HER-2-positive breast cancer

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Impressive Objective Response to Nab Paclitaxel plus Trastuzumab as Fifth Line Therapy in an Elderly HER 2 Positive Breast Cancer Patient

Impressive Objective Response to Nab Paclitaxel plus Trastuzumab as Fifth Line Therapy in an Elderly HER 2 Positive Breast Cancer Patient

Background: Agent targeting HER-2 pathway plus chemotherapy has repre- sented a major progress in the management of patients with breast cancer. However, the role of late-line treatment in heavily pretreated patients is still largely unclear. In the last decade, nab-paclitaxel has shown significant activi- ty and good toxicity profile in metastatic breast cancer. Case Presentation: We report the case of a 76-year-old Caucasian woman with metastatic HER-2 positive ductal infiltrating breast carcinoma treated with a combination of weekly nab-paclitaxel and trastuzumab as fifth-line therapy. She had pre- viously received first-line paclitaxel and trastuzumab, second-line vinorelbine and trastuzumab, third-line TDM1 and fourth-line oral capecitabine and la- patinib. Clinical and radiological staging showed progression at bone, skin and soft-tissue. The patient received weekly nab-paclitaxel plus trastuzumab. Massive objective response was clinically and PET documented which lasted 8 months. Tolerance to treatment was fairly good as well as cardiac safety. Con- clusion: To the best of our knowledge, this is the first reported case of efficacy of nab-paclitaxel in combination with trastuzumab as fifth-line of treatment in a patient with metastatic HER-2 positive breast cancer.
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An In-Vivo Investigation of the Cardio-Protective Potential of Aspirin, β-oestradiol and Calcipotriol for Trastuzumab Treatment of Her-2 Positive Breast Cancer

An In-Vivo Investigation of the Cardio-Protective Potential of Aspirin, β-oestradiol and Calcipotriol for Trastuzumab Treatment of Her-2 Positive Breast Cancer

The 15-25% of breast cancers that overexpress human epidermal growth factor receptor type 2 (Her-2) are aggressive and more difficult to treat with conventional chemotherapy than their oestrogen receptor positive (ER+) counterparts. Adjuvant trastuzumab, a specific Her-2 targeting monoclonal antibody, has significantly improved the prognosis of women with metastatic and early Her-2 positive breast cancer. Yet clinically relevant cardio-toxicity continues to undermine its gains. This study investigated the unexplored potential of aspirin, b-oestradiol and calcipotriol to attenuate the antibody’s cardio-toxicity in an adult female Balb/c mouse model using serial echocardiography to assess left ventricular function at baseline and after treatment. Mean changes in left ventricular function were compared within and between treatment groups. Trastuzumab demonstrated statistically significant left ventricular dysfunction, detectable by reductions in speckle tracking echocardiographic parameters (global radial strain) from baseline. Calcipotriol did not abrogate these cardio-toxic effects. Conversely, â-oestradiol, high and low dose aspirin attenuated these early and subtle signs of trastuzumab-induced cardiac dysfunction. The findings of this pilot study suggest that b-oestradiol or aspirin may provide cardio-protection against trastuzumab in-vivo, and larger definitive studies are justified.
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Compound C enhances the anticancer effect of aspirin in HER-2-positive breast cancer by regulating lipid metabolism in an AMPK-independent pathway

Compound C enhances the anticancer effect of aspirin in HER-2-positive breast cancer by regulating lipid metabolism in an AMPK-independent pathway

AMPK has been implicated in a range of biological functions including cell polarity, autophagy, apoptosis, and cell migration [32]. Compound C, a widely known AMPK inhibitor [33], was used to reverse the aspirin-induced activation of AMPK. Unexpectedly, we found that Compound C pre-treatment, after successfully blocking AMPK activation, enhanced the growth inhibition effect induced by aspirin on HER-2-positive breast cancer cells, but could not affect the anti-growth effect of aspirin in HER-2 negative breast cancer cells. In the Compound C pre-treated group, we observed more robust inhibition of cell proliferation, a reduced colony-forming ability, and a higher apoptosis rate than the aspirin alone-treated HER-2-positive breast cancer cells. The increased inhibition of HER-2-positive breast cancer cell biological function upon Compound C pre-treatment was surprising; thus, we began to study and analyze the mechanisms surrounding this. Interestingly, Compound C, despite being an AMPK inhibitor, can inhibit cell growth in 3T3-L1 preadipocytes [34] and vascular smooth muscle cells [35] independent of AMPK activity. Compound C is also known to enhance tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through a caspase-dependent mechanism in Caki cells, independent of AMPK [33]. The previously reported Compound C-induced inhibition of macrophage migration was shown to be mediated via the inhibition of the focal adhesion kinase, AKT, and NF-κB pathways, but was independent of AMPK activation [36].
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Comparison of the efficacy and survival analysis of neoadjuvant chemotherapy for Her-2-positive breast cancer

Comparison of the efficacy and survival analysis of neoadjuvant chemotherapy for Her-2-positive breast cancer

The advantages of TCH were demonstrated by comparing four chemotherapy regimens. For the remaining three groups, which did not receive trastuzumab, we concluded that the short-term efficacy of the XEC-XT group and the TEC group were not significantly different, and that both were superior to the FEC-T group. However, in terms of long-term efficacy, the XEC-XT group was superior to both the FEC-T group and the TEC group. There was no difference in the long-term prognosis between the TEC and FEC-T groups (Figures 1 and 2). No optimal sequence is currently known, and the choice of individual regimens and drugs depends on patient preferences regarding the schedule and side-effect pattern, as well as the aforementioned therapies and residual toxic effects. Compared with the AC-TH regimen (pirarubicin/ cyclophosphamide follow by docetaxel/trastuzumab), the advantage of the TCH regimen is that the early use of trastu- zumab can rapidly cause tumor reduction and prevent tumor progression. In conclusion, with the promotion and evolution of NAC, the NAC scheme is often varied; however, in Her- 2-positive breast cancer, the TCH regimen would occupy the dominant position.
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Protein tyrosine phosphatase SHP-1 sensitizes EGFR/HER-2 positive breast cancer cells to trastuzumab through modulating phosphorylation of EGFR and HER-2

Protein tyrosine phosphatase SHP-1 sensitizes EGFR/HER-2 positive breast cancer cells to trastuzumab through modulating phosphorylation of EGFR and HER-2

Background: Trastuzumab resistance in HER-2 positive breast cancer cells is closely related to overexpression of both epidermal growth factor receptor (EGFR) and human epidermal recep- tor (HER-2). SHP-1 has been demonstrated to downregulate tyrosine kinase activity including EGFR via its phosphatase function, but its effect on HER-2 activity is still unknown. Here, we examined the hypothesis that SHP-1 enhances the anticancer efficacy of trastuzumab in EGFR/ HER-2 positive breast cancer cells through combining dual inhibition of EGFR and HER-2. Methods: Trastuzumab-resistant breast cancer SKBr-3 cells were generated by long-term in vitro culture of SKBr-3cells in the presence of trastuzumab. The SHP-1 was ectopically expressed by stable transfection. The activity and expression of EGFR, HER-2, and down- stream signaling pathways were tested by Western blot. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was examined by flow cytometry. The binding between SHP-1 and EGFR/HER-2 was evaluated by immunoprecipitation assay and bimolecular fluorescence complementation. The effects of SHP-1 on tumorigenicity and trastuzumab sensitivity were confirmed via in vivo xenograft model. Results: Trastuzumab-resistant SKBr-3 cells showed aberrant co-expression of EGFR and HER-2. Introduction of wild-type SHP-1 inhibited cell proliferation, clone formation, and pro- moted the apoptosis induced by trastuzumab. Meanwhile, SHP-1 overexpression reduced phos- phorylation levels of EGFR and HER-2 both in parental and trastuzumab-resistant SKBr-3 cells. In vivo study showed an increased antitumor effect of trastuzumab in SHP-1 overexpressed xenografts. At last, we discovered that SHP-1 can make complexes with both EGFR and HER-2, and both phospho-EGFR and phosphor-HER-2 levels in wild-type SHP-1 immunoprecipitates were less than those in phosphatase-inactive SHP-1 (C453S) immunoprecipitates, indicating that EGFR and HER-2 are potential substrates of SHP-1.
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Targeted neoadjuvant therapy in the HER-2-positive breast cancer patients: a systematic review and meta-analysis

Targeted neoadjuvant therapy in the HER-2-positive breast cancer patients: a systematic review and meta-analysis

The current analysis also found that application of lapa- tinib alone or in combination with trastuzumab resulted in more toxic side effects including diarrhea, skin rash, and liver function impairment, suggesting lapatinib may be associated with those toxic side effects. Due to 40% of toxic side effects in the combination group (double HER-2 blockade usage) in the NeoALTTO and NSABP protocol B-41 trials, neoad- juvant protocol therapy was discontinued in these trials. 22,25

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<p>A high absolute lymphocyte count predicts a poor prognosis in HER-2- positive breast cancer patients treated with trastuzumab</p>

<p>A high absolute lymphocyte count predicts a poor prognosis in HER-2- positive breast cancer patients treated with trastuzumab</p>

HER2 signalling and through immune mechanisms such as ADCC and complement-dependent cytotoxicity. 17 Thus, trastuzumab can induce a substantial increase in natural killer cells and CD8-positive T cells, implying that trastu- zumab can activate different mechanisms to recruit lym- phocytes to the tumor site. 17 Higher TILs were signi fi cantly associated with a higher pathological com- plete response in patients receiving the neoadjuvant regi- men and better overall survival in HER-2-positive advanced breast cancer. 12,18 However, CD8+TILs and ALC were negatively correlated in breast cancer. 19 HER-2 overexpression in ductal carcinoma was signi fi - cantly associated with higher FOXP3+ TILs, and increased FOXP3+ TILs were associated with more aggressive tumor features. 20 Additionally, in the tumor microenviron- ment, there also co-exist many other in fi ltrating immune cells, such as tumor-associated macrophages (TAMs) and cancer-related neutrophils (CRNs), which can enhance tumor cell invasion and metastasis. 21,22 Beyond that, che- motherapy, like the taxane regimen, can also enhance trastuzumab-mediated ADCC in tumor cells. 23 Therefore, the tumor immune microenvironment is very complex and in fl uenced by numerous factors, such as treatment with trastuzumab and effect of chemotherapy.
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HER 2 positive breast cancer is associated with an increased risk of positive cavity margins after initial lumpectomy

HER 2 positive breast cancer is associated with an increased risk of positive cavity margins after initial lumpectomy

Many studies have demonstrated that patients with HER-2 overexpression and TN BCs are at increased risk of developing LR following BCS [6,13,14]. Does the higher risk of LR in the two subtypes result from an increased microscopic invasive tumor burden that could be indicated by margin status after lumpectomy? We have no definite answer at present. Positive margins were reported to be significantly associated with large tumor size, young age, positive nodes, presence of lym- phovascular invasion (LVI), and presence of an extensive intraductal component (EIC) [15-17]. In addition to the above analyzed clinical and pathologic variables, molecu- lar phenotype may be a relevant factor of positive margins. The purpose of this study was to determine whether BC subtype approximation is associated with positive mar- gins after initial lumpectomy and the extent of initial surgery that should be considered according to molecular subtypes.
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Evidence Based Medicine, in Precision Oncology

Evidence Based Medicine, in Precision Oncology

surviv- al in patients with metastatic breast cancer, as well as disease-free and overall survival in patients with localized invasive breast cancer. That said, Her 2 posi- tive breast cancer response to Herceptin, (if there is no inherent or acquired re- sistance reported) has a quantity and duration with a range of negligible to sig- nificant and between few weeks to years, depending of the clinical study per- formed and the candidates specific tumor character included in the studied. Many of the studies that have looked at application of Gleevec for example in Her 2 positive breast cancer with hormonal blockade again disagree on the out- comes as the candidates were not stratified for the presence of TP53 or PDGF. Such discordance and disagreements merely are caused by the lack of biological information on tumor behavior and its unique character in each case studied in the trial. As a result, next generation clinical trials are suggested to replace the current oncology clinical trial design to avoid the blinded conclusions in blinded trials.
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Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer

Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer

An open-label study was performed in patients with Her-2- positive breast cancer with no brain metastases (cohort 1) and with at least a single brain metastases ≥1 cm (cohort 2) as confirmed by MRI. Other inclusion criteria included fe- male patients aged at least 18 years with histologically or cytologically confirmed advanced or metastatic breast cancer with overexpression of Her-2, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, stable condition as judged by the investigator and adequate hep- atic and renal function. An Allen’s test to check the ad- equacy of collateral circulation of the hand was also performed at screening as radial arterial cannulation was performed on the day of the scan. The protocol stipulated that patients were not allowed to receive concurrent treat- ment with an investigational medicinal product or anti-
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Aloe-emodin inhibits HER-2 expression through the downregulation of Y-box binding protein-1 in HER-2-overexpressing human breast cancer cells

Aloe-emodin inhibits HER-2 expression through the downregulation of Y-box binding protein-1 in HER-2-overexpressing human breast cancer cells

Human epidermal growth factor receptor-2 (HER-2)-positive breast cancer tends to be aggressive, highly metastatic, and drug resistant and spreads rapidly. Studies have indicated that emodin inhibits HER-2 expression. This study compared the HER- 2-inhibitory effects of two compounds extracted from rhubarb roots: aloe-emodin (AE) and rhein. Our results indicated that AE exerted the most potent inhibitory effect on HER-2 expression. Treatment of HER-2-overexpressing breast cancer cells with AE reduced tumor initiation, cell migration, and cell invasion. AE was able to suppress YB-1 expression, further suppressing downstream HER-2 expression. AE suppressed YB-1 expression through the inhibition of Twist in HER-2-overexpressing breast cancer cells. Our data also found that AE inhibited cancer metastasis and cancer stem cells through the inhibition of EMT. Interestingly, AE suppressed YB-1 expression through the downregulation of the intracellular integrin-linked kinase (ILK)/protein kinase B (Akt)/mTOR signaling pathway in HER-2-overexpressing breast cancer cells. In vivo study showed the positive result of antitumor activity of AE in nude mice injected with human HER-2-overexpressing breast cancer cells. These findings suggest the possible application of AE in the treatment of HER-2-positive breast cancer.
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Tumor-targeting, Systemically Delivered Antisense HER-2 Chemosensitizes Human Breast Cancer Xenografts Irrespective of HER-2 Levels

Tumor-targeting, Systemically Delivered Antisense HER-2 Chemosensitizes Human Breast Cancer Xenografts Irrespective of HER-2 Levels

Because of their inherent positive charge, cati- onic liposomes have a high affinity for most neg- atively charged cell membranes. This makes them, so far, the most successful delivery method for ODNs (reviewed in 26, 38, 39). Perhaps the most signifi- cant factor to be considered regarding effective ODN delivery via cationic liposomes is optimization of the complex with respect to, among others, the type of lipids in the complex, their ratios, the ratio of lipid to nucleic acid, and even the method of formation of the complex. This is evident in the data presented here in Figure 1, where significant differences were noted in ODN uptake delivered by five different li- posome complexes. There are numerous reports in the literature using cationic liposomes to deliver AS oligonucleotides in animal models. These include liposomes carrying AS oligonucleotides against the RNA component of human telomerase to treat prostate cancer xenografts (40) or gliomas in nude mice (41); an anti-TGF- ␣ AS oligonucleotide to in- hibit growth of squamous cell carcinoma of the head and neck xenograft tumors (42) and to prevent liver injury during endotoxemia (41); and anti–c-myc AS oligonucleotide to inhibit tumor growth and in- crease survival of mice bearing malignant melanoma xenograft tumors (42). AS-raf-1 ODN has also been Using dynamic light scattering (a Malvern Zetasizer
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Triple-negative (ER, PgR, HER-2/neu) breast cancer in Indian women

Triple-negative (ER, PgR, HER-2/neu) breast cancer in Indian women

Scoring for proportion staining was as follows: 0 denotes no nuclear staining, 1 denotes ,1% nuclei staining, 2 denotes 1%–10% nuclei staining, 3 denotes 11%–33% nuclei stain- ing, 4 denotes 34%–66% nuclei staining, and 5 denotes 67%–100% nuclei staining. Scoring for staining intensity was as follows: 0 denotes no staining, 1 denotes weak staining, 2 denotes moderate staining, and 3 denotes strong staining. The score for proportion staining multiplied by the score for staining intensity is equal to the score. Score 0 indicates that endocrine treatments or tamoxifen will definitely not work and such patients should receive an alternative first-line treatment. Score 2–3 indicates a 20% chance of response to endocrine treatment. Score 4–6 indicates a 50% chance of response to endocrine treatment. Score 7–8 indicates a good (75%) chance of response to endocrine treatment. 0 score is negative, which denotes no staining seen or staining seen in less than 10% of tumor cells. Score 1 + is negative, which denotes that a faint/barely perceptible membrane staining is detected in more than 10% of tumor cells but that the cells are stained in only part of the membrane. Score 2 + shows a borderline or weakly positive result, which denotes that weak to moderate complete membrane staining is seen in more than 10% of tumor cells. Score 3 + is strongly positive, which denotes that strong complete membrane staining is seen in more than 30% of tumor cells. True HER-2/neu positivity is shown by crisp brown-colored membrane staining in at least 30% of the invasive tumor. Score 3 is two steps higher than HER-2/neu expression in surrounding benign breast parenchyma.
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2. STUDY OF METASTATIC CANCER OF BREAST WITH SPECIAL REFERENCE TO BREAST CANCER SUBTYPES

2. STUDY OF METASTATIC CANCER OF BREAST WITH SPECIAL REFERENCE TO BREAST CANCER SUBTYPES

Background: Breast cancer is a major medical problem with significant public health and societal ramifications and is a leading cause of cancer death in women. Gene expression profiling has identified five subtypes of breast cancer (luminal A, luminal B, normal breast like, HER-2neu over expression, and basal-like), each of which has a different prognosis. Aims & Objectives: The aim of the present study to compare the expression of these biomarkers between primary and metastatic breast carcinoma. Material & Methods: All female patients ages >18 years diagnosed with metastatic breast cancer at the Gujarat Cancer and Research Institute from October 2010 to February 2013 were evaluated and taken into the study. The assessment of ER, PR and Her2 for the metastatic tissue was then compared with that of the primary tumour. Results: In our study the youngest patient was 25 years old and the eldest was 75 years old with an average age and median age was 45 years at the time of presentation with breast cancer. Estrogen receptor (ER) was positive in 15 (23%) and negative in 50 (77%) primary tumours while positive in 27 (42%) and negative in 38 (58%) metastatic tumours. Progesterone receptor (PR) was positive in 20 (31%) and negative in 45 (69%) primary tumours while positive in 24 (37%) and negative in 41 (63%) metastatic tumours. HER2 receptor was positive in 25 (38%) and negative in 40 (62%) primary tumours while positive in 22 (34%) and negative in 43 (66%) metastatic tumours. Conclusion: Our study demonstrates important differences in metastatic behaviour between the breast cancer subtypes as defined by a panel of immunohistochemical markers and contributes to an expanding knowledge of prognostic and predictive markers that will allow individualized therapy for metastatic breast cancer.
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Tumor escape and progression of HER 2/neu negative breast cancer under immune pressure

Tumor escape and progression of HER 2/neu negative breast cancer under immune pressure

of patients with HER-2/neu negative tumors compared to those with HER-2/neu positive tumors suggests the presence of high affinity T cells in the former. Weak T cell responses were associated with weak and scattered nuclear and cytosolic IFN-g Ra while stronger T cell responses in patients with HER-2/neu- tumors was asso- ciated with an intense and uniform nuclear IFN-g Ra. Our findings suggest that the increased rate of HER-2/ neu positive DCIS compared with breast cancer may reflect the loss of HER-2/neu during tumorigenesis in premalignant cells where IFN-g signaling pathway is active. This possibility is also supported by a number of observations reported by other groups. For instance, induction of HER-2/neu-specific IFN-g producing T cell responses in patients with DCIS resulted in loss of HER-2/neu expression [7]. It was also reported that overexpression of HER-2/neu in DCIS lesions predicts the presence of invasive foci in patients with DCIS [15]. Others also have suggested that the low frequency of HER-2/neu expression (20-25%) in invasive breast can- cer implies that HER-2/neu loss is an epiphenomenon of disease progression [16].
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A correlation study of the expression of HA-CD44st and HER-2 in breast cancer

A correlation study of the expression of HA-CD44st and HER-2 in breast cancer

were expressed as mean ± SD. One-way analysis of variance (ANOVA) was used to analyze the difference between the transfection groups and the negative control group. One-way ANOVA was used to compare the means of multiple groups. The q test was used for intergroup pairwise comparisons. The chi-squared test was used to analyze the differences in the positive expression rates of CD44st and HER-2 mRNA or protein in breast cancer tissues. The K–S test showed that the P values for the average Δ Ct values of CD44st and HER-2 were 0.12 and 0.19, which indicated that the data met normal distribution. The correlation between CD44 protein expres- sion and the average Δ Ct value of CD44st mRNA expression was evaluated using Spearman correlation analysis. The correlation between the expression of CD44st mRNA and HER-2 mRNA was also analyzed. P , 0.05 was considered
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The Effect of Neoadjuvant Chemotherapy on ER, PR and HER 2 Expression in Breast Cancer

The Effect of Neoadjuvant Chemotherapy on ER, PR and HER 2 Expression in Breast Cancer

Objective: Through comparativing the change of the ER, PR and HER-2 ex- pression in tumor tissue before and after neoadjuvant chemotherapy (NAC) in locally advanced breast cancer patient, to discuss whether there is influence for NACon ER, PR, HER-2 expression for breast cancer. Also, the relation- ship of ER, PR, HER-2 and chemosensitivity is also discussed. Methods: The expressions of ER, PR and HER2 in paraffin sections of breast cancer tissues from 51 patients before and after NAC were detected by immunohistochemi- cal method. The assessment for the relationships between ER, PR, HER-2 and the efficiently of NAC is done. Results: For the 51 peoples, there is no statis- tical significance for change of ER, PR and HER-2 expression before and after NAC (P > 0.05). There is statistical significance for the differences of chemo- therapeutic effectiverate between ER negative and ER positive, PR negative and PR positive, HER2 over-expressed group and HER2 non over-expressed group (P < 0.05). Pathological complete response (pCR) was related to mole- cular classification and the number of chemotherapy cycles. There is statisti- cally significant or prognisis difference about hormone receptor, HER2 over-expressed and three-negative breast cancer (P < 0.05). Conclusion: NAC maybe could not change the expression of ER and PR, and HER2 for breast cancer patients. The patients with HER-2 over-expressed are not sensi- tive to chemotherapy, and the patients with ER or PR negative get more ben- efits from chemotherapy. The breast cancer patients who could obtain pCR could get better prognosis after NAC.
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Association between Overexpression of Her 2 and Other Clinicopathologic Prognostic Factors in Breast Cancer in Morocco

Association between Overexpression of Her 2 and Other Clinicopathologic Prognostic Factors in Breast Cancer in Morocco

analysis. This pattern of overexpression of Her-2 in large tumors has been demonstrated in other studies [27,28] while in some studies this association has not been found [24,29-32]. The prognostic value of grade is currently established. Hoff et al. demonstrated in their series that high-grade tumors were more likely to have a positive HER-2 status as low-grade tumors [33]. Similarly, other studies have also reported the association between HER-2 positive status and a high histological grade [29-31]. This finding was also confirmed in our study. However, some studies have not demonstrated any cor- relation between high-grade status and HER-2 positive [24,34].The axillary lymph node involvement is a major prognostic factor. Most studies that have examined the prognostic role of HER-2 in N + patients showed that amplification of HER-2 gene or overexpression of Her-2/ neu protein is associated with pejorative results whether in univariate or multivariate analysis [35-37]. Our study found this association in univariate analysis, but disap- peared in multivariate analysis. Extra capsular spread and the vascular space invasion are two parameters that have been poorly studied in the literature and found to be as- sociated with overexpression of the protein Her-2/neu in our study. Despite the vast differences at the levels of the positivity of the Her-2, all the researchers report an in- verse correlation between HER-2 status and the hormone receptors [24,28-30,32,35,38-42]. Our data are consistent with those reported in the literature.
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Quantification of HER family receptors in breast cancer

Quantification of HER family receptors in breast cancer

homodimers in formalin-fixed, paraffin-embedded (FFPE) tissue specimens [39,40]. The HERmark assay was devel- oped based on a proprietary proximity-based technology platform that enables accurate quantification of proteins and protein-protein complexes through the release of a fluorescent tag (VeraTag reporter, Monogram Biosciences) conjugated to a pair of monoclonal antibodies directed to unique epitopes on the HER2 receptor in molecular prox- imity [40]. The continuous total HER-2 expression results are grouped as HERmark negative, HERmark equivocal, and HERmark positive. The threshold for a positive HERmark test is based on the comparison with HER2 tests performed in 1,090 breast tumor reference samples (central IHC and central in situ hybridization) from three different study cohorts. The HERmark assay can detect HER2 at amounts of 2,500 up to more than 1 million re- ceptors per cell, and is thus said to be 7 to 10 times more sensitive than IHC. The assay has been validated ac- cording to the specifications prescribed by the Clinical Laboratory Improvement Amendments and is performed only in the CAP-certified clinical reference laboratory at Monogram Biosciences (US). VeraTag™ proximity-based assays have been developed also to measure total EGFR, EGFR-EGFR homodimers and EGFR-HER2 heterodimers [40-42], p95 [43], total HER3, HER3-HER3 homodimers and HER3-phosphoinositide 3-kinase (PI3K) complex het- erodimers [44] and the phosphorylated forms of EGFR, HER2, and HER3.
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Negative genic switch of HER 2 in the primary tumor instead of the synchronous metastatic nodal lesions after neoadjuvant chemotherapy in a patient with primary HER2 positive breast cancer

Negative genic switch of HER 2 in the primary tumor instead of the synchronous metastatic nodal lesions after neoadjuvant chemotherapy in a patient with primary HER2 positive breast cancer

Aitken et al. [20] confirmed by breast tissue micro- array (TMA) and matched node TMA that biomarkers’ status of metastatic nodal lesions could be a more accur- ate measurement for guiding adjuvant therapy. It is postulated that biomarker profiles expressed by locore- gional nodal lesions are more indicative of the biological behaviors of distant micro-metastases and circulating tumor cells (CTCs) that are more invasive and closely correlated with the potential clinical outcomes [21, 22] and vice versa. Onsten et al. [23] elaborated two cases in which gene expression profiles of CTCs bore better re- semblance to that of the nodal metastases than the pri- mary tumor when molecular discordance between CTCs and the primary tumor were investigated by reverse tran- scription quantitative PCR. Aktas et al. [24] demonstrated
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