Top PDF Novel targeted agents in Her-2 positive and triple negative breast cancer

Novel targeted agents in Her-2 positive and triple negative breast cancer

Novel targeted agents in Her-2 positive and triple negative breast cancer

Previous studies have shown that triple negative breast cancer cell lines are more sensitive to dasatinib than luminal or Her-2 positive breast cancer cell lines (33). Our results validated this observation, as triple negative cell lines were more sensitive compared to Her-2 positive cell lines. Among the triple negative cell lines, the MDA-MB-468 and the BT-20 cells were resistant to dasatinib treatment. Interestingly both of these cell lines have amplified EGFR. There is significant evidence for cross-talk between EGFR and Src signalling, and Src has been implicated in resistance to EGFR targeted therapies. However, it is not yet known whether increased EGFR signalling can contribute to resistance to EGFR inhibition. The mesenchymal MDA-MB-231 cells were the most sensitive, followed by the basal BRCA-1 mutated HCC-1937 and the basal HCC-1143. These results are consistent with the results obtained by Finn et al (33), who also showed that cell lines, including the MDA-MB-231 cells, which have undergone an epithelial-to-mesenchymal transition displayed the greatest sensitivity to dasatinib. Our laboratory has also shown that dasatinib inhibited cellular invasion and migration in the MDA-MB-231 cell line (104).
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A case of HER 2 positive recurrent breast cancer showing a clinically complete response to trastuzumab containing chemotherapy after primary treatment of triple negative breast cancer

A case of HER 2 positive recurrent breast cancer showing a clinically complete response to trastuzumab containing chemotherapy after primary treatment of triple negative breast cancer

Compared with hormone receptor status, discordance in the HER-2 status between primary and metastatic lesions is less common, and the impact of this discor- dance on the prognosis of recurrent breast cancer is less clear [6,7]. However, with the introduction of trastuzu- mab, the HER-2 status of metastatic disease has become one of the most important predictive and prognostic factors in patients with recurrent breast cancer. Clinical trials have shown a significant survival benefit from tras- tuzumab in addition to the chemotherapy agent in HER- 2-positive advanced breast cancer [11,12]. An institu- tional-based review also showed that women with HER- 2-positive disease who received trastuzumab had an improved prognosis compared with women who did not receive such treatment [13]. However, it is less clear whether the reevaluation of HER -2 status in metastatic lesions has an impact on the prognosis of patients with recurrent breast cancer. In this case report, the patient was initially diagnosed with triple-negative breast cancer, but a reevaluation of the metastatic disease showed her to be HER-2-positive by FISH, and she was diagnosed with HER-2-positive metastatic breast cancer. Based on these findings, she was administered combination che- motherapy using weekly paclitaxel and trastuzumab, and clinically complete remission was immediately achieved and maintained for over 1 year. She is currently disease- free, and an excellent prognosis is expected. The inci- dence of a discordance in HER-2 status between
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Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand

Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand

The phototoxicity of the scFv-SNAP-IR700 proteins and free IR700 was determined using Cell Proliferation (XTT) Kit II (Roche, Mannheim Germany) as previously described [13]. Briefly, MDA-MB-468, MDA-MB-453, MDA-MB-231, Hs758T and MCF-7 cells were seeded in 96-well plates and incubated overnight at 37°C. The cells were incubated with increasing concentrations (0, 10, 25, 50, 100, 200 and 400 nM) of the scFv-SNAP-IR700 fusion proteins or an equivalent concentration of IR700 for 3 h at 37°C in the dark. As a toxic control, cells were incubated with 500 μg/mL Zeocin. After washing the cells three times with PBS, they were incubated in fresh phenol red-free culture medium and irradiated with visible light (VIS) plus water-filtered infrared light A (wIRA) using a Hydrosun Typ 750 radiator with a water-containing cuvette and orange filter OG590, with a spectrum in the range 580−1400 nm (Hydrosun Medizintechnik GmbH, Müllheim, Germany). The irradiation experiments were carried out according to the physical and photobiological laws described by Piazena and Kelleher [42]. The cells were irradiated at 140 mW/cm 2 , at a dose of 25 J/cm 2 VIS
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A novel fully human anti-NCL immunoRNase for triple-negative breast cancer therapy

A novel fully human anti-NCL immunoRNase for triple-negative breast cancer therapy

To address the hypothesis that NCL protects cancer cell-derived EV-associated miRNAs, we evaluated the ability of anti-NCL 4LB5-HP-RNase and 4LB5 scFv to modify the levels of EV-related miR-21 after the binding and the possible displacement of microRNAs from NCL. To this end, we first isolated EVs from the conditioned serum-deprived medium of lymph node metastatic derivatives of colorectal SW620 cancer cells that are widely used as a model for exosome studies [38]. Then, using a combination of a polymer-based exosome precipitation and a differential centrifugation approach to fractionate the EV-containing medium, we isolated the SW620-derived exosomes and tested them for the presence of NCL by Western blotting (Figure 6E). Once confirmed the presence of NCL, EVs were treated with 4LB5-HP-RNase or 4LB5 scFv at 50 nM for 2 hours at 37°C. Total RNA was extracted and exosome-related miR-21 levels were analyzed by Real-Time PCR analysis. RNU48 cellular snoRNA, served as a negative control, to evidence the potential contamination of cellular RNAs during the EV purification procedure Figure 6D. As shown in Figure 6C, miR-21 levels were much lower in 4LB5- HP-RNase-treated cells than in the untreated control, whereas treatment with an equimolar dose of 4LB5, tested in a parallel assay, only slightly affected miR-21 levels. These data support the hypothesis that the binding of NCL by the scFv 4LB5 may cause displacement of miRNAs from NCL thus enabling the RNase moiety present in 4LB5-HP-RNase to degrade miR-21. Thus, the enzymatic activity of 4LB5-HP-RNase could be responsible for its more potent antitumor effects on extracellular miRNAs, which indicates that the anti-NCL immunoRNase may play a role in the inhibition of the inter-cellular communication involved in tumor progression.
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CXCR2 is a novel cancer stem-like cell marker for triple-negative breast cancer

CXCR2 is a novel cancer stem-like cell marker for triple-negative breast cancer

Background: Breast cancer is the leading cause of mortality from cancer in women worldwide, and cancer stem-like cell (CSC) is responsible for failure treatment of breast cancer. It plays an important role in resistant disease and metastasis. CD44/CD24 and ALDH are well-accepted protein markers of breast CSC, and it was reported that distinct subtypes of breast CSC were identified by the 2 markers. It is possible that there are various kinds of breast CSC which could be identified by different markers, and CSC markers utilized at present are not enough to fully understand breast CSC. Finding out more novel CSC markers is necessary. CXCR2 is involved in breast cancer metastasis, treatment resistance, and recurrence and has positive cross-talk with known breast CSC protein markers. It can be concluded that CXCR2 is related to breast CSC, and further study is in need.
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LncRNAs as new biomarkers to differentiate triple negative breast cancer from non-triple negative breast cancer

LncRNAs as new biomarkers to differentiate triple negative breast cancer from non-triple negative breast cancer

A traditional pathology diagnosis was carried out to detect the ER, PR and Her-2 status of breast cancer samples [37]. The molecular subtypes of these breast cancer patients were defined by IHC staining of ER, PR, and Her-2. The Allred scoring method was employed to classify the expression status of ER and PR. Generally, the proportion score showed the estimated percentage of tumor cells staining positive (0 = 0%; 1 = 1%; 2 ≥ 1 to 10%; 3 ≥ 10 to 33%; 4 ≥ 33 to 66%; 5 ≥ 67%), and the intensity of staining was scored as follows: 1 = weakly; 2 = moderately; and 3 = strongly. The total score was derived from the following equation, with a score of 0 being negative and a score of 2 to 8 being positive. Membranous staining was scored for Her-2/neu according to the HercepTest (Dako) as follows: 0 = negative; 1 = weak incomplete membranous staining of >10% cells (negative); 2 = weak to moderate complete membranous staining of >10% of cells (equivocal-fluorescence in situ hybridization was used to assess amplification in these cases); 3 = strong complete membranous staining of >30% of cells (positive). A standard FISH was performed to confirm the expression level of Her-2. Generally, her- 2 was detected by a Texas-Red labelled probe (red dot); meanwhile, the centromere of chromosome 17 was detected by a FITC labelled probe (green dot). The status of the Her-2 expression level was evaluated by the ratio of Her-2:centromere of chromosome 17 (i.e., red dots:green dots). The status of Her-2 was defined as positive if the ratio was ≥2; otherwise it was defined as negative.
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A novel prognostic two-gene signature for triple negative breast cancer

A novel prognostic two-gene signature for triple negative breast cancer

4 μm TMA Immunostained sections were digitally scanned at 20X magnification using a NanoZoomer machine (Hamamatsu Photonics, Welwyn Garden City, UK). Morphological evaluation of the cytoplasmic immunoreactivity was assessed using the H-score method based on the intensity of protein expression (0 = negative, 1 = weak, 2 = moderate, 3 = strong) and percentage of stained cells (0–100) as previously reported [5]. TMA cores were considered scorable if invasive tumor cells represented >15% of the total TMA core area. In addition, 25% of TMA sections were scored by two scorers (who were blinded to each other’s scores as well as to the clinical data for the samples) to assess inter-observer concordance. The intra-class correlation co-efficient for SPDYC and ACSM4 were 0.77 and 0.80, respectively, indicating substantial concordance between scorers. Moreover, the discordant cases were re-scored by the both observers and a consensus score was agreed upon and assigned.
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ERβ1 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1

ERβ1 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1

The downregulation of ERβ1, the fully functional ERβ isoform (also known as wild-type ERβ), promotes epithelial-mesenchymal transition (EMT) in prostate cancer cells [11]. ERβ1 has also been investigated in breast cancer with contradictory results. Some studies have shown that ERβ1 inhibits the growth and decreases the invasiveness of breast cancer cells, and it predicts a favorable survival for ERα-negative breast cancer [12–14]. Whereas estrogen receptor beta 2 (ERβ2), one of the splice variants of ERβ, has been reported to be associated with poor prognosis in ERα-negative breast cancer [15]. Other studies have indicated that ERβ1 has no prognostic significance in breast cancer [16, 17]. Among TNBC pa- tients, approximately 30% show overexpression of ERβ1 [12, 18]. Patients with TNBC harboring ER β 1-positive tu- mors treated with adjuvant tamoxifen have significantly better survival [19]. However, little is known about the functions and underlying mechanisms of ER β 1 in metas- tasis in AR-positive TNBC. In this study, stable ERβ1- expressing cells were generated using two AR-positive TNBC cell lines. ER β 1 suppressed the invasion and migra- tion abilities of AR-positive TNBC cells by inducing the downregulation of ZEB1. This study also investigated the potential regulatory relationship between ER β 1 and AR as well as the association of ER β 1 with AR and ZEB1 in TNBC clinical samples.
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Targeted therapy in triple-negative metastatic breast cancer: a systematic review and meta-analysis

Targeted therapy in triple-negative metastatic breast cancer: a systematic review and meta-analysis

Results: The final analysis included twelve trials comprising 2,054 patients with TNBC, which compared conventional CT alone against CT combined with targeted therapy (bevacizumab [Bev], sorafenib [Sor], cetuximab, lapatinib, and iniparib). PFS was superior in previously untreated patients with TNBC who received Bev plus CT compared to CT alone (fixed effect, HR 0.62, 95% CI 0.51–0.75; P,0.00001). Also, PFS was higher in one study that tested Bev plus CT combina- tion in previously treated patients (HR 0.49, 95% CI 0.33–0.74; P=0.0006). Sor plus CT was also tested as first-line and second-line treatments. The pooled data of PFS favored the combination CT plus Sor (fixed effect, HR 0.69, 95% CI 0.49–0.98; P=0.04). Comparisons of iniparib plus CT also had a better PFS than CT alone (fixed effect, HR 0.75, 95% CI 0.62–0.90; P=0.002). Conclusion: Targeted therapy, when associated with conventional CT, demonstrated gains in the PFS of patients with TNBC.
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The Correlation Between PARP1 and BRCA1 in AR Positive Triple-negative Breast Cancer

The Correlation Between PARP1 and BRCA1 in AR Positive Triple-negative Breast Cancer

Many researches have proved that PARP inhibition in BRCA1-mutated TNBC cell can induce synthetic lethality [37, 38]. PARP inhibitor AG014699 delayed growth of xenograft tumor generated from TNBC cell MDA-MB-436 and HCC1937 which carried BRCA1 mutation more markedly in contrast with xenograft tumors with BRCA1/2-nonmutated breast cancer cells such as MCF-7,  MDA-MB-231, and  HCC1937-BRCA1 (derived from HCC1937 by correct the BRCA1 mutation)[39]. The previous study indicated that PARP inhibitor could increase sensibility of chemotherapy through DDR via BER pathway in BRCA1 mutation cancers [40]. We hypothesized that combination therapy of PARP1 inhibitor and bicalutamide could also increase anti-tumour growth effect more obviously in BRCA1-muated TNBC cells than BRCA-wild type cells. To examine the hypothesis in vivo, we established two xenograft models with BRCA1-mutation HCC1937 and BRCA1 wild-type MDA-MB-231 cells on either side of a nude mouse (Figure 5A). We assumed the two xenograft models were in the analogous microenvironment, and then
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Clinicopathological Characteristics of Basal Type Breast Cancer in Triple Negative Breast Cancer

Clinicopathological Characteristics of Basal Type Breast Cancer in Triple Negative Breast Cancer

Background: Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor 2 (HER2) expression. Patients with TNBC derive no benefit from molecularly targeted treatments, such as endocrine therapy or trastuzumab, as they lack the appropriate targets for these drugs. TNBC is characterized by its biological aggressiveness and poor prognosis, and consists of two subtypes, basal and nonbasal. The purpose of our study is to differentiate the clinicopathological characteristics of the two subtypes. Methods: 367 patients with primary breast cancer were recruited from April 2004 to December 2010 at 1st Department of Surgery, Sapporo Medical University. ER, PgR, and HER2 status were evaluated in all cases. Moreover, we classi- fied TNBC into basal, nonbasal subtypes on the basis of immunohistochemical staining of epidermal growth factor re- ceptor (EGFR), cytokeratin (CK) 5/6. Basal type was defined as CK5/6-positive and/or EGFR-positive, and nonbasal type was defined as no expression of these two markers. Results: Breast cancer subtypes by molecular classification were Hormone receptor (HR)-positive/HER2-negative (61%), HR-positive/HER2-positive (10%), HR-negative/HER2- positive (14%), and HR-negative/HER2-negative (15%). There was no difference between the basal type and the non- basal type in clinicopathological factors. But, the basal type was significantly associated with Ki67 labeling index (p = 0.0002), p53 expression (p = 0.047), and BRCA1 expression (p = 0.03). Further, patients with the basal type TNBC showed a shorter overall survival (p = 0.032) than did patients with the nonbasal type. Conclusion: Classification of TNBC subtypes by EGFR, CK5/6 is a very useful prognostic factor, and highlights the need for the development of an adequate new strategy for the basal type TNBC.
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Cripto-1 as a novel therapeutic target for triple negative breast cancer

Cripto-1 as a novel therapeutic target for triple negative breast cancer

Microarray analysis was done using Partek Genomic Suite version 6.6 (Partek, Inc.). Microarray CEL files were pre-processed using RMA (Robust Multi-Array Average) background correction and quartile normalization to correct for array biases. Probe intensities were log- transformed and summarized using Median Polish. One sample (6518LM) was excluded from further analysis because it failed multiple quality metrics. After Batch Remove, a standard One-way ANOVA analysis was then performed with tissue type as factor to identify differentially expressed genes (FDR corrected p-value <0.05 and FC cutoff ≤2 unless indicated otherwise). Microarray data in this publication have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE63951. Venn diagrams were generated by Partek Genome Suite 6.6 (PGS, Version 6.6, Partek, Inc.).
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Novel targeted agents for gastric cancer

Novel targeted agents for gastric cancer

Contemporary advancements have had little impact on the treatment of gastric cancer (GC), the world ’ s second highest cause of cancer death. Agents targeting human epidermal growth factor receptor mediated pathways have been a common topic of contemporary cancer research, including monoclonal antibodies (mAbs) and receptor tyrosine kinase inhibitors (TKIs). Trastuzumab is the first target agent evidencing improvements in overall survival in HER2-positive (human epidermal growth factor receptor 2) gastric cancer patients. Agents targeting vascular epithelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and other biological pathways are also undergoing clinical trials, with some marginally positive results. Effective targeted therapy requires patient selection based on predictive molecular biomarkers. Most phase III clinical trials are carried out without patient selection; therefore, it is hard to achieve personalized treatment and to monitor patient outcome individually. The trend for future clinical trials requires patient selection methods based on current understanding of GC biology with the application of biomarkers.
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Hydrophobic Proteome Analysis of Triple Negative and Hormone-Receptor-Positive-Her2-Negative Breast Cancer by Mass Spectrometer

Hydrophobic Proteome Analysis of Triple Negative and Hormone-Receptor-Positive-Her2-Negative Breast Cancer by Mass Spectrometer

In this study, we also found an overall up-regulation of heat shock protein expression in TNBC. Heat shock proteins are a class of functionally related proteins whose expression is transcriptionally regulated and over-expressed when cells are exposed to elevated temperatures, hypoxia, or other stress [45]. Heat shock proteins are named according to their molecular weight. Among them, Hsp60, Hsp70, and Hsp90 are the most widely studied Hsps. Hsps have a dual function depending on their intracellular or extracellular location. The different properties of Hsps allow them to be exploited in therapy. Intracellular Hsps are protective to the cell and are highly expressed in cancerous cells. The elevated Hsp expression has been shown to promote cancer growth through inhibition of programmed cell death (Hsp27, Hsp70), allowance of autonomous tumor growth (Hsp90) and tumor resistance to chemotherapy and hyperthermia [46]. Since they participate in oncogenesis and in resistance to treatment, the inhibition of Hsps has been tested in clinical trial for cancer treatment. Small molecule inhibitors of Hsps, especially Hsp90, show promise as anticancer agents [35]. The potent Hsp90 inhibitor 17-AAG is currently in clinical trials for the treatment of several types of cancer [47]. In contrast to the intracellular Hsps, extracellularly located or membrane- bound Hsps mediate immunological functions. They can elicit an immune response modulated either by the adaptive or innate immune system [35]. Their immunogenicity can be used to form the basis of anticancer vaccines [46].
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Immunotherapeutic interventions of Triple Negative Breast Cancer

Immunotherapeutic interventions of Triple Negative Breast Cancer

The zinc transporter LIV-1 (SLC39A6) is over- expressed in TNBC and is maintained after hormonal therapy in primary and metastatic sites. SGN-LIV1A is an anti-LIV-1 antibody linked to a potent microtube dis- rupting agent monomethyl auristatin E (MMAE) via a cleavable dipeptide linker and displays specific cytotox- icity both in  vitro and in  vivo against LIV-1 expressing cancer cells by internalizing and trafficking to the lyso- some [175]. IMMU-132 is made from a humanized anti- Trop-2 (expressed in TNBC) mAb (hRS7) conjugated with SN-38 (the active metabolite of irinotecan) and is well tolerated and induces early and durable responses in heavily pretreated patients with metastatic TNBC, which mediates early pro-apoptosis signalling events (p53 and p21 WAF1/Cip1) and leads to the cleavage of PARP [176, 177]. A combination of IMMU-132 plus PARP inhibitors, such as olaparib or talazoparib, pro- duces significantly improved anti-tumour effects and delays tumour progression compared with monotherapy in mice bearing BRCA1/2-mutated TNBC [178]. Glyco- protein NMB (gpNMB) is a novel type I transmembrane protein that is overexpressed in most breast cancers and promotes metastases by mediating intercellular adhe- sion, promoting tissue repair, regulating cell growth and differentiation, and down-modulating anti-tumour T-cell responses. CDX-011 is composed of an anti- gpNMB mAb and MMAE and has a clinically acceptable safety profile in its first study in breast cancer, showing 12 weeks of PFS in 60% of TNBC patients treated with CDX-011 [179]. The EMERGE trial also confirmed its enhanced activity in patients with gpNMB-overexpress- ing TNBC [180]. More pivotal clinical trials concerning these promising ADCs are currently underway and more new ADCs, such as protein tyrosine kinase 7 (PTK7)- targeted ADC, and novel potential candidates for ADC, such as STM108, are in development [37, 181].
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THE ROLE OF CHEMOTHERAPY IN TRIPLE NEGATIVE BREAST CANCER

THE ROLE OF CHEMOTHERAPY IN TRIPLE NEGATIVE BREAST CANCER

The New England Journal of Medicine published a report by Bear et al of another trial of neoadjuvant chemotherapy with or without carboplatini. This Phase III randomized trial assigned 46 patients with HER2- negative BC to receive docetaxel (100 mg/m 2 every 21 days) or docetaxel (75 mg/m 2 day 1) plus capecitabine (825 mg/m 2 twice a day days 1 to 14) or docetaxel (75 mg/m 2 day 1) plus gemcitabine (1,000 mg/m 2 days 1 and 8) for four cycles. All regimens were followed by AC for a further four cycles. All patients were also randomized to receive carboplatini (AUC=5) or not for the first six cycles of chemotherapy. Results showed first of all that the addition of carboplatiniand gemcitabine did not improve the rate ofdocetaxel alone and showed increased toxicity and that the toxicity of carboplatini was manageable and as expected from previous trials and, significantly increased the overall pCR rate (34.5% vs 28.2%) (P=0.02). The multiple logistic regression model showed that TNBC subtype, high grade, and smaller tumor size were associated with higher rates in the breast, but when considering the breast and nodes, the addition of carboplatiniwas significantly related to a better result in hormone receptor-positive tumors only.
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Triple negative breast cancer: an Indian perspective

Triple negative breast cancer: an Indian perspective

All histopathologically and cytologically confirmed cases of breast cancer were prospectively enrolled in a longitudinal study at a tertiary care hospital in central India between 2012 and 2014. The present study had an ethical clearance from the Institutional Ethics Committee of the institute and patients were recruited after obtaining an informed consent in local dialect. Using a case sheet, demographic details, risk factors, clinical profile, and staging of disease was recorded. Confirmation of diagnosis was done by fine needle aspiration cytology and trucut biopsy in LABC cases. Metastatic work-up was done for all patients which included ultrasonography of abdomen and pelvis and chest X-ray and Tc 99 bone scan in selected cases. Based on the clinical exami- nations and measurement of breast lump by Vernier caliper and systemic investigations, patients were categorized into three groups, 1) early breast cancer (EBC), 2) LABC, and 3) advanced breast cancer. The patients with EBC were treated with modified radical mastectomy followed by six cycles of adjuvant chemotherapy with cyclophosphamide, Adriamycin, and 5-Fluorouracil (CAF) followed by hormonal therapy depending on hormone receptor and menopausal status. All LABC patients underwent trucut biopsy for hormone receptor study before starting chemotherapy. Operable LABC patients were subjected to modified radical mastectomy and inoper- able LABC patients received neoadjuvant chemotherapy, 2–3 cycles of CAF. Response to chemotherapy was assessed by measuring the lump with Vernier calipers before initiating the next chemotherapy cycle and was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Those patients who showed clinical response by decrease in size of lump were given three cycles of neoadjuvant che- motherapy (CAF) followed by modified radical mastectomy, followed by three cycles of adjuvant chemotherapy (CAF). Those patients showing no clinical response after two cycles underwent modified radical mastectomy followed by six cycles of adjuvant chemotherapy (taxanes). Patients with positive surgical margins received local radiotherapy. Based on hormone receptor status and menopausal status patients were started on hormonal therapy.
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Identification of human triple negative breast cancer subtypes and preclinical models for selection of targeted therapies

Identification of human triple negative breast cancer subtypes and preclinical models for selection of targeted therapies

In addition to cytokeratin expression, breast cancers can be clas- sified by an “intrinsic/UNC” 306-gene set into 5 major subtypes (basal-like, HER2-like, normal breast–like, luminal A, and luminal B) (30). Since TNBCs are largely considered basal-like, we correlated each of the 386 TNBC tumor profiles to the intrinsic gene set cen- troids of the 5 molecular subtypes, as previously described (30). Tumors were assigned to 1 of the molecular subtypes based on the highest correlation coefficient between each TNBC expression pro- file and the 5 molecular subtype centroids. This analysis resulted in 49% (n = 188) of our TNBC training set classified as basal-like, 14% (n = 54) as luminal A, 11% (n = 42) as normal breast–like, 8% (n = 31) as luminal B, 5% (n = 19) as HER2, and 13% (n = 52) as unclas- sifiable (Supplemental Figure 13B and Supplemental Table 9). This confirms that most TNBCs classify to the basal-like molecu- lar subtype. Both the unstable tumors and BL1 tumors correlated strongly to the basal-like intrinsic molecular classification (76% and 85%, respectively). However, the BL2, IM, and M subtypes only moderately correlated to the basal-like molecular class (31%, 58%, and 47%, respectively), with a portion of tumors unclassified (22%, 17%, and 18%, respectively) (Supplemental Figure 13B). The M and MSL subtypes displayed the largest portion of tumors classified as normal breast–like (25%, and 46%, respectively). The BL2, M, and MSL subtypes were a mixture of classifications, suggesting the intrinsic classification system may not be suitable for character- izing these TNBC subtypes. The majority of TNBC tumors within the LAR subtype were classified as either luminal A or luminal B (82%), and none were classified as basal-like, further supporting the luminal origin of the LAR subtype (Supplemental Figure 13). While only 49% of the tumors were classified as basal-like accord- ing to the intrinsic gene set, IHC staining performed on the Van- derbilt subset of tumors (n = 25) showed that the majority (88%) of TNBCs stained positive for the basal cytokeratins CK5/6 (Sup- plemental Table 10). Additionally, 56% of the Vanderbilt tumors stained positive for EGFR, similar to a previous study that found 56% of n = 929 pooled from 34 studies that were positive for EGFR or CK5/6 (31). There were no statistical differences between CK5/6 and EGFR staining across TNBC subtypes. Thus, the majority of TNBCs display a basal-like phenotype by IHC, while only approxi- mately half correlate to the basal-like intrinsic gene set.
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Triple negative breast cancer in South Africa

Triple negative breast cancer in South Africa

The mainstay of the management of triple negative breast cancer involves the use of systemic chemotherapy agents as its unique biology and lack of conventional targets and receptors renders hormonal therapy ineffective. Thus chemotherapy is the mainstay of treatment, usually anthracycline and taxane based regimens (19). Poor disease free outcomes are seen especially if the patient has a poor response to chemotherapy due to the dearth of other treatment options (41). The lack of targeted therapy (both hormonal and biological) has driven research into alternative chemotherapy regimens such as carboplatins (42). These have shown improved response rates with insufficient evidence to support universal use.
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Molecular Classification of Triple-Negative Breast Cancer

Molecular Classification of Triple-Negative Breast Cancer

In 2011, the researchers of the Vanderbilt University report- ed a seminal study classifying TNBC into distinct subtypes [8]. Using gene expression analyses from 587 TNBC tumors, they illustrated that TNBC consists of six distinguished subtypes and displays a unique biology that responds differently to vari- ous therapies. By k-means and consensus clustering, they found the following six subtypes: two basal-like subtypes, one with increased cell cycle and DNA damage response gene sig- natures (BL1) and the other one with high expression growth factor pathway and myoepithelial markers (BL2); two mesen- chymal subtypes with up-regulated gene signatures associated with cell differentiation and growth factor signaling (M and MSL); an immunomodulatory (IM) type with enriched im- mune cell processes; and a luminal androgen subtype charac- terized by androgen signaling (LAR). They found that distinct gene ontologies are involved with each TNBC subtype as brief- ly described above. Furthermore, they identified TNBC cell lines representing these subtypes by using gene expression analysis. They generated preclinical evidence for the clinical application of TNBC subtyping by correlating driver signaling pathways with the results of in vitro drug response assays using pharmacologically targeted treatment, offering distinct gene signatures that could forecast an effective tailored treatment. These experiments showed that DNA damaging agents such as cisplatin are effective for the basal-like subtype, NVP-BEZ335 as an mammalian target of rapamycin (mTOR)-phosphati- dylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) co-inhibitor for the mesenchymal subtype, and bi- calutamide as an androgen receptor (AR) blockade for the LAR subtype.
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