Alterations In Breast Cancer Patients Research Articles

119 (PB-119) Poster - Depression, anxiety and psychological alterations in breast cancer patients under neoadjuvant therapy: A systematic review

119 (PB-119) Poster - Depression, anxiety and psychological alterations in breast cancer patients under neoadjuvant therapy: A systematic review

Resting state functional connectome in breast cancer patients with fear of cancer recurrence.

This study aimed to investigate network-level brain functional changes in breast cancer patients and their relationship with fear of cancer recurrence (FCR). Resting-state functional MRI was collected from 43 patients with breast cancer and 40 healthy controls (HCs). Graph theory analyses, whole-brain voxel-wise functional connectivity strength (FCS) analyses and seed-based functional connectivity (FC) analyses were performed to identify connection alterations in breast cancer patients. Correlations between brain functional connections (i.e. FCS and FC) and FCR level were assessed to further reveal the neural mechanisms of FCR in breast cancer patients. Graph theory analyses indicated a decreased clustering coefficient in breast cancer patients compared to HCs (P = 0.04). Patients with breast cancer exhibited significantly higher FCS in both higher-order function networks (frontoparietal, default mode, and dorsal attention systems) and primary somatomotor networks. Among the hyperconnected regions in breast cancer, the left inferior frontal operculum demonstrated a significant positive correlation with FCR. Our findings suggest that breast cancer patients exhibit less segregation of brain function, and the left inferior frontal operculum is a key region associated with FCR. This study offers insights into the neural mechanisms of FCR in breast cancer patients at the level of brain connectome.

Longitudinal assessment of chemotherapy-induced brain connectivity changes in cerebral white matter and its correlation with cognitive functioning using the GQI.

Breast cancer was the most prevalent type of cancer and had the highest incidence rate among women worldwide. The wide use of adjuvant chemotherapy might have a detrimental effect on the human brain and result in chemotherapy-related cognitive impairment (CICI) among breast cancer patients. Furthermore, prior to chemotherapy, patients reported cancer-related cognitive impairment (CRCI), which might be due to physiological factors or mood symptoms. The present longitudinal study aimed to investigate microstructural and macroscale white matter alterations by generalized q-sampling imaging (GQI). The participants were categorized into a pre-chemotherapy group (BB) if they were diagnosed with primary breast cancer and an age-matched noncancer control group (HC). Some participants returned for follow-up assessment. In the present follow up study, 28 matched pairs of BB/BBF (follow up after chemotherapy) individuals and 28 matched pairs of HC/HCF (follow up) individuals were included. We then used GQI and graph theoretical analysis (GTA) to detect microstructural alterations in the whole brain. In addition, we evaluated the relationship between longitudinal changes in GQI indices and neuropsychological tests as well as psychiatric comorbidity. The results showed that disruption of white matter integrity occurred in the default mode network (DMN) of patients after chemotherapy, such as in the corpus callosum (CC) and middle frontal gyrus (MFG). Furthermore, weaker connections between brain regions and lower segregation ability were observed in the post-chemotherapy group. Significant correlations were observed between neuropsychological tests and white matter tracts of the CC, MFG, posterior limb of the internal capsule (PLIC) and superior longitudinal fasciculus (SLF). The results provided evidence of white matter alterations in breast cancer patients, and they may serve as potential imaging markers of cognitive changes. In the future, the study may be beneficial to create and evaluate strategies designed to maintain or improve cognitive function in breast cancer patients undergoing chemotherapy.

A single chemotherapy administration induces muscle atrophy, mitochondrial alterations and apoptosis in breast cancer patients.

Breast cancer patients are commonly treated with sequential administrations of epirubicin-cyclophosphamide (EC) and paclitaxel (TAX). The chronic effect of this treatment induces skeletal muscle alterations, but the specific effect of each chemotherapy agent is unknown. This study aimed to investigate the effect of EC or TAX administration on skeletal muscle homeostasis in breast cancer patients. Twenty early breast cancer patients undergoing EC followed by TAX chemotherapies were included. Two groups of 10 women were established and performed vastus lateralis skeletal muscle biopsies either before the first administration (pre) of EC (50±14years) or TAX (50±16years) and 4days later (post). Mitochondrial respiratory capacity recording, reactive oxygen species production, western blotting and histological analyses were performed. Decrease in muscle fibres cross-sectional area was only observed post-EC (-25%; P<0.001), associated with a reduction in mitochondrial respiratory capacity for the complex I (CI)-linked substrate state (-32%; P=0.001), oxidative phosphorylation (OXPHOS) by CI (-35%; P=0.002), CI&CII (-26%; P=0.022) and CII (-24%; P=0.027). If H2 O2 production was unchanged post-EC, an increase was observed post-TAX for OXPHOS by CII (+25%; P=0.022). We found a decrease in makers of mitochondrial content, as shown post-EC by a decrease in the protein levels of citrate synthase (-53%; P<0.001) and VDAC (-39%; P<0.001). Despite no changes in markers of mitochondrial fission, a decrease in the expression of a marker of mitochondrial inner-membrane fusion was found post-EC (OPA1; -60%; P<0.001). We explored markers of mitophagy and found reductions post-EC in the protein levels of PINK1 (-63%; P<0.001) and Parkin (-56%; P=0.005), without changes post-TAX. An increasing trend in Bax protein level was found post-EC (+96%; P=0.068) and post-TAX (+77%; P=0.073), while the Bcl-2 level was decreased only post-EC (-52%; P=0.007). If an increasing trend in TUNEL-positive signal was observed post-EC (+68%; P=0.082), upregulation was highlighted post-TAX (+86%; P<0.001), suggesting activation of the apoptosis process. We demonstrated that a single administration of EC induced, in only 4days, skeletal muscle atrophy and mitochondrial alterations in breast cancer patients. These alterations were characterized by reductions in mitochondrial function and content as well as impairment of mitochondrial dynamics and an increase in apoptosis. TAX administration did not worsen these alterations as this group had already received EC during the preceding weeks. However, it resulted in an increased apoptosis, likely in response to the increased H2 O2 production.

Exploring the role of sphingolipid-related genes in clinical outcomes of breast cancer.

Despite tremendous advances in cancer research, breast cancer (BC) remains a major health concern and is the most common cancer affecting women worldwide. Breast cancer is a highly heterogeneous cancer with potentially aggressive and complex biology, and precision treatment for specific subtypes may improve survival in breast cancer patients. Sphingolipids are important components of lipids that play a key role in the growth and death of tumor cells and are increasingly the subject of new anti-cancer therapies. Key enzymes and intermediates of sphingolipid metabolism (SM) play an important role in regulating tumor cells and further influencing clinical prognosis. We downloaded BC data from the TCGA database and GEO database, on which we performed in depth single-cell sequencing analysis (scRNA-seq), weighted co-expression network analysis, and transcriptome differential expression analysis. Then seven sphingolipid-related genes (SRGs) were identified using Cox regression, least absolute shrinkage, and selection operator (Lasso) regression analysis to construct a prognostic model for BC patients. Finally, the expression and function of the key gene PGK1 in the model were verified by in vitro experiments. This prognostic model allows for the classification of BC patients into high-risk and low-risk groups, with a statistically significant difference in survival time between the two groups. The model is also able to show high prediction accuracy in both internal and external validation sets. After further analysis of the immune microenvironment and immunotherapy, it was found that this risk grouping could be used as a guide for the immunotherapy of BC. The proliferation, migration, and invasive ability of MDA-MB-231 and MCF-7 cell lines were dramatically reduced after knocking down the key gene PGK1 in the model through cellular experiments. This study suggests that prognostic features based on genes related to SM are associated with clinical outcomes, tumor progression, and immune alterations in BC patients. Our findings may provide insights for the development of new strategies for early intervention and prognostic prediction in BC.

Molecular and Immunohistochemical Alterations in Breast Cancer Patients in Upper Egypt.

Breast cancer (BC) plays a major public health in Egyptian woman. In Upper Egypt, there is an increase in incidence of BC compared to other Egyptian areas. Triple-negative BC, estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-neu-negative, is a high-risk BC that lacks the benefit of specific therapy that targets these proteins. Accurate determination of Caveolin-1(Cav-1), Caveolin-2 (Cav-2) and HER-2/neu status have become of major clinical significance in BC by focusing about its role as a tumor marker for response to different therapies. The present study was performed on 73 female BC patients in the South Egypt Cancer Institute. Blood samples were used for Cav-1, Cav-2, and HER-2/neu genes amplification and expression. In addition, immunohistological analysis of mammaglobin, GATA3, ER, PR, and HER-2/neu was done. There was a statistically significant association between Cav-1, 2 and HER-2/neu genes expression and the age of patients (P< 0.001). There are increase in the level of Cav-1, 2 and increase in HER-2/neu mRNA expression in groups treated with chemotherapy and group treated with both chemotherapy and radiotherapy compared to each group baseline level of genes mRNA expression before treatment. On the contrary, the group treated with chemotherapy, radiotherapy and hormonal therapy revealed increase on the level of Cav-1, 2 and HER-2/neu mRNA expression when compared with their baseline for the same patients before treatment. Noninvasive molecular biomarkers such as Cav-1 and Cav-2 have been proposed for use in the diagnosis and prognosis for women with BC.

Machine learning on MRI radiomic features: identification of molecular subtype alteration in breast cancer after neoadjuvant therapy.

Recent studies have revealed the change of molecular subtypes in breast cancer (BC) after neoadjuvant therapy (NAT). This study aims to construct a non-invasive model for predicting molecular subtype alteration in breast cancer after NAT. Eighty-two estrogen receptor (ER)-negative/ human epidermal growth factor receptor 2 (HER2)-negative or ER-low-positive/HER2-negative breast cancer patients who underwent NAT and completed baseline MRI were retrospectively recruited between July 2010 and November 2020. Subtype alteration was observed in 21 cases after NAT. A 2D-DenseUNet machine-learning model was built to perform automatic segmentation of breast cancer. 851 radiomic features were extracted from each MRI sequence (T2-weighted imaging, ADC, DCE, and contrast-enhanced T1-weighted imaging), both in the manual and auto-segmentation masks. All samples were divided into a training set (n = 66) and a test set (n = 16). XGBoost model with 5-fold cross-validation was performed to predict molecular subtype alterations in breast cancer patients after NAT. The predictive ability of these models was subsequently evaluated by the AUC of the ROC curve, sensitivity, and specificity. A model consisting of three radiomics features from the manual segmentation of multi-sequence MRI achieved favorable predictive efficacy in identifying molecular subtype alteration in BC after NAT (cross-validation set: AUC = 0.908, independent test set: AUC = 0.864); whereas an automatic segmentation approach of BC lesions on the DCE sequence produced good segmentation results (Dice similarity coefficient = 0.720). A machine learning model based on baseline MRI is proven useful for predicting molecular subtype alterations in breast cancer after NAT. • Machine learning models using MRI-based radiomics signature have the ability to predict molecular subtype alterations in breast cancer after neoadjuvant therapy, which subsequently affect treatment protocols. • The application of deep learning in the automatic segmentation of breast cancer lesions from MRI images shows the potential to replace manual segmentation..

R-spondin-3 is an oncogenic driver of poorly differentiated invasive breast cancer.

R-spondins (RSPOs) are influential signaling molecules that promote the Wnt/β-catenin pathway and self-renewal of stem cells. Currently, RSPOs are emerging as clinically relevant oncogenes, being linked to cancer development in multiple organs. Although this has instigated the rapid development and testing of therapeutic antibodies targeting RSPOs, functional evidence that RSPO causally drives cancer has focused primarily on the intestinal tract. Here, we assess the oncogenic capacity of RSPO in breast cancer in a direct fashion by generating and characterizing a novel mouse model with conditional Rspo3 expression in the mammary gland. We also address the prevalence of RSPO gene alterations in breast cancer patients. We found that a quarter of breast cancer patients harbor RSPO2/RSPO3 copy number amplifications, which are associated with lack of steroid hormone receptor expression and reduced patient survival. Foremost, we demonstrate the causal oncogenic capacity of RSPO3 in the breast, as conditional Rspo3 overexpression consistently drives the development of mammary adenocarcinomas in our novel Rspo3 breast cancer model. RSPO3-driven mammary tumors typically show poor differentiation, areas of epithelial-to-mesenchymal transition, and metastatic potential. Given the reported interplay in the Wnt/β-catenin pathway, we comparatively analyzed RSPO3-driven mouse mammary tumors versus classical WNT1-driven analogues. This revealed that RSPO3-driven tumors are distinct, as the poorly differentiated tumor morphology and metastatic potential were observed in RSPO3-driven tumorigenesis exclusively, further substantiated by differentiating gene expression profiles. Co-expression of Rspo3 and Wnt1 transduced mammary tumors with a mixed phenotype harboring morphological features characteristic of both transgenes. In summary, we report that a quarter of breast cancer patients harbor RSPO2/RSPO3 copy number gains, and these patients have a worse prognosis, whilst providing in vivo evidence that RSPO3 drives poorly differentiated invasive breast cancer in mice. Herewith, we establish RSPO3 as a driver of breast cancer with clinical relevance, proposing RSPO3 as a novel candidate target for therapy in breast cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Effects of a self-monitoring intervention in breast cancer patients suffering from taste alterations induced by chemotherapy: A randomized, parallel-group controlled trial.

This study evaluates the effect of a self-monitoring intervention on taste alterations in breast cancer patients undergoing outpatient chemotherapy. The study was a randomized controlled trial. Thirty-four participants were divided into two groups: a self-monitoring (SMG) group (n=17) and a control group (CG) (n=17). A conceptual framework was developed with reference to the components of self-management, cognitive behavioral therapy, and the concepts of self-monitoring. Interventions were based on this framework. SMGs recorded their taste symptoms as homework and worked with the researcher to set goals and provide feedback four times every three weeks. In the feedback, the researcher actively listened to the SMG about their feelings and coping strategies during the taste changes, and gave approval and praise for these. The implementation period was 9 weeks for each participant; the CG was provided with conventional nursing support. The intervention was evaluated by comparing the items of symptom improvement, quality of life (QOL), and self-efficacy between the groups before and after the start of the intervention using a scale score. Scale scores were also compared for recognition of taste changes, concerns during treatment, distress, and impacts on each treatment day. SMG had significantly lower scores than CG for perceived change in taste (p=0.009), and there was an interaction with CG (p=0.008). SMG had also significantly lower scores than CG in concern during treatment (p=0.015). This study showed that a self-monitoring intervention reduced negative cognition of taste alterations and reduced discomfort. The results suggest that the self-monitoring intervention is effective nursing support for chemotherapy-induced taste alterations.

Investigation of chemotherapy-induced brain structural alterations in breast cancer patients with generalized q-sampling MRI and graph theoretical analysis

BackgroundBreast neoplasms are the most common cancer among women in Taiwan. Cognitive deficits are common complications of breast cancer survivors treated with chemotherapy. The most frequently observed disorders involve executive function and memory impairment. With improvements in tumor intervention and the consequent increase in the number of cancer survivors, the quality of life of patients has become an important issue. We are interested in the early effects of chemotherapy on the brain structures of patients. In addition, generalized q-sampling imaging (GQI), a wide range of q-space datasets for a more accurate and sophisticated diffusion MR approach, was first used in this topic.MethodsAs diffusion tensor imaging (DTI) is associated with restrictions in the resolution of crossing fibers, we attempted to use GQI, which can overcome these difficulties and is advantageous over DTI for tractography of the crossing fibers. This cross-sectional study included two groups: breast cancer survivors who had completed their chemotherapy (n = 19) and healthy controls (n = 20). All participants underwent diffusion MRI exams and neuropsychological assessments. We included four parts in our image analysis, i.e., voxel-based statistical analysis, multiple regression analysis, graph theoretical analysis and network-based statistical analysis.ResultsThe results from the voxel-based statistical analysis showed significantly lower GFA and NQA values in the breast cancer group than those in the control group. We found significant positive correlations between the FACT-Cog and GQI indices. In the graph theoretical analysis, the breast cancer group demonstrated significantly longer characteristic path length. Adjuvant chemotherapy affected the integrity of white matter and resulted in poor cognitive performance, as indicated by the correlations between the neuropsychological assessment scales and the GQI indices. In addition, it was found that the characteristic path lengths in the breast cancer group increased, indicating that the brain network integration became worse.ConclusionsOur study demonstrated alterations in structural brain networks and associated neuropsychological deficits among breast cancer survivors.

Everolimus induced mood changes in breast cancer patients: a case-control study.

Introduction The PI3K/Akt/mTOR pathway plays a critical role in cancer cell growth, proliferation and angiogenesis, but also in brain homeostasis and the pathophysiology of mood disorders. The impact of the mTOR inhibitor everolimus on the mood of breast cancer patients is unknown. Materials and methods Consecutive, post-menopausal metastatic breast cancer patients receiving hormone therapy +/- everolimus were prospectively followed-up using the Beck Depression Inventory (BDI) and the MADRS (Montgomery and Asberg Depression Rating Scale) questionnaires. Results Post hoc tests comparing everolimus + hormonotherapy to hormonotherapy alone demonstrated a significant effect of everolimus after 6weeks of treatment on BDI scores (t(1,38) = -2.0716, p < 0.05), and after 3weeks (t(1,38) = -3.9165, p < 0.001) and 6weeks of treatment (t(1,38) = -2.0373, p < 0.05) on MADRS scores. Analysis within each treatment group showed that the effect of time since treatment initiation on BDI and MADRS scores was specifically observed in the everolimus + hormonotherapy group (F(2,34) = 11.875, p < 0.001 and F(2,34) = 7.820, p < 0.01 respectively), but not in the hormonotherapy alone group (F(2,34) = 1.671, p > 0.2 and F(2,34) = 0.830, p > 0.2 respectively). Conclusions The mTOR inhibitor everolimus induces significant mood alterations in breast cancer patients. The evaluation of psychiatric symptoms is not only mandatory in the context of phase 1, dose-finding studies of PI3K/Akt/mTOR inhibitors, but is also clinically relevant in daily practice.

Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases.

Purpose: Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies, or both. We sought to define the repertoire of genetic alterations in breast cancer patients with de novo metastatic disease who had not received local or systemic therapy.Experimental Design: Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods.Results: Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%-95%) of shared somatic mutations. Although mutations in known driver genes including TP53, PIK3CA, and GATA3 were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intratumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including SMAD4, TCF7L2, and TCF4 (ITF2), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases.Conclusions: Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intratumor genetic heterogeneity. Clin Cancer Res; 23(15); 4402-15. ©2017 AACR.

Serum metabolism during breast cancer treatment.

e23043 Serum metabolism during breast cancer treatment Background: Breast cancer treatment may include surgery, systemic therapy and radiation, often involving side-effects. Many patients experience weight gain during treatment, which is associated with decreased survival rates1. The purpose of this study was to describe serum metabolic alterations in breast cancer patients undergoing treatment, and relate these alterations to weight gain during treatment. Methods: This pilot study includes 60 breast cancer patients, aged 35-75 years, with histologically verified stage I/II disease. All patients underwent tumor surgery, and were treated according to national guidelines. Samples were collected before and 6 months after surgery, and analyzed by MR spectroscopy (MRS) and mass spectrometry (MS). 170 metabolites and 105 lipoprotein subfractions were quantified by combined MRS and MS analyses. Results: Multilevel PLS-DA showed significant alterations in serum metabolite profiles post-treatment, both in patients receiving (n = 35) and not receiving (n = 25) chemotherapy (classification accuracy: 86.7% and 77.0%, resp., p &lt; 0.001). Lipoprotein profiles were also significantly altered in both groups (p &lt; 0.001). Chemotherapy recipients had decreased levels of citrate, ornithine, and methionine after treatment, while non-recipients had increased levels of glutamate, alanine, proline and two biogenic amines, and decreased levels of acylcarnitines. 17/52 patients (32.7%) gained weight (≥ 1.5 kg) during treatment. Weight gain was predicted from pre-treatment samples with accuracy 67.0% (p = 0.020). Weight gain patients had lower levels of three acylcarnitines and 20 phosphocholines, and higher levels of lysine and isoleucine, suggesting aberrant lipid and amino acid metabolism. Weight gain was also reflected in the post-treatment samples (accuracy 66.8%, p = 0.015), with weight gain patients having higher levels of five acylcarnitines, and lower levels of glycine, isoleucine and valine. Conclusions: This study indicates that treatment induces changes in serum metabolite levels. Patients gaining weight had significantly different metabolite profiles than those not gaining weight both before and after treatment. 1. Chan et al, Ann Oncol 25: 1901-14, 2014.

Abstract P6-07-06: Clinicopathologic characterization and comprehensive genomic profiling (CGP) of advanced breast cancer patients with fibroblast growth factor receptor (FGFR) alterations

Abstract BACKGROUND: FGFR family members are infrequently mutated but are frequently overexpressed in breast cancer and often accompanied by increased, or altered, expression of FGF ligands. In this retrospective study, we reviewed a large series of FGFR altered breast cancer cases that received comprehensive genomic profiling (CGP) in the course of clinical care. MATERIAL AND METHODS: CGP was performed on hybridization-captures, adaptor ligation-based libraries using DNA extracted from 40 μm formalin-fixed paraffin-embedded (FFPE) section cut at 10 μm performed in a CLIA-certified lab (Foundation Medicine, Inc.). The pathologic diagnosis of each case was confirmed on routine hematoxylin and eosin-stained slides, and all samples forwarded for DNA extraction contained a minimum of 20% of DNA derived from tumor cells. The FoundationOne test sequences the full coding regions of up to 315 cancer-related genes, and up to 28 genes that are frequently altered in cancer to detect all classes of genomic alterations including base substitutions, indels, copy-number alterations (CNA), and fusions/rearrangements. The average depth of coverage is greater than 600X. The genomic profiles of 2,617 patients with diverse advanced malignancies who were evaluated at Cancer Treatment Centers of America between 12/24/12 and 03/11/15 were reviewed. 176 FGFR alterations (7.8%) were detected, of which 76 (43.5%) were found in breast cancer cases out of 434 (16.5%). The study was carried out in accordance with WIRB Institutional Review Board. RESULTS: A total of 76 female breast cancer patients, having a median age 50 (range, 28-69), with FGFR alterations were reviewed. All patients had metastatic/relapsed advanced breast cancer. 54 patients were Estrogen Receptor-positive (70%), and 15 were HER2+ (20%). 6 patients had gBRCA deleterious mutations. 84% of the samples (n=67) tissue block were analyzed, and the anatomic sites represented by the samples were 24 breast primary tumor (31%), 15 liver (19%), 10 lymph nodes (13%), and other sites (37%). The median number of chemotherapies cycles was 4 (range, 1-12), and the median time to metastasis was 31 months (range, 0-175). At the time of this report, 31 patients (40%) were deceased. 79 FGFR gene alterations were identified in 76 patients, including FGFR1 (65), FGFR2 (6), FGFR3 (2), and FGFR4 (4), with all but 7 of these being amplifications. The most co-existent altered gene was TP53 (66%), and other altered genes included PIK3CA (37%), MYC (28%), FGF3/4/19 (17%), CCND1 (17%), and CCNE1 (16%). The subset of co-amplified FGF3/4/19 and FGFR amplified patients were all (7) ER+ except for 1 patient. CONCLUSIONS: FGFR genomic alterations in breast cancer patients are predominantly amplifications and are most commonly observed in ER+ patients. Further review of treatment history will be performed to evaluate the hypothesis that alterations of FGFR is a modifier of response to endocrine therapy, and co-amplified FGF3/4/19 and FGFR breast cancer cases may be a distinct clinic-pathologic entity. Any patients in this series initiated on anti-FGFR targeted therapy will also be reported. Citation Format: Alvarez RH, Thomas JW, Kramer K, Niu J, Ahn E, McKnight JE, Dhillon N, Pabbathi H, Johnson AT, Wang K, Ross JS, Miller VA, Stephens PJ, Daneker GW, Ali S, Markman M. Clinicopathologic characterization and comprehensive genomic profiling (CGP) of advanced breast cancer patients with fibroblast growth factor receptor (FGFR) alterations. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-07-06.

Neuroimaging, cancer, and cognition: state of the knowledge.

To review neuroimaging research concerning cancer- and cancer treatment-related changes in brain structure and function, clinical perspectives, and future directions. Peer-reviewed literature. Cancer and chemotherapy are associated with cerebral structural and functional alterations in breast cancer patients that may persist for years; many of these changes are correlated with cognitive complaints or performance. In other cancers there is some evidence that metabolism is altered by cancer, but more research is needed. Understanding the role of neuroimaging is important to identify the basis of cognitive changes associated with cancer and cancer treatment.

Genomic Alterations in Breast Cancer Patients in Betel Quid and Non Betel Quid Chewers

Betel Quid (BQ) chewing independently contributes to oral, hepatic and esophageal carcinomas. Strong association of breast cancer risk with BQ chewing in Northeast Indian population has been reported where this habit is prodigal. We investigated genomic alterations in breast cancer patients with and without BQ chewing exposure. Twenty six BQ chewers (BQC) and 17 non BQ chewer (NBQC) breast cancer patients from Northeast India were analyzed for genomic alterations and pathway networks using SNP array and IPA. BQC tumors showed significantly (P<0.01) higher total number of alterations, as compared with NBQC tumors, 48±17% versus 32±25 respectively. Incidence of gain in fragile sites in BQC tumors were significantly (P<0.001) higher as compared with NBQC tumors, 34 versus 23% respectively. Two chromosomal regions (7q33 and 21q22.13) were significantly (p<0.05) associated with BQC tumors while two regions (19p13.3–19p12 and 20q11.22) were significantly associated with NBQC tumors. GO terms oxidoreductase and aldo-keto reductase activity in BQC tumors in contrast to G-protein coupled receptor protein signaling pathway and cell surface receptor linked signal transduction in NBQC tumors were enriched in DAVID. One network “Drug Metabolism, Molecular Transport, Nucleic Acid Metabolism” including genes AKR1B1, AKR1B10, ETS2 etc in BQC and two networks “Molecular Transport, Nucleic Acid Metabolism, Small Molecule Biochemistry” and “Cellular Development, Embryonic Development, Organismal Development” including genes RPN2, EMR3, VAV1, NNAT and MUC16 etc were seen in NBQC. Common alterations (>30%) were seen in 27 regions. Three networks were significant in common regions with key roles of PTK2, RPN2, EMR3, VAV1, NNAT, MUC16, MYC and YWHAZ genes. These data show that breast cancer arising by environmental carcinogens exemplifies genetic alterations differing from those observed in the non exposed ones. A number of genetic changes are shared in both tumor groups considered as crucial in breast cancer progression.

Methylation profile of TP53 regulatory pathway and mtDNA alterations in breast cancer patients lacking TP53 mutations

The present study investigated promoter hypermethylation of TP53 regulatory pathways providing a potential link between epigenetic changes and mitochondrial DNA (mtDNA) alterations in breast cancer patients lacking a TP53 mutation. The possibility of using the cancer-specific alterations in serum samples as a blood-based test was also explored. Triple-matched samples (cancerous tissues, matched adjacent normal tissues and serum samples) from breast cancer patients were screened for TP53 mutations, and the promoter methylation profile of P14(ARF), MDM2, TP53 and PTEN genes was analyzed as well as mtDNA alterations, including D-loop mutations and mtDNA content. In the studied cohort, no mutation was found in TP53 (DNA-binding domain). Comparison of P14(ARF) and PTEN methylation patterns showed significant hypermethylation levels in tumor tissues (P < 0.05 and <0.01, respectively) whereas the TP53 tumor suppressor gene was not hypermethylated (P < 0.511). The proportion of PTEN methylation was significantly higher in serum than in the normal tissues and it has a significant correlation to tumor tissues (P < 0.05). mtDNA analysis revealed 36.36% somatic and 90.91% germline mutations in the D-loop region and also significant mtDNA depletion in tumor tissues (P < 0.01). In addition, the mtDNA content in matched serum was significantly lower than in the normal tissues (P < 0.05). These data can provide an insight into the management of a therapeutic approach based on the reversal of epigenetic silencing of the crucial genes involved in regulatory pathways of the tumor suppressor TP53. Additionally, release of significant aberrant methylated PTEN in matched serum samples might represent a promising biomarker for breast cancer.

Genomic alterations in breast cancer patients from Northeast India using 10K SNP arrays

Background North-east India has always been a ‘hotspot’ for population geneticists because of its unique, strategic geographic location and the presence of linguistically, culturally and demographically diverse populations practicing various tobacco habits. This region reports a high incidence of breast cancer in females with a history of extensive exposure to tobacco. Therefore, this population is constantly exposed to a high level of genotoxic stress. Accumulation of multiple and discrete genetic events during tobacco exposure can combine to drive breast cancer pathogenesis. Direct analysis of the tumor genome can reveal the genomic events accumulated during tumor progression. Hence, we investigated genomic alterations in breast cancer patients with tobacco exposure.

Overexpression of cyclin A overrides the effect of p53 alterations in breast cancer patients with long follow-up time.

The tumour suppressor gene p53 and its protein controls critical cellular functions in cell cycle regulation as well as in apoptosis. Recently, in an in vitro study on breast cancer cell line MCF-7, the apoptotic function of p53 has been shown to be altered by overexpression of cyclin A. In this study we have demonstrated a similar association in a consecutive series of 166 breast cancer patients operated for invasive breast carcinomas. We detected mutations (exon 5-8) in the tumour tissue from 28 (16.0%) of the patients, and positive immunoreactivity of p53 protein was detected in tumour tissue samples from 32 (18.8%) patients. A statistically significant correlation between TP53 gene mutations and positive immunohistochemistry of p53 protein was observed (p = 0.0038). Mutations of the TP53 gene, as well as positive immunoreactivity to p53, were associated with poor prognosis (mutations p = 0.053, HR = 1.8, 95% CI 0.99-3.4; positive immunoreactivity p = 0.029, HR 1.33, 95% CI 1.0-1.7; mutation and/or positive immunoreactivity p = 0.015, HR 2.1, 95% CI 1.2-3.7) when cyclin A was not included in the survival analysis. However, when cyclin A overexpression was included, alteration of the p53 protein (mutations and/or positive immunoreactivity) lost its statistical power (p = 0.088). In a stratified survival analysis the OR fell from 3.0 (95% CI 1.2-8.3, p = 0.03) in the low-expression cyclin A stratum to 1.3 (95% CI 0.42-4.1, p = 0.77) in the overexpression cyclin A stratum.