CYP2C8 rs11572080 and CYP3A4 rs2740574 risk genotypes in paclitaxel-treated premenopausal breast cancer patients.

Breast cancer (BC) is the most prevalent malignancy in women globally. At time of diagnosis, premenopausal BC is considered more aggressive and harder to treat than postmenopausal cases. Cytochrome P450 (CYP) enzymes are responsible for phase I of estrogen metabolism and thus, they are prominently involved in the pathogenesis of BC. Moreover, CYP subfamily 2C and 3A play a pivotal role in the metabolism of taxane anticancer agents. To understand genetic risk factors that may have a role in pre-menopausal BC we studied the genotypic variants of CYP2C8, rs11572080 and CYP3A4, rs2740574 in female BC patients on taxane-based therapy and their association with menopausal status. Our study comprised 105 female patients with histologically proven BC on paclitaxel-therapy. They were stratified into pre-menopausal (n = 52, 49.5%) and post-menopausal (n = 53, 50.5%) groups. Genotyping was done using TaqMan assays and employed on Quantstudio 12 K flex real-time platform. Significant increased frequencies of rs11572080 heterozygous CT genotype and variant T allele were established in pre-menopausal group compared to post-menopausal group (p = 0.023, 0.01, respectively). Moreover, logistic regression analysis revealed a significant association between rs11572080 CT genotype and premenopausal BC. However, regarding rs2740574, no significant differences in genotypes and allele frequencies between both groups were detected. We reported a significant association between CYP2C8 genotypic variants and premenopausal BC risk in Egyptian females. Further studies on larger sample sizes are still needed to evaluate its importance in early prediction of BC in young women and its effect on treatment outcome.

Changes in breast cancer staging trends among Egyptian women after COVID-19: A retrospective single-center study.

OBJECTIVES: Since being declared a global pandemic, the SARS-CoV-2 virus had a significant impact on the entire globe. The pandemic has placed a heavy burden on healthcare systems worldwide, and cancer patients are particularly prone. Despite the fact that initial international reports suggest delays in breast cancer (BC) diagnosis and screening programs, the Egyptian context requires additional research on this topic. To examine whether COVID-19 has changed the pattern of disease presentation before and after the pandemic, focusing on the tumor, node, and metastasis (TNM) staging of the disease at the initial presentation. METHODS: This single-center, retrospective study of female BC patients initially diagnosed at Baheya Foundation was conducted during the following time frames: from Jan 2019 to Jan 2020 (Pre COVID-19 cohort) and from Mar 2020 to Mar 2021 (post-COVID-19 cohort). We compared the two cohorts in terms of clinical characteristics, tumor characteristics, and the number of days from presentation to treatment. Our primary endpoint was the difference in the TNM stage of BC at the initial presentation. RESULTS: This analysis included 710 BC patients, 350 from the pre-COVID cohort and 360 from the post-COVID group. We detected a 27.9% increase in late-stage BC (stages III-IV) in the post-pandemic cohort compared to the pre-pandemic (60.1% vs. 47%, p < 0.001). The time from diagnosis to commencement of treatment was significantly longer (28.34 ± 18.845 vs 36.04 ± 23.641 days, p < 0.001) in the post-COVID cohort (mean difference = 7.702, 95% CI 4.54-10.85, p < 0.001). A higher percentage of patients in the post-pandemic cohort received systemic neoadjuvant therapy (p-value for Exact's test for all treatment options = 0.001). CONCLUSIONS: The number of patients requiring systemic neoadjuvant chemotherapy increased dramatically in the post-pandemic group with advanced stages of BC at presentation. This study highlights the need for proper management of cancer patients during any future pandemic.

The Impact of Tumor Infiltrating Lymphocytes Densities and Ki67 Index on Residual Breast Cancer Burden following Neoadjuvant Chemotherapy.

To avoid unnecessary neoadjuvant chemotherapy in case anticipating a poor therapy response, it is essential to find the pathological parameters that would predict pathological complete response or at least a decrease in tumor burden following neoadjuvant chemotherapy. The purpose of this study is to investigate the hypothesis that tumor infiltrating lymphocytes can predict the efficacy of neoadjuvant chemotherapy and to find the Ki67 cutoff value that best predicts the benefit of chemotherapy. 153 cases of breast cancer were chosen, based on their molecular subtype: triple negative subtype (77) and luminal, HER2-ve subtype (76). Histopathological assessment of pretherapy core biopsies was conducted to assess variable pathological parameters including TILs rates with the aid of immunohistochemical staining for CD20 and CD3. Moreover, core biopsies were stained for Ki67, and the findings were compared to the residual cancer burden following neoadjuvant chemotherapy. On analyzing and contrasting the two groups, a significant association between molecular subtype and pathological complete response was confirmed, while tumor-infiltrating lymphocytes in either group had no effect on therapy response. We used receiver operating characteristic curve analysis to determine that a cutoff of 36% for Ki67 is the most accurate value to predict complete therapy response.

Regulation of CDK inhibitor p27 by microRNA 222 in breast cancer patients.

BACKGROUND: Breast cancer is the most common of all cancers and the second leading cause of cancer-related deaths among women worldwide. MicroRNAs regulate at least 60% of the human genes, including tumor suppressor genes and oncogenes, and can thereby affect cancer risk. In this study, the prognostic values of the CDK inhibitor p27 and miR-222 as biomarkers for breast cancer were evaluated. METHODS: The real-time quantitative polymerase chain reaction method was employed to measure the expression level of miR-222, whereas the serum levels of the CDK inhibitor p27 were measured via enzyme-linked immunosorbent assay. The levels were determined in sera from 110 participants representing three different groups. RESULTS: Patients with breast cancer exhibited significantly higher expression levels of miR-222 and lower levels of CDK inhibitor p27 than the control group. In addition, a statistically significant inverse correlation between miR-222 and the CDK inhibitor p27 was observed. The receiver operating characteristic curves plotted for serum p27 and miR-222 helped in significantly differentiating between breast cancer patients and controls but could not discriminate between those with stage II and stage III cancer. CONCLUSION: Thus, a significant upregulation in the serum miR-222 levels was observed in cancer patients, and a significant inverse correlation was noted between the miR-222 and CDK inhibitor p27 expression levels. These findings indicate that miR-222 may be used as a useful noninvasive screening biomarker for human breast cancer. MICROABSTRACT: Novel biomarkers for prognosis, prediction, and therapeutic purposes are essential as the prognosis and therapeutic targets of breast cancer are dependent on traditional markers, such as the tumor stage and hormonal receptor status. This study aimed to evaluate the diagnostic and prognostic values of the CDK inhibitor p27 and miR-222 in breast cancer. Our results indicated that miR-222 and the CDK inhibitor p27 may be used as noninvasive biomarkers to screen for human breast cancer but cannot discriminate between patients with early breast cancer and patients with advanced breast cancer.

Presence of HPV, EBV and HMTV Viruses Among Egyptian Breast Cancer Women: Molecular Detection and Clinical Relevance.

BACKGROUND: Oncogenic viruses, their possible association with breast cancer (BC) and effect on its clinical course are interesting issue. The present study evaluates the presence of human papillomavirus (HPV), EpsteinBarr virus (EBV), and human mammary tumor virus (HMTV) in BC and their relation with clinico-pathological characteristics. PATIENTS AND METHODS: This study was conducted on 80 Egyptian women with BC and 30 control women without known oncological disease. Forty formalin-fixed paraffin-embedded (FFPE) tissues, forty fresh tissue samples, and white blood cells (WBCs) of BC patients and WBCs of controls were subjected to a qualitative polymerase chain reaction (PCR). Quantitative real-time PCR was used to measure viral loads in fresh tissues of BC. The result was correlated with clinico-pathological characteristics of BC. RESULTS: HPV was detected in 33 (41.25%), EBV in 30 (37.5%) and HMTV in 33 (41.25%) BC patients. None of the control women was positive for HPV or EBV while HMTV was detected in 7 (23.3%). Among 40 BC WBCs specimens, HPV/HMTV were found together in 25%, followed by EBV/HMTV in 2.5% and EBV/HPV in 2.5%. However, the three viruses (HPV/EBV/HMTV) were found together in only 5%. In the 40 fresh BC tissues, the three viruses were found together in 12 (30%), EBV/HMTV in 7 (17.5%), HPV/HMTV in 4 (10%), and HPV/EBV in 4 (10%). EBV, HMTV, or multiple viral infections were associated with younger age of BC women. HPV, EBV, and HMTV median loads in fresh tissues were 4.8×103 copies/µL, 6.3×103 copies/µL, and 97 copies/µL, respectively. CONCLUSION: WBCs could be a more suitable specimen instead of fresh tissue for HMTV detection in BC patients to avoid invasive procedures. The presence of HPV, EBV, and HMTV together in Egyptian women with BC was significantly associated with younger age.

Increased Serum Endoglin and Transforming Growth Factor ß1 mRNA Expression and Risk of Hepatocellular Carcinoma in Cirrhotic Egyptian Patients.

Transforming growth factor-B1 (TGF-ß1 )and its coreceptor endoglin (ENG) have been shown to contribute to hepatocellular tumor development and malignant progression. Our aim was to evaluate the serum expression levels of ENG/ TGF-ß1 mRNAs and risk of hepatocellular carcinoma in cirrhotic Egyptian patients. Our study included 77 subjects. Real time polymerase chain reaction was used to evaluate the expression level of ENG and TGF-ß1mRNAs. The relative expression ratio of ENG mRNA was 0.82 (0.1 -3.2), 0.66 (0.15-5.3), 0.38(0.007-2.8) and 0.12 (0.00-0.22) and the relative expression ratio of TGF-ß1mRNA was 1.4 (0.19 -6.2), 1.2 (0.22-4.3), 1.0 (0.15-4.4) and 0.6 (0.00-2.2) for cirrhotic HCC cirrhotic, HCC only and healthy control groups respectively. Increased ENG and TGF-ß1 mRNA gene expression was correlated with TNM clinical stage. The expression ratio in TNM stage III-IV 1.1 (0.07-3.2), 1.55 (0.15-6.2) was statistically significantly higher than that in stage I-II 0.47 (0.007-2.8), 1.0 (0.31-4.4) (<0.05). Our data suggested that increased ENG and TGF-ß1 gene expression may participate in hepatocarcinogenesis and increased risk of HCC in individuals with cirrhosis. Early screening for evidence of cirrhosis and consideration of ENG and TGF-ß1 as targets for therapy and treatment strategies are warranted.

Tissue CA125 and HE4 Gene Expression Levels Offer Superior Accuracy in Discriminating Benign from Malignant Pelvic Masses.

BACKGROUND: Ovarian cancer remains a major worldwide health care issue due to the lack of satisfactory diagnostic methods for early detection of the disease. Prior studies on the role of serum cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in detecting ovarian cancer presented conflicting results. New tools to improve the accuracy of identifying malignancy are urgently needed. We here aimed to evaluate the diagnostic utility of tissue CA125 and HE4 gene expression in comparison to serum CA125 and HE4 in discriminating benign from malignant pelvic masses. MATERIALS AND METHODS: One-hundred Egyptian women were enrolled in this study, including 60 epithelial ovarian cancer (EOC) patients and 20 benign ovarian tumor patients, as well as 20 apparently healthy women. Preoperative serum levels of CA125 and HE4 were measured by immunoassays. Tissue expression levels of genes encoding CA125 and HE4 were determined by quantitative real time polymerase chain reaction (qRT-PCR). The diagnostic performance of CA125 and HE4, measured either as mRNA or protein levels, was evaluated by receiver operating characteristic (ROC) curves. RESULTS: The serum CA125+HE4 combination and serum HE4, with area under the curve (AUC) values of 0.935 and 0.932, respectively, performed significantly better than serum CA125 (AUC=0.592; P<0.001). Tissue CA125 and HE4 (AUC=1) performed significantly better than serum CA125 (P<0.001), serum HE4 (P=0.016) and the serum CA125+HE4 combination (P=0.018). CONCLUSIONS: Measurement of tissue CA125 and HE4 gene expression not only improves discriminatory performance, but also broadens the range of differential diagnostic possibilities in distinguishing EOC from benign ovarian tumors.

Treatment Outcomes of Epithelial Ovarian Cancers Following Maximum Cytoreduction and Adjuvant Paclitaxel-Carboplatin Chemotherapy: Egyptian NCI Experience.

BACKGROUND: Epithelial ovarian cancer (EOC) is the commonest malignancy involving the ovaries. Maximum surgical cytoreduction (MCR) followed by adjuvant taxane-platinum chemotherapy are the standard of care treatments. AIMS: To study treatment outcomes of EOC patients that were maximally cyto-reduced and received adjuvant paclitaxel-carboplatin (PC) chemotherapy. MATERIALS AND METHODS: This retrospective cohort study included 174 patients with EOC treated at the Egyptian National Cancer Institute between 2006 and 2010. For inclusion, they should have had undergone MCR with no-gross residual followed by adjuvant PC chemotherapy. MCR was total abdominal hysterectomy/bilateral salpingo-oophorectomy [TAH/BSO] or unilateral salpingo- oophorectomy [USO] plus comprehensive staging. RESULTS: The median age was 50 years. Most patients were married (97.1%), had offspring (92.5%), were postmenopausal (53.4%), presented with abdominal/pelvic pain and swelling (93.7%), had tumors involving both ovaries (45.4%) without extra-ovarian extension i.e. stage I (55.2%) of serous histology (79.9%) and grade II (87.4%). TAH/BSO was performed in 97.7% of cases. A total of 1,014 PC chemotherapy cycles were administered and were generally tolerable with 93.7% completing 6 cycles. Alopecia and numbness were the commonest adverse events. The median follow up period was 42 months. The 2-year rates for disease free survival (DFS) and overall survival (OS) were 70.7% and 94.8%, respectively. The respective 5-year rates were 52.6% and 81.3%. Advanced stage and high-grade were significantly associated with poor DFS and OS (p<0.001). Age >65 years was associated with poor OS (p =0.008). Using Cox-regression, stage was independent predictor of poor DFS and OS. Age was an independent predictor of poor OS.

CD11c+ and CD123+ dendritic cell subsets in peripheral blood of lung cancer patients.

Dendritic cells (DCs) play a central role in antitumor immune responses. Recent studies however have emphasized an immunosuppressive tumor influence on DCs in various types of cancer. We evaluated the percentages of myeloid and plasmacytoid related DCs in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Myeloid CD11c+ DCs (mDC) and plasmacytoid CD123+ DCs (pDC) cells were assessed by Flowcytometry in peripheral blood of twenty untreated lung cancer patients (13 NSCLC and 7 SCLC) and 15 healthy subjects. Lower percentages of pDCs and mDCs were found in patient with NSCLC and SCLC as compared to controls, with significant value only between NSCLC patients and controls (P= 0.001and P=0.000 respectively). The percentages of pDCs and mDCs subsets were significantly lower in patient with SCLC than NSCLC (P=0.013 and P=0.005 for pDCs and mDCs respectively). Our results suggest that NSCLC and SCLC might hamper the maturation of DCs, thus escaping an efficient immune response.

Study of endothelin-1 and vascular endothelial growth factor in patients with cancer colon.

PURPOSE: The levels of endothelin-1 and VEGF were evaluated in the sera of newly diagnosed patients with cancer colon and were compared with the routinely used tumor markers; CEA and CA19.9. Their relations with some prognostic factors of cancer colon were also investigated. SUBJECTS AND METHODS: The study included 48 patients with cancer colon and 20 apparently healthy volunteers as a control group. Patients were 23 males and 25 females with age range from 18 to 71 years (mean = 47 +/- 1.8). Both serum and plasma samples were obtained from patients and controls. RESULTS: Six percent of patients had grade 1 tumors, 77 % had grade 2 and 17 % had grade 3 disease. As regard to the stage, 52 % of patients were stage II, 35.5 % were stage III, while 12.5 % were stage IV. Liver metastasis was present in 12.5 %, while 35 % showed lymph node metastasis. The VEGF, endothelin-1, CA19.9 and CEA were significantly higher in the cancer colon patients than in control groups (p-value < 0.001,0.006, < 0.001 and <0.001; respectively). Plasma level of endothelin-1 and serum level of VEGF showed significantly higher levels in advanced stages of the disease (p value < 0.001) and in presence of liver metastasis (p value <0.00l and 0.002 respectively), while VEGF showed significant result when compared with the grade (p value = 0.032). In this study, when comparing the levels of plasma endothelin-1 and serum VEGF between the metastatic, non-metastatic liver patients of the cancer colon group and the control group, the comparison was statistically significant for both markers (p < 0.001). Endothelin-1 and VEGF showed significant positive correlation (r=0.77 and p-value < 0.0001). Serum VEGF and CA19.9 showed good sensitivities which were not different (97.9 % and 87.5 % ,respectively), while there was no significant difference between VEGF, CA19.9 and CEA with respect to specificities (100 %, 90 % and 100 % respectively). CONCLUSION: Both endothelin-1 and VEGF may be used for early detection of liver metastasis in cancer colon and VEGF may be used as a potential new marker for the diagnosis of cancer colon. Further studies with larger number of patients are recommended to establish the value of VEGF and endothelin- 1 as potential diagnostic and prognostic markers for cancer colon. KEY WORDS: Cancer colon - VEGF - Endothelin-1 - Angiogenesis.

Impact of SEN virus on immunoblot INNO-LIA HCV reactivity pattern and disease outcome in Egyptian hepatocellular carcinoma patients.

Recently, a novel virus designated SEN virus (SENV), which is thought to be related to posttransfusion hepatitis, was discovered. The aim of the present study was to investigate the prevalence and clinical significance of 2 SENV variants (SENV-D and SENV-H) in patients with hepatocellular carcinoma (HCC) and healthy adults. Also, to investigate the possible effect of SEN virus on the humoral immune response against different proteins of HCV through analyzing reactivity patterns of the confirmatory INNO-LIA HCV Ab III update in relation to SEN viremia. We investigated SEN virus infection in 41 patients with HCC (25 males and 16 females) and twenty healthy blood donors (12 males and 8 females). All samples were taken from the National Cancer Institute, Cairo University. We used semi nested polymerase chain reaction (PCR) amplification to detect SENV-D and SENV-H strains in serum. All patients were tested against HCV antibody by ELISA and HCV viremia by RT-PCR. Furthermore, nineteen patients positive for HCV antibody by EIA (10 positive for SEN DNA and 9 non viremic for SEN) were confirmed in the immunoblot assay. SENV DNA was detected in 68 % (28 of 41) of patients with HCC and in 64 % (21 of 33) HCV-related HCC, in comparison to 5% (1 of 20) healthy blood donor populations. The blood biochemical parameters, and performance status did not differ significantly between the SENV DNA-positive and- negative patients. However, the overall survival rate was 50 % after two years follow up in SENV DNA-positive and 14 % in SENV DNA-negative HCC patients. Reactivity to NS5 and E2 were less (22 % and 44 % of cases) in SENV negative cases, than in SENV positive cases (70 % and 80 % of cases, respectively). In conclusion, SENV DNA seems to be highly prevalent among Egyptian HCC patients. Cross reactivity between SENV proteins and HCV NS5, E2 or the increased immune response in SENV positive cases and consequently the increased reactivity to HCV NS5 and E2 proteins could not be ruled out. Although there was no apparent effect of SENV on biochemical tests, survival rates of SENV DNA-positive HCC patients were higher thannegative cases, which might be due to other factors affecting survival in our Egyptian HCC patients.