Showing papers in "Journal of the National Cancer Institute in 2007"

Drug Resistance and the Solid Tumor Microenvironment

Abstract: Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.

Lymph Node Evaluation and Survival After Curative Resection of Colon Cancer: Systematic Review

Abstract: Background Adequate lymph node evaluation for cancer involvement is important for prognosis and treatment of patients with colon cancer. The number of lymph nodes evaluated may be a measure of quality in colon cancer care and appears to be inadequate in most patients treated for colon cancer. We performed a systematic review of the evidence for the association between lymph node evaluation and oncologic outcomes in patients with colon cancer. Methods Medline, Scopus, Cochrane, and the National Guidelines Clearinghouse databases were searched from January 1, 1990, through June 30, 2006, for studies in which survival data as a function of number of lymph nodes evaluated were available. These studies were evaluated for methodologic quality, design, and data source. A total of 61,371 patients were included. Results Seventeen studies from nine countries were eligible for systematic review, including two secondary analyses of multicenter randomized trials of adjuvant chemotherapy for colon cancer, five population-based observational studies, and 10 single-institution retrospective cohort studies. Despite heterogeneity in methodology and differences in threshold numbers of lymph nodes evaluated (range = 6-40 lymph nodes), 16 of 17 studies reported that increased survival of patients with stage II colon cancer was associated with increased numbers of lymph nodes evaluated. Four of six studies with data from stage III patients also reported a positive association with survival among patients with stage III colon cancer. Conclusions The number of lymph nodes evaluated after surgical resection was positively associated with survival of patients with stage II and stage III colon cancer. These results support consideration of the number of lymph nodes evaluated as a measure of the quality of colon cancer care.

Arterial Thromboembolic Events in Patients with Metastatic Carcinoma Treated with Chemotherapy and Bevacizumab

Abstract: Background Although combination treatment with bevacizumab (humanized monoclonal antibody against vascular endothelial growth factor) and chemotherapy improves survival of patients with various metastatic carcinomas, an increased risk of arterial thromboembolic events has been observed in some trials. We characterized this risk by performing post hoc analyses of randomized controlled trials that evaluated combination treatment with bevacizumab and chemotherapy versus chemotherapy alone. Low-dose aspirin was permitted in these trials, and its safety was also analyzed. Methods Data were pooled from five randomized controlled trials that included a total of 1745 patients with metastatic colorectal, breast, or non – small-cell lung carcinoma. The risk of an arterial or venous thromboembolic event was assessed by simple incidence rates, rates per 100 person-years, and/or hazard ratios (HRs). The association between patient characteristics and risk of an arterial thromboembolic event was investigated primarily by Cox proportional hazards regression. The relationship between low-dose aspirin and bleeding was explored by incidence rates and rates per 100 person-years. Results Combined treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with increased risk for an arterial thromboembolic event (HR = 2.0, 95% confidence interval [CI] = 1.05 to 3.75; P = .031) but not for a venous thromboembolic event (HR = 0.89, 95% CI = 0.66 to 1.20; P = .44). The absolute rate of developing an arterial thromboembolism was 5.5 events per 100 person-years for those receiving combination therapy and 3.1 events per 100 person-years for those receiving chemotherapy alone (ratio = 1.8, 95% CI = 0.94 to 3.33; P = .076). Development of an arterial thromboembolic event was associated with a prior arterial thromboembolic event ( P <.001) or age of 65 years or older ( P = .01). Baseline or onstudy aspirin use was associated with modest increases in grade 3 and 4 bleeding events in both treatment groups, from 3.6% to 4.7% for bevacizumab-treated patients and from 1.7% to 2.2% for control subjects. Conclusions Combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with an increased risk of arterial thromboembolism but not venous thromboembolism.

Alcohol Drinking in Never Users of Tobacco, Cigarette Smoking in Never Drinkers, and the Risk of Head and Neck Cancer: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium

Abstract: Background At least 75% of head and neck cancers are attributable to a combination of cigarette smoking and alcohol drinking. A precise understanding of the independent association of each of these factors in the absence of the other with the risk of head and neck cancer is needed to elucidate mechanisms of head and neck carcinogenesis and to assess the efficacy of interventions aimed at controlling either risk factor. Methods We examined the extent to which head and neck cancer is associated with cigarette smoking among never drinkers and with alcohol drinking among never users of tobacco. We pooled individual-level data from 15 case – control studies that included 10 244 head and neck cancer case subjects and 15 227 control subjects, of whom 1072 case subjects and 5775 control subjects were never users of tobacco and 1598 case subjects and 4051 control subjects were never drinkers of alcohol. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. All statistical tests were two-sided. Results Among never drinkers, cigarette smoking was associated with an increased risk of head and neck cancer (OR for ever versus never smoking = 2.13, 95% CI = 1.52 to 2.98), and there were clear dose – response relationships for the frequency, duration, and number of pack-years of cigarette smoking. Approximately 24% (95% CI = 16% to 31%) of head and neck cancer cases among nondrinkers in this study would have been prevented if these individuals had not smoked cigarettes. Among never users of tobacco, alcohol consumption was associated with an increased risk of head and neck cancer only when alcohol was consumed at high frequency (OR for three or more drinks per day versus never drinking = 2.04, 95% CI = 1.29 to 3.21). The association with high-frequency alcohol intake was limited to cancers of the oropharynx/hypopharynx and larynx. Conclusions Our results represent the most precise estimates available of the independent association of each of the two main risk factors of head and neck cancer, and they exemplify the strengths of large-scale consortia in cancer epidemiology. J Natl Cancer Inst 2007;99: 777 – 89

Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast Cancer

Abstract: Background Women with HER2-overexpressing breast cancers have poor prognosis, and many are resistant to the HER2 monoclonal antibody trastuzumab. A subgroup of HER2-overexpressing tumors also express p95HER2, an amino terminally truncated receptor that has kinase activity. Because p95HER2 cannot bind to trastuzumab but should be responsive to the HER2 tyrosine kinase inhibitor lapatinib, we compared the sensitivity of tumors expressing p95HER2 and tumors expressing the full-length HER2 receptor to these agents. Methods MCF-7 and T47D breast cancer cells were stably transfected with either full-length HER2 or p95HER2. We studied the effects of trastuzumab and lapatinib on receptor signaling, cell proliferation, and the growth of xenograft tumors. A paraffin-based immunofluorescence assay was developed to study the association between p95HER2 expression and sensitivity to trastuzumab in patients with advanced breast cancer. All statistical tests were two-sided. Results Treatment of p95HER2-expressing cells with lapatinib inhibited p95HER2 phosphorylation, reduced downstream phosphorylation of Akt and mitogen-activated protein kinases, inhibited cell growth (MCF-7p95HER2 clones, lapatinib versus control, mean growth inhibition = 57.6% versus 22.6%, difference = 35%, 95% confidence interval [Cl] = 22.5% to 47.3%; P<.001; T47Dp95HER2 clones, lapatinib versus control, mean growth inhibition = 36.8% versus 20%, difference = 16.8%, 95% Cl = 11.3% to 22.3%, P<.001), and inhibited growth of MCF-7p95HER2 xenograft tumors (lapatinib versus control, mean = 288.8 versus 435 mm 3 , difference = 146.2 mm 3 , Cl = 73.8 to 218.5 mm 3 , P =.002). By contrast, treatment with trastuzumab had no effect on any of these parameters. Of 46 patients with metastatic breast cancer who were treated with trastuzumab, only one of nine patients (11.1%) expressing p95HER2 responded to trastuzumab (with a partial response), whereas 19 of the 37 patients (51.4%) with tumors expressing full-length HER2 achieved either a complete (five patients) or a partial (14 patients) response (P=.029). Conclusions Breast tumors that express p95HER2 are resistant to trastuzumab and may require alternative or additional anti-HER2-targeting strategies.

Long-term risk of cardiovascular disease in 10-year survivors of breast cancer.

Abstract: textBackground: Radiotherapy for breast cancer as delivered in the 1970s has been associated with increased risk of cardiovascular disease, but recent studies of associations with modern regimens have been inconclusive. Few data on long-term cardiovascular disease risk according to specific radiation fields are available, and interaction with known cardiovascular risk factors has not been examined. Methods: The studied treatment-specific incidence of cardiovascular disease in 4414 10-year survivors of breast cancer who were treated from 1970 through 1986. Risk of cardiovascular disease in these patients was compared with general population rates and evaluated in Cox proportional hazards regression models. All statistical tests were two-sided. Results: After a median follow-up of 18 years, 942 cardiovascular events were observed (standardized incidence ratio = 1.30, 95% confidence interval [CI] = 1.22 to 1.38; corresponding to 62.9 excess cases per 10 000 patient-years). Breast irradiation only was not associated with increased risk of cardiovascular disease. However, radiotherapy to either the left or right side of the internal mammary chain was associated with increased cardiovascular disease risk for the treatment period 1970-1979 (for myocardial infarction, hazard ratio [HR] = 2.55, 95% CI = 1.55 to 4.19; P<.001; for congestive heart failure, HR = 1.72, 95% CI = 1.22 to 2.41; P = .002) compared with no radiotherapy. Among patients who received internal mammary chain radiotherapy after 1979, risk of myocardial infarction declined over time toward unity, whereas the risks of congestive heart failure (HR = 2.66, 95% CI = 1.27 to 5.61; P = .01) and valvular dysfunction (HR = 3.17, 95% CI = 1.90 to 5.29; P<.001) remained increased. Patients who underwent radiotherapy plus adjuvant chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) after 1979 had a higher risk of congestive heart failure than patients who were treated with radiotherapy only (HR = 1.85, 95% CI = 1.25 to 2.73; P = .002). Smoking and radiotherapy together were associated with a more than additive effect on risk of myocardial infarction (HR = 3.04, 95% CI = 2.03 to 4.55; P for departure from additivity = .039). Conclusions: Radiotherapy as administered from the 1980s onward is associated with an increased risk of cardiovascular disease. Irradiated breast cancer patients should be advised to refrain from smoking to reduce their risk for cardiovascular disease.

Critical Review of Published Microarray Studies for Cancer Outcome and Guidelines on Statistical Analysis and Reporting

Abstract: Background Both the validity and the reproducibility of microarray-based clinical research have been challenged. There is a need for critical review of the statistical analysis and reporting in published microarray studies that focus on cancer-related clinical outcomes. Methods Studies published through 2004 in which microarray-based gene expression profiles were analyzed for their relation to a clinical cancer outcome were identified through a Medline search followed by hand screening of abstracts and full text articles. Studies that were eligible for our analysis addressed one or more outcomes that were either an event occurring during follow-up, such as death or relapse, or a therapeutic response. We recorded descriptive characteristics for all the selected studies. A critical review of outcome-related statistical analyses was undertaken for the articles published in 2004. Results Ninety studies were identified, and their descriptive characteristics are presented. Sixty-eight (76%) were published in journals of impact factor greater than 6. A detailed account of the 42 studies (47%) published in 2004 is reported. Twenty-one (50%) of them contained at least one of the following three basic flaws: 1) in outcome-related gene finding, an unstated, unclear, or inadequate control for multiple testing; 2) in class discovery, a spurious claim of correlation between clusters and clinical outcome, made after clustering samples using a selection of outcome-related differentially expressed genes; or 3) in supervised prediction, a biased estimation of the prediction accuracy through an incorrect cross-validation procedure. Conclusions The most common and serious mistakes and misunderstandings recorded in published studies are described and illustrated. Based on this analysis, a proposal of guidelines for statistical analysis and reporting for clinical microarray studies, presented as a checklist of "Do's and Don'ts," is provided.

Randomized Controlled Trial of Resection Versus Radiotherapy After Induction Chemotherapy in Stage IIIA-N2 Non–Small-Cell Lung Cancer

Abstract: Background : Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to thoracic radiotherapy as locoregional therapy. Methods : Selected patients with histologic or cytologic proven stage IIIA-N2 NSCLC were given three cycles of platinum- based induction chemotherapy. Responding patients were subsequently randomly assigned to surgical resection or radiotherapy. Survival curves were estimated using Kaplan–Meier analyses from time of randomization. Results : Induction chemotherapy resulted in a response rate of 61% (95% confidence interval [CI] = 57% to 65%) among the 579 eligible patients. A total of 167 patients were allocated to resection and 165 to radiotherapy. Of the 154 (92%) patients who underwent surgery, 14% had an exploratory thoracotomy, 50% a radical resection, 42% a pathologic downstaging, and 5% a pathologic complete response; 4% died after surgery. Postoperative radiotherapy was administered to 62 (40%) of patients in the surgery arm. Among the 154 (93%) irradiated patients, overall compliance to the radiotherapy prescription was 55%, and grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7%; one patient died of radiation pneumonitis. Median and 5-year overall survival for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio = 1.06, 95% CI = 0.84 to 1.35). Rates of progression-free survival were also similar in both groups. Conclusion : In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiother- apy. In view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these patients.

Cisplatin- Versus Carboplatin-Based Chemotherapy in First-Line Treatment of Advanced Non–Small-Cell Lung Cancer: An Individual Patient Data Meta-analysis

Abstract: BACKGROUND Because the efficacy of carboplatin and cisplatin in the treatment of advanced non-small-cell lung cancer (NSCLC) has not been proven to be equivalent, an individual patient data meta-analysis comparing the two treatments was performed. METHODS Randomized trials comparing carboplatin to cisplatin in first-line treatment of advanced NSCLC were identified and their electronic databases obtained. A general variance-based method was used to estimate the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) for mortality, objective response, and toxicity. Cochran's chi-square test (Q test) was used to test for heterogeneity among trials, and the I2 index, which expresses the proportion of variability of the results due to heterogeneity, was calculated. A random-effects model that takes into account interstudy variation was also applied. All statistical tests were two-sided. RESULTS Nine trials that included a total of 2968 patients were analyzed; overall median follow-up was 1021 days. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% versus 24%, respectively; OR = 1.37; 95% CI = 1.16 to 1.61; P<.001). Carboplatin treatment was associated with a non-statistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR = 1.07; 95% CI = 0.99 to 1.15; P = .100). In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR = 1.12; 95% CI = 1.01 to 1.23 and HR = 1.11; 95% CI = 1.01 to 1.21, respectively). Cisplatin-based chemotherapy was associated with more severe nausea and vomiting and nephrotoxicity; severe thrombocytopenia was more frequent during carboplatin-based chemotherapy. CONCLUSIONS Our individual patient data meta-analysis suggests that cisplatin-based chemotherapy is slightly superior to carboplatin-based chemotherapy in terms of response rate and, in certain subgroups, in prolonging survival without being associated with an increase in severe toxic effects. Therefore, cisplatin-based third-generation regimens should remain the standard reference for the treatment of selected patients with advanced-stage NSCLC and of those with earlier-stage disease.

Prognostic Value of Ki67 Expression After Short-Term Presurgical Endocrine Therapy for Primary Breast Cancer

Abstract: Tumor expression of the proliferation antigen Ki67 is widely used to assess the prognosis of cancer patients. A change in the expression of Ki67 after short-term exposure of patients to therapeutic agents is frequently used as a pharmacodynamic marker of efficacy, particularly among breast cancer patients before undergoing surgery. To determine the clinical significance of the level of tumor cell proliferation during endocrine therapy for breast cancer, we measured the expression of Ki67 in tumor biopsy samples taken before and after 2 weeks of presurgical treatment with anastrozole or tamoxifen or the combination of anastrozole plus tamoxifen in 158 patients with hormone receptor-positive primary disease. In a multivariable analysis, we found that higher Ki67 expression after 2 weeks of endocrine therapy was statistically significantly associated with lower recurrence-free survival (P = .004) whereas higher Ki67 expression at baseline was not. Larger baseline tumor size and lower estrogen receptor level after 2 weeks of treatment were also statistically significantly associated with poorer recurrence-free survival (P < .001 and P = .04, respectively). Our data indicate that measurements of tumor Ki67 level after short-term endocrine treatment may improve the prediction of recurrence-free survival by integrating the prognostic value of Ki67 level at baseline with changes in Ki67 level that are associated with treatment benefit.

Multifunctional Nanoparticles for Combining Ultrasonic Tumor Imaging and Targeted Chemotherapy

Abstract: Background Drug delivery in polymeric micelles combined with tumor irradiation by ultrasound results in effective drug targeting, but this technique requires prior tumor imaging. A technology that combined ultrasound imaging with ultrasound-mediated nanoparticle-based targeted chemotherapy could therefore have important applications in cancer treatment. Methods Mixtures of drug-loaded polymeric micelles and perfluoropentane (PFP) nano/microbubbles stabilized by the same biodegradable block copolymer were prepared. Size distribution of nanoparticles was measured by dynamic light scattering. Cavitation activity (oscillation, growth, and collapse of microbubbles) under ultrasound was assessed based on the changes in micelle/microbubble volume ratios. The effect of the nano/microbubbles on the ultrasound-mediated cellular uptake of doxorubicin (Dox) in MDA MB231 breast tumors in vitro and in vivo (in mice bearing xenograft tumors) was determined by flow cytometry. Statistical tests were two-sided. Results Phase state and nanoparticle sizes were sensitive to the copolymer/perfluorocarbon volume ratio. At physiologic temperatures, nanodroplets converted into nano/microbubbles. Doxorubicin was localized in the microbubble walls formed by the block copolymer. Upon intravenous injection into mice, Dox-loaded micelles and nanobubbles extravasated selectively into the tumor interstitium, where the nanobubbles coalesced to produce microbubbles with a strong, durable ultrasound contrast. Doxorubicin was strongly retained in the microbubbles but released in response to therapeutic ultrasound. Microbubbles cavitated under the action of tumor-directed ultrasound, which enhanced intracellular Dox uptake by tumor cells in vitro to a statistically significant extent relative to that observed with unsonicated microbubbles (drug uptake ratio = 4.60; 95% confidence interval [CI] = 1.70 to 12.47; P = .017) and unsonicated micelles (drug uptake ratio = 7.97; 95% CI = 3.72 to 17.08; P = .0032) and resulted in tumor regression in the mouse model. Conclusions Multifunctional nanoparticles that are tumor-targeted drug carriers, long-lasting ultrasound contrast agents, and enhancers of ultrasound-mediated drug delivery have been developed and deserve further exploration as cancer therapeutics.

Androgen Deprivation Therapy for Localized Prostate Cancer and the Risk of Cardiovascular Mortality

Abstract: Background We investigated whether androgen deprivation therapy (ADT) use is associated with an increased risk of death from cardiovascular causes in patients treated for localized prostate cancer. Methods From the Cancer of the Prostate Strategic Urologic Research Endeavor database, data on 3262 patients treated with radical prostatectomy and 1630 patients treated with external beam radiation therapy, brachytherapy, or cryotherapy for localized prostate cancer were included in this analysis. Competing risks regression analyses were performed to assess whether use of ADT was associated with a shorter time to death from cardiovascular causes after controlling for age (as a continuous variable) and the presence of baseline cardiovascular disease risk factors. All tests for statistical significance were two-sided. Results The median follow-up time was 3.8 years (range = 0.1-11.3 years). Among the 1015 patients who received ADT, the median duration of ADT use was 4.1 months (range = 1.0-32.9 months). In a competing risks regression analysis that controlled for age and risk factors for cardiovascular disease, both ADT use (adjusted hazard ratio [HR] = 2.6; 95% confidence interval [CI] = 1.4 to 4.7; P = .002) and age (adjusted HR = 1.07; 95% CI = 1.02 to 1.1; P = .003) were associated with statistically significantly increased risks of death from cardiovascular causes in patients treated with radical prostatectomy. Among patients 65 years or older treated with radical prostatectomy, the 5-year cumulative incidence of cardiovascular death was 5.5% (95% CI = 1.2% to 9.8%) in those who received ADT and 2.0% (95% CI = 1.1% to 3.0%) in those who did not. Among patients 65 years or older treated with external beam radiation therapy, brachytherapy, or cryotherapy, ADT use was associated with a higher cumulative incidence of death from cardiovascular causes, but the difference did not reach statistical significance. Conclusions The use of ADT appears to be associated with an increased risk of death from cardiovascular causes in patients undergoing radical prostatectomy for localized prostate cancer.

Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer—96-Month Follow-up of the Randomized IBIS-I Trial

Abstract: BACKGROUND Initial results from the first International Breast Cancer Intervention Study (IBIS-I) found that tamoxifen reduced the risk of invasive estrogen receptor (ER)-positive tumors by 31% in women at increased risk for breast cancer, but most of the follow-up at this time was during the active treatment phase. We report an updated analysis of IBIS-I that focuses on the period after active treatment was completed, a time for which little evidence from other trials is available. METHODS A total of 7145 women who were aged 35-70 years and at increased risk of breast cancer were randomly assigned to receive either tamoxifen (20 mg/day) or placebo for 5 years. The primary outcome measure was the incidence of breast cancer (including ductal carcinoma in situ), but side effects were also investigated. Relative risks were computed as the ratio of incidence rates. All statistical tests were two-sided. RESULTS After a median follow-up of 96 months after randomization, 142 breast cancers were diagnosed in the 3579 women in the tamoxifen group and 195 in the 3575 women in the placebo group (4.97 versus 6.82 per 1000 woman-years, respectively; risk ratio [RR] = 0.73, 95% confidence interval [CI] = 0.58 to 0.91, P = .004). The prophylactic effect of tamoxifen was fairly constant for the entire follow-up period, and no diminution of benefit was observed for up to 10 years after randomization. However, side effects in the tamoxifen group were much lower after completion of the active treatment period than during active treatment. For example, deep-vein thrombosis and pulmonary embolism were statistically significantly higher in the tamoxifen arm than in the placebo arm during active treatment (52 versus 23 cases, RR = 2.26, 95% CI = 1.36 to 3.87) but not after tamoxifen was stopped (16 versus 14 cases, RR = 1.14, 95% CI = 0.52 to 2.53). The two arms did not differ in the risk of ER-negative invasive tumors (35 in each arm, RR = 1.00, 95% CI = 0.61 to 1.65) across the entire follow-up period, but the risk of ER-positive invasive breast cancer was 34% lower in the tamoxifen arm (87 versus 132 cases, RR = 0.66, 95% CI = 0.50 to 0.87). CONCLUSIONS The risk-reducing effect of tamoxifen appears to persist for at least 10 years, but most side effects of tamoxifen do not continue after the 5-year treatment period.

UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose Matters

Abstract: The Food and Drug Administration and Pfizer changed the package insert for irinotecan to include a patient's UGT1A1*28 genotype as a risk factor for severe neutropenia on the basis of the findings of four pharmacogenetic studies, which found that irinotecan-treated patients who were homozygous for the UGT1A1*28 allele had a greater risk of hematologic toxic effects than patients who had one or two copies of the wild-type allele (UGT1A1*1). Findings of subsequent irinotecan pharmacogenetic studies have been inconsistent. In a meta-analysis, we reviewed data presented in nine studies that included a total of 10 sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III-IV) for patients with a UGT1A1*28/*28 genotype. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.52 to 6.81; P = .008) and high (OR = 27.8, 95% CI = 4.0 to 195; P = .005) doses of irinotecan. However, risk was similar at lower doses (OR = 1.80, 95% CI = 0.37 to 8.84; P = .41). Low doses of irinotecan (100-125 mg/m2) are in the commonly used therapeutic range. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered.

Cancer Mortality in the United States by Education Level and Race

Abstract: BACKGROUND: Although both race and socioeconomic status are well known to influence mortality patterns in the United States, few studies have examined the simultaneous influence of these factors on cancer incidence and mortality. We examined relationships among race, education level, and mortality from cancers of the lung, breast, prostate, colon and rectum, and all sites combined in contemporary US vital statistics. METHODS: Age-adjusted cancer death rates (with 95% confidence intervals [CIs]) were calculated for 137,708 deaths among 119,376,196 individuals aged 25-64 years, using race and education information from death certificates and population denominator data from the US Bureau of the Census, for 47 states and Washington, DC, in 2001. Relative risk (RR) estimates were used to compare cancer death rates in persons with 12 or fewer years of education with those in persons with more than 12 years of education. RESULTS: Educational attainment was strongly and inversely associated with mortality from all cancers combined in black and white men and in white women. The all-cancer death rates were nearly identical for black men and white men with 0-8 years of education (224.2 and 223.6 per 100,000, respectively). The estimated relative risk for all-cancer mortality comparing the three lowest ( 12 years) education categories was 2.38 (95% CI = 2.33 to 2.43) for black men, 2.24 (95% CI = 2.23 to 2.26) for white men, 1.43 (95% CI = 1.41 to 1.46) for black women, and 1.76 (95% CI = 1.75 to 1.78) for white women. For both men and women, the magnitude of the relative risks comparing the three lowest educational levels with the three highest within each race for all cancers combined and for lung and colorectal cancers was higher than the magnitude of the relative risks associated with race within each level of education, whereas for breast and prostate cancer the magnitude of the relative risks associated with race was higher than the magnitude of the relative risks associated with level of education within each racial group. Among the most important and novel findings were that black men who completed 12 or fewer years of education had a prostate cancer death rate that was more than double that of black men with more schooling (10.5 versus 4.8 per 100,000 men; RR = 2.17, 95% CI = 1.82 to 2.58) and that, in contrast with studies of mortality rates in earlier time periods, breast cancer mortality rates were higher among women with less education than among women with more education (37.0 and 31.1 per 100,000, respectively, for black women and 25.2 versus 18.6 per 100,000, respectively, for white women). CONCLUSION: Cancer death rates vary considerably by level of education. Identifying groups at high risk of death from cancer by level of education as well as by race may be useful in targeting interventions and tracking cancer disparities.

Breast Cancer Incidence, 1980–2006: Combined Roles of Menopausal Hormone Therapy, Screening Mammography, and Estrogen Receptor Status

Abstract: Background Breast cancer incidence has been rising since at least 1935 – 1939, but recent US data reveal a statistically significant decline in breast cancer incidence in 2003 that persisted through 2004. Identifying the specific contributions of the potential causes of this long-term increase and the recent decrease in incidence has been challenging. Marked changes in rates of mammography screening and use of menopausal hormone therapy since 1980 have added further complexity. We examined the potential association between menopausal hormone therapy use and recent changes in breast cancer incidence. Methods Using tumor registry, clinical, pathology, and pharmacy data from Kaiser Permanente Northwest, a large prepaid US health plan, we compared age-specific and age-adjusted breast cancer incidence rates (2-year moving averages) with use of screening mammography and dispensed menopausal hormone therapy prescriptions between 1980 and 2006. Temporal changes in incidence rates were assessed via joinpoint regression. Results A total of 7386 incident invasive breast cancers were diagnosed in plan members from 1980 through 2006. Overall age-adjusted breast cancer incidence rates per 100 000 women rose 25% from the early 1980s (105.6) to 1992 – 1993 (131.7) and an additional 15% through 2000 – 2001 (151.3), then dropped by 18% to 2003 – 2004 (123.6) and edged up slightly in 2005–2006 (126.2). These patterns were largely restricted to women aged 45 years or older and to estrogen receptor – positive (ER+) breast cancers. Incidence rates of ER-negative tumors experienced neither of the rises seen for ER+ tumors but also fell precipitously from 2003 through 2006. Rates of mammography screening sharply increased from 1980 to 1993 but then leveled off, and 75% – 79% of women aged 45 years or older received a mammogram at least once every 2 years from 1993 through 2006. Menopausal hormone therapy dispensings, particularly of estrogen-plusprogestin formulations, increased from 1988 to 2002 but then dropped by approximately 75% after 2002. Conclusions From 1980 through 2006, quantitative and qualitative trends in breast cancer incidence rates, particularly for ER+ tumors, parallel major changes in patterns of mammography screening and use of menopausal hormone therapy.

Myocardial Infarction Mortality Risk After Treatment for Hodgkin Disease: A Collaborative British Cohort Study

Abstract: Results A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100 000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracylines (SMR = 14.8, 95% CI = 4.8 to 34.5). Conclusions The risk of death from myocardial infarction after treatment for Hodgkin disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.

Screening for Colorectal Neoplasms With New Fecal Occult Blood Tests: Update on Performance Characteristics

Abstract: Background One type of fecal occult blood test (FOBT), the unrehydrated guaiac fecal occult blood test (GT), is recommended by the United States Preventive Services Task Force and the Institute of Medicine for use in screening programs, but it has relatively low sensitivity as a single test for detecting advanced colonic neoplasms (cancer and adenomatous polyps ≥ 1 cm in diameter). Thus, improving the sensitivity of FOBT should make colon cancer screening programs that use these tests more effective. Methods We assessed prospectively the performance characteristics of two newer FOBTs in 5841 subjects at average risk for colorectal cancer in a large group – model managed care organization. The tests evaluated included a sensitive GT, a fecal immunochemical test (FIT), and the combination of both tests. Patients with positive and negative test results were advised to have colonoscopy and sigmoidoscopy, respectively. Sensitivity and specificity for detecting advanced neoplasms in the left colon within 2 years after the FOBT screening were evaluated for the two tests administered separately and in combination. Results A total of 139 patients were diagnosed with advanced colorectal neoplasms (n = 14 cancers, n = 128 adenomas) within the 2 years following their initial FOBT screening. Sensitivity for detecting cancer was 81.8% (95% confidence interval [CI] = 47.8% to 96.8%) for the FIT alone and 64.3% (95% CI = 35.6% to 86.0%) for the sensitive GT and the combination test. Sensitivity for detecting advanced colorectal adenomas was 41.3% (95% CI = 32.7% to 50.4%) for the sensitive GT, 29.5% (95% CI = 21.4% to 38.9%) for the FIT, and 22.8% (95% CI =16.1% to 31.3%) for the combination test. Specificity for detecting cancer and adenomas was 98.1% (95% CI = 97.7% to 98.4%) and 98.4% (95% CI = 98.0% to 98.7%), respectively, for the combination test; 96.9% (95% CI = 96.4% to 97.4%) and 97.3% (95% CI = 96.8% to 97.7%), respectively, for the FIT; and 90.1% (95% CI = 89.3% to 90.8%) and 90.6% (95% CI = 89.8% to 91.4%), respectively, for the sensitive GT. Conclusions The FIT has high sensitivity and specificity for detecting left-sided colorectal cancer, and it may be a useful

A Risk Model for Prediction of Lung Cancer

Abstract: Background Reliable risk prediction tools for estimating individual probability of lung cancer have important public health implications. We constructed and validated a comprehensive clinical tool for lung cancer risk prediction by smoking status. Methods Epidemiologic data from 1851 lung cancer patients and 2001 matched control subjects were randomly divided into separate training (75% of the data) and validation (25% of the data) sets for never, former, and current smokers, and multivariable models were constructed from the training sets. The discriminatory ability of the models was assessed in the validation sets by examining the areas under the receiver operating characteristic curves and with concordance statistics. Absolute 1-year risks of lung cancer were computed using national incidence and mortality data. An ordinal risk index was constructed for each smoking status category by summing the odds ratios from the multivariable regression analyses for each risk factor. Results All variables that had a statistically significant association with lung cancer (environmental tobacco smoke, family history of cancer, dust exposure, prior respiratory disease, and smoking history variables) have strong biologically plausible etiologic roles in the disease. The concordance statistics in the validation sets for the never, former, and current smoker models were 0.57, 0.63, and 0.58, respectively. The computed 1-year absolute risk of lung cancer for a hypothetical male current smoker with an estimated relative risk close to 9 was 8.68%. The ordinal risk index performed well in that true-positive rates in the designated high-risk categories were 69% and 70% for current and former smokers, respectively. Conclusions If confirmed in other studies, this risk assessment procedure could use easily obtained clinical information to identify individuals who may benefit from increased screening surveillance for lung cancer. Although the concordance statistics were modest, they are consistent with those from other risk prediction models.

Prospective Study of Serum Vitamin D and Cancer Mortality in the United States

Abstract: BACKGROUND Vitamin D has been hypothesized to reduce cancer mortality through its effects on incidence and/or survival. Epidemiologic studies of the association of 25-hydroxyvitamin D [25(OH)D] and the risk of cancer, however, have been largely limited to incident cancers at a few sites. METHODS A total of 16,818 participants in the Third National Health and Nutrition Examination Survey who were 17 years or older at enrollment were followed from 1988-1994 through 2000. Levels of serum 25(OH)D were measured at baseline by radioimmunoassay. Cox proportional hazards regression models were used to examine the relationship between serum 25(OH)D levels and total cancer mortality (in the entire population or according to race/ethnicity, sex, age, and retinol status) and mortality from specific cancers. Because serum was collected in the south in cooler months and the north in warmer months, we examined associations by collection season. All statistical tests were two-sided. RESULTS We identified 536 cancer deaths in 146,578 person-years. Total cancer mortality was unrelated to baseline vitamin D status in the entire population, men, women, non-Hispanic whites, non-Hispanic blacks, Mexican Americans, and in persons younger than 70 or 70 years or older. We found no interaction between vitamin D and season or vitamin D and serum retinol. Colorectal cancer mortality was inversely related to serum 25(OH)D level, with levels 80 nmol/L or higher associated with a 72% risk reduction (95% confidence interval = 32% to 89%) compared with lower than 50 nmol/L, P(trend) = .02. CONCLUSIONS Our results do not support an association between 25(OH)D and total cancer mortality, although there was an inverse relationship between 25(OH)D levels and colorectal cancer mortality.

Twenty-Year Follow-up of the Royal Marsden Randomized, Double-Blinded Tamoxifen Breast Cancer Prevention Trial

Abstract: Twenty-year follow-up of the royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial Background Several clinical trials have reported an early reduction in breast cancer incidence in healthy women using tamoxifen to reduce their risk of breast cancer but have not reported longer follow-up data for the evaluation of breast cancer prevention. We report the blinded 20-year follow-up (median follow-up = 13 years) of the Royal Marsden trial to identify any long-term prevention of breast cancer associated with tamoxifen treatment. Methods We randomly assigned 2494 healthy women to oral tamoxifen (20 mg/day) or placebo for 8 years. The primary outcome was occurrence of invasive breast cancer. A secondary planned analysis of estrogen receptor (ER)-positive invasive breast cancer was also done. Survival was assessed by use of a Cox proportional hazards model in both univariate and multivariable analyses. The durability of the treatment effect was assessed by use of a Cox regression analysis. All statistical tests were two-sided. Results Among the 2471 eligible participants (1238 participants in the tamoxifen arm and 1233 participants in the placebo arm), 186 developed invasive breast cancer (82 on tamoxifen and 104 on placebo; hazard ratio [HR] = 0.78, 95% confidence interval [Cl] = 0.58 to 1.04; P = .1). Of these 186 cancers, 139 were ER positive (53 on tamoxifen and 86 on placebo; HR = 0.61, 95% Cl = 0.43 to 0.86; P=.005). The risk of ER-positive breast cancer was not statistically significantly lower in the tamoxifen arm than in the placebo arm during the 8-year treatment period (30 cancers in the tamoxifen arm and 39 in the placebo arm; HR = 0.77, 95% Cl = 0.48 to 1.23; P = .3) but was statistically significantly lower in the posttreatment period (23 in the tamoxifen arm and 47 in the placebo arm; HR = 0.48, 95% Cl = 0.29 to 0.79; P = .004). Fifty-four participants in each arm have died from any cause (HR = 0.99, 95% Cl = 0.68 to 1.44; P = .95). The adverse event profiles for both arms were similar to those previously reported and occurred predominantly during the treatment period. Conclusions A statistically significant reduction in the incidence of ER-positive breast cancer was observed in the tamoxifen arm that occurred predominantly during the post treatment follow-up, indicating long-term prevention of estrogen-dependent breast cancer by tamoxifen.

Promotion of Bladder Cancer Development and Progression by Androgen Receptor Signals

Abstract: Methods We used N -butyl- N -(4-hydroxybutyl)nitrosamine (BBN) to induce bladder cancer in wild-type male and female mice, with and without castration in males, and in AR knockout (ARKO) male and female mice, with and without dihydrotestosterone (DHT) supplementation in males. We also treated human bladder cancer cell lines, including TCC-SUP and UMUC3, and mouse xenograft models established from these same lines with androgen deprivation therapy (antiandrogen treatment or castration), AR – small- interfering RNA (AR-siRNA), or the anti-AR molecule ASC-J9, which causes selective degradation of the AR. Results More than 92% of wild-type male and 42% of wild-type female mice treated with BBN eventually developed bladder cancer, whereas none of the male or female ARKO mice did. Treatment with BBN induced bladder cancer in 25% of ARKO mice supplemented with DHT and in 50% of castrated wild-type male mice. Androgen deprivation of AR-positive human bladder cancer cells by androgen depletion in vitro or castration in mice and/or by treatment with the antiandrogen flutamide in vitro or in vivo, as well as AR knockdown by AR-siRNA or by ASC-J9, suppressed cell proliferation in vitro and xenograft tumor growth in vivo. Conclusions Our findings implicate the involvement of both androgens and the AR in bladder cancer. Targeting AR and androgens may provide novel chemopreventive and therapeutic approaches for bladder cancer.

The Surgical Learning Curve for Prostate Cancer Control After Radical Prostatectomy

Abstract: Background The learning curve for surgery — i.e., improvement in surgical outcomes with increasing surgeon experience — remains primarily a theoretical concept; actual curves based on surgical outcome data are rarely presented. We analyzed the surgical learning curve for prostate cancer recurrence after radical prostatectomy. Methods The study cohort included 7765 prostate cancer patients who were treated with radical prostatectomy by one of 72 surgeons at four major US academic medical centers between 1987 and 2003. For each patient, surgeon experience was coded as the total number of radical prostatectomies performed by the surgeon before the patient ’ s operation. Multivariable survival – time regression models were used to evaluate the association between surgeon experience and prostate cancer recurrence, defined as a serum prostatespecific antigen (PSA) of more than 0.4 ng/mL followed by a subsequent higher PSA level (i.e., bio che mical recurrence ), with adjustment for established clinical and tumor characteristics. All P values are two-sided. Results The learning curve for prostate cancer recurrence after radical prostatectomy was steep and did not start to plateau until a surgeon had completed approximately 250 prior operations. The predicted probabilities of recurrence at 5 years were 17.9% (95% confidence interval [CI] = 12.1% to 25.6%) for patients treated by surgeons with 10 prior operations and 10.7% (95% CI = 7.1% to 15.9%) for patients treated by surgeons with 250 prior operations (difference = 7.2%, 95% CI = 4.6% to 10.1%; P <.001). This finding was robust to sensitivity analysis; in particular, the results were unaffected if we restricted the sample to patients treated after 1995, when stage migration related to the advent of PSA screening appeared largely complete. Conclusions As a surgeon’s experience increases, cancer control after radical prostatectomy improves, presumably because of improved surgical technique. Further research is needed to examine the specific techniques used by experienced surgeons that are associated with improved outcomes.

Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment.

Abstract: Invasion is a defining hallmark of glioblastoma multiforme, just as metastasis characterizes other high-grade tumors. Glial tumors invariably recur due to the regrowth of invasive cells, which are unaffected by standard treatment modalities. Drivers of glioma invasion include autocrine signals propagated by secreted factors that signal through receptors on the tumor. These secreted factors are able to diffuse through the peritumoral stroma, thereby influencing parenchymal cells that surround the tumor mass. Here we describe various autocrine motility factors that are expressed by invasive glioma cells and explore the effects that they may have on normal cells present in the path of invasion. Conversely, normal brain parenchymal cells secrete ligands that can stimulate receptors on invasive glioma cells and potentially facilitate glioma invasion or create a permissive microenvironment for malignant progression. Parallel observations have been made for solid tumors of epithelial origin, in which parenchymal and stromal cells either support or suppress tumor invasion. Most autocrine and paracrine interactions involved in glioma invasion constitute known signaling systems in stages of central nervous system development that involve the migration of precursor cells that populate the developing brain. Key paracrine interactions between glioma cells and the brain microenvironment can influence glioma pathobiology and therefore contribute to its poor prognosis. Current therapies for glioma that could have an impact on paracrine communication between tumors and normal cells are discussed. We suggest that cells in the normal brain parenchyma be considered as potential targets for adjuvant therapies to control glioma growth because such cells are less likely to develop resistance than glioma cells.

Hypothyroidism in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib

Abstract: Sunitinib is an inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors, and it has antitumor activity in metastatic renal cell carcinoma and gastrointestinal stromal tumors. To further investigate the fatigue associated with sunitinib therapy, thyroid function tests were performed on patients with metastatic renal cell carcinoma who were receiving sunitinib. Seventy-three patients with metastatic renal cell carcinoma were treated with sunitinib at the Cleveland Clinic Taussig Cancer Center, and 66 of them had thyroid function test results available. Fifty-six (85%) of the 66 patients had one or more abnormality in their thyroid function test results, consistent with hypothyroidism, and 47 (84%) of the 56 patients with abnormal thyroid function tests had signs and/or symptoms possibly related to hypothyroidism. Thyroid hormone replacement was undertaken in 17 patients, and symptoms improved in nine of them. Thyroid function test abnormalities appear to be common in patients with metastatic renal cell carcinoma treated with sunitinib, and routine monitoring is warranted.

Novel Cell Culture Technique for Primary Ductal Carcinoma In Situ: Role of Notch and Epidermal Growth Factor Receptor Signaling Pathways

Abstract: BACKGROUND: The epidermal growth factor receptor (EGFR) and Notch signaling pathways have been implicated in self-renewal of normal breast stem cells. We investigated the involvement of these signaling pathways in ductal carcinoma in situ (DCIS) of the breast. METHODS: Samples of normal breast tissue (n = 15), pure DCIS tissue of varying grades (n = 35), and DCIS tissue surrounding an invasive cancer (n = 7) were used for nonadherent (i.e., mammosphere) culture. Mammosphere cultures were treated at day 0 with gefitinib (an EGFR inhibitor), DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester) (a gamma-secretase inhibitor), or Notch 4-neutralizing antibody. Mammosphere-forming efficiency (MFE) was calculated by dividing the number of mammospheres of 60 microm or more formed by the number of single cells seeded and is expressed as a percentage. The Notch 1 intracellular domain (NICD) was detected immunohistochemically in paraffin-embedded DCIS tissue from 50 patients with at least 60 months of follow-up. All statistical tests were two-sided. RESULTS: DCIS had a greater MFE than normal breast tissue (1.5% versus 0.5%, difference = 1%, 95% confidence interval [CI] = 0.62% to 1.25%, P<.001). High-grade DCIS had a greater MFE than low-grade DCIS (1.6% versus 1.09%, difference = 0.51%, 95% CI = 0.07% to 0.94%, P = .01). The MFE of high-grade DCIS treated with gefitinib in the absence of exogenous EGF was lower than that of high-grade DCIS treated with mammosphere medium lacking gefitinib and exogenous EGF (0.56% versus 1.36%, difference 0.8%, 95% CI = 0.33% to 1.4%, P = .004). Increased Notch signaling as detected by NICD staining was associated with recurrence at 5 years (P = .012). DCIS MFE was reduced when Notch signaling was inhibited using either DAPT (0.89% versus 0.51%, difference = 0.38%, 95% CI = 0.2% to 0.6%, P<.001) or a Notch 4-neutralizing antibody (0.97% versus 0.2%, difference = 0.77%, 95% CI = 0.52% to 1.0%, P<.001). CONCLUSION: We describe a novel primary culture technique for DCIS. Inhibition of the EGFR or Notch signaling pathways reduced DCIS MFE.

Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma : A systematic review and meta-analysis

Abstract: Background Addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy (R-chemo) has been shown to improve response rates and progression-free survival in patients with indolent or mantle cell lymphoma. However, the impact of R-chemo on overall survival is unclear. We performed a comprehensive systematic review and meta-analysis to examine the efficacy of combined immunochemotherapy using R-chemo compared with the identical chemotherapy alone with respect to overall survival in patients with advanced indolent lymphoma or mantle cell lymphoma. Methods Medical databases and conference proceedings were searched for randomized controlled trials published from January 1990 through December 2005 that compared R-chemo with chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma or mantle cell lymphoma. We included full-text and

Breast Cancer Risk Among Male BRCA1 and BRCA2 Mutation Carriers

Abstract: Men who carry germline mutations in the BRCA2 gene have a higher risk of developing breast carcinoma than men in the general population. Men who carry germline mutations in the BRCA1 gene may also be at a higher risk for breast carcinoma, but this association is not as well established. We evaluated the risks of developing breast carcinoma for male BRCA1 and BRCA2 mutation carriers in the US population based on data from 1939 families with 97 male subjects with breast carcinoma that were collected from eight centers across the National Cancer Institute's Cancer Genetics Network. At all ages, the cumulative risks of male breast cancer were higher in both BRCA1 and BRCA2 mutation carriers than in noncarriers. The relative risks of developing breast cancer were highest for men in their 30s and 40s and decreased with increasing age. Both the relative and cumulative risks were higher for BRCA2 mutation carriers than for BRCA1 mutation carriers. The estimated cumulative risk of breast carcinoma for male BRCA1 mutation carriers at age 70 years was 1.2% (95% confidence interval [CI] = 0.22% to 2.8%) and for BRCA2 mutation carriers, 6.8% (95% CI = 3.2% to 12%).

Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water.

Abstract: Background Region II of Chile (the second most northerly administrative region) experienced dramatic increases in average arsenic water concentrations beginning in 1958, followed by marked declines in the 1970s when water treatment plants were installed. This history provides a unique opportunity to study time trends in the development of arsenic-related cancers, including lung and bladder cancers. Methods We investigated lung and bladder cancer mortality from 1950 to 2000 for region II compared with region V, where drinking water was not contaminated with arsenic. Mortality data were obtained from 218,174 death certificates for the two regions for 1950-1970 and from mortality data tapes that identified 307,541 deaths in the two regions for 1971-2000. Poisson regression models were used to identify time trends in rate ratios (RRs) of mortality from lung and bladder cancers comparing region II with region V. Results Lung and bladder cancer mortality rate ratios for region II compared with region V started to increase about 10 years after high arsenic exposures commenced and continued to rise until peaking in 1986-1997. The peak lung cancer mortality RRs were 3.61 (95% confidence interval [CI] = 3.13 to 4.16) for men and 3.26 (95% CI = 2.50 to 4.23) for women. The peak bladder cancer RRs were 6.10 (95% CI = 3.97 to 9.39) for men and 13.8 (95% CI = 7.74 to 24.5) for women. Combined lung and bladder cancer mortality rates in region II were highest in the period 1992-1994, with mortality rates of 153 and 50 per 100,000 men and women, respectively, in region II compared with 54 and 19 per 100,000 in region V. Conclusions Such large increases in total population cancer mortality rates have, to our knowledge, not been documented for any other environmental exposure. The long latency pattern is noteworthy, with mortality from lung and bladder cancers continuing to be high until the late 1990s, even though major decreases in arsenic exposure occurred more than 25 years earlier.

Mass Spectrometry to Classify Non–Small-Cell Lung Cancer Patients for Clinical Outcome After Treatment With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Multicohort Cross-Institutional Study

Abstract: Background Some but not all patients with non – small-cell lung cancer (NSCLC) respond to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We developed and tested the ability of a predictive algorithm based on matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) analysis of pretreatment serum to identify patients who are likely to benefit from treatment with EGFR TKIs. Methods Serum collected from NSCLC patients before treatment with gefitinib or erlotinib were analyzed by MALDI MS. Spectra were acquired independently at two institutions. An algorithm to predict outcomes after treatment with EGFR TKIs was developed from a training set of 139 patients from three cohorts. The algorithm was then tested in two independent validation cohorts of 67 and 96 patients who were treated with gefitinib and erlotinib, respectively, and in three control cohorts of patients who were not treated with EGFR TKIs. The clinical outcomes of survival and time to progression were analyzed. Results An algorithm based on eight distinct m/z features was developed based on outcomes after EGFR TKI therapy in training set patients. Classifications based on spectra acquired at the two institutions had a concordance of 97.1%. For both validation cohorts, the classifier identified patients who showed improved outcomes after EGFR TKI treatment. In one cohort, median survival of patients in the predicted “good” and “poor” groups was 207 and 92 days, respectively (hazard ratio [HR] of death in the good versus poor groups = 0.50, 95% confidence interval [CI] = 0.24 to 0.78). In the other cohort, median survivals were 306 versus 107 days (HR = 0.41, 95% CI = 0.17 to 0.63). The classifier did not predict outcomes in patients who did not receive EGFR TKI treatment. Conclusion This MALDI MS algorithm was not merely prognostic but could classify NSCLC patients for good or poor outcomes after treatment with EGFR TKIs. This algorithm may thus assist in the pretreatment selection of appropriate subgroups of NSCLC patients for treatment with EGFR TKIs. J Natl Cancer Inst 2007;99: 838 – 46