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breast cancer  breast  cancer  n     n   pbt  qol  rbp  resistance  systematic  tamoxifen resistance  tamoxifen  therapy   
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Preview: JNCI Journal of the National Cancer Institute - current issue

JNCI: Journal of the National Cancer Institute Current Issue





Published: Wed, 11 Oct 2017 00:00:00 GMT

Last Build Date: Wed, 11 Oct 2017 11:45:52 GMT

 



Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer

2017-10-11

Abstract
Background
Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)–positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer.
Methods
Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided.
Results
RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance–associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor–1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity–independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001).
Conclusions
RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.



Quality of Life and Patient-Reported Outcomes Following Proton Radiation Therapy: A Systematic Review

2017-10-09

Abstract
Background
As costs of cancer care rise, the importance of documenting value in oncology increases. Proton beam radiotherapy (PBT) has the potential to reduce toxicities in cancer patients, but is relatively expensive and unproven. Evaluating quality of life (QOL) and patient-reported outcomes (PROs) is essential to establishing PBT’s “value” in oncologic therapy. The goal of this systematic review was to assess QOL and PROs in patients treated with PBT.
Methods
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)–guided systematic searches were conducted. The PubMed search engine was the primary data source, along with publications found from references of selected articles, and articles known to the authors published through 2017. Seventeen original investigations were found to have sufficient focus and relevance to be incorporated into the systematic review.
Results
Studies of skull base (n = 1), brain (n = 1), head/neck (n = 1), lung (n = 1), breast (n = 2), prostate (n = 8), and pediatric (n = 3) malignancies treated with PBT that met eligibility criteria were included. QOL did not deteriorate during PBT for skull base and after PBT for brain tumors, respectively. PROs were higher for PBT than photon-based radiotherapy for both head/neck and lung cancer. Patient-reported breast cosmesis was appropriate after PBT and comparable to photon modalities. PBT in various settings of prostate cancer displayed an expected post-therapy decline; one study showed improved PROs (rectal urgency, bowel frequency) for PBT, and two others showed PROs/QOL comparable with other modalities. Pediatric studies demonstrated improvements in QOL during therapy, with additional increases thereafter.
Conclusions
Based on limited data, PBT provides favorable QOL/PRO profiles for select brain, head/neck, lung, and pediatric cancers; measures for prostate and breast cancers were more modest. These results have implications for cost-effective cancer care and prudently designed QOL evaluation in ongoing trials, which are discussed. Future data could substantially change the conclusions of this review.