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  • American Association for Cancer Research (AACR)  (27)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 247-247
    Abstract: Colorectal cancer (CRC) is one of the most frequent malignancies in many parts of the world and a leading cause of cancer deaths in both men and women. The identification of rationale therapeutic targets is one possibility to provide personalized medicine to cancer patients. Our approach consisted of identifying overexpressed genes located at sites of recurrent chromosomal amplifications, as these regions are likely to harbor genes required for cancer cell survival. Thirty-one colon cancers and 15 CRC cell lines were analyzed by high-resolution array CGH and microarray gene expression profiling. RNA interference (RNAi)-based analysis identified a subset of genes whose loss-of-function (LOF) reduced the cellular viability of CRC cell lines. Consistent with previous reports, the vast majority of CRC assayed exhibited amplification of the chromosome band 13q12.13-q12.3. Among the genes residing within the 13q12.13-q12.3 amplified region showing an overexpression level of at least two-fold higher in the tumor compared to normal mucosa and whose gene silencing impaired cellular survival, we identified NUPL1, LNX2, POLR1D, CDX2, POMP, and SLC7A1. As little is know of the function of these proteins, we decided to use an unbiased systems biology approach to identify genes, pathways and networks altered following RNAi-mediated LOF of each of these candidate genes. To do this we perturbed the expression of each candidate gene through application of two or more siRNAs corresponding to each gene, followed by whole genome expression profiling to monitor cellular transcriptional responses to gene specific LOF. Concordant gene expression signatures generated using three different RNAi effectors targeting POMP, over a time-course (10, 24, 48, and 72 hours), showed that a decrease in POMP expression of more than 80% at 24 hours initially resulted in only minor downstream changes in gene expression. However, by 48 hours approximately 100 genes exhibited altered expression and by 72 hours nearly 2000 genes. At this last time point a statistically significant enrichment (p & lt;0.05) for the altered expression of genes linked to the gene ontologies of cancer, cell death, and cellular growth was observed. POMP, a proteasome maturation protein, is an essential factor for mammalian proteasome biogenesis. This dynamic loss-of-function approach revealed a regulatory network that controls the transcriptional response of colorectal cancer cells after impairing the function of the proteasome. We are also investigating whether the gene expression profiles observed following silencing of POMP resemble the transcriptomic changes that undergo cells treated with proteasome inhibitors as this may shed further light on the mechanism of action of this new class of anti-cancer drugs particularly in CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 247.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 2
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 1 ( 2023-01-04), p. 92-99
    Abstract: The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment. Patients and Methods: Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A. Results: Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients’ baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P & lt; 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47). Conclusions: When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1942-1942
    Abstract: Background: Preoperative 5-fluorouracil-based chemoradiotherapy is the standard treatment for locally advanced rectal carcinomas. However, the individual tumor response is very heterogeneous, ranging from complete resistance to regression. Therefore, ascertaining the role of microRNAs (miRNAs) in therapy response as well as identification certain miRNA as predictive markers for response remains very crucial. Materials/Methods: Using an in-vitro model of 12 colorectal cancer cell lines, we compare the pretherapeutic miRNA expression profiles of these cell lines with the previously assessed radiochemoresistance of each cell lines, respectively. Differences in treatment sensitivity of the cell lines and miRNAs expression were then correlated. Colony formation assays in two independent cell lines were used for the functional validation in-vitro. To asses the clinical applicability miRNA expressions of 64 pretherapeutic biopsies from patients with locally advanced cancer treated with 5-FU based RCT were analyzed. Results: We identified 36 miRNAs whose expression levels correlated significantly with the heterogeneous sensitivity of the cell lines to chemoradiotherapy (p & lt; 0.05). Microarray measurements were independently validated using semi-quantitative real-time PCR. miR-320, miR-132, miR-429, miR-224 and let-7g were then functionally validated in-vitro by transfection of corresponding miRNA mimics. Analysis of miRNA expression in rectal cancer patients biopsies showed high correlation of miR-224 expression with poor prognosis (p=0.043). Conclusion: We identified 36 miRNAs that associated with response to chemoradiotherapy. Functional validations of miR-320, miR-132, miR-429, miR-224 and let-7g have been undertaken in-vitro underlining the regulatory effects of the specific miRNAs. Further miR-224 found out to be significantly correlated to Disease Free Survival (DFS). An independent prospective validation in a clinical trial will be performed. Citation Format: Junius Salendo, Melanie Spitzner, Frank Kramer, Peter Jo, Tim Beissbarth, Hendrik A. Wolff, Heinz Becker, Mathias Dobbelstein, Michael Ghadimi, Marian Grade, Jochen Gaedcke. Identification of a microRNA expression signature for radiochemosensitivity of colorectal cancer cells, involving miRNAs-320a, -224, -132 and let7g. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1942. doi:10.1158/1538-7445.AM2013-1942
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 798-798
    Abstract: A fundamental challenge for the study and translation of pancreatic ductal adenocarcinoma (PDA) genomes in patients in vivo is the presence of varied admixtures of reactive stroma, inflammatory cells, and necrosis within the tumor. Furthermore biopsies frequently contain multiple clonal populations of neoplastic cells that cannot be distinguished on the basis of morphology alone. To overcome the limitations of histopathology based methods we are using DNA content based flow cytometry to identify and purify distinct clonal PDA populations from over 60 surgical samples from a Stand up to Cancer (SU2C) sponsored clinical trial. Sorted tumor populations from each patient have been interrogated with CGH arrays and whole exome sequencing. In addition we have interrogated the genomes of sorted PDA populations from a SU2C phase II trial of liver metastases from 35 patients with advanced previously treated disease, as well as those from a series of rapid autopsy samples. The genes targeted by the somatic aberrations in each tumor genome are overlaid onto a collection of 33 PDA specific maps, containing 763 genes of interest, developed as part of the Metaminer Oncology initiative. An example of the translational potential of these data includes the detection of a homozygous deletion of STAG2 in an aneuploid tumor population present in the primary and in each metastatic site of a rapid autopsy case. Targeted resequencing identified somatic mutations in a small number of additional sorted samples from our patient cohorts. Strikingly genetic and histopathologic analysis of tumors induced by transposon insertion in a KrasG12D genetically engineered mouse model showed that disruption of STAG2 promotes the development of PDA and its progression to metastatic disease. To assess the clinically significance of STAG2 expression in human tumors we screened a TMA containing a collection of 344 specimens obtained from resected patients. In normal tissue nearly all ductal cells stained with a high intensity. There was a statistically significant loss of STAG2 expression in the tumor tissue (Wilcoxon-Rank test). In univariate Kaplan Meier analysis nearly complete STAG2 positive staining ( & gt; 95% of nuclei positive) was associated with a survival benefit of median survival of 6.41 months (p = 0.031). Interestingly, the survival benefit of adjuvant chemotherapy was only identified in the group of patients with a STAG2 staining of less than 95% (median survival benefit 7.65 months; p = 0.028). Multivariate Cox Regression analysis showed that STAG2 is an independent prognostic factor for survival in PDA patients. We propose that our unbiased clonal profiling of PDA genomes provides a unique and highly efficient framework to identify clinically relevant genomic events in PDA Citation Format: Michael T. Barrett, Elizabeth Lenkiewicz, Evers Lisa, Pedro Perez-Mancera, David Tuveson, Daniela Aust, Christian Pilarsky, Meraj Aziz, Richard Posner, Ramesh Ramanathan, Victor Velculescu, Amy Kramer, Jeffrey Drebin, Daniel D. Von Hoff. Clonal analysis and clinical translation of pancreatic adenocarcinoma genomes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 798. doi:10.1158/1538-7445.AM2013-798
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1379-1379
    Abstract: Mounting evidence indicates that growth of pathologically identical cancers in each individual patient is fueled by different sets of driving mutations. The need to identify these drivers stems from the recognized necessity for tailoring therapy and scheduling future surveillance. This personalized medical approach has been shown to result in better treatment outcomes. We present a novel Precision Cancer Analysis system (PCAS) capable of identifying activated signaling pathways by means of a transfected cell-based fluorescent reporter assay yielding a quantitative output of particular pathway activation levels. Being a functional platform PCAS reveals activated pathways regardless of the type of mutation behind it, i.e. whether it is already a known mutation or a variant of unknown significance (VUS) mutation. 20 cancer patients were sequenced for a panel of 37 genes and analyzed by the PCAS. This system quantifies oncogenic activity in the majority of the oncogenic signaling pathways altered by the patients’ mutations through a functional assay and does not rely on prior knowledge of the mutations. The system produces a quantitative output enabling grading the different mutants of the same patient, providing prioritization for better drug selection. In 3 tested genes, 16 different mutations were identified- 4 in EGFR, 4 in PIK3CA and 8 in KRAS. Of these 10 were classified as known mutations for which functional annotation exists, and 6 were VUS. In addition to correctly annotating all known mutations, the PCAS further quantified oncogenic activity in all the VUS tested. Measuring the functional mechanism behind known mutations and VUS provides another layer of critical information to the physician. These results clearly demonstrate the value of a functional assay in accurately identifying the optimal course of treatment, particularly by its ability to add actionable information to VUS. The study produced a comprehensive delineation of the oncogenic activity of each patient's individual mutations demonstrating the ability of the PCAS to 1) accurately deliver comparable actionable information as found by NGS, 2) functionally characterize mutations annotated as VUS, and 3) monitor oncogenic activity of signaling pathways induced by different mutations and mutation-combinations enabling informed treatment decisions. Citation Format: Gabi Tarcic, Nir Peled, Zohar Barbash, Naama Barabash-Katzir, Shlomo Yaakobi, Naama Barabash-Katzir, Hani Nevo, Michael Vidne, Mariusz Adamek, Mordechai R. Kramer, Nikolai Goncharenko, Yakov Fellig, Karen Meir, Keith Mostov, Yoram Altschuler. Identification of the functional significance of mutations using the novel precision cancer analysis system. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1379.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2508-2508
    Abstract: The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil-based chemoradiotherapy followed by standardized surgery. However, the tumor response to multimodal treatment has varied greatly and ranging from complete resistance to complete pathologic regression. The prediction and treatment of these observed heterogeneous response to therapy in patients is, therefore, an important clinical need. A strategy for studying the molecular basis of this heterogeneous tumor response is to establish the clinical parameters as an in vitro model. For this purpose we used 12 colorectal cancer cell lines and exposed them to 3 µM of 5-fluorouracil and 2 Gy of radiation, which reflect the parameters used in clinical patient treatment. The sensitivity differences of the cell lines to chemoradiotherapy, measured as surviving fractions by a standard colony formation assay, were then correlated with the pretherapeutic gene expression profiles of these cell lines. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions. In the 12 colorectal cancer cell lines we observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q & lt; 0.05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for the treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets. We anticipate that this analysis of a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2508. doi:10.1158/1538-7445.AM2011-2508
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1653-1653
    Abstract: Background: Preoperative chemoradiotherapy represents the standard treatment for patients with rectal cancer. However, the clinical response of individual tumors to multimodal treatment is not uniform, and ranges from complete response to complete resistance. Therefore, the identification of novel therapeutic targets whose modification could be harnessed to sensitize a priori resistant tumors is exceedingly important. Previously, we demonstrated that the Wnt transcription factor TCF7L2 (also known as TCF4) was overexpressed in primary rectal cancers that were resistant to chemoradiotherapy (CRT), and that TCF7L2 functionally mediates resistance of CRC cells to clinically relevant doses of ionizing radiation (IR). Methods: Using siRNAs we silenced CTNNB1 (β-catenin), another key-component of canonical Wnt-signaling, in colorectal cancer cell lines LS1034, SW480, and SW837. To asses influence on CRT, cells were exposed to 0, 1, 2, 4, 6 and 8 Gy of X-rays and 5-FU. Wnt- signaling was stimulated in retinal pigment epithelial cells (RPE) either by adding Wnt-3A, or overexpressing non degradable β-catenin (S33Y-mutated) and analyzed changes in CRT. Finally we repetitively irradiated SW1463 (68Gy) to establish an isogenic radio-resistant cell line and examined changes in protein expression. Results: Silencing of CTNNB1 resulted in (chemo-) radiation-sensitization of all three CRC-cell lines. To further investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, non-tumorigenic RPE cells were stimulated with Wnt-3A, which significantly increased resistance to CRT. This effect could be recapitulated by overexpression of β-catenin (S33Y-mutated), resulting in a significantly increased resistance to CRT. The effect could be rescued by siRNA mediated knockdown of β-catenin. Consistent with these findings, we observed higher expression levels of active (unphosphorylated) β-catenin as well as increased TCF reporter activity in SW1463 cells that were rendered radiation-resistant due to repeated IR treatment. Conclusion: Together, these findings strongly support the interpretation that Wnt/β-catenin signaling plays a central role in mediating resistance of CRC cells to CRT. Hence, pathway inhibition may represent a promising strategy to increase therapeutic responsiveness to CRT, which represents the standard treatment for locally advanced rectal cancers. This would have considerable clinical implications. Citation Format: Georg Emons, Melanie Spitzner, Sebastian Reineke, Frank Kramer, Margret Rave-Fraenk, Jochen Gaedcke, Michael Ghadimi, Thomas Ried, Marian Grade. A novel role for Wnt/β-catenin signaling in mediating resistance of colorectal cancer to chemoradiotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1653.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 3 ( 2020-02-01), p. 624-638
    Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 9
    Online Resource
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    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 31, No. 1_Supplement ( 2022-01-01), p. PO-173-PO-173
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 31, No. 1_Supplement ( 2022-01-01), p. PO-173-PO-173
    Abstract: Introduction: Breast cancer mortality in the US is 40% higher among Black than White women. Even among patients with prognostically favorable tumors, disparities persist, suggesting clinical features do not fully account for mortality differences. Area-level factors (e.g., rurality) influence health outcomes and may explain spatial variation in mortality disparities. Rurality can impact access to and quality of care, and socioeconomic status. Georgia is an ideal place to study spatial heterogeneity in race disparities because of the diverse population ( & gt;30% Black), large number of counties (159), and pronounced disparities in breast cancer mortality in the Atlanta area. Methods: Race-specific standardized mortality ratios (SMRs) were calculated for each county in Georgia to account for sparsely populated areas and areas with high residential segregation. Observed deaths among women diagnosed with localized or regional breast cancer between 2005 and 2013 were obtained from the Georgia Cancer Registry. To ensure equal follow-up, only deaths within five years of diagnosis were included. Expected deaths were estimated using race-specific population counts, race-specific breast cancer incidence rates, and the pooled (Black and White) mortality rate among Georgia women, with indirect age adjustment (20–44, 45–54, 55+ years). Spatial smoothing methods, including adding neighboring data to meet a threshold and Bayesian models with conditionally autoregressive priors, were used to stabilize local estimates. Counties were classified by 2013 RUC codes (urban: 1–3, rural: 4–9). Results: A total of 3,235 breast cancer deaths were observed during the study period, with 42% among Black women. The median SMR was lower for White (0.8, IQR: 0.7, 1.1) than Black women (1.4, IQR: 1.1, 2.0). Among Black women only, median SMR was greater in rural (1.7, IQR: 1.1, 2.5) than urban counties (1.3, IQR: 1.1, 1.6). After sequentially adding neighboring data to meet a race-specific threshold of 30 observed deaths, smoothed median SMRs were 0.9 (IQR: 0.8, 0.9) and 1.4 (IQR: 1.2, 1.6) for White and Black women, respectively. For Black women, median SMR was attenuated in rural counties (1.4, IQR: 1.2, 1.7) but unchanged in urban counties (1.3, IQR: 1.2, 1.5). The greatest SMRs for Black women were observed in urban counties comprising the Atlanta area and rural southeast Georgia. For example, Fulton County SMRs were 1.6 and 0.7, for Black and White women, respectively. Highest SMRs for White women were observed in southwest Georgia, but were similar to SMRs among Black women in this region. The spatial distribution of SMRs using same neighbor smoothing and Bayesian models were similar. Conclusion: Breast cancer mortality race disparities vary widely across Georgia. These results highlight specific areas for public health intervention, especially among Black women. This work presents a potential mechanism to monitor trends in small area cancer mortality race disparities over time. Future work will model the impact of area-level factors on the disparity magnitude. Citation Format: Rebecca J. Nash, Lauren E. McCullough, T.J. Pierce, Lindsay J. Collin, Anne H. Gaglioti, Kevin C. Ward, Michael Kramer, Jeffrey Switchenko. Spatial heterogeneity and rural-urban differences in the Black-White breast cancer mortality disparity in Georgia [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-173.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 10
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 24 ( 2009-12-15), p. 7711-7718
    Abstract: Purpose: The combination of the oral alkylating agent temozolomide and the oral multikinase inhibitor sorafenib was evaluated in advanced melanoma patients. Experimental Design: Patients with metastatic melanoma (n = 167) were treated on four arms. All patients received sorafenib at 400 mg p.o. twice daily without interruption. Patients without brain metastases or prior temozolomide were randomized between arm A: extended dosing of temozolomide (75 mg/m2 temozolomide daily for 6 of every 8 weeks) and arm B: standard dosing (150 mg/m2 temozolomide daily for 5 of every 28 days). Patients previously treated with temozolomide were enrolled on arm C: extended dosing of temozolomide. Patients with brain metastases and no prior temozolomide were assigned to arm D: standard dosing. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included response rate, toxicity rates, and the rates of BRAF or NRAS mutations. Results: The 6-month PFS rate for arms A, B, C, and D were 50%, 40%, 11%, and 23%. The median PFS for patients on arm A, B, C, and D was 5.9, 4.2, 2.2, and 3.5 months, respectively. No significant differences were observed between arms A and B in 6-month PFS rate, median PFS, or response rates. Treatment was well tolerated in all arms. No significant differences in toxicity were observed between arms A and B except for more grade 3 to 4 lymphopenia in arm A. Conclusion: Temozolomide plus sorafenib was well tolerated and showed activity in melanoma patients without prior history of temozolomide. The activity of this combination regimen warrants further investigation. (Clin Cancer Res 2009;15(24):7711–8)
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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