bluuebunny/crossref_metadata_2025 huggingface dataset:
PD07-02: Docetaxel Is Superior to Paclitaxel Given Every Three Weeks in Post Operative Patients with Node-Positive Breast Cancer: Results of the Final Analyses of the NSAS-BC (National Surgical Adjuvant Study of Breast Cancer) 02 Trial from Japan.
Authors: Watanabe T , Kuranami M , Inoue K , Masuda N , Aogi K , Ohno S , Iwata H , Mukai H , Uemura Y , Ohashi Y
Published: June 2012

Background: Four cycles of doxorubicin plus cyclophosphamide (4-AC) followed by four cycles of a taxane is widely used for postoperative chemotherapy in breast cancer (BC). Concern about relatively rare, but life-threatening toxicity of anthracyclines such as heart failure and secondary leukemia has promoted research to seek anthracycline-free regimens. Since 1990's when taxanes were introduced, docetaxel (DTX) is used interchangeably with paclitaxel (PTX) for the treatment of BC, but they may differ more than initially anticipated. We conducted this trial to test two hypotheses: (1) Eight cycles of a taxane is not inferior to 4-AC followed by four cycles of a taxane; (2) one taxane is superior to the other.

Methods: Eligibility included a diagnosis of clinical stage I-IIIA and axillary node-positive BC, an age younger than 71 years and with performance status of 0 to 1. Patients were randomly assigned to receive either one of the following regimens;ACP: 4-AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 q3w x 4) followed by 4-PTX (175 mg/m2 q3w x 4)ACD: 4-AC followed by 4-DTX (75 mg/m2 q3w x 4)8-PTX: PTX (175 mg/m2 q3w x 8)8-DTX: DTX (75 mg/m2 q3w x 8)

Comparisons included PTX vs. DTX (ACP + 8-PTX vs. ACD + 8-DTX) and +AC vs. -AC (ACP + ACD vs. 8-PTX + 8-DTX). The primary endpoint was disease-free survival (DFS), and the secondary endpoints include overall survival (OS). The trial was powered to prove the non-inferiority of +AC to -AC (threshold hazard ratio 1.32) in terms of DFS. DFS was also compared between PTX and DTX to determine any superiority.

Results: A total of 1,060 eligible patients were accrued at 84 centers between December 2001 and April 2006. There were 348 DFS events and 166 deaths after a median followup of 72.2 months. DTX was superior to PTX in terms of both DFS (Hazard ratio(HR) 0.76; 95% Confidence Interval(CI) 0.62−0.95, p=0.012) and OS (HR 0.72;95%CI 0.53−0.97, p=0.033). -AC was not inferior to +AC with respect to DFS (HR: 1.21, 90% CI 1.01−1.44). Among the four arms, 8-PTX alone resulted in poorer DFS (compared with ACP, HR 1.42 95%CI 1.07−1.89).

Nausea and vomiting were more frequent with +AC than -AC. Edema and febrile neutropenia were more frequent with DTX than PTX. The incidence of sensory neuropathy was higher with PTX than DTX and it lasted for more than one year of the end of PTX treatment.

Conclusions: When AC, PTX and DTX were given every three weeks, both DFS and OS were better in the arms including DTX than in those including PTX. AC followed by a taxane can be replaced by 8-DTX.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-02.
PD08-01: JNK2 Regulates Mammary Lineage Differentiation in Tumors and Normal Glands through Notch1 and p53.
Authors: Cantrell MA , Ebelt ND , Van Den Berg CL
Published: June 2012

The classification of patient tumors by clinical subtype has gained wide acceptance due to the implications for prognosis and treatment. However, recent studies have cast doubt on previously advocated normal mammary origins of these subtypes. Thus, the link between the normal mammary gland and mammary tumors is more complex than expected. C-Jun N-Terminal Kinase-2 (JNK2) is a protein that is involved in numerous developmental processes and our previous work has shown it to be important for DNA damage response in mammary tumors. In attempt to gain insight into the link between mammary development and tumorigenesis, we compared normal mammary glands of JNK2 knockout (jnk2ko) mice to jnk2ko mammary tumors expressing or lacking wildtype p53 (p53ko). These studies showed that jnk2ko glands possess 35% fewer basal cells (p=0.0078) with a corresponding increase in luminal epithelial cell populations (p=0.100). This luminal response is corroborated by in vitro 3D assays of primary mammary epithelial cells (MECs) where luminal cell differentiation is normalized by inhibition of Notch signaling. Expression notch-1, a well-known regulator of MEC differentiation, is increased jnk2ko mammary glands. Increased expression of the Notch-1 target gene, hes-1, was also seen (p=0.005). Histology revealed that increased expression of active Notch-1 is localized to the mammary stem cell niche, the terminal end bud. Similar to the normal gland, jnk2ko mammary tumors possessing wildtype p53 exhibit decreased proportions of basal cells (p=0.0002) and increased proportions of luminal cells (p=0.0411) relative to wildtype. Jnk2ko cell lines derived from these tumors show decreased expression of notch-1 (p=0.0018) and hes-1 (p=0.0602) following introduction of JNK2. Luciferase assays comparing activity of the notch-1 promoter to a notch-1 promoter with mutated p53 response elements revealed a dependence of increased notch-1 promoter activity in jnk2ko cells on the p53 response element. P53ko tumor cells, by contrast, do not exhibit alterations in notch-1 promoter activity in the absence of p53 response elements, regardless of JNK2 status. QPCR showed that loss of JNK2 in normal mammary glands and tumors causes increased p53 expression—thus providing a potential mechanism. In support that Notch upregulation in the absence of JNK2 is dependent upon p53, normal glands lacking p53 show no differences in lineage differentiation. P53ko tumors also show no differences in basal lineage differentiation, however, increases in luminal differentiation are maintained in the absence of JNK2. Consistent with increased luminal differentiation, jnk2ko caused decreased expression of markers involved in the epithelial to mesenchymal transition phenotype. This data suggests that JNK2 is important not only for lineage differentiation in normal mammary glands, but in mammary tumors and that the effect is dependent on both Notch1 and p53.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD08-01.
PD08-08: Preclinical Efficacy of the Combination of Met and Src Family Kinase Inhibitors in Triple-Negative Breast Cancer.
Authors: Gartner EM , Kim EMH , Choi L , Boerner J
Published: June 2012

Background: Epidermal growth factor receptor (EGFR), although overexpressed in almost 60% of all triple-negative breast cancers, has yet to be identified as an effective therapeutic target for the treatment of the disease. We have previously shown in cell culture models of triple-negative breast cancer that primary resistance to EGFR tyrosine kinase inhibitors through ligand-independent phosphorylation can be overcome by co-inhibiting EGFR with either Met or Src family kinases (SFKs). We also demonstrated that inhibiting Met kinase activity reduced EGFR and c-Src phosphorylation and inhibiting SFK reduced EGFR phosphorylation. Taken together, these data suggest that EGFR, Met and SFKs regulate the activity of each other through transphosphorylation. This process of transphosphorylation, or crosstalk, allows for the continued activation of key signaling proteins required for proliferation and transformation. Here we demonstrate that inhibiting both Met and SFKs decreases cell viability and eliminates the need for inhibition of EGFR tyrosine kinase activity, as the autophosphorylation sites of EGFR were lost with the combination treatment.

Methods: Seven triple-negative (SUM102, SUM149, SUM229, SUM1315, BT20, BT549, MDA-MB-231), two HER2+ (SUM190 and SKBr3), and two ER/PR+ (MCF7 and T47D) breast cancer cell lines were used to test the efficacy of the combination of Met and SFK inhibitors, Arq-197 and dasatinib, respectively. Cell viability after drug treatment was assessed by MTT assays. IC50 values were calculated and drug synergy calculations were performed. Transphosphorylation was measured by immunoblotting using phospho-specific antibodies. Apoptosis was characterized by immunoblotting.

Results: All seven triple-negative breast cancer cell lines demonstrated decreased cell viability with the combination of Arq-197 and dasatinib when compared with either drug alone. In contrast, none of the HER2+ or ER/PR+ breast cancer cell lines had any additional loss of viability with the combination treatment. We found that the interactions between Arq-197 and dasatinib were synergistic in several of the breast cancer cell lines. Specifically, in one such cell line (BT20), the combinatorial index values were less than 1.0. Interestingly, in this cell line, the tyrosine phosphorylation levels on residues 1068 and 992 of EGFR were significantly altered with the combination treatment and activation of apoptotic proteins, including PARP, occurred.

Conclusions: These data demonstrate that two tyrosine kinases, known to be downstream of EGFR activation, interact to promote resistance to EGFR inhibitors. However, inhibiting both Met and SFKs was sufficient to decrease cell viability and stimulate apoptosis in triple-negative breast cancer cells. Further studies to validate the relevance of these findings are ongoing.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD08-08.
PD10-04: Exploration of the Relationship between Loss of PTEN and BRCA1 Expression in Triple Negative Breast Carcinoma.
Authors: Jones N , Velasco V , Reault M , Dapremont V , Gastaldello B , Rouault A , Bonnet F , Debled M , Tunon de Lara C , Longy M , MacGrogan G , Sevenet N
Published: June 2012

Based on the mechanism of action of PARP inhibitors, BRCAness breast and ovarian cancers could be defined as the optimal group of tumours to target with such drugs. As the BRCAness phenotype is not fully defined at present, a surrogate phenotype of triple negative breast cancer (TNBC) has been proposed. Results of recent clinical trials involving PARP inhibitors in the context of TNBC do not demonstrate a significant improvement in overall survival or progression free survival, partly due to the inaccurate selection of certain tumours. Data from cell culture studies suggests that loss of PTEN expression could be a marker of PARP inhibitor sensitivity.

Materials and Methods: A retrospective study of 160 TNBC resected at Institut Bergonie between 1989 and 2010 was undertaken. Inclusion criteria were: ER & PR immunohistochemcial (IHC) negativity (<10% tumour cells positive), non-amplification of HER2 (IHC score 0, 1, or 2 with negative FISH analysis) and an invasive ductal carcinoma resected before chemotherapy. For some familial cases, germline BRCA1 mutation screening had been performed in a diagnostic setting and was accompanied by genetic counselling. PTEN IHC, point mutation and gross rearrangement screening, along with BRCA1 expression and promoter methylation analysis (through real-time PCR and bisulfite treatment, respectively) and 53BP1 IHC were undertaken on this series of TNBC.

Results: Twenty percent of sporadic and familial TNBC demonstrated reduced BRCA1 expression with a greater than 7 fold reduction in expression. Almost half of tumours demonstrated a complete loss of PTEN expression as assessed by IHC, with a deleterious PTEN point mutation identified in 5% of cases. Although a slight correlation is observed between the complete loss of PTEN and a reduction in BRCA1 expression, a complete overlap of these two alterations was not observed; tumours with reduced BRCA1 expression do not always demonstrate complete negativity on PTEN IHC and certain tumours displaying complete negativity on PTEN IHC do not show a reduction in BRCA1 expression. Full immunohistochemical characterization of the tumour series (ER, PR, HER2, AR, CK5/6 & EGFR) together with the results of PTEN, BRCA1 and 53BP1 analyses will be presented. Conclusion

These results suggest that at present, loss of PTEN expression is not a suitable surrogate marker for tumours with reduced BRCA1 expression. This should be borne in mind for ancillary studies of clinical trials involving PARP inhibitors in the treatment of breast tumours and further investigation is warranted.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD10-04.
S1-6: Characterization of Breast Cancer Distant Metastasis Based on Outcome over Time Using a Gene Expression Profiling Approach and Identification of Pathway Activities of Late Relapse.
Authors: Saghatchian M , Mittempergher L , Michiels S , Casinius S , Glas A , Lazar V , Roepman P , Dessen P , Benz S , Piccart M , Delaloge S , van't Veer L
Published: June 2012

Background

Previous reports have described the use of microarrays to assess the molecular classification of human breast cancers and defined new subgroups based on gene expression that are relevant to patient management through their ability to predict metastatic relapse and survival relapse. However, different mechanisms may be associated with the development of early and late distant metastases. With the hypothesis that tumors may lead to early or distant metastases based on their intrinsic biological initial features, we aimed at defining molecular profiles for several subgroups of patients based on their outcome over time.

Material and methods

Breast primary tumors were selected from retrospective series of patients with frozen material available. These series include patients of all ages, LN- and LN+; Estrogen or Progesteron-receptor positive, Her2-negative, no adjuvant treatment, with a follow-up of more than 10 years (y) for the control group or distant metastatic relapse as first event (DM) for the study group (n=144). Patients tumors were classified in 4 groups: no relapse at 10 y (M0), DM before 3 y (M0-3, n=30), DM between 3 and 7 y (M3-7), DM after 7 y (M7+). Samples were collected in 2 different institutions (NKI series for identifying the signature and IGR series for validation). Gene expression analysis of breast tumor samples was performed using custom-made Agilent 44K high-density microarrays and hybridized against the Mammaprint® reference pool (MRP). Tumors were also assessed for their Mammaprint® status, wound-healing signature status and their intrinsic subtypes based on the Blueprint® signature. Moreover, we identified the pathway-level activities of the patient groups using PARADIGM.

Results and Discussion

For the NKI series, A subset of 144 samples was included based on the selection criteria: 57 M0, 31 M0-3, 25 M3-7, 31 M7+.

None of the 3 previously mentioned signatures correctly identified M0 vs. M7+ patients.

In order to identify a predictive signature of late relapse (after 7y) we considered M0 and M7+ MammaPrint-Low Risk patients and we split them in a training (n=41) and in a test (n=23) sets.

A 73-gene signature was able to classify M7+ patients with 75% of sensitivity and 66% of specificity on the test set. DM after 7yr showed significant activation of pathway related to inflammatory response and angiogenesis.

Detailed results and validation results on the independent IGR series will be presented at the meeting.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-6.
S6-3: Influence of Hospital Factors, Physician Factors and Type of Health Insurance on Receipt of Immediate Postmastectomy Reconstruction in Young Women with Breast Cancer.
Authors: Hershman DL , Neugut AI , Richards CA , Kalinsky K , Charles AS , Wright JD
Published: June 2012

Objective

For women with breast cancer who choose mastectomy, breast reconstruction is known to offer a cosmetic and psychological advantage. Despite this, only a minority of patients undergo post mastectomy reconstruction. Little is known about factors that influence reconstruction in younger women who undergo mastectomy. We evaluated the association of demographic, hospital, physician and insurance factors with receipt of immediate breast reconstruction.

Methods

We used the Perspective database to identify women who underwent a mastectomy for breast cancer from 2000–2010. Perspective is a voluntary, fee-supported database that samples more than 500 acute-care hospitals throughout the United States that contribute data on inpatient hospital admissions. ICD-9 procedure codes were used to identify women who underwent reconstruction at the time of mastectomy. Differences in reconstruction rates over time were examined by age, race, and type of insurance (commercial, Medicaid, Medicare and self-pay). Logistic regression analysis was used to determine factors predictive of immediate breast reconstruction after mastectomy. Additional analyses were done on the population of younger women (<50 years of age).

Results

We identified 106,988 women with breast cancer who underwent mastectomy, and of these, 24,150 (22.6%) underwent immediate reconstruction. From 2000 to 2010,, reconstruction rates increased from 15% to 33.3%, increasing the most for women with commercial insurance (25.3% to 54.6%) and women under the age of 50 (29% to 60%); for women under the age of 50 with commercial insurance the rate in 2010 was 67.5%. Multivariable analysis found that reconstruction was significantly less likely with increasing age, black race (OR=0.66), rural hospital location (OR=0.48), non-teaching hospital (OR=0.82) and >2 co-morbid conditions (OR=0.72). Odds of reconstruction increased with commercial (OR=3.0) and public (OR=1.6) insurance (compared to self-pay), bilateral mastectomies (OR=2.5), being single (OR=1.09) and increased hospital volume (OR=1.94). No association was found with breast surgeon volume. Similar associations were seen in the subgroup of women <50 years of age. Prolonged length of stay was greater for women undergoing reconstruction (29.2% vs. 18.5%, p<0.0001); however, in-hospital complication rates were similar at 5.6% and 5.3%, respectively.

Conclusion

Despite its benefits, less than one-third of all women, and half of women under the age of 50, received post mastectomy reconstruction in 2010. Insurance status was one of the largest predictors of immediate reconstruction, and its influence has increased over time. Public policy should ensure that access to reconstructive surgery is available to all women, regardless of insurance type.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S6-3.
SR1-1: Breast Cancer and the Environment: A Life Course Approach - Report Release from an IOM Committee.
Authors: Hertz-Picciotto I
Published: June 2012

In response to a request from Susan G. Komen for the Cure®, an Institute of Medicine (IOM) committee was convened to review and assess the strength of the science base regarding the relationship between breast cancer and the environment. As part of their charge, the committee members reviewed the evidentiary standards for identifying and measuring cancer risk factors and the methodological challenges involved in conducting research on breast cancer and the environment. They also considered the potential interaction between genetic and environmental risk factors. The committee's report notes evidence-based actions that women could take to reduce their risk of breast cancer and offers recommendations for future research on breast cancer and the environment. The results of this IOM committee's work will be presented.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr SR1-1.
SR2-5: The DNA Copy Number Landscapes and Genomic Architecture; Relevance for Progression and Outcome.
Authors: Børresen-Dale A-L
Published: June 2012

Patterns of genomic aberrations have been defined that underlie specific expression subgroups of breast cancer (BC) that may infer paths of tumor progression and shed light on mechanisms involved. Classifications built on levels of genomic distortion have been shown to have prognostic value. We recently developed two platform-independent algorithms to explore genomic architectural distortion using aCGH data to measure whole-arm gains and losses [whole arm aberration index (WAAI)] and complex rearrangements [complex arm aberration index (CAAI)]. By applying CAAI and WAAI to data from 595 BC patients, we were able to separate the cases into eight subgroups with different distributions of genomic distortion. Within each subgroup data from expression analyses, sequencing and ploidy indicated that progression occurs along separate paths into more complex genotypes. Histological grade had prognostic impact only in the luminal-related groups, whereas the complexity identified by CAAI had an overall independent prognostic power. The results emphasized the relation among structural genomic alterations, molecular subtype, and clinical behavior and showed that objective score of genomic complexity (CAAI) is an independent prognostic marker. The CAAI algorithm calculates complexity scores per chromosome arm and is based on relatively large genomic stretches, in megabase order of magnitude. We have further developed this method to calculate probe-focused complexity scores per sample, a continuous complexity index (CCI), that increases the resolution significantly by calculating complexity scores for every genomic locus. CCI was calculated based on data derived from aCGH analyses of a set of 394 invasive ductal BCs. This approach enabled us to identify novel regions frequently subjected to high levels distortion and furthermore, to pinpoint regions with increased complexity which was associated with more aggressive disease. A total of 25 recurrent regions with high level complexity were identified. Regional complexities on chromosome arms 8p, 11q and 17q were each associated with clinical parameters associated with aggressive disease. Complexity patterns were different between tumors of different gene expression subtypes. Multivariate Cox analysis revealed that regional complexity on 17q21.32-q21.33 was significantly associated with shorter survival, independent of established clinical variables. The new algorithm developed represents a novel tool that can be utilized to identify smaller genomic regions of importance as well the genes therein that could be further explored.

References

Bergamaschi A. et al. Genes Chromosomes. Cancer 45, 1033–1040 (2006).

Hicks J. et al. Genome Res. 16(12):1465–79, (2006)

Kristensen VN and Vaske C et al. (2011) PNAS, spec BC issue (in press)

Russnes HG and Vollan HK et al. (2010) Sci. Transl. Med. 2, 38ra47

Stephens P et al. (2009) Nature. 462, 1005–1010

Aaroe J and Myhre S et al. under review

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr SR2-5.
Abstract A71: BRCA mutations and surgical decision making in a sample of young black women with invasive breast cancer
Authors: Fleming Patrice J. , Vadaparampil Susan T. , Bonner Devon , Monteiro Alvaro N. , Kessler Lisa , Royer Robert , Narod Steven , Pal Tuya
Published: June 2012

Background: On average, Black women develop breast cancer ten years earlier than White women and are more likely to die from the disease. Early onset breast cancer is a hallmark feature of the BRCA1 and BRCA2 (BRCA) gene mutations and may contribute to a portion of breast cancers in Black women. Widespread availability of genetic testing for hereditary breast cancer has resulted in an increasing number of women considering their BRCA test results prior to surgical treatment decisions for their breast cancer surgery (e.g., consideration of a risk-reducing bilateral mastectomy, contralateral prophylactic mastectomy). However, little is known about use of BRCA testing prior to definitive surgery specifically among Black women. The purpose of this abstract is to describe baseline utilization of BRCA testing in Black breast cancer patients prior to surgery and to document the prevalence of BRCA mutations in a cohort of Black women with early onset breast cancer.

Methods: Black women diagnosed with invasive breast cancer ≤ age 50 between the years of 2005 and 2006 were recruited through the Florida Cancer Registry utilizing state-mandated recruitment methods. Participants completed genetic counseling and a comprehensive risk factor questionnaire including 7 items specific to referral and uptake of genetics clinical services. Biological specimens (either blood or saliva) were collected, and BRCA testing was performed.

Results: Of the 209 eligible cases, 48 women consented to study participation. Of the 46 women with usable biological specimens: the average age of diagnosis was 42.8 ±6.14 and 50% (n=23) reported a positive family history of breast cancer (i.e., ≥ 1 first and/or second-degree relative with breast cancer). A previous BRCA test was reported by 30.4% (n=14) of those completing the study with only 2 participants (4.3%) receiving a genetic test result prior to making a breast surgery decision. Seven women (15.2 %) chose a bilateral mastectomy, 4 of which were risk reducing. No association was observed between family history and the type of breast surgery elected. Mutations in the BRCA genes were identified in three participants (including 1 in BRCA1 and 2 in BRCA2). In 16 additional participants, there were a total of 28 variants of uncertain significance (VUS) identified.

Conclusions: Our results suggest that few Black women utilized genetic test results and/or family history to make surgical decisions for their breast cancer treatment despite data documenting similar BRCA prevalence rates in Black women with early onset breast cancers as those previously reported in White women. These findings highlight an important health disparity in access to and utilization of genetics services among Black women with breast cancer.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A71.
Abstract A72: Occupational sunlight exposure, race, and risk of renal cancer
Authors: Karami Sara , Purdue Mark P. , Colt Joanne S. , Schwartz Kendra , Moore Lee E. , Stewart Patricia A. , Davis Faith G. , Ruterbusch Julie J. , Chow Wong-Ho , Wacholder Sholom , Graubard Barry I.
Published: June 2012

Introduction: Vitamin D, obtained primarily from ultraviolet (UV) exposure, is hydroxylated to its biologically active form within the kidneys. Epidemiological evidence supporting a relationship between vitamin D and kidney cancer risk has been inconsistent despite experimental data indicating that vitamin D and its metabolites may inhibit carcinogenesis. Previously we reported an inverse association between renal cell carcinoma (RCC) risk and occupational UV exposure among men in Europe. In the current study, we examined the association between occupational UV exposure and RCC risk among U.S. residents and investigated whether this association varies by race and sex.

Methods: Lifetime occupational data for 1,217 RCC cases and 1,235 controls in a large population-based case-control study were blindly assessed by an industrial hygiene expert to create a job exposure matrix that categorized frequency, duration, confidence, and intensity of occupational UV exposure. Categorical exposure metrics used to evaluate exposure-response relationships with occupational exposure were based on tertiles of exposure levels among controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to examine the association between RCC risk and UV exposure by sex and race.

Results: Across all exposure-response matrices, women in the highest tertile of occupational UV exposure had a 40% reduction in RCC risk compared to those in the lowest tertile; risk decreased significantly as occupational UV exposure increased (p-trend=0.01 to 0.004). A marginally significant, non-linear inverse association was observed among men. Further stratification by race revealed similar findings for black and white women. Significantly decreased associations between RCC risk and occupational UV exposure were observed among black men (p-trend=0.05), but not among white men, although results for blacks were based on small numbers.

Our findings suggest that occupational UV exposure may protect against RCC. We caution any inferences made using race, given power limitations for stratified analyses, until additional well-powered studies can replicate and extend these findings.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A72.
Abstract A84: Race, neighborhood socioeconomic characteristics, and Helicobacter pylori seroprevalence
Authors: Epplein Meira , Cohen Sarah , Sonderman Jennifer , Zheng Wei , Cai Qiuyin , Williams Scott , Blot William J. , Signorello Lisa B.
Published: June 2012

Background: Recently, very high Helicobacter pylori sero-prevalence rates were found among African Americans, especially those of higher percentage of African ancestry, residing in the southeastern US. We sought to determine if neighborhood-level socio-economic characteristics, above and beyond individual-level socio-economic characteristics, are associated with Helicobacter pylori prevalence, and, if so, if this helps to explain the strong association with African ancestry.

Methods: Antibodies to Helicobacter pylori proteins were assessed in the serum of 665 African American and white participants from the Southern Community Cohort Study. African and European admixture was estimated using a panel of 276 ancestry genetic markers. Prevalence odds ratios for CagA-specific Helicobacter pylori status associated with10 block-level measures of socio-economic status, obtained from linkage to the US Census, were calculated using polytomous logistic regression.

Results: After adjusting for individual-level socio-economic characteristics, three neighborhood-level characteristics were significantly inversely related to CagA+ Helicobacter pylori sero-positivity: percent adults completed high school; median value of owner-occupied houses; and percent employed (comparing highest tertile to lowest tertile, OR=0.47, 95%CI: 0.26–0.85; OR=0.56, 95% CI: 0.32–0.99; and OR=0.59, 95% CI: 0.34–1.03, respectively). However, inclusion of these neighborhood-level measures did not attenuate the association of African ancestry and CagA+ Helicobacter pylori sero-prevalence, with African Americans of low, medium, and high African ancestry maintaining 2-, 7-, and 9-fold increased odds compared to whites.

Neighborhood levels of education, house values, and employment are associated with sero-prevalence to CagA+Helicobacter pylori, highlighting high-risk areas for prevention and screening efforts, but the strong relationship between African ancestry level and CagA+ Helicobacter pylori sero-prevalence persisted after adjustment for individual and neighborhood-level socio-economic characteristics, suggesting a biological basis for this association.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A84.
Abstract A96: Breast cancer screening resources and early-stage diagnosis in Appalachia: A geospatial perspective
Authors: Yao Nengliang (Aaron) , Hillemeier Marianne , Anderson Roger
Published: June 2012

Background: National Cancer Institute has designated Appalachia as a priority area characterized by significant disparities in cancer outcomes. However, little research focuses on the availability of cancer care resources in this region and how resource availability may relate to cancer outcomes. This paper will describe the distribution of breast cancer screening resources in Appalachia and examine the relationship between screening resources and breast cancer stage at diagnosis at the population level.

Method: Early stage breast cancer as a percent of all breast cancer cases are computed based on the county-level registry data from the four Appalachian states during 2000–2008. Availability of breast cancer screening providers and facilities are estimated for these Appalachian states. Descriptive analysis, exploratory spatial data analysis, and spatial regression are conducted.

Results: Appalachian counties have significantly fewer primary physicians, OB/GYN specialists, and diagnostic radiologists per capita than non-Appalachian counties. Spatial analysis demonstrates moderate clustering of scarce breast cancer screening resources and low percentages of early stage breast cancer in West Virginia and Appalachian Kentucky. Those diagnosed at early stages were 67.92% of all Appalachian cases vs. 68.34% of non-Appalachian breast cancer patients. The number of diagnostic radiologists per capita is significantly associated with the percentage of early stage breast cancer incidence when controlling for covariates such as county level poverty rates, uninsurance rate, percentage of adults with college degree, and primary care resources.

Conclusions: Fewer diagnostic radiologists per capita in West Virginia and Appalachia Kentucky is associated with lower percentage of early stage breast cancer incidence in the Central Appalachia region. Public health interventions should include policies and regulations to improve breast cancer screening resources in this region.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A96.
Abstract A98: Physician social networks and variation in prostate cancer treatment in three cities
Authors: Pollack Craig Evan , Weissman Gary , Bekelman Justin , Liao K.J. , Armstrong Katrina
Published: June 2012

Background: Racial differences in cancer treatment may result, in part, from distinct physician practice styles in the setting of regional healthcare environments. Emerging methodological tools allow for physician social networks to be constructed and analyzed using claims data.

Objective: To examine whether physician social networks are associated with variation and racial differences in treatment for men with localized prostate cancer.

Research design: We performed a retrospective cohort study using 2004–2005 SEER-Medicare data from three cities. Algorithms were generated to identify a patient's primary care physicians, urologists, and radiation oncologists. Within each city, a network of these physicians was constructed, with physicians as the nodes and shared patients as the links (edges) between nodes. From the overall network structure, distinct subgroups of physicians were identified using the Girvan-Newman algorithm. Subgroups were defined as those physicians who were highly clustered with one another and with relatively sparse connections to physicians in other subgroups. Patients were assigned to the subgroup of their diagnosing urologist. Network measures were then incorporated in logistic regression analyses with robust standard errors to examine the predictors of treatment, adjusting for patient-level factors.

Results: Patients who were seen by different subgroups of physician varied widely in their unadjusted rates of prostatectomy and the racial/ethnic and socioeconomic composition. In city A, for example, rates of prostatectomy varied from 8.6% to 25.3% for patients who saw different subgroups of doctors. Similarly, in city A, the proportion of minority patients ranged from 15.9% in one subgroup to 64.8% in another. After adjustment for patient-level covariates, patients who were diagnosed by a urologist in one of four subgroups had significantly lower odds of prostatectomy compared to those patients who saw urologists in the subgroup with the highest rates of prostatectomy. Similarly, in cities B and C, patients who saw specific subgroups had significantly lower odds of prostatectomy compared to the subgroup with the highest rates of prostatectomy. Contrary to our expectations, accounting for subgroups, did not appear to mediate racial/ethnic differences in rates of active treatment.

Conclusions: Using claims data to map physician networks may provide insight into the observed variation in treatment patterns for men with prostate cancer. Physician networks may be used to identify densely connected physicians who disproportionately care for minority patients.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A98.
Abstract B101: Cost comparison of high-risk targeted breast MRI vs. mammography in screening underserved women
Authors: Banks Lamisha , Ford Anne C. , Seewaldt Victoria L.
Published: June 2012

Background: Our current recommendations for mammographic and MRI screening are based on studies in European, European-Canadian and European-American women. To our knowledge, there has been no large-scale analysis of the effectiveness of mammographic screening in African-American and Latino women. We have little information on the relative benefits of general mammography screening versus high-risk targeted breast Magnetic Resonance Imaging (MRI) screening in underserved women. Mammography has the advantage of being relatively inexpensive and well accepted. In contrast, MRI is expensive and has the potential to increase the number of benign biopsy.

Methods: We compared the ability of mammography screening in a general risk underserved population (standard-of-care) with targeted breast MRI screening in high-risk underserved women to a) detect breast cancer, b) cost of screening/breast diagnosis, c) number of benign biopsies, and d) compliance. From 6/15/2004 to 5/7/2011, 1) 299 general risk women underserved women were underwent digital mammographic screening and 2) 299 high-risk women underwent combined mammogram and breast MRI screening. Women were recruited by our Breast Navigation team from sites throughout central North Carolina and underwent screening accompanied by a member of our Navigation team. Women found to have an abnormal mammogram were evaluated by ultrasound, ultrasound guided biopsy, and/or stereotactic biopsy. Women with an abnormal breast MRI were evaluated with ultrasound, ultrasound guided biopsy, and/or MRI guided biopsy. All follow-up services were provided for free.

Results: The average age of women was 50 years for women undergoing mammographic screening and 47 years for women undergoing MRI. The racial composition of general-risk women undergoing mammographic screening was 40% African American, 25% Caucasian, 25% Hispanic, and 1% other vs. 33% African American, 62% Caucasian, 3% Hispanic, and 2% other for high-risk women undergoing breast MRI. Mammographic screening detected 1 breast cancer vs. 9 for MRI. The cost per diagnosis was $37,375.00 vs. $21,561.22.

The number of benign breast biopsies/total biopsies was 7/8 (88%) for mammographic screening vs. 31/40 (78%) for MRI. Compliance with follow-up studies was 75% for mammographic screening vs. 90% for MRI.

Conclusions: Breast MRI screening in high-risk underserved women is highly feasible and with Navigation, there is a high rate of compliance with follow up studies. The cost per breast cancer diagnosis is significantly lower for targeted breast MRI screening of high-risk women than for mammographic screening of general risk women.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B101.
Abstract B14: Strengthening CBPR collaboration between Pacific Islander community and academic research partners
Authors: DeStefano Anthony , Aromin Jay , Dimaculangan Jeany , Vunileva Isileli , Tanjasiri Sora P. , Peters Ruth , Tui‘one Vanessa , Takahashi Lois , Sablan-Santos Lola , Quitugu Lourdes , Quenga Joey , Hui Brian , Barrera-Ng Angelica
Published: June 2012

Community-based participatory research (CBPR), applied authentically according to its principles, is inherently conducive to empowerment and capacity building for academic and community partners by promoting egalitarian collaborations through all stages of research. During an intensive qualitative study exploring the intersection of HIV-HPV and cancer in the Pacific Islander (PI) communities of Southern California, we strengthen effective collaborations between an academic research team and two PI community-based organizations (CBOs). Responding to an NCI call for research exploring AIDS-related cancers, our CBOs worked closely with the academic team to examine HIV-HPV factors among Chamorro and Tongan young adults. Key informant and focus groups interviews were collaboratively chosen as the grounded theory research design. Community partners lead the process in: 1) determining most locally relevant and culturally appropriate point of entry for the study investigating HIV and its potential connections to HPV; 2) establishing and convening project specific community advisory board; 3) recruiting study participants; and 4) collecting data. The academic team conducted trainings on HIV, HPV, sampling, data collection, and analysis. Partners jointly lead dissemination efforts. The decision-making process incorporated culturally appropriate meeting protocols of sharing food and experiences through “talk story.” Through our successful CBPR collaboration, we ensured a shared discourse on cancer-related and comorbid topics, and we solidified and reaffirmed our relationship for ongoing and future projects. Thus, CBPR is critical, as the need to address cancer health disparities through collaborative research continues to play a key role in shaping the racial/ethnic minority and medically underserved healthcare landscape.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B14.
Abstract B27: The Ohio Patient Navigation Research Program (OPNRP): Does the ACS-patient navigation model improve time to resolution among patients with abnormal screening tests?
Authors: Paskett Electra D.
Published: June 2012

Objectives: To test the Ohio American Cancer Society (ACS) model of patient navigation (PN) as it relates to reducing time to diagnostic resolution among persons with abnormal breast, cervical, or colorectal cancer screening tests or symptoms.

Methods: 862 patients from 18 primary care and specialty clinics within the Ohio State University (OSU) Medical Center and Columbus Neighborhood Health Centers with one of these abnormal findings were eligible to participate in this group-randomized study. Clinics were paired and randomized within pairs to either usual care or PN. Patients were informed about the study, consented, and completed a baseline survey. The navigators were not clinic-based, but followed the Ohio ACS-PN model where navigators mainly used phone contact from a non-clinic location. Chart review was done to capture medical information on the abnormality as well as the date of resolution and follow-up tests received. The primary analysis focused on time to resolution using shared gamma frailty models used to test for effect of navigation on time to resolution. Crude Hazard Ratios (HR) were used, as adjustment for OSU and national variables did not significantly change the hazard ratios. Assessment of effect modification was also conducted.

Results: Crude HR's deviated starting at 6 months, so that by 15 months, participants in the PN arm were 61% more likely to have their abnormality resolved (p=0.004 for difference in risks across arms; p=0.005 for increase in relative risk over time). Effect modifier analysis showed a trend for income (<$50K vs. $50K+; p=0.07) in that lower income participants benefited earlier from PN.

Participants in the navigation arm (N=475) were further assessed in terms of reported barriers and navigator actions documented in the navigation encounters. Almost half reported no barriers (n=226; 46.6%), while the remainder reported one barrier (n=113; 23.8%), or 2+ barriers (n=136; 28.6%). The most frequently reported barriers were perception/beliefs about tests or treatment (n=89), communication with providers (n=84), scheduling problems (n=65), insurance/co-pay problems (n=49), and medical/mental health co-morbidities (n=44). Most frequent action taken by navigators were providing support (n=175), referrals (n=125), and education (n=74). On average, navigated participants with barriers received 3 encounters with a PN, and 90.9% of the encounters lasted <15 minutes. The most frequent actions taken by a PN included: support (n=175); referrals (n=125); and education (n=74).

Conclusions: The OPNRP demonstrated that patients with abnormal cancer screening tests or symptoms are more likely to resolve their abnormality, if assigned to a PN program compared to those not assigned to a PN program, even when navigators are not embedded in the clinic.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B27.
Abstract B34: Increase in EGFR level through SLUG-induced repression of dynactin 5 in triple-negative breast cancer cells
Authors: Mittal Mukul K. , Ramasamy Raju , Chaudhuri Gautam
Published: June 2012

Aggressive breast cancers of the triple negative type (TNBCs) are often characterized with higher levels of receptor tyrosine kinases (RTKs; e.g. EGFR) and G-protein coupled receptors (GPCRs; e.g. PAR1). These receptors are activated by their agonists, induce signal transduction and then are attenuated by signal uncoupling and retrograde recycling endosome transport. We report here that the levels of several of these receptor proteins are elevated and hyperactivated on the surface of aggressive breast cancer cells that have high levels of the transcriptional repressor protein SLUG. Chip-on-chip analysis to identify genes that are repressed by SLUG in the breast cancer cells revealed one of the proteins that are critical for the retrograde recycling transport of the RTKs and GPCRs, namely dynactin 5 (DCTN5). DCTN5 (aka p25) is a member of the dynactin complex. DCTN5 is a subunit of the pointed-end subcomplex of dynactin that is thought to interact with membranous cargo. Interestingly, DCTN5 is expressed from the reverse activity of the bidirectional promoter of human PALB2 (partner and localizer of BRCA2) gene whose product regulates the functions of the tumor suppressor protein BRCA2. We found that SLUG inhibits both PALB2 and DCTN5 gene expression through chromatin remodeling in human breast cancer cells. We hypothesize that the malignant breast cancer cells acquire highly aggressive and metastatic characteristics in part due to the higher levels and hyperactivation of EGFR on their surface. The hyperactivity of EGFR occurs through the SLUG-mediated repression of DCTN5 which mediates the internalization and thus, degradation of activated receptors. We evaluated the role of DCTN5 in the determination of aggressiveness in TNBC cells. We postulate that maintenance of normal levels DCTN5 in the TNBC cells through the inhibition of the functions of SLUG will control the invasive growth of the breast tumors. Supported in parts by the DOD-CDMRP grants BC050641, BC086542 and BC103645.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B34.