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PURPOSE Many targeted therapies are currently available only via clinical trials. Therefore, routine precision oncology using biomarker-based assignment to drug depends on matching patients to clinical trials. A comprehensive and up-to-date trial database is necessary for optimal patient-trial matching. METHODS We describe processes for establishing and maintaining a clinical trial database, focusing on genomically informed trials. Furthermore, we present OCTANE (Oncology Clinical Trial Annotation Engine), an informatics framework supporting these processes in a scalable fashion. To illustrate how the framework can be applied at an institution, we describe how we implemented an instance of OCTANE at a large cancer center. OCTANE consists of three modules. The data aggregation module automates retrieval, aggregation, and update of trial information. The annotation module establishes the database schema, implements data integration necessary for automation, and provides an annotation interface. The update module monitors trial change logs, identifies critical change events, and alerts the annotators when manual intervention may be needed. RESULTS Using OCTANE, we annotated 5,439 oncology clinical trials (4,438 genomically informed trials) that collectively were associated with 1,453 drugs, 779 genes, and 252 cancer types. To date, we have used the database to screen 4,220 patients for trial eligibility. We compared the update module with expert review, and the module achieved 98.5% accuracy, 0% false-negative rate, and 2.3% false-positive rate. CONCLUSION OCTANE is a general informatics framework that can be helpful for establishing and maintaining a comprehensive database necessary for automating patient-trial matching, which facilitates the successful delivery of personalized cancer care on a routine basis. Several OCTANE components are publically available and may be useful to other precision oncology programs.

BACKGROUND Genomic testing is increasingly performed in oncology, but concerns remain regarding the clinician's ability to interpret results. In the current study, the authors sought to determine the agreement between physicians and genomic annotators from the Precision Oncology Decision Support (PODS) team at The University of Texas MD Anderson Cancer Center in Houston regarding actionability and the clinical use of test results. METHODS On a prospective protocol, patients underwent clinical genomic testing for hotspot mutations in 46 or 50 genes. Six months after sequencing, physicians received questionnaires for patients who demonstrated a variant in an actionable gene, investigating their perceptions regarding the actionability of alterations and clinical use of these findings. Genomic annotators independently classified these variants as actionable, potentially actionable, unknown, or not actionable. RESULTS Physicians completed 250 of 288 questionnaires (87% response rate). Physicians considered 168 of 250 patients (67%) as having an actionable alteration; of these, 165 patients (98%) were considered to have an actionable alteration by the PODS team and 3 were of unknown significance. Physicians were aware of genotype-matched therapy available for 119 patients (71%) and 48 of these 119 patients (40%) received matched therapy. Approximately 46% of patients in whom physicians regarded alterations as not actionable (36 of 79 patients) were classified as having an actionable/potentially actionable mutation by the PODS team. However, many of these were only theoretically actionable due to limited trials and/or therapies (eg, KRAS). CONCLUSIONS Physicians are aware of recurrent mutations in actionable genes on “hotspot” panels. As larger genomic panels are used, there may be a growing need for annotation of actionability. Decision support to increase awareness of genomically relevant trials and novel treatment options for recurrent mutations (eg, KRAS) also are needed. Cancer 2017. © 2017 American Cancer Society.

High-throughput genomic and molecular profiling of tumors is emerging as an important clinical approach. Molecular profiling is increasingly being used to guide cancer patient care, especially in advanced and incurable cancers. However, navigating the scientific literature to make evidence-based clinical decisions based on molecular profiling results is overwhelming for many oncology clinicians and researchers. The Personalized Cancer Therapy website (www.personalizedcancertherapy.org) was created to provide an online resource for clinicians and researchers to facilitate navigation of available data. Specifically, this resource can be used to help identify potential therapy options for patients harboring oncogenic genomic alterations. Herein, we describe how content on www.personalizedcancertherapy.org is generated and maintained. We end with case scenarios to illustrate the clinical utility of the website. The goal of this publicly available resource is to provide easily accessible information to a broad oncology audience, as this may help ease the information retrieval burden facing participants in the precision oncology field. Cancer Res; 77(21); e123–6. ©2017 AACR.

The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date. Although the NTRK gene fusions are infrequent in most cancer types, certain rare tumor types are predominately driven by these events. Conversely, in more common histologies, such as lung and colorectal cancers, prevalence of the NTRK fusions is well below 5%. Selective inhibition of TRK signaling may therefore be beneficial among patients whose tumors vary in histologies, but share underlying oncogenic NTRK gene alterations. Currently, several TRK-targeting compounds are in clinical development. The ongoing Phase 2 trials with entrectinib and LOXO-101, two of the leading TRK inhibitors, are designed as 'basket trials', inclusive of patients whose tumors harbor NTRK gene fusions, independent of histology. Additional Phase 1 studies of other TRK inhibitors, including MGCD516, PLX7486, DS-6051b, and TSR-011, are underway. Interim data examining NTRK-rearranged tumors treated with entrectinib or LOXO-101 demonstrate encouraging activity, with patients achieving rapid and durable responses. Consequently, both drugs have achieved orphan designation from regulatory agencies, and efforts are underway to further expedite their development.

// Natalia Paez Arango 1 , Lauren Brusco 2 , Kenna R. Mills Shaw 2 , Ken Chen 3 , Agda Karina Eterovic 4 , Vijaykumar Holla 2 , Amber Johnson 2 , Beate Litzenburger 2 , Yekaterina B. Khotskaya 2 , Nora Sanchez 2 , Ann Bailey 2 , Xiaofeng Zheng 3 , Chacha Horombe 2 , Scott Kopetz 5 , Carol J. Farhangfar 6 , Mark Routbort 7 , Russell Broaddus 8 , Elmer V. Bernstam 9,10 , John Mendelsohn 2,11 , Gordon B. Mills 2,4 and Funda Meric-Bernstam 1,2,12 1 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC, USA 7 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 8 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 School of Biomedical Informatics, The University of Texas Health Science Center at Houston, TX, USA 10 Division of General Internal Medicine, Medical School, The University of Texas Health Science Center at Houston, TX, USA 11 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 12 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Funda Meric-Bernstam, email: // Keywords : precision medicine, genomics, somatic mutation, CLIA, clinical trial Received : November 09, 2016 Accepted : February 27, 2017 Published : March 08, 2017 Abstract Purpose: Molecular profiling performed in the research setting usually does not benefit the patients that donate their tissues. Through a prospective protocol, we sought to determine the feasibility and utility of performing broad genomic testing in the research laboratory for discovery, and the utility of giving treating physicians access to research data, with the option of validating actionable alterations in the CLIA environment. Experimental design: 1200 patients with advanced cancer underwent characterization of their tumors with high depth hybrid capture sequencing of 201 genes in the research setting. Tumors were also tested in the CLIA laboratory, with a standardized hotspot mutation analysis on an 11, 46 or 50 gene platform. Results: 527 patients (44%) had at least one likely somatic mutation detected in an actionable gene using hotspot testing. With the 201 gene panel, 945 patients (79%) had at least one alteration in a potentially actionable gene that was undetected with the more limited CLIA panel testing. Sixty-four genomic alterations identified on the research panel were subsequently tested using an orthogonal CLIA assay. Of 16 mutations tested in the CLIA environment, 12 (75%) were confirmed. Twenty-five (52%) of 48 copy number alterations were confirmed. Nine (26.5%) of 34 patients with confirmed results received genotype-matched therapy. Seven of these patients were enrolled onto genotype-matched targeted therapy trials. Conclusion: Expanded cancer gene sequencing identifies more actionable genomic alterations. The option of CLIA validating research results can provide alternative targets for personalized cancer therapy.

The tools of next-generation sequencing (NGS) technology, such as targeted sequencing of candidate cancer genes and whole-exome and -genome sequencing, coupled with encouraging clinical results based on the use of targeted therapeutics and biomarker-guided clinical trials, are fueling further technological advancements of NGS technology. However, NGS data interpretation is associated with challenges that must be overcome to promote the techniques' effective integration into clinical oncology practice. Specifically, sequencing of a patient's tumor often yields 30–65 somatic variants, but most of these variants are “passenger” mutations that are phenotypically neutral and thus not targetable. Therefore, NGS data must be interpreted by multidisciplinary decision-support teams to determine mutation actionability and identify potential “drivers,” so that the treating physician can prioritize what clinical decisions can be pursued in order to provide cancer therapy that is personalized to the patient and his or her unique genome.

Introduction Genomic profiling information is frequently available to oncologists, enabling targeted cancer therapy. Because clinically relevant information is rapidly emerging in the literature and elsewhere, there is a need for informatics technologies to support targeted therapies. To this end, we have developed a system for Automated Identification of Molecular Effects of Drugs, to help biomedical scientists curate this literature to facilitate decision support. Objectives To create an automated system to identify assertions in the literature concerning drugs targeting genes with therapeutic implications and characterize the challenges inherent in automating this process in rapidly evolving domains. Methods We used subject-predicate-object triples (semantic predications) and co-occurrence relations generated by applying the SemRep Natural Language Processing system to MEDLINE abstracts and ClinicalTrials.gov descriptions. We applied customized semantic queries to find drugs targeting genes of interest. The results were manually reviewed by a team of experts. Results Compared to a manually curated set of relationships, recall, precision, and F2 were 0.39, 0.21, and 0.33, respectively, which represents a 3- to 4-fold improvement over a publically available set of predications (SemMedDB) alone. Upon review of ostensibly false positive results, 26% were considered relevant additions to the reference set, and an additional 61% were considered to be relevant for review. Adding co-occurrence data improved results for drugs in early development, but not their better-established counterparts. Conclusions Precision medicine poses unique challenges for biomedical informatics systems that help domain experts find answers to their research questions. Further research is required to improve the performance of such systems, particularly for drugs in development.

Metastatic dissemination is a multi-step process that depends on cancer cells' ability to respond to microenvironmental cues by adapting adhesion abilities and undergoing cytoskeletal rearrangement. Breast Cancer Metastasis Suppressor 1 (BRMS1) affects several steps of the metastatic cascade: it decreases survival in circulation, increases susceptibility to anoikis, and reduces capacity to colonize secondary organs. In this report, BRMS1 expression is shown to not significantly alter expression levels of integrin monomers, while time-lapse and confocal microscopy revealed that BRMS1-expressing cells exhibited reduced activation of both β1 integrin and focal adhesion kinase, and decreased localization of these molecules to sites of focal adhesions. Short-term plating of BRMS1-expressing cells onto collagen or fibronectin markedly decreased cytoskeletal reorganization and formation of cellular adhesion projections. Under 3D culture conditions, BRMS1-expressing cells remained rounded and failed to reorganize their cytoskeleton and form invasive colonies. Taken together, BRMS1-expressing breast cancer cells are greatly attenuated in their ability to respond to microenvironment changes. © 2013 Wiley Periodicals, Inc.

619 Background: The benefits of matching targeted treatments to aberrations identified by molecular profiling (MP) is unclear. Outcomes in phase 1 settings have been traditionally reported across tumor histologies. We report outcomes based on a metastatic colorectal cancer (mCRC) population. Methods: Patients (pts) with mCRC receiving at least one dose of treatment on a phase 1 study were annotated for variants detected by MP. A precision oncology decision support (PODS) team determined variant function and actionability. A matched therapy (MT) was defined as allocation to a novel agent that targeted the aberration or predicted pathway deemed actionable by PODS. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to estimate hazard ratios (HR). Results: A total of 370 patients enrolled onto 467 phase 1 trials were identified from January 2012 to April 2017. 106 enrolments were assigned to MT. Pts with microsatellite instability-high (MSI-H), BRAFV600E, PIK3CA mutation were more likely to be assigned a MT, while left-sided tumors and RAS mutant patients were less likely to be treated with a MT. Molecularly-targeted regimens (MTR) were utilized more frequently in MT while immune-targeting MTR was more common in non-MT. BRAFV600E mutations and HER2 amplification/overexpression made up 44.3% of MT. There was a significant difference in PFS between the MT vs non-MT group (HR 0.65, 95% CI 0.51-0.83, p = 0.016) in univariate analysis. The 6-month PFS probability was 31% (95% CI; 23-41%) versus 13% (95% CI; 10-17%) respectively. Other significant factors in univariate analysis associated with longer PFS were MSI-H, BRAFV600E and use of a regimen containing cytotoxic chemotherapy while RAS mutations were associated with shorter PFS. In multivariate analysis, after correcting for mutation status, allocation to a MT was associated with improved PFS (HR = 0.72, 95% CI 0.50-0.99, p = 0.043). Conclusions: Matching clinical trial enrollment to MP based on dedicated decision support is associated with improved outcomes in mCRC patients. The MT strategy is still hampered by a limited number of actionable variants, and is driven by a small number of active MTs.

11605Background: Precision oncology is hindered by the lack of decision support for determining whether patients’ genomic alterations are actionable. To bridge this knowledge gap, we established a ...

Human breast cancer cells with restored BRMS1 expression exhibit few in vitro changes when compared to control cells, but demonstrate a very strong suppression of metastasis in in vivo animal models of breast cancer and several other solid tumor types. We have previously shown that in tissue samples collected from breast cancer patients, there exists an inverse correlation between expression of BRMS1 and HER2, an important druggable target in breast cancer. HER2 expression and function are particularly important in the context of inflammatory breast cancer, where up to 60% of all tumors are HER2+, but usually negative for hormone receptors ER and PR. Patients with inflammatory breast cancer have few treatment options and have one of the highest metastatic relapse rate and lowest survival among all breast cancer patients. We identified KPL4 inflammatory breast cancer cell line as a good candidate for re-expression of BRMS1, since there is HER2 amplification and cells were described in the literature as spontaneously metastatic. In subsequent studies, we identified several novel BRMS1- interacting partners, such as AMPK, a major kinase regulating cellular metabolism, and Filamin B, a cytoplasmic protein that participates in cellular adhesion and motility. We also determined that BRMS1 can be phosphorylated on a single Serine residue and that this phosphorylation sites lies within an AMPK consensus sequence. We eventually confirmed that AMPK is the kinase that phosphorylates BRMS1 on S237, and mutating that residue to a non-phosphorylatable amino acid abrogates BRMS1 biological functions. Finally, we determined that BRMS1-expressing cells exhibit a decreased level of phosphorylated STAT3, leading to modulation in expression of pro-apoptotic genes. However, based on new data, we identified a noncononical mechanism responsible for decreased STAT3 phosphorylation.

Proteoglycans are ubiquitous molecules composed of glycosamino-glycan chains attached covalently to core proteins. Proteoglycans perform a myriad of functions and participate in regulating tumor cell growth, survival, adhesion, metastasis and angiogenesis. These functions are largely mediated through inter-actions between their charged glycosaminoglycan chains and effector proteins such as growth factors, cytokines and chemokines. In addition, emerging data is revealing that the core proteins of proteoglycans can also form complexes with other proteins such as integrins and regulate their signaling. Because proteoglycans are at the crossroads of many signaling events, they are currently being extensively investigated for their potential as therapeutic targets for cancer. This review focuses on the expression, structure and function of proteoglycans in cancer and provides an overview of the field as well as specific examples of how these diverse molecules regulate tumor behavior.

Myeloma tumors are characterized by high expression of syndecan-1 (CD138), a heparan sulfate proteoglycan present on the myeloma cell surface and shed into the tumor microenvironment. High levels of shed syndecan-1 in the serum of patients are an indicator of poor prognosis, and numerous studies have implicated syndecan-1 in promoting the growth and progression of this cancer. In the present study we directly addressed the role of syndecan-1 in myeloma by stable knockdown of its expression using RNA interference. Knockdown cells that were negative for syndecan-1 expression became apoptotic and failed to grow in vitro. Knockdown cells expressing syndecan-1 at approximately 28% or approximately 14% of normal levels survived and grew well in vitro but formed fewer and much smaller subcutaneous tumors in mice compared with tumors formed by cells expressing normal levels of syndecan-1. When injected intravenously into mice (experimental metastasis model), knockdown cells formed very few metastases as compared with controls. This indicates that syndecan-1 may be required for the establishment of multi-focal metastasis, a hallmark of this cancer. One mechanism of syndecan-1 action occurs via stimulation of tumor angiogenesis because tumors formed by knockdown cells exhibited diminished levels of vascular endothelial growth factor and impaired development of blood vessels. Together, these data indicate that the effects of syndecan-1 on myeloma survival, growth, and dissemination are due, at least in part, to its positive regulation of tumor-host interactions that generate an environment capable of sustaining robust tumor growth.

Introduction: Breast cancer is the second-leading cause of oncology-related death in US women. Despite extensive research, over 30% of breast cancer patients develop metastatic disease, and metastases account for majority of breast cancer-associated morbidity and mortality. Of all invasive breast cancers, patients with tumors lacking expression of the Estrogen and Progesterone hormone Receptors and Human Epidermal growth factor Receptor 2 have the poorest clinical prognosis. These triple-negative tumors (TNBC) represent an aggressive form of the disease that is marked by an early-onset metastasis, a high tumor recurrence rate, and a low overall survival during the first three years post-diagnosis. However, few TNBC mouse models of metastasis currently exist. Results: We noticed that a well-established MDA-MB-231 TNBC cell line produces rapid and extremely lytic bone lesions in lumbar, sacral and caudal vertebrae, and hind limbs in about 10% of animals injected intravenously. We biopsied one of these bone metastases and established a new metastatic MDA-MB-231-1566 cell line. Following an intravenous injection, MDA-MB-231-1566 cells produce early-onset metastasis to bone in up to 70% of animals with concurrent metastases to lungs, liver, and soft tissues. We demonstrate that 100% of animals injected with MDA-MB-231-1566 cells developed metastasis and had median survival of 60 days vs. 80 days in mice injected with the parental cell line. We also demonstrate that ribosomal protein S6 is highly phosphorylated on Ser235/236 in metastatic TNBC tumors, and that this phosphorylation is indicative of upstream S6 kinase (S6K) activity. Lastly, we provide evidence that targeting S6K with a highly specific inhibitor, PF-4708671, at sub-lethal doses inhibits cell migration without inducing cell death, and thus may provide a potent anti-metastatic adjuvant therapy approach. Conclusion: We established a new model of rapid TNBC metastases to multiple organs following a simple intravenous injection. We believe this model provides a valuable tool for screening new therapeutics aimed to stop growth of metastases. Citation Format: Yekaterina B. Khotskaya, Aarthi Goverdhan, Jia Shen, Mariano Ponz Sarvice, Shih-Shin Chang, Ming-Chuan Hsu, Yongkun Wei, Weiya Xia, Patricia Steeg, Dihua Yu, Mien-Chie Hung. S6K1 promotes invasiveness of breast cancer cells in a novel model of triple-negative breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A49.

American women carry a lifetime risk of 1:8 of developing breast cancer, with metastatic disease remaining incurable. Between 70-80% of breast cancer patients diagnosed with metastases will exhibit lesions in their skeleton and in 25% of patients bone is the first site of metastasis. Breast cancer bone metastases are most frequently osteolytic. Thus, patients exhibiting bone lesions might suffer from nerve compression, bone fractures, hypercalcemia, pain, or paralysis. Existing treatment strategies for patients with bone metastases are palliative and designed to limit cancer-associated bone loss. It has been difficult to study breast cancer dissemination to bone due to lack of good animal models and little biopsy tissue availability. For human xenografts to establish bone lesions, human breast cancer cells are injected into the left ventricle of the heart, a procedure technically challenging and not 100% efficient. Resulting bone lesions are slow to develop and may be easy to miss on x-ray examination. Here, we show that a well-described parental MDA-MB-231 breast cancer cell line recapitulates progression of human disease when injected intravenously through the lateral tail vein into athymic nude mice. For reasons yet unclear, 30-50% of animals develop rapid and extremely lytic bone lesions in lumbar, sacral and caudal vertebrae and hind limbs. Similar to breast cancer patients, these animals exhibit pathologic fractures and paralysis, necessitating euthanasia within 4 weeks after cell inoculation. Interestingly, animals not affected by bone metastases go on to develop overt lung metastases within 10-12 weeks after cell inoculation. Bioluminescence imaging studies indicated presence of luciferase-tagged MDA-MB-231 cells in lungs of all mice at 2 and 24 hours post-cell inoculation. Within three weeks post-injection, large lesions were detected in the lumbar to caudal vertebrae regions and hind limbs of mice injected with luciferase-tagged (6/15 mice) or parental MDA-MB-231 cells (7/13 mice). Bone osteolysis was confirmed by x-ray, and paralysis occurred as early as 3 weeks after cell injection. Cytogenetic “finger printing” preformed by the institutional core facility confirmed that cell lines used exhibit properties of MDA-MB-231 cells consistent with ATCC profile. Furthermore, molecular comparison of these cell lines with MDA-MB-231 cells obtained from other sources, including ATCC, revealed no differences. Unexpectedly, when examined in an orthotopic breast cancer model, MDA-MB-231 cells used in these studies produced rapidly growing tumors that spontaneously metastasized to lymph nodes and lungs, while MDA-MB-231 cells purchased from ATCC were completely non-tumorigenic. Studies are underway to determine a molecular mechanism responsible for this aggressive metastatic phenotype. This model may serve as a valuable tool for screening new therapeutics aimed to stop growth of metastases at multiple sites. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3290. doi:1538-7445.AM2012-3290

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Metastatic dissemination of cancer cells from primary tumor to secondary sites is a multi-step process that depends heavily on the ability of cancer cells to respond to the microenvironmental cues, such as changes in composition of surrounding extracellular matrix (ECM), by adapting their adhesion abilities and undergoing cytoskeletal rearrangement. Many of these interactions between cancer cells and ECM are mediated by signaling cascades initiated at the cell surface through activation of integrins and growth factor receptors. BRMS1, or Breast cancer Metastasis Suppressor 1, belongs to a family of metastasis suppressor genes and has been shown to affect several steps of the metastatic cascade. BRMS1-expressing cells shed by the primary tumor can enter the circulation and reach secondary sites, where they remain largely as single cells. Moreover, ectopic expression of BRMS1 results in a significant decrease in survival of tumor cells within blood stream, increased susceptibility to anoikis and inability to form colonies at secondary organ sites, all events that could be attributed to failure of BRMS1 expressing cells to activate integrins and strongly adhere to ECM components. Here, we show that BRMS1 expression in MDA-MB-231 and MDA-MB-435 cells did not significantly alter expression levels of the integrin monomers tested. However, after short-term (15-30 minutes) plating of cells onto mixed ECM or individual ECM components (collagen I, collagen IV, or fibronectin) under 2D conditions, BRMS1-expressing cells exhibited reduced activation of β1 integrin, focal adhesion kinase (FAK), and scaffolding protein Talin1, as well as a decrease in their localization to focal adhesions. Furthermore, short-term plating of BRMS1-expressing cells on collagens I or IV or fibronectin resulted in marked inhibition of cytoskeletal rearrangement and failure to form cellular adhesion projections, as compared to cells vector-transfected cells. In addition, under 3D conditions, BRMS1-expressing cells remained rounded and failed to reorganize their cytoskeleton even after 24-hour stimulation with serum. Taken together, we believe that these findings demonstrate that BRMS1-expressing breast cancer cells are inherently unable to respond to microenvironment changes, which may explain why they exhibit reduced survival in circulation, increased susceptibility to anoikis, and decreased colonization of secondary sites. YBK was supported in part by NIH T32 ([AR047512][1]-09) and DOD CDMRP BCRP Postdoctoral Fellowship ([BC096855][2]) 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 1438. doi:10.1158/1538-7445.AM2011-1438 [1]: /lookup/external-ref?link_type=GEN&access_num=AR047512&atom=%2Fcanres%2F71%2F8_Supplement%2F1438.atom [2]: /lookup/external-ref?link_type=GEN&access_num=BC096855&atom=%2Fcanres%2F71%2F8_Supplement%2F1438.atom