A novel prognostic signature based on centrosome amplification-based genes to predict clinical outcomes in breast tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11604-11604
Author(s):  
Angela Ogden ◽  
Padmashree C.G. Rida ◽  
Ritu Aneja
Keyword(s):  
Breast Cancer ◽  
Clinical Outcomes ◽  
Chromosomal Instability ◽  
Prognostic Value ◽  
Breast Tumors ◽  
Centrosome Amplification ◽  
Age At Diagnosis ◽  
Breast Cancers ◽  
Cox Models ◽  
Tcga Dataset

11604 Background: A majority of breast tumors exhibit centrosome amplification (CA), which imparts aggressive phenotypes like chromosomal instability and invasive behavior. Nevertheless, it is unclear whether CA is associated with poor clinical outcomes after adjusting for potentially confounding factors, like stage and age at diagnosis. Methods: We developed a twenty-gene signature, “CA20,” composed of genes related to centrosome structure and/or whose dysregulation induces CA and tested its prognostic value compared with that of CIN25, a chromosomal instability (CIN) signature, in combined multivariable Cox models using the METABRIC and TCGA microarray breast datasets. The n = 1,969 primary breast cancers of the METABRIC dataset were split randomly and approximately equally into training and validation sets, unlike the n = 524 primary invasive breast cancers of the TCGA dataset, which could not be split to preserve power ≈ 0.80, so bootstrapping was instead used. CA20 and CIN25 were dichotomized by average scores and optimal cutpoints based on the log-rank test. Results: In both discovery and validation METRABRIC sets, CA20 was a significant independent predictor of worse breast cancer-specific survival (HR = 2.9, p < 0.001 and 2.4, p < 0.001, respectively, using average scores as cutpoints; similar results obtained using optimal cutpoints) in multivariable Cox models, unlike CIN25. CA20 score was highly correlated with CIN25 score (ρ = 0.93, p < 10-6). In the TCGA dataset, high CA20 score was associated with 3.8- and 3.7-fold worse overall survival (bootstrap-p = 0.001 and 0.002, respectively, for average and optimal cutpoints) after adjusting for tumor stage and age at diagnosis, unlike CIN25. Also in the TCGA dataset, CA20 correlated very strongly with CIN25 (ρ = 0.95, p < 10-6). Finally, using the TCGA dataset, we identified processes and pathways enriched in the CA20-high group (q < 0.05) that may be potential therapeutic targets, such as DNA repair processes, the DNA integrity checkpoint, and regulation of microtubule dynamics. Conclusions: CA20 is a novel signature with robust prognostic value in breast cancer and identifies patients who might respond to centrosome declustering drugs.

Predominance of RAD21 and ERBB2 amplification and progesterone receptor positivity in tumors of the right breast support breast cancer lateralization.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12557-e12557
Author(s):  
Zachary Spigelman ◽  
Jo-Ellen Murphy
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Cancer Patients ◽  
Breast Tumors ◽  
Left Breast ◽  
Breast Cancers ◽  
Her2 Expression ◽  
Breast Cancer Patients ◽  
The Right ◽  
Chi Square Analysis

e12557 Background: Biologic lateralization broadly impacts breast cancer. Malignancies originating in the left breast compared to the right breast tend to be more frequent, larger and of poorer prognosis. Left breast tumors respond differently to HER2-neu signaling and have lateralized Ki67 expression. In a prior study a right-left asymmetry in the neutrophil/lymphocyte ratio (NLR) of breast cancers was identified (ASCO 2018, e13094). As a follow-up, retrospective analysis of results from comprehensive genomic profiling (CGP) of right and left side breast cancer specimens was performed to determine a potential genomic etiology for the observed NLR lateralization. Methods: Tumors from 43 consecutive breast cancer patients underwent analysis for all classes of genomic alterations by hybrid capture-based CGP (Foundation Medicine). The CGP results from the 25 left- and 18 right-sided breast cancer samples were analyzed along with the histologic grade and status of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Results: In this cohort of advanced breast cancer patients (stage 3-4), no statistically significant differences in lateralization were identified based on patient age, tumor stage, or frequency of ER or Her2 expression (Table). A predominance of PR positivity (p=0.14 chi square analysis) and amplifications in the ERBB2 (p=0.37) and RAD21 (p=0.08) genes were detected in right side tumors. Conclusions: Together with the prior study, trends in asymmetry based on genomic, pathologic, and immunohistologic differences have been detected in breast cancers, including an increased incidence of ERBB2 and RAD21 amplification in right-side breast tumors in this cohort. The predominance of lower PR positivity in the left breast tumors may be due to preferential hypermethylation, consistent with reports that it mediates biologic lateralization changes, downregulates PR expression, and alters amplification rates. Epigenetic methylation, may contribute to asymmetric breast cancer biology and have implications for therapeutic strategy. Further study is warranted.[Table: see text]

scholarly journals Drug-Induced Resistance and Phenotypic Switch in Triple-Negative Breast Cancer Can Be Controlled via Resolution and Targeting of Individualized Signaling Signatures

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5009
Author(s):  
Swetha Vasudevan ◽  
Ibukun A. Adejumobi ◽  
Heba Alkhatib ◽  
Sangita Roy Chowdhury ◽  
Shira Stefansky ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Patient Specific ◽  
Network Structures ◽  
Breast Cancers ◽  
Drug Induced ◽  
Tcga Dataset

Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancers which is treated mainly with chemotherapy and radiotherapy. Epidermal growth factor receptor (EGFR) was considered to be frequently expressed in TNBC, and therefore was suggested as a therapeutic target. However, clinical trials of EGFR inhibitors have failed. In this study, we examine the relationship between the patient-specific TNBC network structures and possible mechanisms of resistance to anti-EGFR therapy. Using an information-theoretical analysis of 747 breast tumors from the TCGA dataset, we resolved individualized protein network structures, namely patient-specific signaling signatures (PaSSS) for each tumor. Each PaSSS was characterized by a set of 1–4 altered protein–protein subnetworks. Thirty-one percent of TNBC PaSSSs were found to harbor EGFR as a part of the network and were predicted to benefit from anti-EGFR therapy as long as it is combined with anti-estrogen receptor (ER) therapy. Using a series of single-cell experiments, followed by in vivo support, we show that drug combinations which are not tailored accurately to each PaSSS may generate evolutionary pressure in malignancies leading to an expansion of the previously undetected or untargeted subpopulations, such as ER+ populations. This corresponds to the PaSSS-based predictions suggesting to incorporate anti-ER drugs in certain anti-TNBC treatments. These findings highlight the need to tailor anti-TNBC targeted therapy to each PaSSS to prevent diverse evolutions of TNBC tumors and drug resistance development.

scholarly journals Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

2021 ◽  
Author(s):  
Samah El Ghamrasni ◽  
Rene Quevedo ◽  
James R Hawley ◽  
Parisa Mazrooei ◽  
Youstina Hanna ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factors ◽  
Somatic Mutations ◽  
Breast Tumors ◽  
Regulatory Elements ◽  
Luminal Breast Cancer ◽  
Breast Cancers ◽  
Driver Genes ◽  
Cancer Driver ◽  
Personalized Cancer

Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and non-coding cancer driver plexuses from somatic mutations. However, differentiating driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform the delivery of personalized cancer medicine. Herein, we reveal an enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of ~100,000 unique cis-regulatory elements from ATACseq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors in luminal breast cancer, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

scholarly journals Centrosome amplification: a suspect in breast cancer and racial disparities

2017 ◽  
Vol 24 (9) ◽  
pp. T47-T64 ◽  
Author(s):  
Angela Ogden ◽  
Padmashree C G Rida ◽  
Ritu Aneja
Keyword(s):  
Breast Cancer ◽  
Centrosome Amplification ◽  
Breast Cancers ◽  
Breast Tumorigenesis ◽  
Breast Cancer Outcomes ◽  
Clinically Significant ◽  
Cellular Tolerance ◽  
Cellular Phenotypes

The multifaceted involvement of centrosome amplification (CA) in tumorigenesis is coming into focus following years of meticulous experimentation, which have elucidated the powerful abilities of CA to promote cellular invasion, disrupt stem cell division, drive chromosomal instability (CIN) and perturb tissue architecture, activities that can accelerate tumor progression. Integration of the extantin vitro,in vivoand clinical data suggests that in some tissues CA may be a tumor-initiating event, in others a consequential ‘hit’ in multistep tumorigenesis, and in some others, non-tumorigenic. However,in vivodata are limited and primarily focus on PLK4 (which has CA-independent mechanisms by which it promotes aggressive cellular phenotypes).In vitrobreast cancer models suggest that CA can promote tumorigenesis in breast cancer cells in the setting of p53 loss or mutation, which can both trigger CA and promote cellular tolerance to its tendency to slow proliferation and induce aneuploidy. It is thus our perspective that CA is likely an early hit in multistep breast tumorigenesis that may sometimes be lost to preserve aggressive karyotypes acquired through centrosome clustering-mediated CIN, both numerical and structural. We also envision that the robust link between p53 and CA may underlie, to a considerable degree, racial health disparity in breast cancer outcomes. This question is clinically significant because, if it is true, then analysis of centrosomal profiles and administration of centrosome declustering drugs could prove highly efficacious in risk stratifying breast cancers and treating African American (AA) women with breast cancer.

Stage at breast cancer diagnosis is more advanced in BRCA1 carriers but not in BRCA2 carriers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10540-10540
Author(s):  
B. Kaufman ◽  
A. Lahad ◽  
M. Krieger ◽  
M. Gal ◽  
E. Friedman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Medullary Carcinoma ◽  
Breast Cancer Diagnosis ◽  
Age At Diagnosis ◽  
Stage At Diagnosis ◽  
Breast Cancers ◽  
Pathological Features ◽  
Breast Cancer Patients ◽  
Brca1 Carriers

10540 Background: BRCA1-associated tumors are known to have less favorable pathological characteristics, but there is little information on whether this is also reflected in the stage at diagnosis. Methods: Clinical and pathological information was collected on 1,122 consecutive Ashkenazi Jewish breast cancer patients who were tested post-diagnosis for the BRCA1/2 mutations common in this population. Results: Of 1,122 patients, 70 (6.2%) were BRCA1 and 50 (4.5%) were BRCA2 carriers. Mean age at diagnosis was 49.9 yrs. in BRCA1 carriers (p=.0001 vs. non-carriers (NC)) vs. 52.0 yrs. in BRCA2 carriers (p=.02 vs. NC) and 56.0 yrs. in NC. Pure DCIS was less common in BRCA1 carriers (3%) than in BRCA2 carriers (8.2%) and NC (11.8%) (p=.03). Medullary carcinoma was more common in BRCA1 (9.8%) and BRCA2 carriers (6.7%) than in NC (1.5%) (p<.001). Invasive lobular carcinomas were rarer in BRCA1 (1.6%) and BRCA2 (2.2%) compared to NC (8.8%) (p=.012). Hormone receptors (HR) negative was more common in BRCA1 (62%) compared to BRCA2 carriers (21%) (p=.00006) and NC (17%) (p<0.0001). Triple negative tumors (HR and HER2 negative) were more common in BRCA1 carriers (60%) than in BRCA2 carriers (14%) and NC (8.3%) (p=0.001). High grade was more common in BRCA1 (60.4%) and BRCA2 (51.4%) carriers than in NC (36.7%, p=.001). Less favorable pathological features and younger age at diagnosis in BRCA1 carriers were reflected in a more advanced stage at diagnosis. Stage I at diagnosis was found in 34% of BRCA1 carriers (p=.05 vs. NC), 43% of BRCA2 carriers and 46% of NC, stage II in 48% of BRCA1 carriers, 41% of BRCA2 carriers and 37% of NC, and stage III in 17% of BRCA1 carriers, 13.5% of BRCA2 carriers and 13.5% of non-carriers. Conclusions: This consecutive cohort study demonstrates that breast cancers in BRCA1 carriers are characterized by more aggressive pathological features and are diagnosed at more advanced stages than in BRCA2 carriers and non-carriers. This may suggest a differential approach for prevention and surveillance in BRCA1 compared to BRCA2 carriers. No significant financial relationships to disclose.

Smoking and increased breast cancer risk in younger women in Appalachian Kentucky.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11097-e11097
Author(s):  
Indraneel Reddy ◽  
Anjali Shankar ◽  
Priya Mallikarjun ◽  
Nicola Jabbour ◽  
Mark Dignan
Keyword(s):  
Breast Cancer ◽  
Smoking Status ◽  
Adult Population ◽  
Current Smoker ◽  
The State ◽  
Age At Diagnosis ◽  
Breast Cancers ◽  
Exact Test ◽  
Cancer Data ◽  
Appalachian Kentucky

e11097 Background: Smoking rates in Kentucky are among the highest in the US. Data from the Centers for Disease Control and Prevention for 2011 showed that in Kentucky 25.2% of the adult population are current smokers compared to 18.4% nationwide. In addition, smoking rates in the Appalachian region are substantially higher than the state rate. Breast cancer rates are also elevated in Appalachian Kentucky, with data from the Kentucky State Cancer Registry for 2004-2008 showing an incidence rate of 67.3 per 100,000 in Appalachia compared to 65.6 per 100,000 for the state. Our objective was to evaluate the association of smoking and breast cancer among women in Appalachian Kentucky. Methods: We reviewed all the breast cancer data from a large community hospital serving the Appalachian areas of Kentucky. Data were collected from the hospital tumor registry for the period 1996-2005 and included demographic characteristics and smoking status, in addition to information about the breast cancer. No personal identifiers were collected. Breast cancers were coded as invasive or non-invasive and smoking status was coded as current smoker, non-smoker or unknown. Results: Data from records of 392 patients were included in the analyses. Over 90% of the breast cancers in the 392 were invasive. Age at diagnosis ranged from 24 to 92 and the mean was 59.9 years (standard deviation= 13.5. 21.2% of the records indicated a family history of breast cancer. Of the 392 patients, 162 (41.3%) were smokers. Analysis of the data by age at diagnosis showed that of the 120 women diagnosed with breast cancer at age less than 65, 46.5% were smokers, compared to 31.3% of those age 65 or older (p=.005, Fisher’s Exact Test). Conclusions: The risk of breast cancer in women under age 65 appears to be associated with smoking in this population. Additional research is needed to more fully explore this association.

Evaluation of the prognostic value of guanylyl cyclase C (GCC) lymph node (LN) classification in patients with stage II colon cancer: A pooled analysis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 443-443
Author(s):  
Daniel J. Sargent ◽  
Qian Shi ◽  
Murray B. Resnick ◽  
Stephen Lyle ◽  
Michael O. Meyers ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Clinical Outcomes ◽  
Prognostic Value ◽  
Disease Free Survival ◽  
Strong Relationship ◽  
Low Risk ◽  
Stage Ii ◽  
Risk Status ◽  
Cox Models

443 Background: Identification of a sensitive and specific prognostic marker would aid in the management of patients (pts) with standard histopathology node negative colon cancer (CC). We conducted a pooled individual pt data analysis to confirm the prognostic value of GCC for disease recurrence in untreated stage II CC. Methods: GCC mRNA was quantified by RT-qPCR using formalin-fixed LN from 310 stage II pts diagnosed from 1991-2006 enrolled in two studies (Sargent 2011 [study1] and Haince 2009 [study2]). Patients were classified by GCC LN ratio (LNR) (high risk: LNR ≥ 0.1; low risk: LNR < 0.1), with LNR defined as number of GCC positive LN divided by number of informative LNs. Clinical outcomes included time to recurrence (TTR), overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS). Stratified log-rank tests and multivariate Cox models assessed the association between clinical outcomes and GCC LN status. Results: The 5-year recurrence rate in study 1 (n=241) was 15.8%, 24.9% in study 2 (n=69). GCC LNR high risk pts had significantly higher risk of TTR, OS, DSS and DFS, which remained after adjusting for age, T stage, grade, number of LNs examined, and presence of lymphovascular invasion ( Table ). In a secondary analysis of low risk stage II pts (T3, ≥12 LNs examined, and negative surgical margins, n=241), a strong relationship between GCC LNR and each endpoint remained (TTR HR=4.34, 95% CI=2.07 – 9.13, p<0.001). Conclusions: Pts with GCC LNR high risk status have significantly poorer outcomes compared to pts with low risk status, particularly among those traditionally considered to be low risk. [Table: see text]

Breast cancer subtypes in Chinese Americans: A study from the Mount Sinai Health System.

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 39-39
Author(s):  
Camila Masias ◽  
Theresa H. Shao
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Chinese Americans ◽  
Breast Cancer Subtypes ◽  
Age At Diagnosis ◽  
Chinese Patients ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Her2 Breast Cancer ◽  
Mount Sinai

39 Background: Breast cancer has been increasing in many Asian countries, as well as among Asian Americans. While many studies have examined breast cancer subtypes in African American and Caucasian populations, few have looked at tumor subtypes in the Asian population. We aimed to examine breast cancer subtypes in Chinese Americans. Methods: We identified all Chinese patients diagnosed with invasive breast cancers between 2005 and 2012 from the Cancer Registry of Mount Sinai Beth Israel, Mount Sinai St. Luke’s, and Roosevelt Hospitals. The following clinical data were collected for each patient: age at diagnosis, year of diagnosis, largest tumor size (cm), lymph node status, estrogen receptor (ER), progesterone receptor (PR) and HER2 status. Based on ER, PR, and HER2, patients were categorized into three molecular subtypes: 1) Hormone receptor (HR)+ (ER and/or PR positive, HER2 negative), HER2+ and triple negative (TN) (ER, PR, and HER2 negative). Descriptive variables were analyzed using one-way Anova test. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from logistic regression models. Results: There were 175 Chinese patients diagnosed with invasive breast cancers from 2005 to 2012. Median age at diagnosis was 54 (range 27-90). One hundred fourteen (65%) were HR+, 41 (23%) were HER2+, and 20 (11%) were TN. There were 59 (34%) patients diagnosed at age ≤ 50 and twelve patients (7%) were diagnosed at age < 40. There were more HER2+ and TN breast cancers diagnosed in women age ≤ 50 compared to age > 50, but the difference was not statistically significant. Women in the HR+ group were diagnosed at an older age compared to the other two subgroups (57 ± 12, 52 ± 8, and 52 ± 10 for HR+, HER2+, and TN, respectively, p = 0.036). Patients with TN breast cancers were more likely to have lymph node involvement compared to HR+ or HER2+ patients (p = 0.02). There was a trend of increasing prevalence of HER2+ breast cancer observed in recent years: 18.5% in 2005-2006, 23.8% in 2007-2008, 18.4% in 2009-2010, and 29.8% in 2011-2012. Conclusions: We observed a high proportion of breast cancer among young Chinese Americans as well as an increasing prevalence of HER2+ breast cancer in this population in recent years. Further studies are warranted.

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