2)–Independent Anticarcinogenic Effects of Selective COX-2 Inhibitors

Abstract: Nonsteroidal antiinflammatory drugs (NSAIDs) appear to reduce the risk of developing cancer. One mechanism through which NSAIDs act to reduce carcinogenesis is to inhibit the activity of cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in various cancer tissues. Overexpression of COX-2 increases cell proliferation and inhibits apoptosis. However, selective COX-2 inhibitors can also act through COX-independent mechanisms. In this review, we describe the COX-2-independent molecular targets of these COX-2 inhibitors and discuss how these targets may be involved in the anticarcinogenic activities of these selective COX-2 inhibitors. We also compare the concentrations of these inhibitors used in in vitro and in vivo experiments and discuss the implications of the in vitro studies for clinical management of cancer with these drugs.

Prospective Breast Cancer Risk Prediction Model for Women Undergoing Screening Mammography

Abstract: Background: Risk prediction models for breast cancer can be improved by the addition of recently identifi ed risk factors, including breast density and use of hormone therapy. We used prospective risk information to predict a diagnosis of breast cancer in a cohort of 1 million women undergoing screening mammography. Methods: There were 2 392 998 eligible screening mammograms from women without previously diagnosed breast cancer who had had a prior mammogram in the preceding 5 years. Within 1 year of the screening mammogram, 11 638 women were diagnosed with breast cancer. Separate logistic regression risk models were constructed for premenopausal and postmenopausal examinations by use of a stringent ( P <.0001) criterion for the inclusion of risk factors. Risk models were constructed with 75% of the data and validated with the remaining 25%. Concordance of the predicted with the observed outcomes was assessed by a concordance (c) statistic after logistic regression model fi t. All statistical tests were twosided. Results: Statistically signifi cant risk factors for breast cancer diagnosis among premenopausal women included age, breast density, family history of breast cancer, and a prior breast procedure. For postmenopausal women, the statistically signifi cant factors included age, breast density, race, ethnicity, family history of breast cancer, a prior breast procedure, body mass index, natural menopause, hormone therapy, and a prior false-positive mammogram. The model may identify high-risk women better than the Gail model, although predictive accuracy was only moderate. The c statistics were 0.631 (95% confi dence interval [CI] = 0.618 to 0.644) for premenopausal women and 0.624 (95% CI = 0.619 to 0.630) for postmenopausal women. Conclusion: Breast density is a strong additional risk factor for breast cancer, although it is unknown whether reduction in breast density would reduce risk. Our risk model may be able to identify women at high risk for breast cancer for preventive interventions or more intensive surveillance. [J Natl Cancer Inst 2006;98: 1204 – 14 ]

Meta-Analysis of Soy Intake and Breast Cancer Risk

Abstract: Background: High intake of soy foods has been proposed to contribute to the low breast cancer risk in Asian countries. However, results of epidemiologic studies of this association are highly variable, and experimental data suggest that soy constituents can be estrogenic and potentially risk enhancing. Thus, rigorous evaluation of available epidemiologic data is necessary before appropriate recommendations can be made, especially for women at high risk of breast cancer or those who have survived the disease. Methods: We performed a meta-analysis of 18 epidemiologic studies (12 case – control and six cohort or nested case – control) published from 1978 through 2004 that examined soy exposure and breast cancer risk. Pooled relative risk estimates were based on either the original soy exposure measure defi ned in each study or on an estimate of daily soy protein intake. Results: Risk estimates, levels and measures of soy exposure, and control for confounding factors varied considerably across studies. In a pooled analysis, among all women, high soy intake was modestly associated with reduced breast cancer risk (odds ratio [OR] = 0.86, 95% confi dence interval [CI] = 0.75 to 0.99); the association was not statistically signifi cant among women in Asian countries (OR = 0.89, 95% CI = 0.71 to 1.12). Among the 10 studies that stratifi ed by menopausal status the inverse association between soy exposure and breast cancer risk was somewhat stronger in premenopausal women (OR = 0.70, 95% CI = 0.58 to 0.85) than in postmenopausal women (OR = 0.77, 95% CI = 0.60 to 0.98); however, eight studies did not provide menopausespecifi c results, six of which did not support an association. When exposure was analyzed by soy protein intake in grams per day, a statistically signifi cant association with breast cancer risk was seen only among premenopausal women (OR = 0.94, 95% CI = 0.92 to 0.97). Conclusions: Soy intake may be associated with a small reduction in breast cancer risk. However, this result should be interpreted with caution due to potential exposure misclassifi cation, confounding, and lack of a dose response. Given these caveats and results of some experimental studies that suggest adverse effects from soy constituents, recommendations for high- dose isofl avone supplementation to prevent breast cancer or prevent its recurrence are premature. [J Natl Cancer Inst 2006;98:459 – 71]

China Approves World's First Oncolytic Virus Therapy For Cancer Treatment

Abstract: Oncolytic virus research got a welcome boost last November when Chinese regulators approved the world’s fi rst oncolytic viral therapy for cancer, Shanghai Sunway Biotech’s genetically modifi ed adenovirus H101. “ It’s fantastic for the fi eld, ” said John Bell , Ph.D., of the Ottawa Health Research Institute in Canada. “ We needed to have something that was a success, and so I think this is a good fi rst start. ” Oncolytic viruses are live viruses that selectively kill cancer cells. Shanghai Sunway Biotech expects to begin marketing H101 in July for treating head and neck cancer. The company is also testing the virus in lung cancer and has bought the rights to Onyx-15, an almost identical virus that Onyx Pharmaceuticals took into phase III trials in 2000 but later dropped after its marketing partner bailed out. Now the Chinese effort has breathed new life into the Onyx virus. Sunway’s next step, says company president Hu Fang, M.D., is to compare it with H101 in a Chinese trial. The company will then apply to test one of the viruses in Europe and the United States. “ The fi rst choice is Onyx-15, but we can’t exclude the H101, ” Hu said.

Antitumor Activity of ZSTK474, a New Phosphatidylinositol 3-Kinase Inhibitor

Abstract: Background We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its antitumor efficacy and toxicity in vivo. Methods We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its activity was measured by assessing the incorporation of 32P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream activity was analyzed by immunoblotting. Antitumor activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 microM, ZSTK474 and LY2194002 reduced PI3K activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3beta, and mediated a decrease in cyclin D1 levels. ZSTK474 administered orally to mice had strong antitumor activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion ZSTK474 is a new PI3K inhibitor with strong antitumor activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.

A Model of Human Tumor Dormancy: An Angiogenic Switch From the Nonangiogenic Phenotype

Abstract: Background: Microscopic human cancers can remain dormant for life Tumor progression depends on sequential events, including a switch to the angiogenic phenotype, ie, initial recruitment of new vessels We previously demonstrated that human tumors contain tumor cell populations that are heterogeneous in angiogenic activity Here, we separated angiogenic from nonangiogenic human tumor cell populations and compared their growth Methods: Severe combined immunodefi cient (SCID) mice were inoculated with nonangiogenic human MDA-MB-436 breast adenocarcinoma, KHOS-24OS osteosarcoma, or T98G glioblastoma cells Most of the resulting tumors remained microscopic (<1 mm diameter), but some eventually became angiogenic and enlarged and were used to isolate angiogenic tumor cells Angiogenic and nonangiogenic tumor cells were inoculated into SCID mice, and time to the development of palpable tumors was determined Cell proliferation was assayed in vitro by growth curves and in vivo by staining for proliferating cell nuclear antigen or Ki67 Microscopic tumors from both tumor cell populations were examined for histologic evidence of vascular development 14 days after inoculation in mice Expression of the angiogenesis inhibitor thrombospondin-1 was examined by immunoblotting Results: Nonangiogenic tumors of each tumor type developed palpable tumors after means of 119 days (range: 53 – 185 days) for breast cancer, 238 days (184 – 291 days) for osteosarcoma, and 226 days (150 – 301 days) for glioblastoma Angiogenic cells de veloped palpable tumors within 20 days after inoculation However, nonangiogenic and angiogenic cells of each tumor type had similar proliferation rates Fourteen days after tumor cell inoculation, tumors from angiogenic cells showed evidence of functional vasculature In contrast, nonangiogenic tumors remained microscopic in size with absent or nonfunctional vasculature Thrombospondin-1 expression was statistically signifi cantly lower (by fi ve- to 23-fold, depending on tumor type) in angiogenic than nonangiogenic cells Conclusions: This model provides a conceptual framework and a reproducible in vivo system to study unresolved central questions in cancer biology regarding the initiation, reversibility, and molecular regulation of the timing of the angiogenic switch [J Natl Cancer Inst 2006;98:316 – 25]

Randomized Double-Blind Factorial Trial of Three Treatments To Reduce the Prevalence of Precancerous Gastric Lesions

Abstract: Background: Randomized trials have yielded mixed results on the effects of treatment for Helicobacter pylori and little information on the effects of vitamins or garlic supplements on precancerous gastric lesions. We conducted a randomized trial to test the effects of one-time H. pylori treatment and long-term vitamin or garlic supplements in reducing the prevalence of advanced precancerous gastric lesions. Methods: Most of the adults aged 35 – 64 years in 13 randomly selected villages in Linqu County, Shandong Province, China, were identifi ed and given baseline endoscopies in 1994. In 1995, 3365 eligible subjects were randomly assigned in a factorial design to three interventions or placebos: amoxicillin and omeprazole for 2 weeks in 1995 ( H. pylori treatment); vitamin C, vitamin E, and selenium for 7.3 years (vitamin supplement); and aged garlic extract and steam-distilled garlic oil for 7.3 years (garlic supplement). Subjects underwent endoscopies with biopsies in 1999 and 2003, and the prevalence of precancerous gastric lesions was determined by histopathologic examination of seven standard biopsy sites. The 3365 eligible randomized subjects represented 93.5% of those with baseline endoscopy and included all baseline histologic categories except gastric cancer. Only 0.18% had normal gastric mucosa. Logistic regression was used to estimate the intervention effects on the odds of advanced precancerous gastric lesions, and t -tests were used to assess effects on histologic severity. All statistical tests were two-sided. Results: H. pylori treatment resulted in statistically signifi cant decreases in the combined prevalence of severe chronic atrophic gastritis, intestinal metaplasia, dysplasia, or gastric cancer in 1999 (odds ratio [OR] = 0.77; 95% confi dence interval [CI] = 0.62 to 0.95) and in 2003 (OR = 0.60; 95% CI = 0.47 to 0.75), and had favorable effects on the average histopathologic severity and on progression and regression of precancerous gastric lesions in 2003. H. pylori treatment did not reduce the combined prevalence of dysplasia or gastric cancer. However, fewer subjects receiving H. pylori treatment (19/1130; 1.7%) than receiving placebo (27/1128; 2.4%) developed gastric cancer (adjusted P = .14). No statistically signifi cant favorable effects were seen for garlic or vitamin supplements. Conclusion: H. pylori treatment reduces the prevalence of precancerous gastric lesions and may reduce gastric cancer incidence, but further data are needed to prove the latter point. Long-term vitamin or garlic supplementation had no benefi cial effects on the prevalence of precancerous gastric lesions or on gastric cancer incidence. [J Natl Cancer Inst 2006;98: 974 – 83 ]

Statin Drugs and Risk of Advanced Prostate Cancer

Abstract: ARTICLES 1819 Background: Statins are commonly used cholesterol-lowering drugs that have proapoptotic and antimetastatic activities that could affect cancer risk or progression. Results from previous epidemiologic studies of the association between statin use and cancer have been inconsistent. We investigated the association of statin use with total and advanced prostate cancer, the latter being the most important endpoint to prevent. Methods: We analyzed data from an ongoing prospective cohort study of 34 989 US male health professionals who were cancer free in 1990 and were followed to 2002. Participants reported their use of cholesterol-lowering drugs on biennial questionnaires. Prostate cancer diagnosis was confi rmed by medical record review. Multivariable-adjusted relative risks (RRs) were estimated from Cox proportional hazards regression models. Statistical tests were two-sided. Results: During 376 939 person-years of follow-up, we ascertained 2579 prostate cancer cases, 316 of which were advanced (regionally invasive, metastatic, or fatal). The age-standardized incidence rates of advanced prostate cancer were 38 and 89 per 100 000 person-years in current statin users and in past or never users, respectively. The multivariable-adjusted relative risk of advanced disease was 0.51 (95% confi dence interval [CI] = 0.30 to 0.86) and of metastatic or fatal disease was 0.39 (95% CI = 0.19 to 0.77) for current statin use compared with no current use. The associations remained after adjusting for prostate-specifi c antigen screening history (advanced disease: RR = 0.57, 95% CI = 0.30 to 1.11; metastatic or fatal disease: RR = 0.35, 95% CI = 0.14 to 0.92). Risk of advanced disease was lower with longer statin use ( P trend = .003); compared with never use, the relative risk for less than 5 years of use was 0.60 (95% CI = 0.35 to 1.03) and for 5 or more years of use was 0.26 (95% CI = 0.08 to 0.83). We found no association between statin use and risk of total prostate cancer (RR = 0.96, 95% CI = 0.85 to 1.09). Conclusions: In this cohort of male health professionals, use of statin drugs was not associated with risk of prostate cancer overall but was associated with a reduced risk of advanced (especially metastatic or fatal) prostate cancer. [J Natl Cancer Inst 2006;98: 1819 – 25 ]

Effect of Surgeon Specialty on Processes of Care and Outcomes for Ovarian Cancer Patients

Abstract: BACKGROUND For many diseases, specialized care (i.e., care rendered by a specialist) has been associated with superior-quality care (i.e., better outcomes). We examined associations between physician specialty and outcomes in a population-based cohort of elderly ovarian cancer surgery patients. METHODS We analyzed the Medicare claims, by physician specialty, of all women aged 65 years or older who underwent surgery for pathologically confirmed invasive epithelial ovarian cancer between January 1, 1992, and December 31, 1999, while living in an area monitored by the Surveillance, Epidemiology, and End Results (SEER) program to assess important care processes (i.e., the appropriate extent of surgery and use of adjuvant chemotherapy) and outcomes (i.e., surgical complications, ostomy rates, and survival). All statistical tests were two-sided. RESULTS Among 3067 ovarian cancer patients who underwent surgery, 1017 patients (33%) were treated by a gynecologic oncologist, 1377 patients (45%) by a general gynecologist, and 673 patients (22%) by a general surgeon. Among patients with stage I or II disease, those treated by a gynecologic oncologist (60%) were more likely to undergo lymph node dissection than those treated by a general gynecologist (36%) or a general surgeon (16%). Patients with stage III or IV disease were more likely to undergo a debulking procedure if the initial surgery was performed by a gynecologic oncologist (58%) than by a general gynecologist (51%) or a general surgeon (40%; P < .001) and were more likely to receive postoperative chemotherapy when operated on by a gynecologic oncologist (79%) or a general gynecologist (76%) than by a general surgeon (62%, P < .001). Survival among patients operated on by gynecologic oncologists (hazard ratio [HR] of death from any cause = 0.85, 95% confidence interval [CI] = 0.76 to 0.95) or general gynecologists (HR = 0.86, 95% CI = 0.78 to 0.96) was better than that among patients operated on by general surgeons. CONCLUSIONS Ovarian cancer patients treated by gynecologic oncologists had marginally better outcomes than those treated by general gynecologists and clearly superior outcomes compared with patients treated by general surgeons.

Autoimmune and Chronic Inflammatory Disorders and Risk of Non-Hodgkin Lymphoma by Subtype

Abstract: BACKGROUND: Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms. METHODS: In a population-based case-control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes. RESULTS: Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjogren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype. CONCLUSIONS: Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.

Endogenous Steroid Hormone Concentrations and Risk of Breast Cancer Among Premenopausal Women

Abstract: Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women Background. Higher levels of endogenous sex steroid hormones are associated with increased risks of breast cancer in postmenopausal women. Data for premenopausal women are sparse, in part because of the complexity of measuring hormone levels that vary cyclically. We prospectively evaluated associations between plasma sex hormone levels and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II. Methods: From 1996 to 1999, blood samples were collected from 18 521 premenopausal women during the early follicular and mid-luteal phases of their menstrual cycles. A total of 197 cases of breast cancer were diagnosed among these women after blood collection and before June 1, 2003; these case subjects were matched to 394 control subjects. Logistic regression models, controlling for breast cancer risk factors, were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: Women in the highest (versus the lowest) quartiles of follicular total and free estradiol levels had statistically significantly increased risks of breast cancer (RR = 2.1 [95% CI = 1.1 to 4.1], P-trend = .08, and RR = 2.4 [95% CI = 1.3 to 4.5], P-trend = .01, respectively); the associations were stronger for invasive breast cancer and for estrogen and progesterone receptor-positive (ER+/PR+) tumors. Luteal estradiol levels were not associated with breast cancer risk. Higher levels of total and free testosterone and androstenedione in both menstrual cycle phases were associated with modest, non-statistically significant increases in overall risk of breast cancer and with stronger, statistically significant increases in risks of invasive and ER+/PR+ cancers (e.g., RR of invasive cancers for the top [versus bottom] quartile of luteal total testosterone levels = 2.0 [95% CI = 1.1 to 3.6], P-trend = .05, and RR of ER+/PR+ cancers = 2.9 [95% CI = 1.4 to 6.9] P-trend = .02). Levels of estrone, estrone sulfate, progesterone, and sex hormone-binding globulin were not associated with breast cancer risk. The absolute number of cases observed over 3 years were 30 among women in the lowest 25% of follicular total estradiol levels and 50 among women in the highest 25%. Conclusions: Levels of circulating estrogens and androgens may be important in the etiology of premenopausal breast cancer.

Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density.

Abstract: Background: To improve the discriminatory power of the Gail model for predicting absolute risk of invasive breast cancer, we previously developed a relative risk model that incorporated mammographic density (DENSITY) from data on white women in the Breast Cancer Detection Demonstration Project (BCDDP). That model also included the variables age at birth of first live child (AGEFLB), number of affected mother or sisters (NUMREL), number of previous benign breast biopsy examinations (NBIOPS), and weight (WEIGHT). In this study, we developed the corresponding model for absolute risk. Methods: We combined the relative risk model with data on the distribution of the variables AGEFLB, NUMREL, NBIOPS, and WEIGHT from the 2000 National Health Interview Survey, with data on the conditional distribution of DENSITY given other risk factors in BCDDP, with breast cancer incidence rates from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute, and with national mortality rates. Confidence intervals (CIs) accounted for variability of estimates of relative risks and of risk factor distributions. We compared the absolute 5-year risk projections from the new model with those from the Gail model on 1744 white women. Results: Attributable risks of breast cancer associated with DENSITY, AGEFLB, NUMREL, NBIOPS, and WEIGHT were 0.779 (95% CI = 0.733 to 0.819) and 0.747 (95% CI = 0.702 to 0.788) for women younger than 50 years and 50 years or older, respectively. The model predicted higher risks than the Gail model for women with a high percentage of dense breast area. However, the average risk projections from the new model in various age groups were similar to those from the Gail model, suggesting that the new model is well calibrated. Conclusions: This new model for absolute invasive breast cancer risk in white women promises modest improvements in discriminatory power compared with the Gail model but needs to be validated with independent data.