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1.  Comparative Proteome Analysis Revealing an 11-Protein Signature for Aggressive Triple-Negative Breast Cancer 
Background
Clinical outcome of patients with triple-negative breast cancer (TNBC) is highly variable. This study aims to identify and validate a prognostic protein signature for TNBC patients to reduce unnecessary adjuvant systemic therapy.
Methods
Frozen primary tumors were collected from 126 lymph node–negative and adjuvant therapy–naive TNBC patients. These samples were used for global proteome profiling in two series: an in-house training (n = 63) and a multicenter test (n = 63) set. Patients who remained free of distant metastasis for a minimum of 5 years after surgery were defined as having good prognosis. Cox regression analysis was performed to develop a prognostic signature, which was independently validated. All statistical tests were two-sided.
Results
An 11-protein signature was developed in the training set (median follow-up for good-prognosis patients = 117 months) and subsequently validated in the test set (median follow-up for good-prognosis patients = 108 months) showing 89.5% sensitivity (95% confidence interval [CI] = 69.2% to 98.1%), 70.5% specificity (95% CI = 61.7% to 74.2%), 56.7% positive predictive value (95% CI = 43.8% to 62.1%), and 93.9% negative predictive value (95% CI = 82.3% to 98.9%) for poor-prognosis patients. The predicted poor-prognosis patients had higher risk to develop distant metastasis than the predicted good-prognosis patients in univariate (hazard ratio [HR] = 13.15; 95% CI = 3.03 to 57.07; P = .001) and multivariable (HR = 12.45; 95% CI = 2.67 to 58.11; P = .001) analysis. Furthermore, the predicted poor-prognosis group had statistically significantly more breast cancer–specific mortality. Using our signature as guidance, more than 60% of patients would have been exempted from unnecessary adjuvant chemotherapy compared with conventional prognostic guidelines.
Conclusions
We report the first validated proteomic signature to assess the natural course of clinical TNBC.
doi:10.1093/jnci/djt376
PMCID: PMC3952199  PMID: 24399849
2.  Gene Expression Signatures That Predict Outcome of Tamoxifen-Treated Estrogen Receptor-Positive, High-Risk, Primary Breast Cancer Patients: A DBCG Study 
PLoS ONE  2013;8(1):e54078.
Background
Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy.
Methodology/Principal Findings
Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by >1% IHC staining and having a frozen tumor sample with >50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric bootstrap (1000x re-sampling). The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (n = 623). Three gene signatures were identified, the strongest being a 2-gene combination of BCL2-CDKN1A, exhibiting an accuracy of 75% for prediction of outcome. Independent examination using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (n = 503) confirmed the potential of BCL2-CDKN1A. The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015) and untreated patients (n = 62, p = 0.25).
Conclusions/Significance
A novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential.
doi:10.1371/journal.pone.0054078
PMCID: PMC3546921  PMID: 23342080
3.  Comparison of prognostic gene expression signatures for breast cancer 
BMC Genomics  2008;9:394.
Background
During the last years, several groups have identified prognostic gene expression signatures with apparently similar performances. However, signatures were never compared on an independent population of untreated breast cancer patients, where risk assessment was computed using the original algorithms and microarray platforms.
Results
We compared three gene expression signatures, the 70-gene, the 76-gene and the Gene expression Grade Index (GGI) signatures, in terms of predicting distant metastasis free survival (DMFS) for the individual patient. To this end, we used the previously published TRANSBIG independent validation series of node-negative untreated primary breast cancer patients. We observed agreement in prediction for 135 of 198 patients (68%) when considering the three signatures. When comparing the signatures two by two, the agreement in prediction was 71% for the 70- and 76-gene signatures, 76% for the 76-gene signature and the GGI, and 88% for the 70-gene signature and the GGI. The three signatures had similar capabilities of predicting DMFS and added significant prognostic information to that provided by the classical parameters.
Conclusion
Despite the difference in development of these signatures and the limited overlap in gene identity, they showed similar prognostic performance, adding to the growing evidence that these prognostic signatures are of clinical relevance.
doi:10.1186/1471-2164-9-394
PMCID: PMC2533026  PMID: 18717985
4.  Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature 
BMC Cancer  2008;8:339.
Background
Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times.
Methods
197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A "metastasis score" (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women.
Results
A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91–8.44) for the endpoint of DMFS and 1.97 (95% CI 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90–99%) and 72% (64–78%) respectively, for DMFS and 91% (84–95%) and 68% (61–75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86–15.14).
Conclusion
The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.
doi:10.1186/1471-2407-8-339
PMCID: PMC2631011  PMID: 19025599
5.  Genomic Index of Sensitivity to Endocrine Therapy for Breast Cancer 
Journal of Clinical Oncology  2010;28(27):4111-4119.
Purpose
We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy.
Methods
A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively).
Results
The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine–treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET.
Conclusion
The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.
doi:10.1200/JCO.2010.28.4273
PMCID: PMC2953969  PMID: 20697068
6.  A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study 
The 70-gene signature (MammaPrint™) has been developed on retrospective series of breast cancer patients to predict the risk of breast cancer distant metastases. The microarRAy-prognoSTics-in-breast-cancER (RASTER) study was the first study designed to prospectively evaluate the performance of the 70-gene signature, which result was available for 427 patients (cT1–3N0M0). Adjuvant systemic treatment decisions were based on the Dutch CBO 2004 guidelines, the 70-gene signature and doctors' and patients' preferences. Five-year distant-recurrence-free-interval (DRFI) probabilities were compared between subgroups based on the 70-gene signature and Adjuvant! Online (AOL) (10-year survival probability <90% was defined as high-risk). Median follow-up was 61.6 months. Fifteen percent (33/219) of the 70-gene signature low-risk patients received adjuvant chemotherapy (ACT) versus 81% (169/208) of the 70-gene signature high-risk patients. The 5-year DRFI probabilities for 70-gene signature low-risk (n = 219) and high-risk (n = 208) patients were 97.0% and 91.7%. The 5-year DRFI probabilities for AOL low-risk (n = 132) and high-risk (n = 295) patients were 96.7% and 93.4%. For 70-gene signature low-risk–AOL high-risk patients (n = 124), of whom 76% (n = 94) had not received ACT, 5-year DRFI was 98.4%. In the AOL high-risk group, 32% (94/295) less patients would be eligible to receive ACT if the 70-gene signature was used. In this prospective community-based observational study, the 5-year DRFI probabilities confirmed the additional prognostic value of the 70-gene signature to clinicopathological risk estimations such as AOL. Omission of adjuvant chemotherapy as judged appropriate by doctors and patients and instigated by a low-risk 70-gene signature result, appeared not to compromise outcome.
doi:10.1002/ijc.28082
PMCID: PMC3734625  PMID: 23371464
breast cancer; gene expression profiling; prognosis prediction; adjuvant systemic treatment
7.  Association between genomic recurrence risk and well-being among breast cancer patients 
BMC Cancer  2013;13:295.
Background
Gene expression profiling (GEP) is increasingly used in the rapidly evolving field of personalized medicine. We sought to evaluate the association between GEP-assessed of breast cancer recurrence risk and patients’ well-being.
Methods
Participants were Dutch women from 10 hospitals being treated for early stage breast cancer who were enrolled in the MINDACT trial (Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy). As part of the trial, they received a disease recurrence risk estimate based on a 70-gene signature and on standard clinical criteria as scored via a modified version of Adjuvant! Online. \Women completed a questionnaire 6–8 weeks after surgery and after their decision regarding adjuvant chemotherapy. The questionnaire assessed perceived understanding, knowledge, risk perception, satisfaction, distress, cancer worry and health-related quality of life (HRQoL), 6–8 weeks after surgery and decision regarding adjuvant chemotherapy.
Results
Women (n = 347, response rate 62%) reported high satisfaction with and a good understanding of the GEP information they received. Women with low risk estimates from both the standard and genomic tests reported the lowest distress levels. Distress was higher predominately among patients who had received high genomic risk estimates, who did not receive genomic risk estimates, or who received conflicting estimates based on genomic and clinical criteria. Cancer worry was highest for patients with higher risk perceptions and lower satisfaction. Patients with concordant high-risk profiles and those for whom such profiles were not available reported lower quality of life.
Conclusion
Patients were generally satisfied with the information they received about recurrence risk based on genomic testing. Some types of genomic test results were associated with greater distress levels, but not with cancer worry or HRQoL.
Trial registration
ISRCTN: ISRCTN18543567
doi:10.1186/1471-2407-13-295
PMCID: PMC3689597  PMID: 23777535
Personalized medicine; Genomic profile; 70-gene signature; Patient-centered care; Breast cancer; Chemotherapy
8.  A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study 
BMC Cancer  2012;12:161.
Background
In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen.
Methods
Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups.
Results
Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer.
Conclusion
Toremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer.
doi:10.1186/1471-2407-12-161
PMCID: PMC3503787  PMID: 22548922
Tamoxifen; Toremifene; Breast cancer; Adjuvant endocrine therapy; Premenopausal
9.  Predicting a local recurrence after breast-conserving therapy by gene expression profiling 
Breast Cancer Research  2006;8(5):R62.
Introduction
To tailor local treatment in breast cancer patients there is a need for predicting ipsilateral recurrences after breast-conserving therapy. After adequate treatment (excision with free margins and radiotherapy), young age and incompletely excised extensive intraductal component are predictors for local recurrence, but many local recurrences can still not be predicted. Here we have used gene expression profiling by microarray analysis to identify gene expression profiles that can help to predict local recurrence in individual patients.
Methods
By using previously established gene expression profiles with proven value in predicting metastasis-free and overall survival (wound-response signature, 70-gene prognosis profile and hypoxia-induced profile) and training towards an optimal prediction of local recurrences in a training series, we establish a classifier for local recurrence after breast-conserving therapy.
Results
Validation of the different gene lists shows that the wound-response signature is able to separate patients with a high (29%) or low (5%) risk of a local recurrence at 10 years (sensitivity 87.5%, specificity 75%). In multivariable analysis the classifier is an independent predictor for local recurrence.
Conclusion
Our findings indicate that gene expression profiling can identify subgroups of patients at increased risk of developing a local recurrence after breast-conserving therapy.
doi:10.1186/bcr1614
PMCID: PMC1779489  PMID: 17069664
10.  A gene expression signature that can predict the recurrence of tamoxifen-treated primary breast cancer 
Clinical Cancer Research  2008;14(6):1744-1752.
Purpose
Identification of a molecular signature predicting the relapse of tamoxifen-treated primary breast cancers should help the therapeutical management of ER-positive cancers.
Experimental Design
A series of 132 primary tumors from patients who received adjuvant tamoxifen were analysed for expression profiles at the whole genome level by 70-mer oligonucleotide microarrays. A supervised analysis was performed to identify an expression signature.
Results
We defined a 36-gene signature that classified correctly 78% of patients with relapse and 80% of relapse-free patients (79% accuracy). Using 23 independent tumors, we confirmed the accuracy of the signature (78%), whose relevance was further demonstrated by using published microarray data from 60 tamoxifen-treated patients (63% accuracy).
Univariate analysis using the validation set of 83 tumors demonstrated that the 36-gene classifier was more efficient to predict disease-free survival than the traditional histo-pathological prognostic factors and as effective as the Nottingham Prognostic Index or the “Adjuvant!“ software. Multivariate analysis demonstrated that the molecular signature was the only independent prognostic factor. Comparison with several already published signatures demonstated that the 36-gene signature was among the best to classify tumors from both training and validation sets. Kaplan-Meier analyses emphasized its prognostic power both on the whole cohort of patients and on a subgroup with an intermediate risk of recurrence as defined by the St Gallen criteria.
Conclusion
This study identifies a molecular signature specifying a subgroup of patients who do not gain benefits from tamoxifen treatment. These patients may therefore be eligible for alternative endocrine therapies and/or chemotherapy.
doi:10.1158/1078-0432.CCR-07-1833
PMCID: PMC2912334  PMID: 18347175
Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; therapeutic use; Breast Neoplasms; diagnosis; drug therapy; genetics; Carcinoma; diagnosis; drug therapy; genetics; Chemotherapy, Adjuvant; Cluster Analysis; Disease-Free Survival; Drug Resistance, Neoplasm; genetics; Female; Follow-Up Studies; Gene Expression Profiling; Humans; Middle Aged; Neoplasm Recurrence, Local; diagnosis; genetics; Oligonucleotide Array Sequence Analysis; Prognosis; Receptors, Estrogen; genetics; Receptors, Progesterone; genetics; Sensitivity and Specificity; Tamoxifen; therapeutic use; Treatment Outcome; gene expression profiling; classifier; tamoxifen; breast cancer
11.  Improved breast cancer prognosis through the combination of clinical and genetic markers 
Motivation
Accurate prognosis of breast cancer can spare a significant number of breast cancer patients from receiving unnecessary adjuvant systemic treatment and its related expensive medical costs. Recent studies have demonstrated the potential value of gene expression signatures in assessing the risk of post-surgical disease recurrence. However, these studies all attempt to develop genetic marker-based prognostic systems to replace the existing clinical criteria, while ignoring the rich information contained in established clinical markers. Given the complexity of breast cancer prognosis, a more practical strategy would be to utilize both clinical and genetic marker information that may be complementary.
Methods
A computational study is performed on publicly available microarray data, which has spawned a 70-gene prognostic signature. The recently proposed I-RELIEF algorithm is used to identify a hybrid signature through the combination of both genetic and clinical markers. A rigorous experimental protocol is used to estimate the prognostic performance of the hybrid signature and other prognostic approaches. Survival data analyses is performed to compare different prognostic approaches.
Results
The hybrid signature performs significantly better than other methods, including the 70-gene signature, clinical makers alone and the St. Gallen consensus criterion. At the 90% sensitivity level, the hybrid signature achieves 67% specificity, as compared to 47% for the 70-gene signature and 48% for the clinical makers. The odds ratio of the hybrid signature for developing distant meta-stases within five years between the patients with a good prognosis signature and the patients with a bad prognosis is 21.0 (95% CI: 6.5–68.3), far higher than either genetic or clinical markers alone.
doi:10.1093/bioinformatics/btl543
PMCID: PMC3431620  PMID: 17130137
12.  A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance 
Purpose
Although most patients with estrogen receptor α (ER)-positive breast cancer initially respond to endocrine therapy, many ultimately develop resistance to antiestrogens. However, mechanisms of antiestrogen resistance and biomarkers predictive of such resistance are underdeveloped.
Experimental Design
We adapted four ER+ human breast cancer cell lines to grow in an estrogen-depleted medium. A gene signature of estrogen independence was developed by comparing expression profiles of long-term estrogen-deprived (LTED) cells to their parental counterparts. We evaluated the ability of the LTED signature to predict tumor response to neoadjuvant therapy with an aromatase inhibitor, and disease outcome following adjuvant tamoxifen. We utilized Gene Set Analysis (GSA) of LTED cell gene expression profiles and a loss-of-function approach to identify pathways causally associated with resistance to endocrine therapy.
Results
The LTED gene expression signature was predictive of high tumor cell proliferation following neoadjuvant therapy with anastrozole and letrozole, each in different patient cohorts. This signature was also predictive of poor recurrence-free survival in two studies of patients treated with adjuvant tamoxifen. Bioinformatic interrogation of expression profiles in LTED cells revealed a signature of MYC activation. The MYC activation signature and high MYC protein levels were both predictive of poor outcome following tamoxifen therapy. Finally, knockdown of MYC inhibited LTED cell growth.
Conclusions
A gene expression signature derived from ER+ breast cancer cells with acquired hormone independence predicted tumor response to aromatase inhibitors and associated with clinical markers of resistance to tamoxifen. In some cases, activation of the MYC pathway was associated with this resistance.
doi:10.1158/1078-0432.CCR-10-2567
PMCID: PMC3221728  PMID: 21346144
aromatase; tamoxifen; myc; LTED; breast
13.  A Transcriptional Fingerprint of Estrogen in Human Breast Cancer Predicts Patient Survival12 
Neoplasia (New York, N.Y.)  2008;10(1):79-88.
Estrogen signaling plays an essential role in breast cancer progression, and estrogen receptor (ER) status has long been a marker of hormone responsiveness. However, ER status alone has been an incomplete predictor of endocrine therapy, as some ER+ tumors, nevertheless, have poor prognosis. Here we sought to use expression profiling of ER+ breast cancer cells to screen for a robust estrogen-regulated gene signature that may serve as a better indicator of cancer outcome. We identified 532 estrogen-induced genes and further developed a 73-gene signature that best separated a training set of 286 primary breast carcinomas into prognostic subtypes by stepwise cross-validation. Notably, this signature predicts clinical outcome in over 10 patient cohorts as well as their respective ER+ subcohorts. Further, this signature separates patients who have received endocrine therapy into two prognostic subgroups, suggesting its specificity as a measure of estrogen signaling, and thus hormone sensitivity. The 73-gene signature also provides additional predictive value for patient survival, independent of other clinical parameters, and outperforms other previously reported molecular outcome signatures. Taken together, these data demonstrate the power of using cell culture systems to screen for robust gene signatures of clinical relevance.
PMCID: PMC2213902  PMID: 18231641
14.  Prognostic and Predictive Markers for Treatment Decisions in Early Breast Cancer 
Breast Care  2011;6(3):193-198.
Summary
Breast cancer clinically represents a heterogeneous disease. Over the last decades, the integration of prognostic and predictive markers in treatment decisions has led to a more individualized and optimized therapy. While prognosis describes the risk of disease recurrence and disease-related death after diagnosis without the influence of therapy, prediction illustrates the probability of efficacy or response of a specific therapeutic measure. The substantial decline in breast cancer mortality seen over the last 20 years is primarily due to the delivery of adjuvant systemic therapy. It is important that clinical decisions are made to minimize overtreatment, under-treatment, and incorrect treatment. Improved understanding of breast cancer biology together with the utilization of classical biomarkers and the identification of new markers or profiles is increasingly defining who should receive cancer therapy and what therapy offers the best efficacy. The molecular targets as the prerequisite for successful concepts of specific therapies like anti-estrogens, antibodies, or small molecules, have therefore high clinical value in regards to prognosis as well as prediction.
doi:10.1159/000329471
PMCID: PMC3132966  PMID: 21779224
Prognosis; Prediction; Early breast cancer; Biomarkers
15.  Identification of Prognostic Genes for Recurrent Risk Prediction in Triple Negative Breast Cancer Patients in Taiwan 
PLoS ONE  2011;6(11):e28222.
Discrepancies in the prognosis of triple negative breast cancer exist between Caucasian and Asian populations. Yet, the gene signature of triple negative breast cancer specifically for Asians has not become available. Therefore, the purpose of this study is to construct a prediction model for recurrence of triple negative breast cancer in Taiwanese patients. Whole genome expression profiling of breast cancers from 185 patients in Taiwan from 1995 to 2008 was performed, and the results were compared to the previously published literature to detect differences between Asian and Western patients. Pathway analysis and Cox proportional hazard models were applied to construct a prediction model for the recurrence of triple negative breast cancer. Hierarchical cluster analysis showed that triple negative breast cancers from different races were in separate sub-clusters but grouped in a bigger cluster. Two pathways, cAMP-mediated signaling and ephrin receptor signaling, were significantly associated with the recurrence of triple negative breast cancer. After using stepwise model selection from the combination of the initial filtered genes, we developed a prediction model based on the genes SLC22A23, PRKAG3, DPEP3, MORC2, GRB7, and FAM43A. The model had 91.7% accuracy, 81.8% sensitivity, and 94.6% specificity under leave-one-out support vector regression. In this study, we identified pathways related to triple negative breast cancer and developed a model to predict its recurrence. These results could be used for assisting with clinical prognosis and warrant further investigation into the possibility of targeted therapy of triple negative breast cancer in Taiwanese patients.
doi:10.1371/journal.pone.0028222
PMCID: PMC3226667  PMID: 22140552
16.  Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors 
We used bioluminescence imaging to reveal patterns of metastasis formation by human breast cancer cells in immunodeficient mice. Individual cells from a population established in culture from the pleural effusion of a breast cancer patient showed distinct patterns of organ-specific metastasis. Single-cell progenies derived from this population exhibited markedly different abilities to metastasize to the bone, lung, or adrenal medulla, which suggests that metastases to different organs have different requirements. Transcriptomic profiling revealed that these different single-cell progenies similarly express a previously described “poor-prognosis” gene expression signature. Unsupervised classification using the transcriptomic data set supported the hypothesis that organ-specific metastasis by breast cancer cells is controlled by metastasis-specific genes that are separate from a general poor-prognosis gene expression signature. Furthermore, by using a gene expression signature associated with the ability of these cells to metastasize to bone, we were able to distinguish primary breast carcinomas that preferentially metastasized to bone from those that preferentially metastasized elsewhere. These results suggest that the bone-specific metastatic phenotypes and gene expression signature identified in a mouse model may be clinically relevant.
doi:10.1172/JCI200522320
PMCID: PMC539194  PMID: 15630443
17.  Low expression of a few genes indicates good prognosis in estrogen receptor positive breast cancer 
BMC Cancer  2009;9:243.
Background
Many breast cancer patients remain free of distant metastasis even without adjuvant chemotherapy. While standard histopathological tests fail to identify these good prognosis patients with adequate precision, analyses of gene expression patterns in primary tumors have resulted in more successful diagnostic tests. These tests use continuous measurements of the mRNA concentrations of numerous genes to determine a risk of metastasis in lymph node negative breast cancer patients with other clinical traits.
Methods
A survival model is constructed from genes that are both connected with relapse and have expression patterns that define distinct subtypes, suggestive of different cellular states. This in silico study uses publicly available microarray databases generated with Affymetrix GeneChip technology. The genes in our model, as represented by array probes, have distinctive distributions in a patient cohort, consisting of a large normal component of low expression values; and a long right tail of high expression values. The cutoff between low and high expression of a probe is determined from the distribution using the theory of mixture models. The good prognosis group in our model consists of the samples in the low expression component of multiple genes.
Results
Here, we define a novel test for risk of metastasis in estrogen receptor positive (ER+) breast cancer patients, using four probes that determine distinct subtypes. The good prognosis group in this test, denoted AP4-, consists of the samples with low expression of each of the four probes. Two probes target MKI67, antigen identified by monoclonal antibody Ki-67, one targets CDC6, cell division cycle 6 homolog (S. cerevisiae), and a fourth targets SPAG5, sperm associated antigen 5. The long-term metastasis-free survival probability for samples in AP4- is sufficiently high to render chemotherapy of questionable benefit.
Conclusion
A breast cancer subtype defined by low expression of a few genes, using a minimum of statistical modeling, has significant prognostic power. This test is of potential clinical benefit in deciding a course of treatment for early stage breast cancer patients.
doi:10.1186/1471-2407-9-243
PMCID: PMC2718903  PMID: 19619298
18.  Recent advances in systemic therapy. New diagnostics and biological predictors of outcome in early breast cancer 
The key to optimising our approach in early breast cancer is to individualise care. Each patient has a tumour with innate features that dictate their chance of relapse and their responsiveness to treatment. Often patients with similar clinical and pathological tumours will have markedly different outcomes and responses to adjuvant intervention. These differences are encoded in the tumour genetic profile. Effective biomarkers may replace or complement traditional clinical and histopathological markers in assessing tumour behaviour and risk. Development of high-throughput genomic technologies is enabling the study of gene expression profiles of tumours. Genomic fingerprints may refine prediction of the course of disease and response to adjuvant interventions. This review will focus on the role of multiparameter gene expression analyses in early breast cancer, with regards to prognosis and prediction. The prognostic role of genomic signatures, particularly the Mammaprint and Rotterdam signatures, is evolving. With regard to prediction of outcome, the Oncotype Dx multigene assay is in clinical use in tamoxifen treated patients. Extensive research continues on predictive gene identification for specific chemotherapeutic agents, particularly the anthracyclines, taxanes and alkylating agents.
doi:10.1186/bcr2238
PMCID: PMC2688942  PMID: 19435470
19.  Correlation of microarray-based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization 
BMC Cancer  2011;11:143.
Background
Optimizing treatment through microarray-based molecular subtyping is a promising method to address the problem of heterogeneity in breast cancer; however, current application is restricted to prediction of distant recurrence risk. This study investigated whether breast cancer molecular subtyping according to its global intrinsic biology could be used for treatment customization.
Methods
Gene expression profiling was conducted on fresh frozen breast cancer tissue collected from 327 patients in conjunction with thoroughly documented clinical data. A method of molecular subtyping based on 783 probe-sets was established and validated. Statistical analysis was performed to correlate molecular subtypes with survival outcome and adjuvant chemotherapy regimens. Heterogeneity of molecular subtypes within groups sharing the same distant recurrence risk predicted by genes of the Oncotype and MammaPrint predictors was studied.
Results
We identified six molecular subtypes of breast cancer demonstrating distinctive molecular and clinical characteristics. These six subtypes showed similarities and significant differences from the Perou-Sørlie intrinsic types. Subtype I breast cancer was in concordance with chemosensitive basal-like intrinsic type. Adjuvant chemotherapy of lower intensity with CMF yielded survival outcome similar to those of CAF in this subtype. Subtype IV breast cancer was positive for ER with a full-range expression of HER2, responding poorly to CMF; however, this subtype showed excellent survival when treated with CAF. Reduced expression of a gene associated with methotrexate sensitivity in subtype IV was the likely reason for poor response to methotrexate. All subtype V breast cancer was positive for ER and had excellent long-term survival with hormonal therapy alone following surgery and/or radiation therapy. Adjuvant chemotherapy did not provide any survival benefit in early stages of subtype V patients. Subtype V was consistent with a unique subset of luminal A intrinsic type. When molecular subtypes were correlated with recurrence risk predicted by genes of Oncotype and MammaPrint predictors, a significant degree of heterogeneity within the same risk group was noted. This heterogeneity was distributed over several subtypes, suggesting that patients in the same risk groups require different treatment approaches.
Conclusions
Our results indicate that the molecular subtypes established in this study can be utilized for customization of breast cancer treatment.
doi:10.1186/1471-2407-11-143
PMCID: PMC3094326  PMID: 21501481
20.  Oncologist use of the Adjuvant! model for risk communication: a pilot study examining patient knowledge of 10-year prognosis 
BMC Cancer  2009;9:127.
Background
Our purpose was to collect preliminary data on newly diagnosed breast cancer patient knowledge of prognosis before and after oncology visits. Many oncologists use a validated prognostic software model, Adjuvant!, to estimate 10-year recurrence and mortality outcomes for breast cancer local and adjuvant therapy. Some oncologists are printing Adjuvant! screens to use as visual aids during consultations. No study has reported how such use of Adjuvant! printouts affects patient knowledge of prognosis. We hypothesized that Adjuvant! printouts would be associated with significant changes in the proportion of patients with accurate understanding of local therapy prognosis.
Methods
We recruited a convenience sample of 20 patients seen by 2 senior oncologists using Adjuvant! printouts of recurrence and mortality screens in our academic medical center. We asked patients for their estimates of local therapy recurrence and mortality risks and counted the number of patients whose estimates were within ± 5% of Adjuvant! before and after the oncology visit, testing whether pre/post changes were significant using McNemar's two-sided test at a significance level of 5%.
Results
Two patients (10%) accurately estimated local therapy recurrence and mortality risks before the oncology visit, while seven out of twenty (35%) were accurate afterwards (p = 0.125).
Conclusion
A majority of patients in our sample were inaccurate in estimating their local therapy recurrence and mortality risks, even after being shown printouts summarizing these risks during their oncology visits. Larger studies are needed to replicate or repudiate these preliminary findings, and test alternative methods of presenting risk estimates. Meanwhile, oncologists should be wary of relying exclusively on Adjuvant! printouts to communicate local therapy recurrence and mortality estimates to patients, as they may leave a majority of patients misinformed.
doi:10.1186/1471-2407-9-127
PMCID: PMC2684746  PMID: 19400938
21.  Kinome expression profiling and prognosis of basal breast cancers 
Molecular Cancer  2011;10:86.
Background
Basal breast cancers (BCs) represent ~15% of BCs. Although overall poor, prognosis is heterogeneous. Identification of good- versus poor-prognosis patients is difficult or impossible using the standard histoclinical features and the recently defined prognostic gene expression signatures (GES). Kinases are often activated or overexpressed in cancers, and constitute targets for successful therapies. We sought to define a prognostic model of basal BCs based on kinome expression profiling.
Methods
DNA microarray-based gene expression and histoclinical data of 2515 early BCs from thirteen datasets were collected. We searched for a kinome-based GES associated with disease-free survival (DFS) in basal BCs of the learning set using a metagene-based approach. The signature was then tested in basal tumors of the independent validation set.
Results
A total of 591 samples were basal. We identified a 28-kinase metagene associated with DFS in the learning set (N = 73). This metagene was associated with immune response and particularly cytotoxic T-cell response. On multivariate analysis, a metagene-based predictor outperformed the classical prognostic factors, both in the learning and the validation (N = 518) sets, independently of the lymphocyte infiltrate. In the validation set, patients whose tumors overexpressed the metagene had a 78% 5-year DFS versus 54% for other patients (p = 1.62E-4, log-rank test).
Conclusions
Based on kinome expression, we identified a predictor that separated basal BCs into two subgroups of different prognosis. Tumors associated with higher activation of cytotoxic tumor-infiltrative lymphocytes harbored a better prognosis. Such classification should help tailor the treatment and develop new therapies based on immune response manipulation.
doi:10.1186/1476-4598-10-86
PMCID: PMC3156788  PMID: 21777462
breast cancer; basal-like; gene expression profiling; prognosis; immune response
22.  Adjuvant Therapy of Triple Negative Breast Cancer 
Patients with the triple negative subtype of breast cancer have an overall poor outcome, with earlier relapses, distinct patterns of metastases, and lack of specific targets for treatment selection. Classification of these tumors has begun to be modified by inclusion of immunohistochemistry for various markers, and gene profiling, to further characterize this subtype of breast cancer, may aid in the identification of new targeted therapies. Anthracyclines and taxanes remain the standard of care in the adjuvant setting. However, novel anti-angiogenesis, anti-tubulin, and DNA repair agents are already under evaluation in (neo) adjuvant trials. Molecular characterization is being included in trials to identify optimal adjuvant strategies. The aim of this manuscript is to review data concerning the molecular characterization of triple negative breast cancers as well as the clinical outcomes of treating patients with existing adjuvant treatments, and to highlight newer adjuvant research strategies in development.
doi:10.1007/s10549-010-0736-z
PMCID: PMC3918886  PMID: 20094772
Breast cancer; triple negative; basal-like breast cancer; adjuvant therapy
23.  Genomic signatures for predicting survival and adjuvant chemotherapy benefit in patients with non-small-cell lung cancer 
BMC Medical Genomics  2012;5:30.
Background
Improved methods are needed for predicting prognosis and the benefit of delivering adjuvant chemotherapy (ACT) in patients with non-small-cell lung cancer (NSCLC).
Methods
A novel prognostic algorithm was identified using genomic profiles from 332 stage I-III adenocarcinomas and independently validated on a separate series of 264 patients with stage I-II tumors, compiled from five previous studies. The prognostic algorithm was used to interrogate genomic data from a series of patients treated with adjuvant chemotherapy. Those genes associated with outcome in the adjuvant treatment setting, independent to prognosis were used to train an algorithm able to classify a patient as either a responder or non-responder to ACT. The performance of this signature was independently validated on a separate series of genomic profiles from patients enrolled in a randomized controlled trial of cisplatin/vinorelbine vs. observation alone (JBR.10).
Results
NSCLC patients exhibiting the high-risk, poor-prognosis form of the 160-gene prognosis signature experienced a 2.80-times higher rate of 5-year disease specific death (log rank P < 0.0001) compared to those with the low-risk, good prognosis profile, adjusted for covariates. The prognosis signature was found to especially accurate at identifying early stage patients at risk of disease specific death within 24 months of diagnosis when compared to traditional methods of outcome prediction.
Separately, NSCLC patients with the 37-gene ACT-response signature (n = 70, 64 %), benefited significantly from cisplatin/vinorelbine (adjusted HR: 0.23, P = 0.0032). For those patients predicted to be responders, receiving this form of ACT conferred a 25 % improvement in the probability of 5-year-survival, compared to observation alone and adjusted for covariates. Conversely, in those patients predicted to be non-responders, ACT was observed to offer no significant survival benefit (adjusted HR: 0.55, P = 0.32).
The two gene signatures overlap by one gene only SPSB3, which interacts with the oncogene MET. In this study, higher levels of SPSB3 which were associated with favorable prognosis and benefit from ACT.
Conclusions
These complimentary prognostic and predictive gene signatures may assist physicians in their management and treatment of patients with early stage lung cancer.
doi:10.1186/1755-8794-5-30
PMCID: PMC3407714  PMID: 22748043
24.  A population-based gene signature is predictive of breast cancer survival and chemoresponse 
International journal of oncology  2010;36(3):607-616.
It remains a critical issue to improve the survival rate in patients with recurrent or metastatic breast cancer. This study sought to develop a prognostic scheme based on a 28-gene signature in a broad patient population, including those with advanced disease. Clinically annotated transcriptional profiles of 1,734 breast cancer patients were obtained to validate the 28-gene signature in prognostic categorization. The 28-gene signature generated significant patient stratification with regard to breast cancer disease-free survival (log-rank P < 0.0001; n = 1,337) and overall survival (log-rank P < 0.0001; n = 806) in Kaplan-Meier analyses. The gene expression signature provides refined prognosis of disease-free survival (log-rank P < 0.006; Kaplan-Meier analysis) within each classic clinicopathologic factor-defined subgroup, including LN-, LN+, ER-, ER+, and tumor Grade II. Furthermore, it was investigated whether this gene signature predicts chemoresponse to drugs commonly used to treat breast cancer. The mRNA expression levels of this gene signature in NCI-60 cell lines were used to predict chemoresponse to CMF, Tamoxifen, Paclitaxel, Docetaxel, and Doxorubicin (Adriamycin). The 28-gene prognostic signature accurately (P < 0.02) predicted chemotherapeutic response to the studied drugs. This study confirmed the prognostic applicability of the breast cancer gene signature in a broad clinical setting. This prognostic signature is also predictive of drug response in cancer cell lines.
PMCID: PMC3103999  PMID: 20126981
gene signature; breast cancer prognosis; chemosensitivity prediction; NCI-60 cell lines
25.  Emerging drug discovery approaches for selective targeting of “precursor” metastatic breast cancer cells: highlights and perspectives 
Breast cancer is a prevalent disease and a major cause of morbidity and cancer-related deaths among women worldwide. A significant number of patients at the time of primary diagnosis present metastatic disease, at least to locoregional lymph nodes, which results in somewhat unpredictable prognosis that often prompts adjuvant systemic therapies of various kinds. The time course of distant recurrence is also unpredictable with some patients sustaining a recurrence within months after diagnosis, even during adjuvant treatments, while others can experience recurrence years or decades after initial diagnosis. To date, clinically approved therapeutics yielded marginal benefits for patients with systemic metastatic breast disease, since despite high clinical responses to various therapies, the patients virtually always become resistant and tumor relapses. Molecular profiling studies established that breast cancer is highly heterogeneous and encompasses diverse histological and molecular subtypes with distinct biological and clinical implications in particular in relation to the incidence of progression to metastasis. The latter has been recognized to result from late genetic events during the multistep progression proposed by the dominant theory of carcinogenesis. However, there is evidence that the dissemination of primary cancer can also be initiated at a very early stage of cancer development, originating from rare cell variants, possibly cancer stem-like cells (CSC), with invasive potential. These precursor metastatic cancer cells with stem-like properties are defined by their ability to self-renew and to regenerate cell variants, which have high plasticity and intrinsic invasive properties required for dissemination and tropism toward specific organs. Equally relevant to the CSC hypothesis for metastasis formation is the epithelial-mesenchymal transition (EMT) process, which is critical for the acquisition of cancer cell invasive behavior and for selection/gain of CSC properties. These exciting concepts have led to the formulation of various approaches for targeting precursor metastatic cells, and these have taken on greater priority in therapeutic drug discovery research by both academia and pharmaceuticals. In this review, we focus on current efforts in medicinal chemistry to develop small molecules able to target precursor metastatic cells via interference with the CSC/EMT differentiation program, self-renewal, and survival. It is not meant to be comprehensive and the reader is referred to selected reviews that provide coverage of related basic aspects. Rather, emphasis is given to promising molecules with CSC/EMT signaling at the preclinical stage and in clinical trials that are paving the way to new generations of anti-metastasis drugs.
PMCID: PMC3204890  PMID: 22046485
Breast cancer; metastasis; cancer stem cells; EMT; experimental therapy

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