bluuebunny/crossref_metadata_2025 huggingface dataset:
P5-18-09: The Incidence of Febrile Neutropenia in the First Course of Adjuvant Chemotherapy with Docetaxel/Cyclophosphamide with or without Pegfilgrastim.
Authors: Jones S , Paul D , Sedlacek S , Vukelja S , Wilks ST , Stokoe C , Osborne CR , Krekow L , McIntyre K , Holmes FA , Guerra L , Zhan F , Asmar L , O'Shaughnessy J , Blum JL
Published: June 2012

Background

In our original doxorubicin-cyclophosphamide/docetaxel-cyclophosphamide (AC/TC) adjuvant study (JCO 27: 1177–1183, 2009), we reported an incidence of febrile neutropenia (FN) of 5% (8% in women ≥65 years) with the TC regimen without prophylactic WBC growth factors but with a recommendation for prophylactic antibiotics. There is a paucity of data on the incidence of FN with the TC regimen aside from this clinical trial. Because we have been conducting a randomized adjuvant study of TC compared to other regimens, we used this opportunity to analyze the incidence of FN during the first course of chemotherapy with TC in the first cohort of randomized patients (US Oncology Network study 06090). The prophylactic use of WBC growth factors was at the investigator's discretion.

Patients and Methods

The study included 1298 patients entered between May 2007 and May 2009. Of these, 649 were included in the TC arm. Median age was 54 years (range 27–71), 75.5% were Caucasian, 561 (86.4%) were in PS 0 at baseline, and about half were node negative. Eight patients did not receive study treatment for various reasons. Among the 641 patients who received TC; 213 (33.3%) received pegfilgrastim, 48 (7.5%) received filgrastim and were not included in this analysis, and 380 (59.2%) patients did not receive either during the first cycle. Thus, this analysis focused on 593 women who did or did not receive prophylactic pegfilgrastim in cycle 1.

Results: All patients with a reported adverse event of FN or with a reported AE of fever with some degree of neutropenia (in order to capture all possible cases of FN) during the first cycle of TC were identified [Table 1]. FN and fever + neutropenia occurred in a total of 6 (2.8%) patients who received pegfilgrastim and 36 (9.5%) patients who did not. A comparison of age, race, performance status and stage of disease between these 2 groups revealed that they were similar. The 213 patients who received pegfilgrastim were slightly older (median 56 years, range 27–71) compared to those who did not (median 53 years, range 30–71).

During all 6 cycles, 41 patients reported FN, and 30 (73%) of these patients experienced FN during cycle 1.

Conclusion: Among 593 women who received TC as adjuvant chemotherapy, the incidence of FN during the first cycle was under 10% whether or not the patients received prophylactic pegfilgrastim.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-09.
PD07-08: The Effect on Surgical Complications of Bevacizumab Added to Neoadjuvant Chemotherapy: NSABP Protocol B-40.
Authors: Bear HD , Tang G , Rastogi P , Geyer CE , André R , Atkins JN , Baez-Diaz L , Brufsky AM , Mehta RS , Fehrenbacher L , Pajon ER , Senecal FM , Gaur R , Margolese RG , Adams PT , Gross HM , Costantino JP , Swain SM , Mamounas EP , Wolmark N
Published: June 2012

The NSABP trial B-40 was designed to determine whether adding capecitabine or gemcitabine to docetaxel followed by AC would increase the pathologic complete response (pCR) rates in patients with operable HER2−negative breast cancer and to determine whether the addition of bevacizumab to three docetaxel-based regimens followed by AC would increase pCR rates. Secondary endpoints include the percentage of surgical complications after mastectomy, lumpectomy, and axillary staging procedures in the patients who received chemotherapy versus those who received chemotherapy and bevacizumab.

Methods: Women with HER2−negative operable breast cancer received one of the following docetaxel-based regimens with or without bevacizumab (15mg/kg) every 3 weeks for four cycles: docetaxel 100 mg/m2 IV; docetaxel 75 mg/m2 and capecitabine 825 mg/m2 po BID days 1–14; and docetaxel 75 mg/m2 day 1 and gemcitabine 1000 mg/m2 IV days 1 and 8. These regimens were followed by preoperative standard AC on day 1 every 21 days for four cycles with or without bevacizumab 15 mg/kg given with the initial 2 cycles of AC. Treatment groups randomized to receive bevacizumab resumed postoperative bevacizumab 15 mg/kg IV every 3 weeks for an additional 10 doses. Assessment of surgical complications was performed from the date of surgery through 24 months following study entry.

Results: Planned analysis for surgical complications will be conducted in October 2011 and will be presented along with breast reconstruction data.

Funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U10-CA-52667, with additional support from F. Hoffmann La-Roche, Ltd., Genentech, USA, and Eli Lilly and Company.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-08.
Abstract A25: Patient Navigation Research Program: Time to diagnostic resolution
Authors: Battaglia Tracy A. , Freund Karen M. , Bak Sharon , Kalish Richard L. , Egan A. Patrick , Heeren Tim C. , Lottero Barbara , Taylor James , Thakrar Nisha , Tringale Stephen M.
Published: June 2012

There is a need for controlled research studies to assess the impact of patient navigation on patient outcomes. The goal is to evaluate whether patient navigation decreased time to diagnosis for subjects with a breast or cervical cancer screening abnormality. Boston Patient Navigation Research Program collected baseline data (2004–2005) and intervention data (2007–2008) at 6 community health center sites. Kaplan-Meier survival curves and proportional hazards regression examined the effect of navigation on time to definitive diagnosis, adjusting for clustering by clinic and adjusting for age, race, language, and insurance. Hazard ratios greater than 1.0 indicate a decrease in time to diagnosis. We enrolled N = 997 subjects in the baseline period and N = 3,041 subjects during the intervention period (n = 1,499 navigated, n = 1,542 control); 66% were Non-White. Among those with a breast screening abnormality, there was a significant decrease in time to diagnosis for navigated subjects who resolved after 60 days [aHR 1.49, 95% CI: 1.2–1.8] compared with controls, but no differences for those who resolved before 60 days. Among those with a cervical screening abnormality, there was a significant decrease in time to diagnosis for all navigated subjects when compared with controls (aHR 1.33, 95% CI: 1.13–1.56). This controlled study documents a benefit of patient navigation on time to diagnosis among a racially/ethnically diverse inner city population.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A25.
Abstract A41: Does medical mistrust influence black women's participating in BRCA1/2 genetic counseling and testing?
Authors: Sheppard Vanessa D. , Mays Darren , Tercyak Kenneth
Published: June 2012

Approximately 5%-10% of breast cancers are heritable. Clinical evidence supports the value of BRCA1/2 genetic counseling and testing (GC/T) for hereditary breast and ovarian cancer risk. However, BRCA1/2 GC/T is underutilized among Black women and reasons are not well understood. We examined the potential influence of medical mistrust on GC/T participation in a sample of 100 Black women at increased risk for carrying a BRCA1/2 mutation. Eligible participants fell into one of three groups: 1) healthy women with > 1 first-degree relative (FDR) affected by breast and/or ovarian cancer, 2) women diagnosed with breast cancer at < 50 years of age, and 3) women diagnosed with breast and/or ovarian cancer at > 50 years of age with either one FDR or two second degree relatives with breast and/or ovarian cancer. Participants were recruited from hospital and community settings and completed a researcher-administered survey. The dependent variable indicated women's GC/T participation (0 = unaware, 1=aware but had no referral, and; 2 = received a referral and/or GC/T). Medical Mistrust was assessed using the 7-item Medical Mistrust Index (Cronbach's α ≥ 0.70) Bivariate tests and multivariate regression analyses were employed. GC/T participation was only 28%. After accounting for sociodemographic factors and self-efficacy (B = 0.37, p < .001), multivariate analysis revealed that women with higher medical mistrust had lower GC/T participation (B = −0.26, p <.01). Interventions to improve utilization of GC/T in Black women at increased risk should incorporate strategies to enhance their personal confidence and address women's concerns about the medical system.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A41.
Abstract A74: A dichotomy between the risk and histology in bladder cancer among blacks and whites: An epidemiological study
Authors: Paskow Michael J. , Henson Donald E. , Young Heather A. , Patierno Steven R.
Published: June 2012

Background: Urinary bladder cancer, despite being the second most common genitourinary disease in the U.S. still presents a number of as yet unsolved complexities. Known to much of the literature is the 2:1 trend of the White to Black cancer rate, the three main histological types of bladder cancer – transitional cell carcinomas (90%), squamous cell carcinomas (5%), and adenocarcinomas (2%), and that smoking is the main etiologic factor contributing to bladder cancer. Historically, Blacks have been identified as having higher smoking rates than Whites. Therefore, the racial discrepancy in bladder cancer rates remains to be explored at the cellular level in light of the contrasting trend in smoking rates.

Objective: To demonstrate that higher transitional cell carcinoma (TCC) incidences prevail in the bladder in Whites compared with Blacks, even though Blacks have a higher rate of smoking than Whites.

Methods: The National Cancer Institute's SEER*stat program version 7.0.4 was used to collect bladder cancer rates for each histological type by age, sex, race, U.S. county, and year of diagnosis. Additionally, lung cancer rates, used as a surrogate for smoking, by county and overall case-specific data were obtained. SAS 9.1 and Microsoft Excel were used to analyze the data in the production of trend, frequency-density, and log-linear plots, correlation analyses, and linear regressions.

Results: The 1973–2008 age-adjusted incidence of TCC of the bladder among Blacks and Whites was 11 and 21 cases per 100,000 persons respectively. Similarly, Black and White rates for TCCs of the renal pelvis were 0.54 and 0.95 cases per 100,000 persons and were 0.21 and 0.61 cases per 100,000 persons for TCCs of the ureter. However, in contrast, lung cancer rates for Blacks and Whites were 82 and 64 cases per 100,000 persons respectively. Frequency-density plots revealed similarity in curves among Blacks and Whites, peaking once between the ages of 65 and 80 years and showing bell-shaped distribution. Bivariate correlation analysis indicated that bladder and lung cancer rates were significantly correlated at about 77%. A statistically significant linear model (R2=0.75) regressing bladder cancer rates on age group, race, sex, and lung cancer rates, was evaluated and revealed that in a population that does not smoke, there were 105 White and 47 Black cases per 100,000 persons on average.

Conclusions: Regardless of higher smoking rates in Blacks than in Whites, Whites have higher rates of TCCs of the bladder as well as of other sites including the renal pelvis and ureter. Even in a population considered without smoking, the trend persists with Whites having higher incidences of bladder cancer than Blacks.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A74.
Abstract A87: Do combinations of similar prognostic factor have similar effect on breast cancer survival in blacks and whites?
Authors: Lu Xiaoxiao , Henson Donald , Young Heather , Patierno Steven R.
Published: June 2012

Background: Breast cancer is the most common cancer in women. The differences in clinical outcomes are often associated with racial/ethnic background. Although the prognostic factors are associated with cancer outcome, it may not be obvious whether a factor truly makes the same contribution to outcome in racial/ethnic groups. There is currently no study for integrating and comparing combinations of tumor size, lymph node status, histological grade, ER status and age in Black and White women. Objective: To conduct comparative survival analyses for breast cancer according to similar combinations of prognostic factors in black and white women.

Methods: Breast cancer data were obtained from SEER Cancer Registry (1990–2000). An algorithm was created with the statistical programming language “R”. Disease specific survival rates were calculated by the Kaplan-Meier method. Patients who were lost to follow-up or died from causes other than breast cancer were censored by the algorithm. Survival rates were compared by the log-rank test, and the level of significance set at p < 0.05.

Results: Without including histologic grade and ER status, the effect of T and N alone on survival was evident, the survival rates decrease as increase in T and N among both black and white women. After 10 years, the proportion surviving among white women with grade 1 was 95%, whereas for grade 2 this decreased to 87%, and for grade 3 was 79%. For black women, the proportion surviving with grade 1 was 92%, for grade 2 was 74%, and for grade3 was 66%. When comparing increased grade with ER+ status, there was a decrease in survival among both black and white; however, the decrease in survival were more pronounced when considering increased grade with ER- status, with lowest survival overall evidenced in G3, ER- status. The survival rates of white women were always more favorable than blacks for any combinations of the five prognostic factors. The case fatality rate was always less favorable for black women than for whites when similar combinations of prognostic factors were compared.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A87.
Abstract B23: Socioeconomic factors and correlates of prostatespecific antigen testing in urban African-American Medicare beneficiaries
Authors: Hararah Mohammad K. , Johnson Lawrence B. , Ford Jean G. , Garza Mary A. , Yeh Hsin-Chieh , Pollack Craig Evan , Markakis Diane , Phelan Darcy F. , Wenzel Jennifer , Shapiro Gary , Bone Lee
Published: June 2012

Background: Prostate specific antigen (PSA) testing is frequently used for early detection of prostate cancer, including among older adults. Since both race and socioeconomic status are associated with prostate cancer incidence and outcomes, it is often difficult to separate race from socioeconomic status as a determinant of prostate cancer screening. We sought to describe the relationship between socioeconomic status and PSA testing in a sample of urban, African American Medicare beneficiaries, and to examine factors that may contribute to this relationship.

Methods: We examined baseline questionnaire data collected from the Cancer Prevention and Treatment Demonstration, a community-based randomized, controlled trial in Baltimore, MD. The study population consisted of 511 community-dwelling African-American men, age 65–75, without a history of prostate cancer. Our main outcome was PSA testing within the past year. Sequential multivariate logistic regression models were performed to study factors that may mediate the relationship between socioeconomic status and PSA screening.

Results: Eighty percent of participants reported having had at least one PSA test in their lifetime, and approximately 50% reported having one within the past year. About half of the sample population reported a household income of less than $30,000 a year and one-third reported education past high school, but only 14% reported a bachelor's degree or higher. In bivariate analyses both higher income ($30,000 vs. < $10,000) (Odds Ratio [OR] 3.14, 95% Confidence Interval [CI] 1.79, 5.52) and higher levels of education (Bachelor's degree vs. less than high school) (OR 3.19, CI 1.72, 5.71) were associated with screening in the past year. In a multivariable regression model, which controlled for marital status, family history, and self-reported health status, income was no longer a significantly associated with PSA testing while the association between educational attainment and PSA testing was reduced (OR 2.13, 95% CI 1.07–4.22). The addition of increased healthcare access and patient-provider relationship measures in sequential models did not alter the relationship between educational attainment and screening. However, upon inclusion of cancer knowledge and belief measures the association between education and PSA testing was no longer significant (OR 1.84, 95% CI 0.90–3.75).

Conclusions: In this urban, African American Medicare population, socioeconomic status was associated with PSA testing. This relationship may be explained, in part, by demographic factors and cancer knowledge and beliefs.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B23.
Abstract B33: Differential responses of Caucasian and African American breast cancer cell lines after EGCG and sulforaphane treatment
Authors: Hardy Tabitha M. , Tollefsbol Trygve O.
Published: June 2012

Breast cancer is the second leading cause of cancer death among American women. African American (AA) women are more likely to die from breast cancer than their Caucasian (CAU), Hispanic, Asian and Native American counterparts revealing a clear disparity between AA women and women of other races and ethnicities. Data collected by The American Cancer Society and others reveal that although AA women have a lower incidence of breast cancer than CAU women, AA women tend to have larger, more aggressive tumors, and have a lower 5-year survival rate. Importantly, AA women are more likely to die from breast cancer than any other ethnic group. While socio-economic, cultural and environmental factors are thought to contribute to these disparities, little is known as to whether biological differences exist between CAU and AA women with breast cancer. To determine the effects of bioactive dietary compounds, (–)-epigallocatechin-3-gallate (EGCG), found in green tea, and sulforaphane (SFN), found in broccoli, were administered to breast cancer cells derived from AA and CAU women. Our results reveal that the AA breast cancer cells showed dissimilarities in response to ECGG and SFN treatments when compared to CAU cell lines. Additionally, differential expression of several cancer related genes, including the human telomerase reverse transcriptase gene (hTERT), was seen in AA cells when compared to CAU cells. These data support the hypothesis that biological differences may contribute to the disparity among AA and CAU women with breast cancer and that these variations may be influenced by diet.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B33.
Abstract B62: Beta-2 adrenergic receptor polymorphisms and risk of breast cancer among Hispanic and non-Hispanic white women: The 4-Corners Breast Cancer Study
Authors: Connor Avonne E. , Baumgartner Richard , Kerber Richard , O'Brien Liz , Rai Shesh , Slattery Marty L. , Wolff Roger K. , Giuliano Anna R. , Byers Tim , Baumgartner Kathy B.
Published: June 2012

Polymorphisms in the adrenergic receptor beta-2 (ADRB2) gene have been studied in relation to risk of type 2 diabetes and obesity, but few studies have investigated associations with breast cancer. The purpose of this research was to evaluate the hypothesis that ADRB2 variants (rs1042713-Arg16Gly and rs1042714-Glu27Gln) are associated with breast cancer risk in non-Hispanic white (NHW) and Hispanic (H) women using data from a population-based case-control study conducted in the southwestern United States: ‘The 4-Corners Breast Cancer Study’. A total of 1,244 NHW and 606 H cases with incident primary breast were ascertained and 1,330 NHW and 728 H population-based controls were selected. Information on lifestyle and physical activity, diet, demographics, and reproductive background was collected through an in-person questionnaire, and blood samples were taken for genetic analyses from consenting participants. ADRB2 genotypes for rs1042713 and rs1042714 were determined using PCR. Each genotype as well as their combined haplotype was evaluated in multivariable logistic regression models to estimate the associations with breast cancer risk while adjusting for potential confounders, including study center, history of diabetes, body mass index, family history of breast cancer, genetic admixture, and menopausal status. ADRB2 genotype frequencies were significantly different between NHW and H women. Individually, the ADRB2 polymorphisms were not associated with breast cancer in either ethnic group. However, having 2 copies compared to one or zero copies of the ADRB2 G-G haplotype was associated significantly with increased risk of breast cancer among NHW women [odds ratio (OR), 1.95; 95% confidence interval (95% CI), 1.26–3.01] but reduced risk among Hispanic women [OR, 0.74; 95% CI, 0.50–1.09], (p-for interaction=0.004). Risk was significantly decreased in Hispanic women with a history of type 2 diabetes and 2 copies of the G-G haplotype [OR, 0.33; 95% CI, 0.12–0.92] while the association was increased, but not statistically significant among NHW women, [OR, 4.91; 95% CI, 0.52–46.60], (p-for interaction = 0.025). While the interaction between obesity (body mass index (BMI) ≥ 30 kg/m2) and the G-G haplotype was not significant (p=0.200), the association in NHW obese women with 2 copies of the G-G haplotype was similarly increased [OR, 3.01; 95% CI, 1.22–7.44], but decreased in Hispanics [OR, 0.42; 95% CI, 0.20–0.56]. These data suggest that ethnicity modifies the association between the ADRB2 G-G haplotype and breast cancer risk and history of type 2 diabetes and obesity enhances the divergence of risk between Hispanic and NHW women.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B62.
Abstract B68: The influence of primary care on breast cancer outcomes among Medicare beneficiaries
Authors: Roetzheim Richard G. , Ferrante Jeanne M. , Lee Ji-Hyun , Chen Ren , Love-Jackson Kymia M. , Gonzalez Eduardo C. , McCarthy Ellen P.
Published: June 2012

Introduction: Primary care physicians (PCP) are integral in the early detection of cancer. Patients who are referred to a PCP, or who are assigned a PCP, are more likely to undergo most forms of cancer screening including mammograms and clinical breast examinations. PCPs may also ensure more timely diagnosis after screening abnormalities and prevent diagnostic delay. The Medicare-SEER database was used to explore the possibility of an association between primary care visits and breast cancer outcomes. With the usage of Medicare-SEER data, age, gender, and racial disparities exist.

Methods: A retrospective cohort study design was used to evaluate 109,188 women that were Medicare beneficiaries and diagnosed with breast cancer in SEER registries during the years of 1994–2005. This data was used to analyze the association between primary care encounters and breast cancer outcomes. Health services related to cancer prevention and screening have been shown to occur in the ambulatory setting. The total number of ambulatory physician encounters and the percentage of such encounters with a primary care physician (PCP) were examined over a 24 month period before cancer diagnosis. Women with invasive cancers odds of late American Joint Commission on Cancer (AJCC) stage at diagnosis (stages III and IV vs. stages I and II) and survival (breast cancer specific and all cause) were examined using logistic regression and proportional hazards models respectively. Whether including non-invasive cancers (such as ductal carcinoma in situ, DCIS) would alter results and whether prior mammography was a potential mediator of associations was also explored.

Results: Increasing numbers of ambulatory physician encounters were associated with improved breast cancer outcomes. In addition, subjects having between 40 and 60 percent of all encounters with PCPs were most likely to have had prior mammograms, least likely diagnosed at late stage, and to have lower breast cancer and all-cause mortality. Prior mammography mediated these associations in part but not completely. Results were unchanged when women with DCIS were included in the analysis. The average age of women involved in this study was 77 years old and 86 percent of the sample were non-minority.

Conclusions: Although there is the existence of age, racial, and gender disparities because of the use of the Medicare-SEER data, using this information helps to identify better care tactics for aging women. Medicare beneficiaries with breast cancer had better outcomes if they had greater use of ambulatory care and care that was balanced between primary and specialty providers. These findings suggest adequate primary medical care may be an important factor in achieving optimal breast cancer outcomes.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B68.
Abstract B71: Segmental analysis of colorectal cancer in California by race/ethnicity, 2001–2008
Authors: Cho Myung Mi , Nagavedu Kshema , Chenna Sumana , Morgan John W.
Published: June 2012

Purpose: This study seeks to identify the independent predictive roles of selected demographic variables for invasive colorectal cancer (CRC) sub-sites.

Methods: Demographic and sub-site variables were extracted from the California Cancer Registry (CCR) for 117,354 invasive colon cancer cases diagnosed from 2001–2008. Stratified and Logistic regression analyses were used to distinguish individual predictive effects of demographic variables on odds of CRC in contrasting bowel segments.

Results: Multivariable odds ratios (OR) for binary bowel segment categories contrasting <40 (OR =1.20; 95% CI =1.11-1.30), 40–49 (1.48; 95% =1.41-1.55) and 75+ (0.54; 0.53–0.56) relative to age 50–74 years reveal independent associations. Contrast with non-Hispanic white, ORs for left to non-left bowel cancer were 1.68; 95% CI =1.56-1.81 (Asian/Other), 0.73; 0.62–0.84 (non-Hispanic black) and 1.12; 1.01–1.24 (Hispanic). Females showed lower odds of left to non-left bowel cancer than males (OR =0.75 CI =0.73-0.77). Descending ORs were seen for sequentially lower SES quintiles (OR1:5 = 1.11; 1.05–1.17, OR2:5 = 1.07; 1.02–1.12, OR3:5 = 1.02; 0.978–1.06 and OR4:5 = 0.98; 0.94–1.02) (Trend p <0.0001) adjusting for other covariates. No significant multiplicative interaction was detected between race/ethnicity and SES variables. Findings were similar for contrasts of distal to non-distal and sigmoid colon to non-sigmoid CRC.

Conclusions: Younger than age 50–74; male gender; Asian/Other or Hispanic ethnicity, and lower SES were each independent predictors of left to non-left CRC. Progressively lower SES showed an inverse dose-response relationship with odds of left to non-left CRC, independent of other covariates. These findings reveal demographic predictors of CRC bowel segment origin that may influence screening success.

Funding: The California Department of Public Health, National Cancer Institute (Grant N01-PC-35136 and N01-PC-35139), and Centers for Disease Control & Prevention (CDC) (Grant N02-PC-54404) funded cancer surveillance necessary for this study.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B71.
Abstract B96: Trends in colorectal cancer screening with home-based fecal occult blood test (FOBT) in adults aged 50–64 years, 2000–2008
Authors: Bandi Priti , Cokkinides Vilma , Smith Robert A. , Jemal Ahmedin
Published: June 2012

Introduction: Screening for colorectal cancer (CRC) in asymptomatic average risk populations reduces CRC incidence and mortality. Annual home-based fecal occult blood testing (FOBT) has been recommended as a CRC screening modality in average-risk adults aged 50 and older. National surveys have reported declines in FOBT screening rates in the last decade, but it is unknown whether these declines have extended across all socioeconomic status (SES) and racial/ethnic groups, and the changes relative to endoscopic screening have not been evaluated.

Methods: Data on respondents aged 50–64 years were from the Cancer Control Module administered to sampled adults National Health Interview Surveys in 2000, 2005, and 2008. Weighted analyses and multivariate logistic regression were used to study trends in the use of home FOBT testing in the past year and endoscopic test in the past 10 years.

Results: Overall, the prevalence of home FOBT in the past year declined 5.9% points (95% CI: 4.5%, 7.3%) between 2000 and 2008. SES differences in trends were observed wherein significant declines were restricted to higher-SES groups (those with private and military insurance, those with a usual source of care, those with a high school degree or higher, those classified as not poor, those born in the US), whereas lower-SES (uninsured and the publicly-insured, those without a usual source of care, those with less than a high school education, the poor and the near poor, and immigrants to the US) did not experience significant changes in FOBT prevalence during this time period. FOBT rates in Hispanics did not change significantly during this time, whereas non-Hispanic whites and non-Hispanic blacks experienced significant declines. Coincident with declines in FOBT prevalence during this time, endoscopic screening prevalence increased consistently in higher-SES groups. Fewer lower-SES groups experienced increases in endoscopic screening prevalence, with most increases being of a lower magnitude than in the higher-SES subgroups.

Conclusions: Socially and economically disadvantaged groups experienced little or no change in FOBT rates from 2000 to 2008. There has been a significant shift from FOBT to endoscopic screening in higher-SES and a few lower-SES groups, but the extent of this shift in lower-SES groups appeared to be smaller than in higher-SES groups. Programs promoting annual screening with high-sensitivity guaiac-based or immunochemical FOBT represent an appropriate and low cost alternative to colonosopy screening, provided that these programs consider patient- and physician attitudes, knowledge and preferences, and systems-issues related to referral, adherence, test quality assurance, and adequate follow-up of positive test results.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B96.
Abstract ED02-02: How we measure and track health disparities in the Healthy People 2010 Final Review
Authors: Talih Makram
Published: June 2012

The Healthy People 2010 Final Review presents a quantitative end-of-decade assessment of progress in achieving the Healthy People 2010 objectives and goals over the course of the decade. It provides the most recent tracking data available on or before March 1, 2011, for the 970 objectives in each of the 28 Healthy People 2010 Focus Areas. We will describe the procedures used to measure disparities among population subgroups in connection with the second goal of Healthy People 2010, which is to “eliminate health disparities.” We will discuss methodological issues that arise in the selection of the best group rate, as well as in the definition of a summary (or average) index of disparities. Those considerations impact how changes in disparities over time are ascertained.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):ED02-02.
Abstract A115: Contextual synthetic lethality: Repair-deficient hypoxic tumor cells are sensitized to poly(ADP-ribose) polymerase (PARP) inhibition
Authors: Chan Norman , Pires Isabel M. , Bencokova Zuzana , Coackley Carla , Bhogal Nirmal , Lakshman Minalini , Gottipati Ponnari , Oliver F Javier , Helleday Thomas , Hammond Ester M. , Bristow Robert G.
Published: June 2012

Acute and chronic hypoxia exists within the 3D microenvironment of solid tumors and drives therapy resistance, genetic instability and metastasis. Replicating cells exposed to either severe acute hypoxia (16 h with 0.02% O2) followed by reoxygenation or moderate chronic hypoxia (72 h with 0.2% O2) treatments had decreased RAD51 protein expression and homologous recombination (HR) function. As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of HR-defective hypoxic cells to PARP inhibition. Although PARP inhibition did not affect HR, we observed increased clonogenic killing in HR-deficient hypoxic cells following inhibition or siRNA depletion of PARP1. PARP1−/− MEFs showed a proliferative disadvantage and a lack of cell adaption to hypoxia when compared to PARP1+/+ MEFs. PARP-inhibited hypoxic cells accumulated H2AX and 53BP1 foci as a consequence of altered DNA replication firing leading to S phase-specific cell killing. In support of this proposed mode of action, PARP inhibitor treated RKO xenografts showed increased H2AX-positivity and cell death across hypoxic cell gradients in subregions with suppressed RAD51 expression.

We conclude that the repair defects observed in hypoxic cells can sensitize hypoxic cells to PARP inhibition as a consequence of microenvironment-mediated “contextual synthetic lethality”. As all solid tumors contain hypoxic cells, this may broaden the clinical utility of PARP inhibition in cancer therapy.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A115.
Abstract A12: Variation in response to triple VEGFR inhibitor tivozanib in mouse models of hepatocellular carcinoma
Authors: Farlow Samuel , Potz Darren , Zi Tong , Sun Xiaojian , Lin Jie , Chiu Maria Isabel , Robinson Murray O. , Heyer Joerg , Zhou Yinghui
Published: June 2012

Liver cancer is the 5th most common cancer type and the 3rd leading cause of cancer related death worldwide. In the US, the number of new cases continues to rise and reached 19,000 per year in 2004, more than doubling the number twenty years ago. The limited treatment options include surgery, radiation therapy and chemotherapy. Unfortunately, the prognosis for most liver cancer patients is extremely poor due to late diagnosis, and the 5 year overall survival rate is less than 10%. Recent approval of sorafenib suggests that VEGFR inhibition might be beneficial to the survival of HCC patients. Hepatocellular carcinoma (HCC) originates from hepatocytes and accounts for 80–90% of the cases of liver cancer. Genetic alterations found in human HCCs include loss of major tumor suppressor genes (p53, Ink4a/Arf, PTEN, and NF1) as well as activation of oncogenic pathways through mutation and/or amplification (RAS/MapK, PI3K, and Wnt/beta-catenin pathways). We generated primary HCCs in mouse using a recently-developed tissue reconstitution approach. Briefly, we isolated hepatoblasts from p53 deficient donor embryos, infected the cells with retroviruses carrying the clinically relevant human oncogenes Myc or mutant Kras, and transplanted them back to the liver of recipient mice through intra-splenic injection. These mice developed tumors in the liver with a latency of 2–5 months and penetrance of 30–50%. Histological examination demonstrated that these tumors resemble the features of human HCCs.

Interestingly, a quantitative analysis of the vasculature in these tumors revealed a broad range of vessel size and vessel density, indicating that angiogenesis in these tumors are likely driven by different molecular mechanisms. We sought to explore the variation in angiogenic phenotypes by examining the response of various tumors with the ATP competitive small molecule VEGFR inhibitor tivozanib (AV-951). Tivozanib exhibits picomolar inhibitory activity against all three VEGF receptors, a multi-day T1/2 in humans, and demonstrates robust clinical activity demonstrated in renal cell carcinoma, the signal tumor type for VEGF pathway inhibition.

Consistent with the variation in angiogenic phenotypes, variation in response to tivozanib was observed: a subset of these tumors exhibited exquisite sensitivity to tivozanib, whereas other tumors were significantly less sensitive. These results are in line with the clinical benefit of Sorafenib on patients with hepatocellular carcinoma. These data, taken together, strongly suggest that anti-angiogenesis therapy can be a potential treatment option for a subset of HCC patients. Since our HCC models captured the response of human HCCs, they provide a valuable tool for identification of biomarkers for patient selection.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A12.
Abstract A121: Novel PARP inhibitors with potent antitumor activity as single-agent and combination therapies
Authors: Wang Bing , Chu Daniel , Feng Ying , Yu Xin , Myers Peter , Post Leonard , Shen Yuqiao (Jerry)
Published: June 2012

Poly (ADP-ribose) polymerases (PARP) -1 and -2 are key enzymes that are activated by DNA damage and play a critical role in the base excision DNA repair (BER) pathway. Previous studies have indicated that inhibitors of PARP-1 and -2 could enhance the efficacy of radiation therapy and chemotherapies by preventing cancer cells from repairing DNA damage. In addition, PARP inhibitors have been shown to selectively kill cancer cells that are deficient in BRCA-1 or BRCA-2 function. In this study, we describe the antitumor activity of a series of novel PARP inhibitors in single-agent therapy and in combination with standard chemotherapies. One of the compounds in this series, LT-00673, inhibits PARP-1 with IC50 at sub-nanomolar (nM) concentration. In cultured human cancer cells, LT-00673 significantly enhances the cytotoxic efficacy of both Temozolomide and SN-38 (active metabolite of Irinotecan). LT-00673 also demonstrates single-agent cytotoxicity in BRCA-1 mutant (MX-1, IC50 = 0.3 nM) and BRCA-2 mutant cells (Capan-1, IC50 = 5 nM). In contrast, in MRC-5 normal human fibroblast and other tumor cell lines with wild-type BRCA-1 and BRCA-2 genes, IC50 of LT-00673 ranges between 90 nM and 1.9 µM. In rat pharmacokinetic studies, LT-00673 displays >50% oral bioavailability and pharmacokinetic properties that enable single daily dosing. In xenograft tumor model studies, daily oral dosing of LT-00673 significantly enhances the antitumor effects of cytotoxic therapies in a dose-dependent manner. In addition, once daily oral dosing of LT-00673 at 0.33 mg/kg/day results in complete response in the MX-1 tumor model. Pharmacodynamic studies have demonstrated potent PARP inhibition by LT-00673 in tumor biopsies. Off-target molecular screening did not identify significant non-specific activity for this class of PARP inhibitors. In summary, LT-00673 displays potent antitumor activity, along with oral bioavailability and pharmacokinetic properties that support in vivo efficacy on single daily doses, both as single-agent therapy and in combination with cytotoxic chemotherapies.

Conclusion: LT-00673 shows promising in vitro and in vivo activities and is currently in preclinical development.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A121.
Abstract A125: Profound impact of the nucleotide excision repair proteins XPC and CSB, but not ERCC1, on the resistance to an antitumor alkylator destabilizing local DNA duplex structure
Authors: Poindessous Virginie , Rocca Céline J. , Soares Daniele G. , El Ouadrani Karima , Sarasin Alain , Guérin Eric , Henriques João A. P. , de Gramont Aimery , Escargueil Alexandre E. , Larsen Annette K.
Published: June 2012

Backgound: Nucleotide excision repair (NER) is one of our most versatile DNA repair pathways. NER plays an important role in the repair of platinum adducts, and expression levels of the ERCC1 endonuclease, the last step in the NER process, is widely considered as a useful clinical marker for NER activity. S23906 is an antitumor alkaloid forming bulky monofunctional adducts with the capacity to destabilize local base pairing, which is a unique feature among anticancer agents. The purpose of the present study was to determine the influence of NER on the sensitivity to this unusual agent.

Experimental: A panel of primary and transformed cell lines derived from patients with xeroderma pigmentosum or Cokayne syndrome was used to determine the role of each step in the NER pathway on the response to S23906. KB carcinoma cells with acquired resistance to S23906 were used for further characterization.

Results: We here show that cells deficient for either global genome NER or transcription-coupled NER are profoundly sensitive to S23906, which for cells deficient in XPC, CSB and XPA far exceed the sensitivity observed for cisplatin and UV, two classical NER substrates. In contrast, cells deficient in ERCC1 and XPF, the last step in the NER pathway, showed modest sensitivity to S23906, compared to wt cells. Acquired resistance to S23906 was accompanied by cross-resistance to cisplatin and UV irradiation as well as by an important increase in NER activity as determined by unscheduled DNA synthesis and transcriptional recovery. Accordingly, resistant cells show up to 5-fold upregulation of XPC, CSB and XPA proteins. In contrast, no detectable alterations were observed for ERCC1.

Conclusions: These results show that upregulation of NER activity in cells with acquired resistance to S23906 is associated with upregulation of XPC and CSB, the two proteins needed for the initial steps of the NER pathway, but without detectable changes in ERCC1 expression, which is needed for the last step of the pathway. Our results suggest that ERCC1 is neither rate-limiting nor representative of NER activity, and is unlikely to be of value as a predictive marker for bulky monofunctional compounds. We further suggest that the value of ERCC1 as a predictive marker for platinum compounds and other cross-linking agents may be based on its functions in recombination repair, cross link repair and telomere maintenance, rather than its role in NER.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A125.
Abstract A146: The role of cystine transport in darinaparsin-induced cell death
Authors: Garnier Nicolas M. , Gu Yuxuan , Kourelis Maria , Mann Koren K. , Bohle David S. , Miller Wilson H.
Published: June 2012

Darinaparsin (ZIO-101; S-dimethylarsino-glutathione; Dar) is a promising novel organic arsenical, currently undergoing clinical studies in various malignancies. Dar is synthesized by conjugating dimethylarsenic (DMA) to glutathione (GSH) and shows enhanced activity as compared to arsenic trioxide (ATO). Dar induces more intracellular arsenic accumulation, oxidative stress (OS) and cell death than ATO. However, Dar has a maximum tolerated dose that is 35-fold higher than ATO. The mechanisms responsible for the lower toxicity and higher anti-tumor efficacy associated with Dar remains to be elucidated. Here, we propose a mechanism for Dar import that might, at least partially, explain the enhanced efficacy.

Preliminary results show that both ATO and Dar induce the expression of the cystine importer xCT and that high levels of xCT expression correlates with high sensitivity to Dar, as shown in a NCI60 panel. The cystine/cysteine redox cycle consists of cystine uptake, intracellular reduction to cysteine which is secreted into the extracellular space where it is oxidized back to cystine. Intracellular cysteine (Cys-SH) can be used for the synthesis of GSH, the major intracellular OS scavenger. We find that increased extracellular concentration of L-cysteine or equivalent thiols during Dar treatment inhibits intracellular arsenic accumulation, measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), as well as apoptosis, assessed by propidium iodide staining quantitated by flow cytometry. Thus, we hypothesized that L-cysteine or equivalent thiols might prevent Dar import.

GSH itself is not imported in the cell, so we thought it unlikely that darinaparsin would enter the cell without being somehow modified. Structural analysis of darinaparsin reveals putative break-down products: dimethylarsino-cysteine (DMAC), dimethylarsenic III (DMA III) and dimethylarsenic V (DMA V). ICP-MS experiments showed that treatment with DMA III and DMA V does not lead to significant intracellular accumulation of arsenic, and correlates with their inability to induce cell death. However, DMAC is very similar to Dar in terms of intracellular accumulation of arsenic, G2/M arrest and cell death. As with Dar, thiols were able to inhibit DMAC-induced cell death.

In summary, we hypothesize that darinaparsin gets transformed extracellularly into DMAC, which is imported via xCT or another cystine/cysteine importing system. Cells respond to arsenic-induced OS by increasing cystine uptake, which may selectively increase the anti-cancer activity of Dar. The fact that cancer cells, under a high OS state, have an increase need for GSH, i.e. for cystine, might explain the fewer systemic toxicities reported with Dar. Moreover, cystine/cysteine importers may be valuable biomarkers to predict Dar sensitivity.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A146.
Abstract A158: Development of CYP26 inhibitors to optimize the treatment of neuroblastoma with retinoic acid
Authors: Bridgens Caroline E. , Veal Gareth J. , Redfern Christopher P. F. , Gomaa Mohamed S. , Brancale Andrea , Armstrong Jane L. , Simons Claire
Published: June 2012

Neuroblastoma is the most common extra-cranial malignant solid tumor of childhood. It is diagnosed in approximately 800 children per annum in the USA, and currently has a poor prognosis for high-risk patients.

Neuroblastoma treatment is limited by the development of resistance to retinoic acid (RA). Inhibition of CYP26, the enzyme primarily associated with RA-metabolism, has been demonstrated to enhance concentrations of RA both in vitro and in vivo. It is anticipated that these results may be translated into improved clinical therapy for neuroblastoma.

We have designed, prepared and performed extensive in vitro testing of a small library of novel CYP26 inhibitors. A microsomal CYP26 inhibition assay was used to screen all novel inhibitors to generate initial IC50 values. The most promising compounds were further investigated in cellular assays, employing SH-SY5Y neuroblastoma cells, including proliferation assays and measurement of CYP26A1 mRNA induction, a sensitive biomarker reflecting intracellular RA concentrations. CYP selectivity assays have also been performed, providing data to assist in the selection of lead compounds that will have a reduced probability of possessing off-target effects on other CYP enzymes, a fundamental limitation in previous attempts to target CYP26. A number of compounds have exhibited impressive CYP26 inhibitory potency, with IC50 values <10 nM observed in microsomal assays. Co-incubation of SH-SY5Y cells with lead compounds and low levels of RA increased the level of expression of CYP26A1 mRNA up to 30-fold, relative to SH-SY5Y cells treated with RA alone. This potentiation reflects the ability of these novel inhibitors to enhance and prolong the in vitro effects of RA. Our research program has generated a number of highly potent CYP26 inhibitors to be tested in vivo. It is anticipated that these studies will lead to the generation of compounds which may be used in combination with RA to improve the future treatment of neuroblastoma.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A158.