Adherence to dietary recommendations and risk of esophageal squamous cell carcinoma: a case-control study in Iran.

BACKGROUND/AIM: The Dietary Guidelines for Americans Adherence Index (DGAI) 2005 was developed to assess the contribution of dietary patterns to chronic disease risk. The objective of this study was to evaluate the association of dietary patterns as measured by the DGAI 2005 with the esophageal squamous cell carcinoma (ESCC) risk in Iran. METHODS: This case-control study was conducted on 50 ESCC cases and 100 hospital controls aged 40-75 years. Participants were interviewed using validated food frequency questionnaires and the DGAI score was calculated subsequently. RESULTS: Generally, the mean DGAI 2005 score for this population was low (9.54 ± 1.79) and the control group scored significantly higher compared to the ESCC cases (p < 0.001). Being in the highest tertile of DGAI scores reduced the risk of ESCC by 31%. Consumption of salty, peppery, and sour foods in combination increased the ESCC risk by 7.23%, followed by consumption of fried/barbecued meals (OR 3.79; 95% CI 1.10-5.44; p < 0.001) and high-temperature food/beverages (OR 3.68; 95% CI 1.20-8.99; p < 0.001). CONCLUSIONS: Consumption of a diet in accordance with dietary recommendations was associated with a lower risk of ESCC. Preventive strategies to reduce the ESCC risk in high-risk regions of the world should focus on overall dietary patterns and dietary habits in order to be effective.

A case-match study comparing unilateral with synchronous bilateral breast cancer outcomes.

PURPOSE: There is controversy about whether patients with synchronous bilateral breast cancer (SBBC) have similar or worse outcomes compared with patients with unilateral breast cancer. The purpose of this study was to determine whether survival outcomes for patients with SBBC can be estimated from the characteristics of their individual cancers. PATIENTS AND METHODS: Patients had invasive breast cancer, without metastases or inflammatory disease, diagnosed in British Columbia between 1989 and 2000. There were 207 cases with SBBC (diagnosed ≤ 2 months apart) and 15,497 with unilateral breast cancer. By using 10-year breast cancer-specific survival (BCSS) estimates, the higher-risk cancer of each SBBC case was determined and matched with three breast cancers from the unilateral cohort to select 621 high-risk matches. The priority sequence of matching the prognostic and predictive variables was positive lymph node number, primary tumor size, age, grade, lymphovascular invasion, estrogen receptor status, local therapy used, margin status, treating clinic, diagnosis year, and type of systemic therapy used. RESULTS: With a median follow-up of 10.2 years, the overall 10-year BCSS was significantly higher for the unilateral cohort (81%; 95% CI, 81% to 82%) than for the SBBC cases (71%; 95% CI, 63% to 77%). The SBBC cases had significantly higher mean age and stage at presentation. The 10-year BCSS was 74% (95% CI, 69% to 77%) for the high-risk matches. CONCLUSION: BCSS was not significantly different between the SBBC cases and their high-risk matches.

The prognostic effect of ethnicity for gastric and esophageal cancer: the population-based experience in British Columbia, Canada.

BACKGROUND: Gastric and esophageal cancers are among the most lethal human malignancies. Their epidemiology is geographically diverse. This study compares the survival of gastric and esophageal cancer patients among several ethnic groups including Chinese, South Asians, Iranians and Others in British Columbia (BC), Canada. METHODS: Data were obtained from the population-based BC Cancer Registry for patients diagnosed with invasive esophageal and gastric cancer between 1984 and 2006. The ethnicity of patients was estimated according to their names and categorized as Chinese, South Asian, Iranian or Other. Cox proportional hazards regression analysis was used to estimate the effect of ethnicity adjusted for patient sex and age, disease histology, tumor location, disease stage and treatment. RESULTS: The survival of gastric cancer patients was significantly different among ethnic groups. Chinese patients showed better survival compared to others in univariate and multivariate analysis. The survival of esophageal cancer patients was significantly different among ethnic groups when the data was analyzed by a univariate test (p = 0.029), but not in the Cox multivariate model adjusted for other patient and prognostic factors. CONCLUSIONS: Ethnicity may represent underlying genetic factors. Such factors could influence host-tumor interactions by altering the tumor's etiology and therefore its chance of spreading. Alternatively, genetic factors may determine response to treatments. Finally, ethnicity may represent non-genetic factors that affect survival. Differences in survival by ethnicity support the importance of ethnicity as a prognostic factor, and may provide clues for the future identification of genetic or lifestyle factors that underlie these observations.

Breast cancer treatment and ethnicity in British Columbia, Canada.

BACKGROUND: Racial and ethnic disparities in breast cancer incidence, stage at diagnosis, survival and mortality are well documented; but few studies have reported on disparities in breast cancer treatment. This paper compares the treatment received by breast cancer patients in British Columbia (BC) for three ethnic groups and three time periods. Values for breast cancer treatments received in the BC general population are provided for reference. METHODS: Information on patients, tumour characteristics and treatment was obtained from BC Cancer Registry (BCCR) and BC Cancer Agency (BCCA) records. Treatment among ethnic groups was analyzed by stage at diagnosis and time period at diagnosis. Differences among the three ethnic groups were tested using chi-square tests, Fisher exact tests and a multivariate logistic model. RESULTS: There was no significant difference in overall surgery use for stage I and II disease between the ethnic groups, however there were significant differences when surgery with and without radiation were considered separately. These differences did not change significantly with time. Treatment with chemotherapy and hormone therapy did not differ among the minority groups. CONCLUSION: The description of treatment differences is the first step to guiding interventions that reduce ethnic disparities. Specific studies need to examine reasons for the observed differences and the influence of culture and beliefs.

Ultraviolet radiation.

The major source of ultraviolet radiation is solar radiation or sunlight. However, exposure to artificial sources particularly through tanning salons is becoming more important in terms of human health effects, as use of these facilities by young people, has increased. The International Agency for Research on Cancer has noted that there is sufficient evidence from studies in animals and in man to establish ultraviolet radiation as a human carcinogen. Skin cancer has been the most commonly studied cancer site with respect to UV radiation. The nature and timing of sun exposure appear to be important determinants of both the degree of risk and the type of skin cancer. Cutaneous malignant melanoma and basal cell cancer are much more strongly related to measures of intermittent ultraviolet exposure (particularly those of childhood or adolescence) than to measures of cumulative exposure. In contrast, squamous cell cancer is more strongly related to constant or cumulative sun exposure. Lip cancer is causally related to lifetime sun exposure. It has been estimated that solar ultraviolet radiation accounts for approximately 93 percent of skin cancers and about half of lip cancers. This translates to approximately 4,500 life-threatening cancers (cutaneous malignant melanoma) per year in Canada, as well as 65,000 less serious cancers (basal cell cancer, squamous cell cancer and lip cancer). Appropriate clothing use, care not to sunburn and judicious use of sunscreens could prevent at least half of these and save approximately 450 lives per year. In addition, physician and public education programs can significantly increase the proportion of melanomas diagnosed early. Lesions that have not yet penetrated deeply are associated with a mortality rate of less than five percent. Several recent studies suggest a possible inverse relationship between ultraviolet radiation exposure and risk of non-Hodgkin lymphoma, colon, breast and prostate cancer, and investigators have speculated that this might be due to the higher serum levels of vitamin D stimulated by high lifetime sun exposure. Further, studies conducted within cohorts using stored pre-diagnostic serum suggest that those with high levels of vitamin D have lower incidence rates of a number of malignancies, particularly colon cancer. However, since serum vitamin D levels can be raised through the use of supplements without increasing risk for skin lip and other known UV-related cancers, changes to health policy with regard to exposure are not merited at this point. Further research is needed in this area.

Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer.

Lynch syndrome is defined by the presence of germline mutations in mismatch repair (MMR) genes. Several models have been recently devised that predict mutation carrier status (Myriad Genetics, Wijnen, Barnetson, PREMM and MMRpro models). Families at moderate-high risk for harboring a Lynch-associated mutation, referred to the BC Cancer Agency (BCCA) Hereditary Cancer Program (HCP), underwent mutation analysis, immunohistochemistry and/or microsatellite testing. Seventy-two tested cases were included. Twenty-five patients were mutation positive (34.7%) and 47 were mutation negative (65.3%). Nineteen of 43 patients who were both microsatellite stable and normal on immunohistochemistry for MLH1 and MSH2 were also genotyped for mutations in these genes; all 19 were negative for MMR gene mutations. Model-derived probabilities of harboring a MMR gene mutation in the proband were calculated and compared to observed results. The area under the ROC curves were 0.75 (95%CI; 0.63-0.87), 0.86 (0.7-0.96), 0.89 (0.82-0.97), 0.89 (0.81-0.98) and 0.93 (0.86-0.99) for the Myriad, Barnetson, Wijnen, MMRpro and PREMM models, respectively. The Amsterdam II criteria had a sensitivity and specificity of 0.76 and 0.74, respectively, in this cohort. The PREMM model demonstrated the best performance for predicting carrier status based on the positive likelihood ratios at the >10%, >20% and >30% probability thresholds. In this referred cohort, the PREMM model had the most favorable concordance index and predictive performance for carrier status based on the positive LR. These prediction models (PREMM, MMRPro and Wijnen) may soon replace the Amsterdam II and revised Bethesda criteria as a prescreening tool for Lynch mutations.

Hepatitis B testing and vaccination in immigrants attending English as a second language classes in British Columbia, Canada.

BACKGROUND: Hepatitis B virus (HBV) is a growing health issue in Canada, especially given that population growth is now largely the result of immigration. Immigrants from countries with high HBV prevalence and low levels of HBV vaccination have an excess risk of liver disease and there is a need for increased diligence in HBV blood testing and possibly vaccination among these populations. OBJECTIVE: This study describes the sociodemographic characteristics associated with a history of HBV testing and HBV vaccination in immigrants from several countries with high HBV prevalence who are attending English classes. METHODS: 759 adult immigrants attending English as a Second Language classes completed a self-administered questionnaire asking about sociodemographic characteristics and history of HBV testing and HBV vaccination. Descriptive statistics and adjusted ORs were calculated to explore these associations. RESULTS: 71% reported prior HBV testing, 8% reported vaccination without testing, and 21% reported neither testing nor vaccination. Age, education and country of birth all showed significant effects for both testing and vaccination. CONCLUSIONS: Health care practitioners need to be cognizant of HBV testing, and possibly vaccination, in some of their patients, including immigrants from countries with endemic HBV infection. Infected persons need to be identified by blood testing in order receive necessary care to prevent or delay the onset of liver disease as well as to adopt appropriate behaviours to reduce the risk of transmission to others. Close contacts of infected persons also require HBV testing and subsequent vaccination (if not infected) or medical management (if infected).

Agreement between birthplace and self-reported ethnicity in a population-based mammography service.

BACKGROUND: Ethnicity is associated with genetic, environmental, lifestyle and social constructs. Difficult to define using a single variable, but strongly predictive of health outcomes and useful for planning healthcare services, it is often lacking in administrative databases, necessitating the use of a surrogate measure. A potential surrogate for ethnicity is birthplace. Our aim was to measure the agreement between birthplace and ethnicity among six major ethic groups as recorded at the population-based mammography service for British Columbia, Canada (BC). METHODS: We used records from the most-recent visits of women attending the Screening Mammography Program of British Columbia to cross-tabulate women's birthplaces and self-reported ethnicities, and separately considered results for the time periods 1990-1999 and 2000-2006. In general, we combined countries according to the system adopted by the United Nations, and defined ethnic groups that correspond to the nation groups. The analysis considered birthplaces and corresponding ethnicities for South Asia, East/Southeast Asia, North Europe, South Europe, East Europe, West Europe and all other nations combined. We used the kappa statistic to measure the concordance between self-reported ethnicity and birthplace. RESULTS: Except for the 'Other' category, the most-common birthplace was East/Southeast Asia and the most-common ethnicity was East/Southeast Asian. The agreement between birthplace and self-reported ethnicity was poor overall, as evidenced by kappa scores of 0.22 in both 1990-1999 and 2000-2006. There was substantial agreement between ethnicity and birthplace for South Asians, excellent agreement for East/Southeast Asians, but poor agreement for Europeans. CONCLUSION: Birthplace can be used as a surrogate for ethnicity amongst people with South Asian and East/Southeast Asian ethnicity in BC.

Basal breast cancer molecular subtype predicts for lower incidence of axillary lymph node metastases in primary breast cancer.

BACKGROUND: Axillary lymph node involvement remains the most important prognostic factor in early-stage breast cancer. We hypothesized that molecular classification based on breast cancer biology would predict the presence of nodal involvement at diagnosis, which might aid treatment decisions regarding the axilla. PATIENTS AND METHODS: From a clinically annotated tissue microarray of 4444 early-stage breast cancers, expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, epidermal growth factor receptor, and cytokeratin 5/6 was determined by immunohistochemistry. Cases were classified by published criteria into molecular subtypes of luminal, luminal/HER2 positive, HER2 positive/ER negative/PgR negative, and basal. Risk of axillary nodal involvement at diagnosis was determined in 2 multivariable logistic regression models: a "core biopsy model" including molecular subtype, age, grade, and tumor size and a "lumpectomy model," which also included lymphovascular invasion. Luminal was used as the reference group. After internal validation of findings in 2 independent sets, we conducted combined analysis of both. RESULTS: In the core biopsy model, the molecular subtypes had a predictive effect for nodal involvement (P= .000001), with the basal subtype having an odds ratio for axillary lymph node involvement of 0.53 (95% CI, 0.41-0.69). Tumor grade (P=5.43 x 10(-12)) and size (P=8.52 x 10(-35)) were also predictive for nodal involvement. Similar results were found in the lumpectomy model, where lymphovascular invasion was also predictive (P=2.74 x 10(-115)). CONCLUSION: These results indicate that the basal breast cancer molecular subtype predicts a lower incidence of axillary nodal involvement, and including biomarker profiles to predict nodal status at diagnosis could help stratification for decisions regarding axillary surgery and locoregional radiation.

Can clinically relevant prognostic subsets of breast cancer patients with four or more involved axillary lymph nodes be identified through immunohistochemical biomarkers? A tissue microarray feasibility study.

INTRODUCTION: Primary breast cancer involving four or more axillary lymph nodes carries a poor prognosis. We hypothesized that use of an immunohistochemical biomarker scoring system could allow for identification of variable risk subgroups. METHODS: Patients with four or more positive axillary nodes were identified from a clinically annotated tissue microarray of formalin-fixed paraffin-embedded primary breast cancers and randomized into a 'test set' and a 'validation set'. A prospectively defined prognostic scoring model was developed in the test set and was further assessed in the validation set combining expression for eight biomarkers by immunohistochemistry, including estrogen receptor, human epidermal growth factor receptors 1 and 2, carbonic anhydrase IX, cytokeratin 5/6, progesterone receptor, p53 and Ki-67. Survival outcomes were analyzed by the Kaplan-Meier method, log rank tests and Cox proportional-hazards models. RESULTS: A total of 313 eligible patients were identified in the test set for whom 10-year relapse-free survival was 38.3% (SEM 2.9%), with complete immunohistochemical data available for 227. Tumor size, percentage of positive axillary nodes and expression status for the progesterone receptor, Ki-67 and carbonic anhydrase IX demonstrated independent prognostic significance with respect to relapse-free survival. Our combined biomarker scoring system defined three subgroups in the test set with mean 10-year relapse-free survivals of 75.4% (SEM 7.0%), 35.3% (SEM 4.1%) and 19.3% (SEM 7.0%). In the validation set, differences in relapse-free survival for these subgroups remained statistically significant but less marked. CONCLUSION: Biomarkers assessed here carry independent prognostic value for breast cancer with four or more positive axillary nodes and identified clinically relevant prognostic subgroups. This approach requires refinement and validation of methodology.

Ethnic differences in survival for female cancers of the breast, cervix and colorectum in British Columbia, Canada.

BACKGROUND: Chinese and South Asians are among the fastest growing minority populations in Canada; however little is known about the burden of cancer in these populations. OBJECTIVE: The objective is to examine survival rates for breast, cervical and colorectal cancers in women within these two ethnic populations, as compared to the BC general population. METHODS: Survival rates were calculated for three time periods in the Chinese, South Asian and BC general populations, using the BC cancer registry. Ethnicity within the registry was determined using surnames. RESULTS: Survival rates for female breast, cervical and colorectal cancers have improved over time in all three population groups, however general differences were found among the groups. Chinese women had higher survival rates than both South Asians and all BC women for breast and cervical cancer, and intermediate survival rates between South Asians and all BC women for colorectal cancer. South Asian women had the highest survival rates for colorectal cancer, similar survival rates to all BC women for breast cancer, and lower survival rates for cervical cancer. INTERPRETATION: Differences in the observed survival rates may be explained by variations in screening and early detection, treatment practices, and cancer biology. This is discussed more fully for each cancer site.

Cancer incidence in Indians from three areas: Delhi and Mumbai, India, and British Columbia, Canada.

BACKGROUND: Studies of immigrants have provided unique opportunities for examining disparities in cancer screening and the impact of lifestyles and environmental exposures on cancer risk. Findings have been useful for planning cancer control strategies and generating etiological hypotheses. Although India is a leading source of immigration to British Columbia (BC), Canada, little is known about the cancer profiles of Indo-Canadians, information needed for planning health services and health promotion initiatives for this population. METHODS: Using data from three population-based cancer registries, cancer incidence was compared for four population groups (in each of Delhi and Mumbai, India; Indo-Canadians in BC, Canada; and the BC general population) over three time periods (1976-1985, 1986-1995 and 1996-2003). BC Indo-Canadians were identified by using Indian surnames. RESULTS: Age-standardized incidence rates (ASRs) for all cancers combined were lowest for men and women in Delhi and Mumbai, intermediate for BC Indo-Canadians, and highest for the BC general population. Ranking of common cancer sites and ASRs for Indo-Canadian men and women more closely resembled those for the BC general population, rather than those for either Delhi or Mumbai. ASRs and rankings of common cancer sites are presented by gender for the four population groups. CONCLUSIONS: Cancer incidence patterns in BC Indo-Canadian men and women differed from those in India, being more similar to the BC general population.

Predicting the performance of a genetic testing service for cancer susceptibility.

A genetic testing service can determine which members of a population might benefit most from cancer prevention. The eligibility criteria will affect the number of people who use a service and the proportion who test positive. This affects both the service's costs and benefits. The goal of this study was to create computer software that predicts the effect of eligibility restrictions on the performance of a genetic testing service. The software allows eligibility restrictions based on age, gender, and family history of disease. As performance measures, we considered the sensitivity and specificity of eligibility criteria to identify people with genetic cancer susceptibility, the likelihood of genetic susceptibility among people who are eligible for the service, and the likelihood of genetic susceptibility among people who are ineligible. We compared the performance predicted by our model with the observed performance of the Hereditary Cancer Program at the BC Cancer Agency, and studied the effects of changes to model parameters. There was good agreement between model predictions and observed outcomes, however, performance measures were affected by changes to the underlying model parameters. Computer software to predict the performance of a genetic testing service for cancer susceptibility is implemented on the website http://142.103.207.51:8080/gtsim.

Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival.

PURPOSE: Estrogen receptor (ER) expression predicts improved breast cancer-specific survival and reduced risk of recurrence and is targeted in breast cancer therapy. A high-quality antibody to identify ER-positive patients plays an important role in clinical decision making for women with breast cancer. This study evaluates immunohistochemistry using two anti-ER antibodies, a new rabbit monoclonal antibody (SP1) and the mouse monoclonal antibody (1D5), in relation to biochemical ER assay results and clinical data on survival and adjuvant systemic therapy. PATIENTS AND METHODS: A population-based tissue microarray series of 4,150 invasive breast cancers was constructed. All patients had staging, pathology, treatment, and follow-up information. The median follow-up was 12.4 years and the median age at diagnosis 60 years. Survival analysis and log-rank tests were used to evaluate the prognostic value of ER status and correlations with clinical data. RESULTS: Among the 4,105 samples interpretable for both antibodies, SP1 detected ER positivity in 69.5% and 1D5 in 63.1% of cases. Both monoclonal antibodies are demonstrated to be good prognostic indictors for breast cancer-specific and relapse-free survival. In multivariate analysis, including age, tumor size, grade, and lymphovascular and nodal status, SP1 was a better independent prognostic factor than 1D5. Among patients with discrepant ER results, the 8% of patients who were SP1 positive/1D5 negative showed good outcomes, and the 2% SP1-negative/1D5 positive had poor outcomes. Maintaining the same 92% specificity and 98% positive predictive value, SP1 is 8% more sensitive than 1D5 using biochemical assay as gold standard. CONCLUSION: SP1 represents an improved standard for ER immunohistochemistry assessment in breast cancer.

Identifying related cancer types based on their incidence among people with multiple cancers.

BACKGROUND: There are several reasons that someone might be diagnosed with more than one primary cancer. The aim of this analysis was to determine combinations of cancer types that occur more often than expected. The expected values in previous analyses are based on age-and-gender-adjusted risks in the population. However, if cancer in people with multiple primaries is somehow different than cancer in people with a single primary, then the expected numbers should not be based on all diagnoses in the population. METHODS: In people with two or more cancer types, the probability that a specific type is diagnosed was determined as the number of diagnoses for that cancer type divided by the total number of cancer diagnoses. If two types of cancer occur independently of one another, then the probability that someone will develop both cancers by chance is the product of the individual probabilities for each type. The expected number of people with both cancers is the number of people at risk multiplied by the separate probabilities for each cancer. We performed the analysis on records of cancer diagnoses in British Columbia, Canada between 1970 and 2004. RESULTS: There were 28,159 people with records of multiple primary cancers between 1970 and 2004, including 1,492 people with between three and seven diagnoses. Among both men and women, the combinations of esophageal cancer with melanoma, and kidney cancer with oral cancer, are observed more than twice as often as expected. CONCLUSION: Our analysis suggests there are several pairs of primary cancers that might be related by a shared etiological factor. We think that our method is more appropriate than others when multiple diagnoses of primary cancer are unlikely to be the result of therapeutic or diagnostic procedures.

Physical and emotional health effects and social consequences after participation in a low-fat, high-carbohydrate dietary trial for more than 5 years.

PURPOSE: Little is known about the potential adverse effects of interventions to reduce dietary fat. We examined the physical and emotional health effects, and social consequences experienced by women at high risk for breast cancer who had participated in a low-fat diet intervention, randomized, controlled trial for at least 5 years. METHODS: Participants in the Canadian Diet and Breast Cancer Prevention Trial from British Columbia were mailed a survey questionnaire that included the validated Medical Outcomes Study 36-item Short Form Health Survey (SF-36) and Women's Health Questionnaire (WHQ), and a series of questions on health-related and social constructs. Responses were compared between the diet intervention and control groups by menopausal status. RESULTS: Completed questionnaires were returned by 359 women in the diet intervention group and 382 in the control group. No significant differences were found between these groups for SF-36 and WHQ health outcomes, hair/nail changes, physical activity levels, family/friend support levels, and doctor visits. Significantly more women in the intervention group reported taking products for arthritis (other than pain medication), greater difficulty in maintaining eating habits in social situations and at work, greater stress, and guilt related to personal eating habits. These findings persisted for both premenopausal and postmenopausal women. CONCLUSION: Changes resulting from a low-fat diet intervention can be incorporated into women's daily lives with limited long-term negative effects.

MDM2 protein expression is a negative prognostic marker in breast carcinoma.

The protein encoded by the MDM2 oncogene inhibits the function of p53, leading to increased cell growth, avoidance of apoptosis, tolerance of genetic instability, and resistance to chemotherapy. The present study was performed to evaluate the relationship between MDM2 protein expression and survival in breast carcinoma. Two series of cases were used in this study: the first to identify the cutoff to be used in the interpretation of MDM2 immunostaining and perform preliminary survival analysis, and a second, independent series, to validate the findings from the first series and to perform multivariate analysis. For both series, archival sections of tissue microarrays were stained with anti-MDM2 antibody (NeoMarkers, Fremont, CA, USA) and MDM2 staining intensity was scored semiquantitatively. In the first series, 49 of 362 (14%) interpretable cases were positive for MDM2 expression, with 35 (10%) showing weak positivity and 14 (4%) strong positivity. Patients with MDM2-positive tumours had a significantly worse disease-specific survival than patients with MDM2-negative tumours (P=0.0022, 10-year DSS 61% (95% CI: 45-73) vs 73% (95% CI: 67-77)). No significant difference in survival was observed between patients with strongly and weakly MDM2-positive tumours (P=0.3). Accordingly, in the independent validation series weak and strong MDM2 positivity were combined and considered to be MDM2 positive. MDM2 expression was seen in 230/1747 (13%) interpretable cases in this series, with a significant difference (P<0.0001) in DSS between MDM2-negative and MDM2-positive cases (10 year DSS 58% (95% CI: 51-64) vs 73% (95% CI: 70-75)). MDM2 was an independent prognostic marker (HR=1.35, P=0.02) in a Cox regression model including MDM2 expression, tumour grade, nodal status, ER status and tumour size. Immunohistochemical studies of MDM2 in more than 2000 breast carcinomas show that MDM2 is an independent negative prognostic marker.

Population-based validation of the prognostic model ADJUVANT! for early breast cancer.

PURPOSE: Adjuvant! (www.adjuvantonline.com) is a web-based tool that predicts 10-year breast cancer outcomes with and without adjuvant systemic therapy, but it has not been independently validated. METHODS: Using the British Columbia Breast Cancer Outcomes Unit (BCOU) database, demographic, pathologic, staging, and treatment data on 4,083 women diagnosed between 1989 and 1993 in British Columbia with T1-2, N0-1, M0 breast cancer were abstracted and entered into Adjuvant! to calculate predicted 10-year overall survival (OS), breast cancer-specific survival (BCSS), and event-free survival (EFS) for each patient. Individual BCOU observed outcomes at 10 years were independently determined. Predicted and observed outcomes were compared. RESULTS: Across all 4,083 patients, 10-year predicted and observed outcomes were within 1% for OS, BCSS, and EFS (all P > .05). Predicted and observed outcomes were within 2% for most demographic, pathologic, and treatment-defined subgroups. Adjuvant! overestimated OS, BCSS, and EFS in women younger than age 35 years (predicted-observed = 8.6%, 9.6%, and 13.6%, respectively; all P < .001) or with lymphatic or vascular invasion (LVI; predicted-observed = 3.6%, 3.8%, and 4.2%, respectively; all P < .05); these two prognostic factors were not automatically incorporated within the Adjuvant! algorithm. After adjusting for the distribution of LVI, using the prognostic factor impact calculator in Adjuvant!, 10-year predicted and observed outcomes were no longer significantly different. CONCLUSION: Adjuvant! performed reliably. Patients younger than age 35 or with known additional adverse prognostic factors such as LVI require adjustment of risks to derive reliable predictions of prognosis without adjuvant systemic therapy and the absolute benefits of adjuvant systemic therapy.

CGMIM: automated text-mining of Online Mendelian Inheritance in Man (OMIM) to identify genetically-associated cancers and candidate genes.

BACKGROUND: Online Mendelian Inheritance in Man (OMIM) is a computerized database of information about genes and heritable traits in human populations, based on information reported in the scientific literature. Our objective was to establish an automated text-mining system for OMIM that will identify genetically-related cancers and cancer-related genes. We developed the computer program CGMIM to search for entries in OMIM that are related to one or more cancer types. We performed manual searches of OMIM to verify the program results. RESULTS: In the OMIM database on September 30, 2004, CGMIM identified 1943 genes related to cancer. BRCA2 (OMIM *164757), BRAF (OMIM *164757) and CDKN2A (OMIM *600160) were each related to 14 types of cancer. There were 45 genes related to cancer of the esophagus, 121 genes related to cancer of the stomach, and 21 genes related to both. Analysis of CGMIM results indicate that fewer than three gene entries in OMIM should mention both, and the more than seven-fold discrepancy suggests cancers of the esophagus and stomach are more genetically related than current literature suggests. CONCLUSION: CGMIM identifies genetically-related cancers and cancer-related genes. In several ways, cancers with shared genetic etiology are anticipated to lead to further etiologic hypotheses and advances regarding environmental agents. CGMIM results are posted monthly and the source code can be obtained free of charge from the BC Cancer Research Centre website http://www.bccrc.ca/ccr/CGMIM

Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin.

Urokinase plasminogen activator (uPA) expression in breast cancer is associated with relapse and a reduction in disease-specific survival. Thus, efforts are under way to identify uPA inhibitors. By screening a chemical library of >1000 compounds, 17-allyaminogeldanamycin (17AAG) was identified as a potent inhibitor of uPA by the National Cancer Institute and is now in Phase I clinical trials. At this time, it remains unclear how 17AAG blocks uPA; one possibility is through disruption of the insulin-like growth factor I receptor (IGF-IR) pathway. This would be consistent with studies from our laboratory showing that activation of IGF-IR results in the induction of uPA protein. In the study described herein, we observed that IGF-IR and uPA were highly expressed in 87 and 55% of breast cancer by screening tumor tissue microarrays representing 930 cases. A significant proportion (52.1% = 354 of 680 cases, P < 0.0001) of the patients had tumors expressing both proteins. uPA alone (P = 0.033) or in combination with IGF-IR (P = 0.0104) was indicative of decreased disease-specific survival. Next, we demonstrated that treating MDA-MB-231 cells with increasing concentrations of 17AAG resulted in IGF-IR degradation (IC(50) = 1.0 micro M) and blocked signal transduction through the Akt and mitogen-activated protein kinase pathways. Finally, we found that 17AAG had a robust inhibitory effect on the production of uPA mRNAand protein in the presence of IGF-I. Thus, our study raises the possibility that 17AAG could prove to be an effective therapeutic agent for a large number of breast cancer patients by inhibiting the IGF-IR and ultimately uPA.