Browsing by Author "Sledge, George"

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    3rd ESO–ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3)
    (Elsevier, 2017-02) Cardoso, F.; Costa, A.; Senkus, E.; Aapro, M.; André, F.; Barrios, C. H.; Bergh, J.; Bhattacharyya, G.; Biganzoli, L.; Cardoso, M. J.; Carey, L.; Corneliussen-James, D.; Curigliano, G.; Dieras, V.; El Saghir, N.; Eniu, A.; Fallowfield, L.; Fenech, D.; Francis, P.; Gelmon, K.; Gennari, A.; Harbeck, N.; Hudis, C.; Kaufman, B.; Krop, I.; Mayer, M.; Meijer, H.; Mertz, S.; Ohno, S.; Pagani, O.; Papadopoulos, E.; Peccatori, F.; Penault-Llorca, F.; Piccart, M. J.; Pierga, J. Y.; Rugo, H.; Shockney, L.; Sledge, George; Swain, S.; Thomssen, C.; Tutt, A.; Vorobiof, D.; Xu, B.; Norton, L.; Winer, E.; Department of Medicine, School of Medicine
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    DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer
    (Oxford University Press) Woditschka, Stephan; Evans, Lynda; Duchnowska, Renata; Reed, L. Tiffany; Palmieri, Diane; Qian, Yongzhen; Badve, Sunil; Sledge, George; Gril, Brunilde; Aladjem, Mirit I.; Fu, Haiqing; Flores, Natasha M.; Gökmen-Polar, Yesim; Biernat, Wojciech; Szutowicz-Zielińska, Ewa; Mandat, Tomasz; Trojanowski, Tomasz; Och, Waldemar; Czartoryska-Arlukowicz, Bogumiła; Jassem, Jacek; Mitchell, James B.; Steeg, Patricia S.; Department of Medicine, IU School of Medicine
    Background Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. Methods Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis–specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). Results Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. Conclusions BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species–mediated genotoxic stress in the metastatic brain.
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    Quality of Life in Younger versus Older Breast Cancer Survivors
    (Office of the Vice Chancellor for Research, 2011-04-08) Ziner, Kim; Champion, Victoria; Sledge, George; Monahan, Patrick; Zho, Qian Qian
    Background: Breast cancer is one of the most frequently occurring cancers in the developing world, but with earlier detection and better treatment, the majority of breast cancer survivors will live many years after diagnosis. Breast cancer survivors may experience many symptoms that impact their quality of life, and these symptoms may vary by age. The purpose of this study is to compare breast cancer survivors who were diagnosed at 45 and under (n=469) with survivors diagnosed at 55 to 70 (n=584) years of age. Materials and methods: Participants were identified through a large cooperative group (Eastern Cancer Cooperative Group). Eligibility criteria included use of chemotherapy at initial diagnosis, being 3 to 8 years from diagnosis, and not having a recurrence of breast cancer. The mean current age of younger survivors was 45.2 and for older survivors was 66.7. Women who agreed to participate were sent a survey and informed consent which was completed and returned via mail. Overall, 80% of eligible women contacted by researchers agreed to participate. Measures included physical, psychological, social, spiritual, and overall quality of life constructs. All measurements had good reported validity and reliability. A total of 469 younger and 584 older breast cancer survivors are included. Linear regression was used to compare the two groups on continuous outcomes while adjusting for the following potentially confounding covariates: marital status (married versus not), years of education, and total household income, and years since diagnosis. Results: Younger survivors scored significantly worse than older survivors on gynecological problems, sexual enjoyment, attention function, and overall reported symptoms. Psychologically, younger survivors demonstrated greater symptom distress, greater depression, and greater state and trait anxiety than older survivors. Younger survivors had lower marital satisfaction scores. Younger survivors reported greater fear of recurrence and less favorable body image. Younger survivors reported lower perceived social support from their partners and greater social constraint. Older survivors held higher spiritual beliefs and behaviors as compared to younger survivors. Perceived self efficacy for dealing with problems related to cancer survivorship was lower in younger survivors as compared to older survivors. For overall quality of life measures, younger survivors reported lower index of well being scores than older survivors and reported that breast cancer had a greater impact on their life. Health care service use was greater for younger as opposed to older survivors both during and after treatment. Conclusions: Younger survivors reported significantly more problems on several, physical, psychological, social and generic quality of life issues as compared to older survivors. Results indicate a need to proactively assess quality of life issues in younger women at time of diagnosis.