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2.  Lymphovascular Invasion and Lobular Histology are Associated with Increased Incidence of Isolated Tumor Cells in Sentinel Lymph Nodes from Early-Stage Breast Cancer Patients 
Annals of surgical oncology  2008;15(12):3369-3377.
Background
Isolated tumor cells (ITC) are more likely to be identified when serial sectioning and immunohistochemical staining are used to evaluate sentinel lymph nodes (SLN). Our goal was to identify clinicopathologic features associated with ITC in patients undergoing sentinel lymph node dissection (SLND).
Methods
We reviewed clinicopathologic data for 3557 patients with no clinical evidence of lymph node metastases undergoing SLND between November 1993 and March 2007. Patients were staged according to the 6th edition of the American Joint Committee on Cancer staging system, with metastasis ≤.2 mm classified as ITC.
Results
A SLN was identified in 3475 patients (97.7%), including 2518 (72.4%) with negative nodes and 169 (4.9%) with ITC. A statistically significant association existed between lobular histology and the identification of ITC; 13.6% of patients with ITC had lobular histology versus 7.3% of patients with a negative SLN (P = .003). The presence of lymphovascular invasion (LVI) was also associated with ITC; 18.3% of patients with ITC had LVI in the primary tumor versus 8.5% of patients with a negative SLN (P < .001). No difference existed between patients with and without ITC with respect to T stage, grade, estrogen receptor, progesterone receptor, HER2/neu status, or biopsy method.
Conclusion
The association between ITC and LVI, a known predictor of poor outcome, suggests ITC may have clinical relevance. The relationship between lobular histology and ITC is consistent with the known pattern of lobular metastases, which frequently present as small foci requiring immunohistochemistry for detection. Longer follow-up is needed to determine whether ITC have prognostic significance.
doi:10.1245/s10434-008-0153-2
PMCID: PMC4331098  PMID: 18815841
3.  POSTMASTECTOMY RADIATION IMPROVES THE OUTCOME OF PATIENTS WITH LOCALLY ADVANCED BREAST CANCER WHO ACHIEVE A PATHOLOGIC COMPLETE RESPONSE TO NEOADJUVANT CHEMOTHERAPY 
Purpose
The aim of this study was to investigate the role of postmastectomy radiation therapy in women with breast cancer who achieved a pathologic complete response (pCR) to neoadjuvant chemotherapy.
Methods and Materials
We retrospectively identified 226 patients treated at our institution who achieved a pCR at surgery after receiving neoadjuvant chemotherapy. Of these, the 106 patients without inflammatory breast cancer who were treated with mastectomy were analyzed. The patients’ clinical stages at diagnosis were I in 2%, II in 31%, IIIA in 30%, IIIB in 25%, and IIIC in 11% (American Joint Committee on Cancer 2003 system). Of the patients, 92% received anthracycline-based chemotherapy, and 38% also received a taxane. A total of 72 patients received postmastectomy radiation therapy, and 34 did not. The actuarial rates of local-regional recurrence (LRR) and survival of the two groups were compared using the log-rank test.
Results
The median follow-up of surviving patients was 62 months. Use of radiation therapy did not affect the 10-year rates of LRR for patients with Stage I or II disease (the 10-year LRR rates were 0% for both groups). However, the 10-year LRR rate for patients with Stage III disease was significantly improved with radiation therapy (7.3% ± 3.5% with vs. 33.3% ± 15.7% without; p = 0.040). Within this cohort, use of radiation therapy was also associated with improved disease-specific and overall survival.
Conclusion
Postmastectomy radiation therapy provides a significant clinical benefit for breast cancer patients who present with clinical Stage III disease and achieve a pCR after neoadjuvant chemothearpy.
doi:10.1016/j.ijrobp.2007.01.023
PMCID: PMC4329732  PMID: 17418973
Neoadjuvant chemotherapy; Pathologic complete response; pCR; Breast cancer; Postmastectomy radiation
4.  Increased gene copy number of the vesicle SNARE VAMP7 disrupts human male urogenital development through altered estrogen action 
Nature medicine  2014;20(7):715-724.
Vesicle transport is intimately connected with key nuclear functions and transcriptional regulation. Here, children born with congenital genitourinary tract masculinization disorders were analyzed by array-Comparative Genomic Hybridization, which revealed the presence of de novo copy number gains on Xq28 encompassing the VAMP7 gene encoding a vesicle-trafficking protein. Humanized VAMP7 BAC transgenic mice displayed cryptorchidism, urethral defects, and hypospadias. Mutant mice exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility, and subfertility. VAMP7 colocalized with estrogen receptor alpha (ESR1) in the presence of ligand. Elevated levels of VAMP7 markedly intensified ESR1 transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and up-regulated the expression of estrogen-responsive genes including ATF3, CYR61, and CTGF, all of which are implicated in human hypospadias. Hence, increased gene dosage of the SNARE protein, VAMP7, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract, and results in genitourinary birth defects in humans.
doi:10.1038/nm.3580
PMCID: PMC4283218  PMID: 24880616
5.  Genomic Copy Number Imbalances Associated with Bone and Non-bone Metastasis of Early-Stage Breast Cancer 
Purpose
To identify and validate copy number aberrations in early-stage primary breast tumors associated with bone or non-bone metastasis.
Patients and Methods
Whole-genome molecular inversion probe arrays were used to evaluate copy number imbalances (CNIs) in breast tumors from 960 early-stage patients with information about site of metastasis. The CoxBoost algorithm was used to select metastasis site-related CNIs and to fit a Cox proportional hazards model.
Results
Gains at 1q41 and 1q42.12 and losses at 1p13.3, 8p22, and Xp11.3 were significantly associated with bone metastasis. Gains at 2p11.2, 3q21.3–22.2, 3q27.1, 10q23.1, and 14q13.2–3 and loss at 7q21.11 were associated with non-bone metastasis. To examine the joint effect of CNIs and clinical predictors, patients were stratified into three risk groups (low, intermediate, and high) based on the sum of predicted linear hazard ratios (HRs). For bone metastasis, the hazard (95% confidence interval) for the low-risk group was 0.32 (0.11–0.92) compared to the intermediate-risk group and 2.99 (1.74–5.11) for the high-risk group. For non-bone metastasis, the hazard for the low-risk group was 0.34 (0.17–0.66) and 2.33 (1.59–3.43) for the high-risk group. The prognostic value of loss at 8p22 for bone metastasis and gains at 10q23.1 for non-bone metastasis, and gain at 11q13.5 for both bone and non-bone metastases were externally validated in 335 breast tumors pooled from four independent cohorts.
Conclusions
Distinct CNIs are independently associated with bone and non-bone metastasis for early-stage breast cancer patients across cohorts. These data warrant consideration for tailoring surveillance and management of metastasis risk.
doi:10.1007/s10549-013-2796-3
PMCID: PMC3993091  PMID: 24305980
Breast cancer; bone metastasis; non-bone metastasis; copy number imbalances; molecular inversion probe array
6.  Elafin is downregulated during breast and ovarian tumorigenesis but its residual expression predicts recurrence 
Breast Cancer Research : BCR  2014;16(6):3417.
Introduction
Elafin is an endogenous serine protease inhibitor. The majority of breast cancer cell lines lack elafin expression compared to human mammary epithelial cells. In this study, we hypothesized that elafin is downregulated during breast and ovarian tumorigenesis.
Methods
We examined elafin expression by immunohistochemistry (IHC) in specimens of normal breast tissue (n = 24), ductal carcinoma in situ (DCIS) (n = 54), and invasive breast cancer (n = 793). IHC analysis of elafin expression was also performed in normal fallopian tube tissue (n = 20), ovarian cystadenomas (n = 9), borderline ovarian tumors (n = 21), and invasive ovarian carcinomas (n = 216). To understand the significance of elafin in luminal breast cancer cell lines, wild-type or M25G elafin (lacking the protease inhibitory function) were exogenously expressed in MCF-7 and T47D cells.
Results
Elafin expression was downregulated in 24% of DCIS and 83% of invasive breast tumors when compared to elafin expression in the normal mammary epithelium. However, the presence of elafin-positive cells in invasive breast tumors, even at low frequency, correlated with poor recurrence-free survival (RFS), reduced overall survival (OS), and clinicopathological markers of aggressive tumor behavior. Elafin-positive cells were an especially strong and independent prognostic marker of reduced RFS in IHC-defined luminal A-like tumors. Elafin was also downregulated in 33% of ovarian cystadenomas, 43% of borderline ovarian tumors, and 86% of invasive ovarian carcinomas when compared to elafin expression in the normal fallopian tube. In ovarian tumors, elafin-positive cells were correlated with reduced RFS, OS and disease-specific survival (DSS) only in stage I/II patients and not in stage III/IV patients. Notably, exogenous expression of elafin or elafin M25G in the luminal breast cancer cell lines MCF-7 and T47D significantly decreased cell proliferation in a protease inhibitory domain-independent manner.
Conclusions
Elafin predicts poor outcome in breast and ovarian cancer patients and delineates a subset of endocrine receptor-positive breast cancer patients susceptible to recurrence who could benefit from more aggressive intervention. Our in vitro results suggest that elafin arrests luminal breast cancer cells, perhaps suggesting a role in tumor dormancy.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0497-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0497-4
PMCID: PMC4326485  PMID: 25551582
7.  Breast Cancer Molecular Signatures as Determined by SAGE: Correlation with Lymph Node Status 
Molecular cancer research : MCR  2007;5(9):881-890.
Global gene expression measured by DNA microarray platforms have been extensively used to classify breast carcinomas correlating with clinical characteristics, including outcome. We generated a breast cancer Serial Analysis of Gene Expression (SAGE) high-resolution database of ~2.7 million tags to perform unsupervised statistical analyses to obtain the molecular classification of breast-invasive ductal carcinomas in correlation with clinicopathologic features. Unsupervised statistical analysis by means of a random forest approach identified two main clusters of breast carcinomas, which differed in their lymph node status (P = 0.01); this suggested that lymph node status leads to globally distinct expression profiles. A total of 245 (55 up-modulated and 190 down-modulated) transcripts were differentially expressed between lymph node (+) and lymph node (−) primary breast tumors (fold change, ≥2; P < 0.05). Various lymph node (+) up-modulated transcripts were validated in independent sets of human breast tumors by means of real-time reverse transcription-PCR (RT-PCR). We validated significant overexpression of transcripts for HOXC10 (P = 0.001), TPD52L1 (P = 0.007), ZFP36L1 (P = 0.011), PLINP1 (P = 0.013), DCTN3 (P = 0.025), DEK (P = 0.031), and CSNK1D (P = 0.04) in lymph node (+) breast carcinomas. Moreover, the DCTN3 (P = 0.022) and RHBDD2 (P = 0.002) transcripts were confirmed to be overexpressed in tumors that recurred within 6 years of follow-up by real-time RT-PCR. In addition, meta-analysis was used to compare SAGE data associated with lymph node (+) status with publicly available breast cancer DNA microarray data sets. We have generated evidence indicating that the pattern of gene expression in primary breast cancers at the time of surgical removal could discriminate those tumors with lymph node metastatic involvement using SAGE to identify specific transcripts that behave as predictors of recurrence as well.
doi:10.1158/1541-7786.MCR-07-0055
PMCID: PMC4186709  PMID: 17855657
8.  DEAR1 is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGFβ-Driven Epithelial-Mesenchymal Transition 
Cancer discovery  2013;3(10):1172-1189.
Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum with both Dear1−/− and Dear1+/− mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice. DEAR1 loss of function in the presence of TGFβ results in failure of acinar morphogenesis, upregulation of EMT markers, anoikis resistance, migration and invasion. Furthermore, DEAR1 blocks TGFβ-SMAD3 signaling resulting in decreased nuclear phosphorylated SMAD3 by binding to and promoting the ubiquitination of SMAD3, the major effector of TGFβ-induced EMT. Moreover, DEAR1 loss increases levels of SMAD3 downstream effectors, SNAI1 and SNAI2, with genetic alteration of DEAR1/SNAI2 serving as prognostic markers of overall poor survival in an 889 invasive breast cancer cohort.
doi:10.1158/2159-8290.CD-12-0499
PMCID: PMC4107927  PMID: 23838884
DEAR1; tumor suppressor; EMT; TGFβ; Signaling; SMAD3 ubiquitination
9.  From Mice to Humans: Identification of Commonly Deregulated Genes in Mammary Cancer via Comparative SAGE Studies 
Cancer research  2004;64(21):7748-7755.
Genetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mouse mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (>300,000 mouse mam-mary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (>2.5 million human breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all of the tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKBα), GADD45B, and CDKN1A (p21); transcription-related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets.
This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.
doi:10.1158/0008-5472.CAN-04-1827
PMCID: PMC4170686  PMID: 15520179
10.  Identification of Novel Amplification Gene Targets in Mouse and Human Breast Cancer at a Syntenic Cluster Mapping to Mouse Identification of Novel Amplification Gene Targets in Mouse and Human Breast Cancer at a Syntenic Cluster Mapping to Mouse ch8A1 and Human ch13q34 
Cancer research  2007;67(9):4104-4112.
Serial analysis of gene expression from aggressive mammary tumors derived from transplantable p53 null mouse mammary outgrowth lines revealed significant up-regulation of Tfdp1 (transcription factor Dp1), Lamp1 (lysosomal membrane glycoprotein 1) and Gas6 (growth arrest specific 6) transcripts. All of these genes belong to the same linkage cluster, mapping to mouse chromosome band 8A1. BAC-array comparative genomic hybridization and fluorescence in situ hybridization analyses revealed genomic amplification at mouse region ch8A1.1. The minimal region of amplification contained genes Cul4a, Lamp1, Tfdp1, and Gas6, highly overexpressed in the p53 null mammary outgrowth lines at preneoplastic stages, and in all its derived tumors. The same amplification was also observed in spontaneous p53 null mammary tumors. Interestingly, this region is homologous to human chromosome 13q34, and some of the same genes were previously observed amplified in human carcinomas. Thus, we further investigated the occurrence and frequency of gene amplification affecting genes mapping to ch13q34 in human breast cancer. TFDP1 showed the highest frequency of amplification affecting 31% of 74 breast carcinomas analyzed. Statistically significant positive correlation was observed for the amplification of CUL4A, LAMP1, TFDP1, and GAS6 genes (P < 0.001). Meta-analysis of publicly available gene expression data sets showed a strong association between the high expression of TFDP1 and decreased overall survival (P = 0.00004), relapse-free survival (P = 0.0119), and metastasis-free interval (P = 0.0064). In conclusion, our findings suggest that CUL4A, LAMP1, TFDP1, and GAS6 are targets for overexpression and amplification in breast cancers. Therefore, overexpression of these genes and, in particular, TFDP1 might be of relevance in the development and/or progression in a significant subset of human breast carcinomas.
doi:10.1158/0008-5472.CAN-06-4672
PMCID: PMC4166497  PMID: 17483321
11.  Src family kinases as novel therapeutic targets to treat breast cancer brain metastases 
Cancer research  2013;73(18):5764-5774.
Despite better control of early stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer, and we show how a Src-targeting combinatorial regimen can treat HER2+ brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients’ brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, a Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells_through the induction of cell cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat breast cancer patients suffering from brain metastasis.
doi:10.1158/0008-5472.CAN-12-1803
PMCID: PMC3781592  PMID: 23913825
Src; Breast cancer; Brain metastasis; Blood brain barrier; Lapatinib; Saracatinib
12.  Genitourinary Defects Associated with Genomic Deletions in 2p15 Encompassing OTX1 
PLoS ONE  2014;9(9):e107028.
Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1–4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2–7 had large de novo CNVs (2.39–6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.
doi:10.1371/journal.pone.0107028
PMCID: PMC4159299  PMID: 25203062
13.  Frequent loss of WWOX expression in breast cancer: correlation with estrogen receptor status 
Summary
WWOX is a cancer gene, spanning the common chromosomal fragile site 16D. Genomic and expression aberrations affecting this gene and locus are common in various neoplasias including breast cancer. The aim of the present study was to evaluate the relationship between WWOX expression at the protein level with respect to clinico-pathological characteristics. We performed immunohistochemical analyses on breast specific tissue microarrays representing, human normal breast epithelium (n=16), ductal carcinoma in situ (n=15) and invasive breast cancer cases (n=203). Staining intensity measurements were objectively determined utilizing an image analysis system. Western blot analyses were also performed on an independent set of 23 invasive breast carcinomas. All normal breast epithelial samples express WWOX protein abundantly while 34% (69/203 cases) of invasive breast carcinomas were ‘completely negative’ for WWOX expression and an additional 26% (52/203) of cases expressed WWOX very weakly. For DCIS samples five out of 15 (33%) were negative or weak for WWOX staining. Interestingly, we found a statistically significant correlation between WWOX expression and estrogen receptor (ER) status, 27% of ER+ breast carcinomas were completely negative for WWOX expression versus 46% for ER−cases ( p = 0.0054). Furthermore, when negative plus weakly WWOX stained cases were considered the difference became more significant with 51% of ER+ cases and 73% for the ER − group, with a p=0.003. These data indicate that loss of WWOX expression is a common event in breast cancer. It is unclear at this point whether loss of WWOX expression is a consequence of tumor progression or represents a subclass of breast carcinomas. The strong association of WWOX expression with ER status reinforces the suggested role of this protein as an enzyme involved in sex steroid metabolism.
doi:10.1007/s10549-004-1474-x
PMCID: PMC4145848  PMID: 15692750
breast cancer; estrogen receptor; FRA16D; tumor suppressor; WWOX
14.  Age and Survival Estimates in Patients Who Have Node-Negative T1ab Breast Cancer by Breast Cancer Subtype 
Clinical breast cancer  2011;11(5):325-331.
The treatment of tumors ≤1 cm are difficult to treat as recurrence rates are difficult to assess. The purpose of this study was to assess recurrence by underlying triple receptor subtype and by age, both of which had significant impact on outcomes.
Aim
This article evaluates the risk of recurrence for patients who have small node-negative breast cancer by age and tumor subtype.
Methods
One thousand twelve patients with a T1a,bN0 breast cancer diagnosed between 1990 and 2002 who did not receive chemotherapy or trastuzumab were included. Patients and tumor characteristics were compared using the χ2 or Wilcoxon’s rank sum tests. Survival outcomes were estimated with the Kaplan-Meier method and compared using the log-rank statistic. Cox proportional hazards models were used to determine association of breast cancer subtypes and age at diagnosis with other covariates.
Results
Median age was 51.5 years. There were 771 hormone receptor (HR)-positive, 98 HER2-positive, and 143 triple-negative breast cancers (TNBC). Six hundred ninety-three patients were > 50 years, and 33 patients were ≤ 35 years. For 5-year survival estimates, there were 118 deaths and overall survival was 94.6% (95% confidence interval [CI] = 93.2%, 96.1%). After adjusting for breast cancer subtype and other tumor characteristics, patients ≤ 35 had 2.51 (95% CI = 1.21–5.22) times greater risk of worse recurrence-free survival (RFS), and 2.60 (95% CI = 1.05–6.46) times greater risk of worse distant RFS (DRFS) compared to patients > 50 years old. Compared to patients with HR-positive disease, patients with HER2-positive breast cancer had 4.98 (95% CI = 2.91–8.53) times the risk of worse RFS and 4.70 (95% CI = 2.51–8.79) times greater risk of worse DRFS, and patients with TNBC had 2.71 (95% CI = 1.59–4.59) times greater risk of worse RFS and 2.08 (95% CI = 1.04–4.17) times greater risk of worse DRFS.
Conclusions
In this cohort, patients with T1a,bN0 breast cancer, young age and breast cancer subtype were significantly associated with RFS and DRFS.
doi:10.1016/j.clbc.2011.05.002
PMCID: PMC4104010  PMID: 21764391
Distant recurrence-free survival; HER2; Hormone receptor; Recurrence-free survival; Triple-negative breast cancer
15.  The Relationship Between Eight GWAS-Identified Single-Nucleotide Polymorphisms and Primary Breast Cancer Outcomes 
The Oncologist  2013;18(5):493-500.
Several single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies. This study investigated the association of eight risk SNPs with breast cancer disease-free survival and overall survival rates. Results suggest that two previously identified breast cancer risk susceptibility loci may influence breast cancer prognosis or comorbid conditions associated with overall survival.
Learning Objectives
Describe the results of genome-wide association studies (GWAS) that have identified genetic variants associated with breast cancer risk.Discuss whether genetic risk variants identified through genome-wide association studies (GWAS) are also associated with breast cancer prognosis.Describe molecular mechanisms through which germline genetic variants may influence breast cancer survival.
Background.
Several single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies (GWAS). We investigated whether eight risk SNPs identified in GWAS were associated with breast cancer disease-free survival (DFS) and overall survival (OS) rates.
Patients and Methods.
A cohort of 739 white women with early-stage breast cancer was genotyped for eight GWAS-identified SNPs (rs2981582, rs1219648 [FGFR2], rs3803662, rs12443621, rs8051542 [TOX3], rs999737 [RAD51L1], rs6504950 [17q23], and rs4973768 [3p24]). Relationships between SNPs and breast cancer outcomes were evaluated using Cox proportional hazard regression models. The cumulative effects of SNPs on breast cancer outcomes were assessed by computing the number of at-risk genotypes.
Results.
At a median follow-up of 121 months (range: 188–231 months) for survivors, 237 deaths (32%) and 186 breast cancer events (25%) were identified among the 739 patients. After adjusting for age, clinical stage, and treatment, rs12443621 (16q12; p = .03) and rs6504950 (17q23; p = .008) were prognostic for OS but not DFS. A higher risk for death was also found in the multivariable analysis of patients harboring three or four at-risk genotypes of the GWAS SNPs compared to patients carrying two or less at-risk genotypes (hazard ratio: 1.60, 95% confidence interval: 1.23–2.24; p = .0008).
Conclusion.
The study results suggest that previously identified breast cancer risk susceptibility loci, rs12443621 (16q12) and rs6504950 (17q23), may influence breast cancer prognosis or comorbid conditions associated with overall survival. The precise molecular mechanisms through which these risk SNPs, as well as others that were not included in the analysis, influence clinical outcomes remain to be determined.
doi:10.1634/theoncologist.2012-0419
PMCID: PMC3662839  PMID: 23635555
Breast cancer; Prognosis; Single-nucleotide polymorphisms; TNRC9; 17q23
16.  Prognostic Value of Single Nucleotide Polymorphisms of Candidate Genes Associated with Inflammation in Early Stage Breast Cancer 
To examine the role of germline genetic variations in inflammatory pathways as modifiers of time to recurrence (TTR) in patients with early stage breast cancer (BC), DNA from 997 early stage BC patients was genotyped for 53 tagging single nucleotide polymorphisms (SNPs) in 12 genes involved in inflammation. SNPs were analyzed separately for Caucasians versus African Americans and Hispanics. Cox proportional hazards models were used to evaluate the association between SNPs in the inflammatory genes and time to recurrence (TTR), adjusted for clinical and pathologic covariates. In univariable analyses of Caucasian women, the homozygous genotype of 12 SNPs, including 6 NFKB1 SNPs, 4 IL4 SNPs, and 2 IL13 SNPs, were significantly associated with a decrease in TTR compared with the heterozygous and/ or corresponding homozygous genotype (P <0.05). The significant NFKB1 and IL4 SNPs were in an area of high linkage disequilibrium (D'>0.8). After adjusting for stage, age, and treatment, carriage of the homozygous genotypes for NFKB1rs230532 and IL13rs1800925 were independently associated with a shorter TTR (P=0.001 and p=0.034, respectively). In African-American and Hispanic patients, expression of NFKB1rs3774932, TNFrs1799964, and IL4rs3024543 SNPs were associated with a shorter TTR in univariable model. Only NFKB1 rs3774932 (P=0.02) and IL4Rrs3024543 (P=0.03) had independent prognostic value in the multivariable model These data support the existence of host genetic susceptibility as a component in recurrence risk mediated by pro-inflammatory and immune factors, and suggest the potential for drugs which modify immune responses and inflammatory genes to improve prognosis in early stage BC.
doi:10.1007/s10549-013-2445-x
PMCID: PMC3746974  PMID: 23529385
gene polymorphisms; inflammation; breast cancer
17.  Genetic variants in the vitamin D pathway and breast cancer disease-free survival 
Carcinogenesis  2012;34(3):587-594.
Epidemiological studies have investigated the association between vitamin D pathway genes and breast cancer risk; however, little is known about the association between vitamin D pathway genes and breast cancer prognosis. In a retrospective cohort of 1029 patients with early-stage breast cancer, we analyzed the association between 106 tagging single nucleotide polymorphisms (SNPs) in eight vitamin D pathway genes and breast cancer disease-free survival (DFS) using Cox regression analysis adjusted for known prognostic variables. Using a false discovery rate of 10%, six intronic SNPs were significantly associated with poorer DFS: retinoid-X receptor alpha (RXRA) SNPs (rs881658, rs11185659, rs10881583, rs881657 and rs7864987) and plasminogen activator and urokinase receptor (PLAUR) SNP (rs4251864). Treatment received (no systemic therapy, hormone therapy alone or chemotherapy) was an effect modifier of the RXRA SNPs association with DFS (P < 0.05); therefore, we stratified further analysis by treatment group. Among patients who did not receive systemic therapy, RXRA SNP [rs10881583 (P = 0.02)] was associated with poorer DFS, and among patients who received chemotherapy, RXRA SNPs (rs881658, rs11185659, rs10881583, rs881657 and rs7864987) were associated with poorer DFS (P < 0.001 for all SNPs). However, RXRA SNPs: rs10881583 (P < 0.001) and rs881657 (P = 0.02) were associated with improved DFS in patients treated with hormone therapy alone. Our results suggest that SNPs in the RXRA and PLAUR genes in the vitamin D pathway may contribute to breast cancer DFS. In particular, SNPs in RXRA may predict for poorer or improved DFS in patients, according to type of systemic treatment received. If validated, these markers could be used for risk stratification of breast cancer patients.
doi:10.1093/carcin/bgs369
PMCID: PMC3581599  PMID: 23180655
18.  Outcomes of Sentinel Lymph Node Dissection Alone vs. Axillary Lymph Node Dissection in Early Stage Invasive Lobular Carcinoma: A Retrospective Study of the Surveillance, Epidemiology and End Results (SEER) Database 
PLoS ONE  2014;9(2):e89778.
Background
The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in local-regional recurrence (LRR), disease-specific survival (DSS) or overall survival (OS) for sentinel lymph node dissection (SLND) and completion axillary lymph node dissection (ALND) among patients undergoing breast-conserving therapy for clinical T1–T2, N0 breast cancer with 1 or 2 positive SLNs. However, Only 7% of study participants had invasive lobular carcinoma (ILC). Because ILC has a different pattern of metastases, frequently presenting as small foci requiring immunohistochemistry for detection, the applicability of ACOSOG Z0011 trial data to ILC patients is unclear.
Study Design
We identified all ILC patients in the Surveillance, Epidemiology, and End Results (SEER) database (1998–2009) who met the ACOSOG Z0011 eligibility criteria. Patients were evaluated on the basis of the extent of axillary surgery (SLND alone or ALND), and the clinical outcomes of these 2 groups were compared.
Results
1269 patients (393 SLND and 876 ALND) were identified from the SEER database. At a median follow-up time of 71 months, there were no differences in OS or disease-specific survival between the two groups.
Conclusion
SLND alone may result in outcomes comparable to those achieved with ALND for patients with early-stage ILC who meet the ACOSOG Z0011 eligibility criteria.
doi:10.1371/journal.pone.0089778
PMCID: PMC3934955  PMID: 24587029
19.  Hormone Receptor Status Influences the Locoregional Benefit of Trastuzumab in Patients with Non-metastatic Breast Cancer 
Cancer  2012;118(20):4936-4943.
BACKGROUND
Previous studies have shown that hormone receptor (HR) and HER2 status influence the outcome of locoregional treatments. However, the interrelationship of these factors with trastuzumab is unclear. We sought to determine the role of HR and HER2 status on the locoregional benefit of trastuzumab treatment in patients with non-metastatic breast cancer.
METHODS
Locoregional outcomes of 5683 women treated in our institution from 2000–2008 for invasive breast cancer were analyzed using Kaplan-Meier and Cox regression methods to compare 6 subgroups: HR+/HER2−, HR−/HER2− (triple-negative), HR+/HER2+ with or without trastuzumab, and HR−/HER2+ with or without trastuzumab.
RESULTS
Overall, LRR was 5% at 5 years among patients with HER2+ disease. Patients with HR+/HER2+ disease treated with trastuzumab had half the rate of LRR as patients that did not receive trastuzumab, whereas patients with HR−/HER2+ disease had similar rates of LRR regardless of trastuzumab treatment. On Cox regression analysis comparing LRR risk to the cohort with HR+/HER2− disease, only the HR+/HER2+ cohort treated with trastuzumab had similar LRR risk (HR 1.24, 95% CI 0.56–2.73, p=0.591). All other subgroups, including the HR+/HER2+ cohort who did not receive trastuzumab, had significantly worse outcomes. LRR risk was highest among patients with triple-negative disease (HR 4.73, 95% CI 3.42–6.54, p<0.001).
CONCLUSION(S)
Among patients with HR+/HER2+ disease, treatment with trastuzumab reduces LRR risk to the more favorable outcome of patients with HR+/HER2− disease. In contrast, the increased LRR risk among patients with HR−/HER2+ disease remains despite treatment with trastuzumab. Additional locoregional strategies are needed in this subgroup of patients.
doi:10.1002/cncr.27502
PMCID: PMC3888990  PMID: 22511276
Hormone receptor; locoregional; trastuzumab; non-metastatic; breast cancer
20.  Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways 
Nature medicine  2011;17(4):10.1038/nm.2309.
Trastuzumab is a successful rationally designed ERBB2-targeted therapy. However, about half of individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies, owing to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. We show that the nonreceptor tyrosine kinase c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. We find that SRC is activated in both acquired and de novo trastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involving dephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.
doi:10.1038/nm.2309
PMCID: PMC3877934  PMID: 21399647
21.  Cancer stem cell markers are enriched in normal tissue adjacent to triple negative breast cancer and inversely correlated with DNA repair deficiency 
Introduction
We hypothesized that cells present in normal tissue that bear cancer stem cell markers may represent a cancer cell of origin or a microenvironment primed for tumor development, and that their presence may correlate with the clinically defined subtypes of breast cancer that show increased tumorigenicity and stem cell features.
Methods
Normal tissues sampled at least 5 cm from primary tumors (normal adjacent tissue) were obtained from 61 chemotherapy-naive patients with breast cancer treated with mastectomy. Samples were stained simultaneously with immunofluorescence for CD44/CD49f/CD133/2 stem cell markers. We assessed the association between CD44+CD49f+CD133/2+ staining in normal adjacent tissue and breast cancer receptor subtype (defined by the expression of the estrogen (ER), progesterone (PR), or human epidermal growth factor-2 (Her2) receptors). We also examined the correlation between CD44+CD49f+CD133/2+ immunofluorescence and each of two previously published gene signatures, one derived from stem-cell enriched tissue and one from BRCA mutated tissue expected to have defective DNA repair.
Results
Patients with triple negative breast cancer (ER–/PR–/HER2–) expressed CD44+CD49f+CD133/2+ in 9 of 9 normal adjacent tissue samples compared with 7 of 52 ER+ and/or Her2+ tumors (P < 0.001). Further, expression of CD44+CD49f+CD133/2+ by normal adjacent tissue correlated positively with a stem cell-derived tumorigenic signature (P <0.001) and inversely with a defective DNA-repair signature (P <0.001).
Conclusion
Normal cells bearing cancer stem cell markers are associated with the triple negative receptor subtype of breast cancer. This study suggests stem cell staining and gene expression signatures from normal breast tissues represent novel tissue-based risk biomarkers for triple negative breast cancer. Validation of these results in additional studies of normal tissue from cancer-free women could lay the foundation for future targeted triple negative breast cancer prevention strategies.
doi:10.1186/bcr3471
PMCID: PMC4053576  PMID: 24008095
23.  Efficacy of Neoadjuvant Therapy with Trastuzumab Concurrent with Anthracycline- and Non-anthracycline-based Regimens for HER2-Positive Breast Cancer 
Cancer  2011;118(9):2385-2393.
Background
To evaluate the pathologic complete response (pCR) rates and relapse-free survival (RFS) and overall survival (OS) of patients receiving neoadjuvant systemic therapy (NST) with trastuzumab in combination with an anthracycline- or a non-anthracycline-based regimen.
Methods
In this retrospective non-randomized study, we reviewed records of 300 patients with HER2-positive breast cancer treated with either sequential paclitaxel and trastuzumab and FEC75 in combination with trastuzumab (PH-FECH) or docetaxel, carboplatin and trastuzumab (TCH). The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models and Cox proportional hazards models were fit to determine the associations between NST, pCR and survival.
Results
There was no significant difference in the decline in cardiac ejection fraction, however, patients who received PH-FECH had less cardiac comorbidities at baseline (P = 0.002). pCR rates were 60.6% and 43.3% for patients who received PH-FECH(n=235) and TCH(n=65), respectively (P=0.016). Patients who received PH-FECH were 1.45 times more likely to have a pCR (Odds ratio [OR]:1.45; 95% confidence interval (CI):1.06-1.98; P=0.02). Three-year RFS rates were 93% and 71% (P<0.001), and 3-year OS rates were 96% and 86% (P=0.008) for patients who received PH-FECH and TCH, respectively. Patients who received PH-FECH had a lower risk of recurrence (Hazard ratio [HR]:0.27; 95% CI:0.12-0.60; P=0.001) and death (HR:0.37; 95% CI:0.12-1.13; P=0.08) than those treated with TCH.
Conclusion
The type of NST in HER2-positive breast cancer is predictive of pCR rate independent of disease and patient characteristics. While TCH is active, PH-FECH shows a higher pCR rate and RFS advantage.
doi:10.1002/cncr.26555
PMCID: PMC3274632  PMID: 21953213
HER2-positive breast cancer; neoadjuvant therapy; trastuzumab; anthracyclines; pCR; survival
24.  Metastasis associated protein 1 short-form stimulates Wnt1 pathway in mammary epithelial and cancer cells 
Cancer research  2010;70(16):6598-6608.
Although Wnt1 downstream signaling components as well as cytoplasmic level of metastatic tumor antigen 1 short-form (MTA1s) have been shown to be elevated in human breast cancer, it remains unknown whether a regulatory cross-talk exists between these two pathways. Here we provide evidence of a remarkable correlation between the levels of MTA1s and stimulation of the Wnt1 signaling components, leading to increased stabilization of β-catenin, and stimulation of Wnt1 target genes in the murine mammary epithelial and human breast cancer cells. We found that MTA1s influences Wnt1 pathway via ERK signaling as selective silencing of the endogenous MTA1s or ERK or its target GSK-3β resulted in a substantial decrease in β-catenin expression, leading to inhibition of Wnt1-target genes. Furthermore, downregulation of β-catenin in cells with elevated MTA1s level was accompanied by a corresponding decrease in the expression of Wnt1 target genes, establishing a mechanistic role for the ERK/GSK-3β/ β-catenin pathway in the stimulation of the Wnt1 target genes by MTA1s in mammary epithelial cells. In addition, mammary glands from the virgin MTA1s transgenic mice mimicked the phenotypic changes found in the Wnt1 transgenic mice and exhibited an overall hyperactivation of the Wnt1 signaling pathway, leading to increased stabilization and nuclear accumulation of β-catenin. Mammary glands from the virgin MTA1s-TG mice revealed ductal hyperplasia and ductal carcinoma in situ, and low incidence of palpable tumors. These findings reveal a previously unrecognized role for MTA1s as an important modifier of the Wnt1 signaling in mammary epithelial and cancer cells.
doi:10.1158/0008-5472.CAN-10-0907
PMCID: PMC3617568  PMID: 20710043
25.  Impact of low estrogen/progesterone receptor expression on survival outcomes in breast cancers previously classified as triple negative breast cancers 
Cancer  2011;118(6):1498-1506.
Purpose
To evaluate the impact of low ER/PR expression and effect of endocrine therapy on survival outcomes in HER2-negative tumors with ER/PR < 10%, previously labeled as triple negative.
Methods
In a retrospective review, 1257 patients were categorized according their ER/PR percentages into three groups, ER/PR <1% (Group A), ER/PR 1–5% (Group B) and ER/PR 6–10% (Group C). Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics.
Results
Group A, B and C had 897 (71.4%), 241 (19.2%) and 119 (9.4%) patients respectively. After a median follow up of 40 months there was no significant difference in 3-year recurrence free survival (RFS): 64%, 67% and 77% (P = 0.34) or overall survival (OS): 79%, 81% and 88% (P = 0.33) for groups A, B and C respectively. ER/PR expression was not an independent predictor for RFS (HR=1.10, 95% CI: 0.86–1.39, P=0.46 for group B and HR=0.96, 95% CI: 0.66–1.38, P=0.81 for group C, compared to group A), or OS (HR=1.11, 95% CI: 0.84–1.46, P=0.46 for group B and HR=0.94, 95% CI: 0.63–1.42, P=0.78 for group C, compared to group A). Endocrine therapy had no impact on survival outcomes (RFS: P=0.10; OS: P=0.45) among groups.
Conclusions
In this cohort, a low ER/PR level (1–5%) does not appear to have any significant impact on survival outcomes. There was a tendency for survival advantages in the ER/PR 6–10% is seen. Benefit of endocrine therapy in these patients is unclear.
doi:10.1002/cncr.26431
PMCID: PMC3217101  PMID: 21837669
Estrogen Receptor; Progesterone Receptor; Breast cancer; Prognosis; Immunohistochemistry

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