The Prevalence of HER2 Positivity In HER2 Borderline Tumors In Iranian Breast Cancer Patients And Predictive Variables

Background: Human epidermal growth receptor-2 (HER2) gene amplification is an important predictive and prognostic factor in breast cancer treatment. However, the expression of HER2 by immunohistochemistry (IHC) is determined as borderline in some cases and confirmation of the HER2 status by in situ hybridization either fluorescent (FISH) or bright field chromogenic (CISH) is necessary for correct treatment decision-making. Considering the high cost of FISH and CISH, we aimed to investigate whether the HER2 status could be predicted by other histological and cellular characteristics of the tumor by evaluating the association of these characteristics with the actual tumor HER2 status. Methods: Data of 438 breast cancer patients with IHC-determined HER-2 borderline disease was evaluated retrospectively. FISH or CISH results, pathologic tumor size and type, node involvement, Ki67%, presence of estrogen and progesterone receptor (ER, PR), HER2 status, lymphovascular invasion (LVI), perineural invasion (PNI), and stage were retrieved from clinic records. Results: Seventy-four (16.9%) patients had positive results for HER2 status with FISH or CISH. Logistic regression analysis showed that the pathologic size had a positive association with HER2 positivity with an OR equal to 1.03 (Odds ratio (OR):1.03, 95% CI: 1.01-1.05). In addition, the adjusted OR illustrated a statistically significant association between HER2 positivity and PR negativity (OR=2.14, 95% CI: 1.14-4.02). The invasive lobular carcinoma histology had a reverse association with HER2 positive status, with a borderline significance level (OR=0.15, 95% CI: 0.02-1.18).Conclusion: We could not find an applicable model to predict the actual status of HER2 in borderline cases and still, we have to recommend further assay by FISH or CISH in these patients.

ELISA and Fourier-transform infrared spectroscopy

ELISA and FTIR assay techniques were used to identify HER2 gene expression in the blood serum of female dogs and to characterise the biochemical composition. ELISA tests assess the stage of primary tumour development and evolution, while FTIR allows for a complete characterisation of biomolecules associated with the tumoral process. Blood serum samples from 30 female dogs were analysed. Concentrations of the HER2/neu protein were detected using ELISA kits specific for canine and human detection. Infrared spectroscopy (IR) was conducted in absorbance mode at a frequency range of 400–4000 cm-1 and a resolution of 4 cm-1 over 50 scans. The ELISA cut-off for HER2 protein concentration in blood serum was determined using the receiver operating characteristic (ROC) curve and by estimating the area under the curve (AUC) at a 95% confidence interval (CI=95%). The ROC curves in the canine and human ELISA tests were 0.75 and 0.45, respectively. The representative IR spectra for HER2 gene expression corresponded to lipids (1161 cm-1, 1452 cm-1, 2851 cm-1). This study contributes to the knowledge of HER2 through the identification of biochemical features associated with the changes in the HER2/neu+ and HER2/neu- states.

Detection of Genetic Polymorphism of HER2 Gene in HER2 Positive Breast Cancer Women in Iraq

The human epidermal growth factor receptor-2 (HER2) gene plays a critical role in breast cancer development and progression. HER2 overexpression characterizes a biologically and clinically aggressive breast cancer subtype. In this study, 60 samples from Iraqi women with breast cancer were collected and investigated for HER2 protein in the tissue by immunohistochemistry. Also, 20 samples from healthy Iraqi women were used as a control. The results showed that 18 (30 %) patients expressed the HER2 protein. A molecular study for single nucleotide polymorphism (SNP) was conducted on samples metastasizing to lymph nodes. DNA was extracted and polymerase chain reaction (PCR) was performed to amplify exon 17 and intron 17 of HER2 gene. Sequencing of PCR product was achieved and two SNPs of HER2 gene, one in exon 17 (Ile655Val) and another close to it in intron 17 (rs903506) were studied. In exon 17, SNP Ile655Val was found in 41% of patients, while in intron 17, the non-coding SNP rs903506 was found in 27% of patients. However, no polymorphism was found in the control group. The results may suggest that HER2 gene can be used as a molecular marker for breast cancer.

Association of HER1 and HER2 Gene Variants in the Predisposition of Colorectal Cancer

Background. Colorectal cancer (CRC) is a major health concern worldwide. A series of sequential accumulation of genetic and epigenetic changes are responsible for the initiation and progression of diseases via the normal > adenoma > carcinoma sequence. Genetic variants in crucial cancer-causing genes are known to mediate the risk of cancer. Objective. In this case-control study, we examined single nucleotide polymorphism (SNP) in HER1 (rs763317 and rs3752651) and HER2 (rs1136201 and rs1058808) genes to assess their role in the susceptibility of CRC in a Saudi population. Methods. TaqMan allelic discrimination assay was utilized to identify the genotypes in 163 normal and 143 CRC patients. Results. In the overall analysis, the rs3752651 and rs1136201 were significantly associated with the risk of CRC. Although none of the examined SNPs had any impact on the age at which CRC was diagnosed, interestingly, three SNPs showed a significant association based on gender. The rs3752651 conferred significant protection only in men, whereas rs1136201 diminished the risk and rs1058808 considerably increased the susceptibility of CRC only in women. Conclusions. Our result suggests that these SNPs in HER1 and HER2 after validation in larger cohorts of different ethnicities may be utilized as genetic screening markers for predicting colorectal cancer predisposition.

Diagnostic Potential of miR-30a and miR-200c in Invasive Breast Ductal Carcinoma

Background: Breast cancer is one of the most common cancers worldwide and is responsible for the death of many people. It is mainly found in women; however, it is rarely observed in men. Nowadays, extensive research has been conducted on the detection, diagnosis, and prognosis of biomarkers of this type of cancer, as well as other types. MicroRNAs play a major role in regulating the onset and progression of breast cancer. To date, many significant increases and decreases in microRNAs levels have been reported during various cancers, and also tumor inhibitory roles have been reported for these small non-coding RNA molecules. Methods: In this study, miR-30a and miR-200c were studied to find new expression patterns in breast cancer patients. For this purpose, a quantitative polymerase chain reaction was used to analyze the relationships between expression levels of miR-30a and miR-200c and several clinical and pathological features of the disease, such as tumor stage, HER2 gene expression, and lymphatic metastasis. Results: Our results showed that the expression of miR-200c and miR-30a in tumor samples was significantly lower than in normal samples (P < 0.01). Also, at higher stages of the disease, the expression of both miRNAs was remarkably reduced (P < 0.01). We also found that the expression of two miRNAs in patients with HER2 gene expression and metastasis in lymphatic regions was significantly lower than in HER2-negative and non-metastatic patients (P < 0.05 and P < 0.01, respectively). Conclusions: We identified the relationship between miR-200c and miR-30a and breast cancer. These findings indicate that these microRNAs can be considered biomarkers in breast cancer.

Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance

Trastuzumab, a targeted anti-human epidermal-growth-factor receptor-2 (HER2) monoclonal antibody, represents a mainstay in the treatment of HER2-positive (HER2+) breast cancer. Although trastuzumab treatment is highly efficacious for early-stage HER2+ breast cancer, the majority of advanced-stage HER2+ breast cancer patients who initially respond to trastuzumab acquire resistance to treatment and relapse, despite persistence of HER2 gene amplification/overexpression. Here, we sought to leverage HER2 overexpression to engage antibody-dependent cellular phagocytosis (ADCP) through a combination of trastuzumab and anti-CD47 macrophage checkpoint immunotherapy. We have previously shown that blockade of CD47, a surface protein expressed by many malignancies (including HER2+ breast cancer), is an effective anticancer therapy. CD47 functions as a “don’t eat me” signal through its interaction with signal regulatory protein-α (SIRPα) on macrophages to inhibit phagocytosis. Hu5F9-G4 (magrolimab), a humanized monoclonal antibody against CD47, blocks CD47’s “don’t eat me” signal, thereby facilitating macrophage-mediated phagocytosis. Preclinical studies have shown that combining Hu5F9-G4 with tumor-targeting antibodies, such as rituximab, further enhances Hu5F9-G4’s anticancer effects via ADCP. Clinical trials have additionally demonstrated that Hu5F9-G4, in combination with rituximab, produced objective responses in patients whose diffuse large B cell lymphomas had developed resistance to rituximab and chemotherapy. These studies led us to hypothesize that combining Hu5F9-G4 with trastuzumab would produce an anticancer effect in antibody-dependent cellular cytotoxicity (ADCC)-tolerant HER2+ breast cancer. This combination significantly suppressed the growth of ADCC-tolerant HER2+ breast cancers via Fc-dependent ADCP. Our study demonstrates that combining trastuzumab and Hu5F9-G4 represents a potential new treatment option for HER2+ breast cancer patients, even for patients whose tumors have progressed after trastuzumab.

Breast Epithelial-myoepithelial Carcinoma With HER2 Gene Amplification: a Rare Case and Review of Literature

Background: Epithelial-myoepithelial carcinoma is a very rare carcinoma that both luminal and myoepithelial components are malignant. What’s more, HER2 gene amplification has not been detected in the literature up to now. Herein, we report a rare case of breast epithelial-myoepithelial carcinoma with HER2 gene amplification.Case presentation: An 80-year-old woman presented with a mass in the upper outside region of her left breast. The core needle biopsy of the left breast mass revealed invasive breast carcinoma, and then modified radical mastectomy of left breast was performed. Macroscopically, the tumor was measured 6cm in diameter, and it was a solid and lobulated mass with areas of cystic and hemorrhagic lesions. Microscopically, the histological findings of tumor were consisted of 3 components. One component showed biphasic proliferation of both eosinophilic luminal epithelial and pale abluminal myoepithelial cells, arranging predominantly in dilated tubular architecture, which accounted for most of the lesion. Papillary architecture and eosinophilic secretions could be seen in some dilated ducts. The second component was proliferation of myoepithelial cells with pale cytoplasm around the glandular epithelium forming casing-like structures. The third component was few solid-appearing areas which was displayed a predominance of monophasic proliferation of myoepithelial cells. Both cell types exhibited enlarged and markedly atypical nuclei, with obvious nucleoli and prominent mitoses (up to 10-15/10 high power fields). Foci of infiltration were identified at the periphery of the lobules and the surrounding adipose tissue. Areas of central necrosis and stromal hyalinization could be seen. A diagnosis of EMC was made by morphology and immunohistochemistry. It's worth noting that HER2 gene amplification has not been detected in malignant adenomyoepitheIioma in the literature up to now; While in our present report, HER2 was 2+ membranous immunoreactivity, and then HER2 gene amplification was detected by fluorescence in situ hybridization. Conclusion: Accurate diagnosis of malignant adenomyoepitheIioma is challenging but of great importance, and the management of malignant adenomyoepitheIioma would be made according to histologic features.