Negative Breast Carcinoma Research Articles

Prevalence, clinicopathological characteristics and short term survival of triple negative and basal like breast carcinoma in a cohort of Sri Lankan patients

Introduction Information on triple-negative (TNBC) and basal-like (BLBC) breast carcinoma (BCa) is limited in South-Asia. We aimed to determine the prevalence and clinicopathological characteristics of TNBC and BLBC and shortterm survival of TNBC among a cohort of BCa patients. Methodology Clinicopathological characteristics and short term survival of 211 women with BCa treated at the National Hospital of Sri Lanka from 2012-2014 were analyzed, excluding postneoadjuvant chemotherapy cases. Immunohistochemistry for hormonal and HER2 receptors and basal markers (CK5/6, CK14, EGFR, 34βE12) were performed on TNBCs. Data was analyzed using chi-squared test, logistic and Cox-regression. Results Forty-five (21.33%) were TNBC (95%, CI=15.8%-26.86%), correlating with younger age (p=0.03), premenopausal state (p=0.047), negative lymph nodes (p=0.016), lower stage (p=0.011), higher Nottingham grade (p Discussion TNBC prevalence was comparable to studies from the Indian-subcontinent, however, higher than in the West. Clinicopathological characteristics were similar. Lack of association with adverse short-term survival was possibly due to exclusion of postchemotherapy cases. Conclusion Triple negative breast carcinoma prevalence was 21.33%. Younger age, premenopausal status, low TNM stage, high tumour grade, necrosis, pushing margins, lymphoid infiltrate at tumour margin, absent DCIS and absent/mild central desmoplasia were predictive of triple negative breast carcinoma. Moderate/extensive necrosis in a tumour with this morphology was predictive of basal like breast carcinoma. Triple negative breast carcinoma was not predictive of adverse short-term survival.

Anti-Invasive and Anti-Proliferative Synergism between Docetaxel and a Polynuclear Pd-Spermine Agent.

The present work is aimed at evaluating the antitumour properties of a Pd(II) dinuclear complex with the biogenic polyamine spermine, by investigating: i) the anti-angiogenic and anti-migration properties of a Pd(II) dinuclear complex with spermine (Pd2Spm); ii) the anti-proliferative activity of Pd2Spm against a triple negative human breast carcinoma (MDA-MB-231); and finally iii) the putative interaction mediated by combination of Pd2Spm with Docetaxel. Anti-invasive (anti-angiogenic and anti-migratory) as well as anti-proliferative capacities were assessed, for different combination schemes and drug exposure times, using the CAM assay and VEGFR2 activity measurement, the MatrigelTM method and the SRB proliferation test. The results thus obtained evidence the ability of Pd2Spm to restrict angiogenesis and cell migration: Pd2Spm induced a marked inhibition of migration (43.8±12.2%), and a higher inhibition of angiogenesis (81.8±4.4% for total length values, at 4 μM) as compared to DTX at the clinical dosage 4x10-2 μM (26.4±14.4%; n = 4 to 11). Combination of Pd2Spm/DTX was more effective as anti-invasive and anti-proliferative than DTX or Pd2Spm in sole administration, which is compatible with the occurrence of synergism: for the anti-angiogenic effect, IC50(Pd2Spm/DTX) = 0.5/0.5x10-2 μM vs IC50(DTX) = 1.7x10-2 μM and IC50(Pd2Spm) = 1.6 μM. In conclusion, the reported effects of Pd2Spm on angiogenesis, migration and proliferation showed that this compound is a promising therapeutic agent against this type of breast cancer. Moreover, combined administration of Pd2Spm and DTX was found to trigger a substantial synergetic effect regarding angiogenesis inhibition as well as anti-migratory and anti-proliferative activities reinforcing the putative use of Pd(II) complexes in chemotherapeutic regimens. This is a significant outcome, aiming at the application of these combined strategies towards metastatic breast cancer (or other type of resistant cancers), justifying further studies that include pre-clinical trials.

Preliminary study on quantitative proteomic analysis of differentially expressed proteins in HER-2 positive and negative breast cancer

Objective To seek differentially expressed proteins for human epithelial growth factor receptor-2 (HER-2) negative and positive breast carcinoma through establishing proteins profiles, and to provide new prognostic markers and therapeutic targets for patients with breast cancer. Methods HER-2 positive and negative breast cancer protein expression profiles were established using proteomic isobaric tags for relative and absolute quantitation (iTRAQ) technology. Differences of protein expression were identified and parts of differential expression proteins were analyzed by bio-informatics, including protein function annotation and GO classification analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis. Results Proteomic analysis of breast cancer tissue with identified HER-2 positive and negative groups showed 4 999 diffe-rentially expressed proteins by iTRAQ. Based on the criteria of the ratio of HER-2(+ )/HER-2(-)≥3, 119 up-regulated proteins were identified in HER-2 positive group. Based on the criteria of the ratio of HER-2(+ )/HER-2(-)≤0.5, 47 down-regulated proteins were identified in HER-2 positive group. The results of GO analysis showed that the molecular function, biological process and cellular composition of differentially expressed proteins were complex between HER-2 positive and negative breast cancer. There were differences in the distribution of up-regulated proteins and down-regulation of proteins. KEGG pathway analysis showed that differentially expressed proteins involved in 168 signal pathways. Conclusion There are differentially expressed proteins between HER-2 positive and negative breast cancer, which involve complex molecular function, biological process and signaling pathway. Key words: Breast neoplasms; Receptor, epidermal growth factor; Proteomics; Computational biology

1539P - Androgen receptor and estrogen receptor beta interplay in triple negative breast carcinomas

1539P - Androgen receptor and estrogen receptor beta interplay in triple negative breast carcinomas

Breast carcinoma with an Oncotype Dx recurrence score

A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse transcriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall chemotherapy use. The current study examined the treatments and outcomes in patients with low RS. The authors reviewed the institutional database to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institution between September 2008 and August 2013 and their 21-gene RS results. A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0-10 and 896 patients had an RS of 11-17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged <40 years. Overall, 1361 patients (97%) received endocrine therapy and 170 patients (12%) received chemotherapy. The median follow-up was 46 months. Six patients (0.4%) developed distant metastases (1 patient with an RS of 5 and 5 patients with an RS of 11-17). In the cohorts of patients with an RS of 11 to 17, the absolute rate of distant metastasis among patients aged <40 years was 7.1% (3 of 42 patients) versus 0.2% among patients aged ≥40 years (2 of 854 patients). The data from the current study document a 0.4% rate of distant metastasis within 5 years of BC diagnosis among patients with lymph node-negative ER+/HER2- BC with an RS <18. Patients aged <40 years at the time of BC diagnosis were observed to have a higher rate of distant metastases. Analysis of data from other studies is necessary to validate this observation further. Cancer 2017;131-137. © 2016 American Cancer Society.

Prognostic value of androgen receptor expression in triple negative breast carcinomas: personal experience and comments on a review about "Triple-negative breast cancer: treatment challenges and solutions" by Collignon et al.

Prognostic value of androgen receptor expression in triple negative breast carcinomas: personal experience and comments on a review about "Triple-negative breast cancer: treatment challenges and solutions" by Collignon et al.

Abstract 2271: bcl-2 expression in HER2-positive breast carcinoma subtypes

Abstract Background: HER2-positive breast cancers comprise 20-30% of all breast cancers; amplification of HER2 confers a poorer prognosis. While treatment with anti-HER2 targeted therapies has dramatically improved outcomes in this group, a significant subset of patients develops resistance, highlighting the need for novel therapeutic options. In addition, like triple negative breast carcinomas, HER2-positive invasive carcinomas also consist of different intrinsic subtypes with different responses to therapy and different overall prognosis. Finally, recent reports suggest that bcl-2 expression contributes to resistance to anti-HER2 therapies. In this study, we evaluated expression of bcl-2 in HER2-positive breast tumors and correlated the expression of bcl-2 with HER2 subtype, patient demographics and histologic and molecular characteristics. Design: The study population consisted of 114 patients with HER2-positive invasive breast carcinoma treated with surgical excision or mastectomy at Northwestern Memorial Hospital (2009-14) (mean age 53, range 18-80). Electronic medical records were reviewed for patient demographics. Pathologic tumor characteristics (histologic type, size, grade, lymph node status) and tumor marker profile (ER, PR, p53 and Ki-67) were evaluated. Tissue microarrays were constructed (3 cores from each case to account for tumor heterogeneity) for immunohistochemical evaluation of bcl-2 (Dako, clone 124). Results: Overall, these HER2-pos breast carcinomas were almost exclusively of ductal histologic type (101/114, 88.6%). Almost ¾ of the cases were poorly differentiated, grade 3 carcinomas (83/114, 73%), while the other 31 were grade 2 tumors. No grade 1 tumors were seen. bcl-2 was expressed in 64/114 (56%) of the HER2-pos carcinomas. No association of the bcl-2 expression with age, race, tumor size, lymph node status, p53 expression, or Ki-67 proliferation index was seen. Of interest, this sample of HER2-pos carcinomas was almost equally balanced between ER-neg/HER2-pos (HER2 subtype) and ER-pos/HER2-pos (Luminal B subtype), 54 vs 60 cases respectively. bcl-2 was differentially expressed in these two HER2-pos tumor subtypes: only 9/54 (14%) of the HER2 subtype expressed bcl-2 compared to 55/64 (85.9%) of the Luminal B subtype (p&amp;lt;0.0001). Conclusions: 1. bcl-2 is expressed in just over half of the HER2-pos carcinomas. 2. bcl-2 expression is far more common in Luminal B compared to the HER2-pos subtype of breast carcinomas. 3. bcl-2 expression does not appear to have a differential expression between age or racial groups and does not correlate with tumor size or lymph node status. Our findings add to the understanding of the molecular mechanisms that drive the different subtypes of HER2-pos breast carcinomas and raise the possibility that bcl-2 targeted therapies may lead to novel therapeutic approaches for the management of subgroups of patients with HER2-pos breast tumors. Citation Format: Kalliopi P. Siziopikou, Alexandra Larson, Luis Z. Blanco, Virginia Kaklamani. bcl-2 expression in HER2-positive breast carcinoma subtypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2271.

Metaplastic carcinoma of the breast, clinico-pathological and prognosis comparison with triple negative breast carcinoma: Experience of the Kuwait Cancer Control Center.

e12549Background: Metaplastic breast carcinoma (MBC) is a rare category of breast malignancy of unique biology. The prognosis of MBC is reported to be worse than that of triple negative invasive du...

Synthesis and evaluation of substituted 4-(N-benzylamino)cinnamate esters as potential anti-cancer agents and HIV-1 integrase inhibitors

Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50⩾3.0μM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50⩾9.6μM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters. The potential of the ligands as HIV-1 integrase inhibitors has also been examined.

Formulation and antitumorigenic activities of nanoencapsulated nifetepimine: A promising approach in treating triple negative breast carcinoma

Triple negative breast cancer (TNBC) is one of the most common invasive malignancies among women, associated with poor prognosis. Standard chemotherapy targets all dividing cells, resulting in dose-limiting toxicities. In this study, we demonstrated a strategy of encapsulating a hydrophobic synthetic compound, nifetepimine, having anticancer properties, in poly (lactic-co-glycolic acid) nanoparticles to increase selectivity of drug to cancerous cells with minimum toxicity towards normal cells. Nanoencapsulated nifetepimine (30-100nm) having loading and encapsulation efficiency of 7.45% and 75% respectively, was successfully internalized inside TNBC cells upon sustained release resulting in apoptosis. An in vivo bio-distribution study indicated that nanonifetepimine selectively accumulated into breast tumor sites of mice, primarily due to prolonged blood circulation time and binding of nifetepimine to epidermal growth factor receptor that remains overexpressed in most of the TNBC tumors. Moreover, we observed significant reduction in breast tumor volume with improved survival implying high tumor targetability of nanonifetepimine.

Human umbilical cord matrix-derived stem cells expressing interferon-β gene inhibit breast cancer cells via apoptosis.

Human umbilical cord mesenchymal stem cells (hUCMSCs) derived from the umbilical cord matrix have been reported to be used as anti-tumor gene carrier for attenuation of tumor growth, which extends the half-life and lowers the unexpected cytotoxicity of the gene in vivo. Interferon-β (IFNβ) is known to possess robust antitumor effects on different types of cancer cell lines in vitro. The present study was aimed to investigate the anti-tumor effect of IFNβ gene-transfected hUCMSCs (IFNβ-hUCMSCs) on breast cancer cells with emphasis on triple negative breast carcinoma. Our findings revealed that the co-culture of IFNβ-hUCMSCs with the human triple negative breast carcinoma cell lines MDA-MB-231 or Hs578T significantly inhibited growth of both carcinoma cells. In addition, the culture medium conditioned by these cells also significantly suppressed the growth and induced apoptosis of both carcinoma cells. Further investigation showed that the suppressed growth and the apoptosis induced by co-culture of IFNβ-hUCMSCs or conditioned medium were abolished by pretreating anti-IFNβ neutralizing antibody. These findings indicate that IFNβ-hUCMSCs triggered cell death of breast carcinoma cells through IFN-β production, thereby induced apoptosis and suppressed tumor cell growth. In conclusion, we demonstrated that IFNβ-hUCMSCs inhibited the growth of breast cancer cells through apoptosis. with potent anti-cancer activity, it represents as an anti-cancer cytotherapeutic modality against breast cancer.

CD44 positive/CD24 negative (stem cell like property) breast carcinoma cells as marker of tumor aggression

BackgroundCells with stem cell like properties in solid organ malignancies like breast and pancreas have been studied over the last decade and have been found to be associated with poor prognosis. Presence of CD44 positive and CD24 negative tumor cells in breast carcinoma (cells with ‘stem cell’ like property) as marker of aggressiveness and poor prognosis was checked for association with various markers of disease aggression like age at presentation, size of tumor, histological grade of tumor, triple negative status, level of micro-vessel density, and nodal status. MethodsSingle and double staining immunohistochemistry protocol was used for CD24 and CD44 staining. The staining protocol was repeated with more contemporary techniques using fluorescent chromogen also. Results52 cases, all females who underwent modified radical mastectomy at a tertiary care hospital over a period of 3 years, were evaluated. No association was found between presence of stem cells and size of lesion, histological grade, triple negative status or micro-vessel density. However, significant association was found with respect to younger age of presentation (p value=0.044). 20 out of 25 cases with nodal metastasis were positive for presence of stem cells (p value is 0.0003). Further, 18 of these 20 cases also had stem cells in the metastatic nodule. Fluorescent chromogens (FITC and Cyanine Red) revealed similar results. ConclusionCases positive for stem cells showed earlier onset of disease and proneness to nodal metastasis.

Low Concordance between Gene Expression Signatures in ER Positive HER2 Negative Breast Carcinoma Could Impair Their Clinical Application.

BackgroundNumerous prognostic gene expression signatures have been recently described. Among the signatures there is variation in the constituent genes that are utilized. We aim to evaluate prognostic concordance among eight gene expression signatures, on a large dataset of ER positive HER2 negative breast cancers.MethodsWe analysed the performance of eight gene expression signatures on six different datasets of ER+ HER2- breast cancers. Survival analyses were performed using the Kaplan–Meier estimate of survival function. We assessed discrimination and concordance between the 8 signatures on survival and recurrence rates The Nottingham Prognostic Index (NPI) was used to to stratify the risk of recurrence/death.ResultsThe discrimination ability of the whole signatures, showed fair discrimination performances, with AUC ranging from 0.64 (95%CI 0.55–0.73 for the 76-genes signatures, to 0.72 (95%CI 0.64–0.8) for the Molecular Prognosis Index T17. Low concordance was found in predicting events in the intermediate and high-risk group, as defined by the NPI. Low risk group was the only subgroup with a good signatures concordance.ConclusionGenomic signatures may be a good option to predict prognosis as most of them perform well at the population level. They exhibit, however, a high degree of discordance in the intermediate and high-risk groups. The major benefit that we could expect from gene expression signatures is the standardization of proliferation assessment.

Abstract P5-02-05: Prediction of response to neoadjuvant chemotherapy in ER+ breast cancer: Magee equation recurrence versus oncotype DX® recurrence score

Abstract Background and Aim: The Magee equation recurrence score (MS) based on tumor pathological characteristics can be used to estimate the actual Oncotype DX® recurrence score (RS). This study's aim was to test the correlation of MS with RS and their usefulness in predicting tumor response to neoadjuvant chemotherapy (NCT) in patients with estrogen receptor (ER) positive, HER2 negative invasive breast carcinoma (BC). Methods: Pathological data required for MS calculation such as Nottingham Score, H-scores for ER and PR, HER2, Ki 67 and tumor size were obtained via pre-therapy slide review or pathology/electronic medical record. Actual RS was measured (at Genomic Health) on core biopsies from 60 patients who received NCT. Pre-therapy tumor size was measured using imaging. Percentage tumor volume reduction (%TR) was measured. %TR was based on pre-therapy tumor size by MRI and US and detailed pathology evaluation of the resection specimen. Substantial %TR was defined as at least 50% reduction in tumor size (&amp;gt;50%TR). MS was calculated using Magee equation (http://path.upmc.edu/onlineTools/ptvr.html). MS and RS were categorized by score &amp;lt;18 (referred as MS18 and RS18, respectively) and ≥31 (referred as MS31 and RS31, respectively). Correlation between MS, RS and &amp;gt;50%TR were determined by using the Spearman's correlation coefficient. The mean levels of pathological parameters and score levels which had &amp;gt;50%TR or &amp;lt;50%TR were compared by ANOVA at a 2-sided α level of 0.05. The impact of the scoring systems for &amp;gt;50%TR by the scoring systems was assessed by calculating the area under (AUC) the receiver operating characteristic curve (ROC); AUC values between 0.7–0.8 represent considerable discrimination. Results: The mean patient age was 52 ±13 years. The mean pre-NCT tumor size was 48 ±36 mm.&amp;gt;50%TR was observed in 27 (45%) patients, but there was no pathological complete response. Low level of ER H-score (&amp;lt;100) was significantly associated with &amp;gt;50%TR (p=0.01). The Spearman's correlation coefficient (rs) for the MS and RS was 0.522 (p&amp;lt;0.001) with an average coefficient of determination (r2) of 0.298. Neither, MS nor RS correlated with &amp;gt;50%TR (p=0.08, p=0.2, respectively). The AUC values were calculated from the MS, RS, MS18, RS18, MS31 and RS31 (AUC=0.625, 0.602, 0.589, 0.572, 0.525 and 0.522, respectively).Conclusions: MS and Oncotype DX® RS have a good correlation in this small ER+ neoadjuvant cohort. However, neither MS nor RS correlated with %TR. Lower ER expression as a single variable is an excellent predictor of response to NCT and may be used alone in making therapy decisions in small number of cases. For moderate to strongly ER+ cases, the decision between primary surgery versus neoadjuvant systemic therapy may be difficult, but MS may be used in lieu of actual Oncotype DX® RS when it is not available. Citation Format: Soran A, Johnson R, Menekse E, Bhargava R, McGuire K, McAuliffe P, Ahrendt G, Dabbs D, Bonaventura M. Prediction of response to neoadjuvant chemotherapy in ER+ breast cancer: Magee equation recurrence versus oncotype DX® recurrence score. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-02-05.

Abstract P6-03-13: The genomic landscape of PD-L1, PD-L2, Jak2 (PDJ) amplified triple negative breast carcinoma

Abstract Introduction: Triple negative breast carcinoma (TNBC) is a subtype of breast cancer with a paucity of therapeutic targets and a poor prognostic phenotype. In a retrospective cohort, we sought to determine the prevalence of the amplicon targeting the 9p24.1 locus, resulting in over-expression of PD-L1, PD-L2, and JAK2 (PDJ), and potentially actionable therapeutic targets. We then probed the genomic landscape of these PDJ positive tumors and identified co-occurring copy number aberrations, including focal amplifications and homozygous deletions. The presence of the PDJ amplicon and selected co-occurring aberrations provide a unique description of a clinically relevant subtype of TNBC. Methods: We evaluated fresh frozen and formalin-fixed paraffin embedded tumor samples from 64 patients with triple negative breast cancer whom underwent definitive surgical resection. Clinical annotation was available in 60 of the samples. Tumor populations (diploid, tetraploid, and aneuploidy) were sorted from each biopsy using DNA content flow cytometry. Each sorted sample was interrogated with oligonucleotide array comparative genomic hybridization (aCGH). All microarray slides were scanned using an Agilent 2565C DNA scanner and the images were analyzed with Agilent Feature Extraction version 10.7. The aCGH data was assessed with a series of QC metrics then analyzed using an aberration detection algorithm. Results: We detected a high level (log2ratio greater than or equal to 2) amplicon targeting 9p24.1 in 18 of 64 patients (28%) genomic profiles with triple negative breast carcinoma. In the PDJ positive population, we detected 8 of 18 patients (44%) with co-amplification targeting myc at 8q24, 3 of 18 patients (17%) with co-amplifications targeting EGFR at 7p11, 3 of 18 patients (17%) with co-amplifications targeting PIK3CA. These co-occurring genomic events in PDJ positive tumors may provide clinically actionable targets. Other selected amplifications detected included NOTCH3, KRAS, RUNX1, TUBAL3, FGFR2, AKT1, AKT2, YPEL2, PBXL7, KIT. We detected PTEN homozygous deletion in 2 of 18 patients (11%) PDJ positive tumors. Other homozygous deletions identified in the genomic landscape included FAT1, SOX3, Park2, TNFAIP3, GPC3, RB1, and CREBBP. Conclusions: In our retrospective analysis, the amplification of chromosome 9p24.1 involving PD-L1, PD-L2, and JAK2 is present in approximately 28% of triple negative breast cancer patients. The genomic landscape of these PDJ positive TNBCs include recurring high-level focal amplifications and targeted homozygous deletions of clinically relevant genes. The clinical implications of these data are under current investigation using model systems and are in early phase clinical trials. The efficacy of immune checkpoint inhibitors including nivolumab, pembrolizumab, and JAK2 inhibitors including ruxolitinib, in PDJ positive triple negative breast carcinoma is intriguing and remains to be elucidated. Citation Format: Gawryletz CD, Anderson KS, Cunliffe HE, Northfelt DW, McCullough AE, Lenkiewicz E, Malasi S, Pockaj BA, Barrett MT. The genomic landscape of PD-L1, PD-L2, Jak2 (PDJ) amplified triple negative breast carcinoma. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-13.

Abstract P3-05-08: High prevalence of splicing variant AR-V7 in triple negative breast carcinoma

Abstract The androgen receptor (AR) and its pathway have been implicated in tumorigenesis and progression of breast cancer. Anti-androgen therapy has shown efficacy in the metastatic breast cancer and numerous clinical trials are underway to study efficacy in various clinical settings. 15 splicing variants of AR (AR-Vs) have been described in prostate cancer. Structurally, AR-Vs have insertions of cryptic exons downstream of the exons that encode the DNA-binding domain or deletions of the exons encoding the ligand-binding domain, resulting in a disrupted AR open reading frame and expression of ligand-binding-domain-truncated AR proteins. In prostate cancer, some of the AR-Vs especially AR-V7 are associated with aggressive disease and resistance to anti-AR therapy. The AR-V prevalence in human breast cancer specimens has hitherto not been studied. We aimed at studying the expression of AR-Vs in breast cancer specimens and present the data on AR-V1, AR-V7, AR8, and ARV567, in AR-positive triple negative (TNBC) and ER+/Her2- breast cancer. Design: 98 cases of TNBC, 40 cases of ER+/Her2 breast cancer and 17 cases with reduction mammoplasty were abstracted from NYULMC pathology database and screened for AR expression by immunohistochemistry (IHC). IHC for AR was performed using antibody clone N-20 (Santa Cruz) at 1:100 dilution. Normal breast tissue was used as internal control and 10% nuclear staining was used for categorizing a tumor as AR positive. A subset of cases which over-expressed AR were macrodissected from formalin fixed paraffin embedded sections with total RNA extracted by using the PureLink® FFPE RNA Isolation Kit (Invitrogen). Reverse-transcription was performed by using the SuperScript® III Reverse Transcriptase Kit (Invitrogen). AR-V expression was presented as cycle number difference to housekeeping gene (delta CT) for real-time PCR or as absolute copy number for digital PCR. Results: AR+ TNBC and AR+/ER+ cases ranged from stage 1A to IIIA. IHC for AR showed &amp;gt; 10% staining in 27 of 98 TNBC cases and in 39 of 40 ER+/Her2- cases. AR Positive Prevalence in TNBC and ER+ Breast Carcinoma AR+AR-TNBC2771ER+/Her2-391 AR-V7 was expressed in 11 of 13 AR+/TNBC cases (p &amp;lt; 0.05); AR-V1 and AR-V4 were expressed in 4; ARV8 and ARv567es were expressed in 3 and 2 cases respectively. In 25 AR+/ER+/Her2- cases AR-V7 was expressed in 14; AR-V4 in 9; ARV567 in 5, AR-V1 in 3 cases. AR Spliced Variant Incidence in TNBC, ER+ and Benign breast tissue Benign (N=17)ER+/AR+ (N=25)TNBC+/AR+(N=13)P ValueAR-V113(12%)4(25%)0.145AR-V419(36%)4(25%)0.35AR-V78(47%)14(56%)11(85%)0.021AR-V801(4%)3(19%)0.474AR-V56715(20%)2(12.5%)0.092 Conclusion: We report expression of various spliced variants in TNBC, ER+/Her2- breast cancer. A statistically significant expression of AR-V7 is seen in TNBC. Since AR-V7 predicts for poor prognosis and lack of response to anti-AR therapy in prostate cancer, AR-V7 expression maybe a useful biomarker to analyze response data in on going breast cancer clinical trials. Citation Format: Singh B, Deng F-M, Kane Y, Zhan Y, Qi Y, Liu X, Zhang H, Dong Y, Brody R, Wieczorek R, Lee P. High prevalence of splicing variant AR-V7 in triple negative breast carcinoma. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-08.

Neuroendocrine tumor of the breast: Is it primary or metastatic?

Introduction: Neuroendocrine breast carcinoma is a rare form of tumor that may be either primary or metastatic. Case Report: We present the case of a patient who was referred to our outpatient office with the diagnosis of a triple negative invasive breast carcinoma on an ultrasound-guided core needle biopsy. The patient subsequently underwent a lumpectomy with sentinel lymph node biopsy. Postoperative pathology revealed neuroendocrine carcinoma of the breast with sentinel lymph node biopsy negative for carcinoma. The tumor cells were positive for AE1/AE3, chromogranin, synaptophysin and CD-56 but negative for estrogen, progesterone and HER2. To exclude a primary carcinoma elsewhere, we obtained a whole body PET scan which showed a mildly hypermetabolic mesenteric mass in the midline with curvilinear calcification. Computed tomography scan of the abdomen and pelvis with oral and IV contrast showed a mass-like soft tissue within the terminal ileum with thickening of the cecum. An octreotide scan of the whole body revealed

Validation of Intratumoral T-bet+ Lymphoid Cells as Predictors of Disease-Free Survival in Breast Cancer.

We previously observed T-bet(+) lymphocytes to be associated with a good prognosis in a cohort of women with familial breast cancer. To validate this finding, we evaluated lymphocyte T-bet expression in an independent unselected prospectively accrued series of women with lymph node-negative breast carcinoma. T-bet and clinicopathologic data were available for 614 women. Hormone receptors, HER2, Ki-67, CK5, EGFR, p53, and T-bet status were determined using IHC and/or biochemical methods. Tumors were assigned to luminal A, luminal B, HER2, and basal subtypes based on the expression of IHC markers. Multiple cutpoints were examined in a univariate penalized Cox model to stratify tumors into T-bet(+/high) and T-bet(-/low). Fisher exact test was used to analyze T-bet associations with clinicopathologic variables, IHC markers, and molecular subtype. Survival analyses were by the Cox proportional hazards model. All tests were two sided. A test with a P value < 0.05 was considered statistically significant. T-bet(+/high) tumor status was significantly associated with large tumor size, high grade, hormone receptor negativity, CK5, EGFR and p53 positivity, high Ki-67, and basal subtype. With a median follow-up of 96.5 months, T-bet(-/low) tumor status was associated with a reduced disease-free survival compared with T-bet(+/high) tumor status in multivariate analysis (P = 0.0027; relative risk = 5.62; 95% confidence intervals, 1.48-50.19). Despite being associated with adverse clinicopathologic characteristics, T-bet(+) tumor-infiltrating lymphoid cells are associated with a favorable outcome. This supports their role in Th1-mediated antitumor activity and may provide insight for the development of new therapeutic strategies.

Decreased Survival in African Patients with Triple Negative Breast Cancer

Introduction: Triple Negative Breast Carcinomas (TNBC) are more prevalent in younger women especially those with African Ancestry, in whom the disease appears to be more aggressive. Since there are no data on Africans living in continental Europe, we sought to analyse a sample of African women from a European country and determine if, like African Americans, they have more aggressive tumor biology and poorer outcomes. Methods: We performed a retrospective review of TNBC to compare clinical and pathological features and survival between African and non-African patients. All women presented with breast cancer (BC), between 2005 and 2014, to a single general hospital, in Portugal. Results: A total of 144 (9.3% of the whole sample) TNBC patients were identified and amongst these, 17 were African (12%). African patients were not significantly younger than non-African patients (median age of 60 years vs 57.2 years, respectively, p=0.59). Regarding tumor size, nodal status and histologic grade at presentation, these variables were very similar between the two cohorts. Nevertheless, the prevalence of initially metastatic BC was significantly higher among the African population (41.2% vs 11%, p<0,005) and the outcome was worse for these patients (median survival: 62 vs 15 months, p<0.005). Conclusions: Our study demonstrated that African patients more frequently presented with late stage disease and worse survival outcome than the non-African population. These findings may be explained by more aggressive tumor biology.

Androgen Receptor Expression in Breast Carcinoma of Egyptian Patients.

Breast carcinoma (BC) is a heterogeneous disease, with distinctive molecular sub-types, influencing BC patients prognosis and therapeutic options. Androgen Receptor (AR) is a steroid nuclear receptor involved in complex signaling pathways, that are thought to play a role in cell proliferation. AR expression in relation to different molecular sub-types of BC is not clearly understood. The aim of this study was to evaluate the expression of AR in BC from Egyptian patients and correlate it with the standard clinico-pathologic variables, molecular sub-type of BC and the Overall Survival (OS). This retrospective study was conducted on 81 cases of BC from egyptian patients, stained immunohistochemically with AR. Chi-Square and Kaplan-Meier tests were applied to study the correlation between AR expression and clinicopathologic variables and the OS of BC patients respectively. Among studied BC cases, 37.04% were immunoreactive to AR. AR immunoreactivity was significantly corrrelated with older age (p=0.03), post-menopausal status (p=0.001), lower grade (p=0.003), the presence of in-situ component (p= 0.014), early stage of presentation (p=0.03) and good-moderate NPI (0.009). It was also correlated with Positive ER, negative HER-2/neu, low Ki-67 proliferation index and luminal A subtype. AR expression didn't correlate with the OS in the studied cases. AR was found to be related to favourable prognostic factors in BC but not to OS. It was particularly expressed in luminal A group and in significant proportion in Triple Negative Breast Carcinoma (TNBC), providing an opportunity for AR targeted therapy.