ERCC1 Expression in Metastatic Triple Negative Breast Cancer Patients Treated with Platinum-Based Chemotherapy

Background: Possible targeted therapies for metastatic triple negative breast cancer (TNBC) include cytotoxic chemotherapy that causes interstrand breaks (platinum-based drugs). The excision repair cross-complementation 1 (ERCC1) enzyme plays an essential role in the nucleotide excision repair pathway, removing platinum-induced DNA adducts and contributing to cisplatin resistance. Detecting ERCC1 overexpression is important in considering treatment options for metastatic TNBC, including individualized approaches to therapy, and may facilitate improved responses or reduction of unnecessary toxicity. We hypothesized that assigning cisplatin based on pretreatment ERCC1 expression would improve response and survival. This study was conducted to assess the impact of ERCC1 expression on PFS, OS and response rates in metastatic triple negative breast cancer patients treated with platinum-based chemotherapy. Methods: From June 2012 to November 2013, 52 metastatic triple negative breast cancer patients were enrolled. ERCC1 protein expression was detected from pretreatment biopsies by Immunohistochemistry. All patients received cisplatin plus paclitaxel. The primary end point was the impact of ERCC1 expression on PFS and OS. Results: 34 patients (65.4%) showed positive ERCC1 expression while 18 (34.6%) proved negative. Positive ERCC1 expression was associated with short PFS (median, 5 months vs. 7 months; P = 0.043), short OS (median, 9 months vs. 11 months; P = 0.033) and poor response to cisplatin based chemotherapy (P = 0.046). Conclusions: This prospective study further validated ERCC1 as a reliable biomarker for customized chemotherapy in metastatic triple negative breast cancer patients. High expression of ERCC1 was thereby fond to be significantly associated with poor outcome in patients treated with platinum based chemotherapy.

Clinicopathologic Effect of DNMT3A Mutation in Adult T-Cell Acute Lymphoblastic Leukemia.

BACKGROUND: The present study aimed to determine the frequencies and clinicopathologic effect of a DNMT3A [DNA (cytosine-5)-methyltransferase 3A] mutation in patients with adult T-cell acute lymphoblastic leukemia (T-ALL). PATIENTS AND METHODS: A total of 64 patients with T-ALL who had been admitted to Mansoura University Oncology Center were included in the present study. For all patients, DNA extraction and amplification with sequencing analysis using the 310 ABI genetic analyzer for detection of a mutation (R882H). RESULTS: The DNMT3A mutation (R882H) was found in 12 of the 64 patients (18.8%). The DNMT3A mutation was frequently detected in the older age group and was associated with high leukocytic counts, a high bone marrow blast cell percentage, and the frequent presence of extramedullary disease. However, it was not associated with the hemoglobin level, red blood cell count, or platelet count. The patients with mutant T-ALL had a low tendency to achieve remission after induction. These patients had significantly shorter overall survival and shorter disease-free survival compared with those with wild-type T-ALL (P = .037 and P = .006, respectively). CONCLUSION: DNMT3A is frequently mutated in T-ALL and is associated with distinct clinicopathologic entities and a poor prognosis. These findings could help in risk stratification and treatment decisions for patients with T-ALL.

Prevalence and Clinical Effect of IDH1 and IDH2 Mutations Among Cytogenetically Normal Acute Myeloid Leukemia Patients.

BACKGROUND: The frequencies of isocitrate dehydrogenase (IDH) 1 and IDH2 mutations among patients with de novo acute myeloid leukemia (AML) are different among different ethnic groups. The aim of this study was to determine the frequencies of IDH1 and IDH2 mutations among Egyptian AML patients and its effect on patient outcomes. PATIENTS AND METHODS: This study was conducted in 211 adult patients (104 men; 107 women; age range, 18-68 years) with cytogenetically normal AML. DNA was extracted from bone marrow samples at the time of diagnosis. The exon 4 of IDH1 and IDH2 were amplified using polymerase chain reaction and sequenced for detection of mutations. RESULTS: IDH1 mutations were detected in 18 of 211 AML patients (8.5%) in the form of 8 cases, R132H; 6 cases, R132C; 2 cases, R132S; 1 case, R132G; and 1 case, R132V mutations). IDH2 mutations were detected in 22 of 211 AML patients (10.4%) in the form of 20 cases, R140Q; and 2 cases, R172K mutations. The overall survival after correction for nucleophosmin 1 and fims- related tyrosine kinase internal tandem duplication was significantly shorter in AML patients with the IDH mutation compared with those with wild type (P = .02). CONCLUSION: IDH1 and IDH2 mutations are negative prognostic markers in AML patients. A novel mutation (R132V) was detected in IDH1 in our cohort of AML patients. We recommend molecular testing for IDH1 and IDH2 mutations for proper risk stratification of AML patients before the start of therapy.

Telomerase reverse transcriptase (TERT) A1062T mutation as a prognostic factor in Egyptian patients with acute myeloid leukemia (AML).

This study aimed to evaluate the incidence and clinical and prognostic impact of TERT A1062T mutation in AML patients treated at Mansoura Oncology Center. Screening for TERT A1062T mutation in exon 15 of the TERT gene was performed on diagnostic DNA samples from 153 AML patients and 197 healthy subjects as a control group by using sequence-specific primers. TERT A1062T mutation was detected in 18 cases out of 153 patients (11.8 %) and in one out of 197 control group subjects (0.51 %). The achievement of complete remission was significantly higher in AML group with wild type as compared to that in the mutant one (53.3 vs 16.7 %, respectively). In addition, the relapse rate was significantly higher in the mutant patients as compared to those with wild type (62.5 vs 28.2 %, respectively). The AML patients with TERT (A1062T) mutation had shorter overall survival than patients with wild type (P = 0.001). In a multivariable analysis, TERT (A1062T) mutational status is independently worse predictor factor (P = 0.007) when controlling for cytogenetic status (P = <0.001), performance status (P = <0.001) and bone marrow blast cells (P = 0.001). In conclusion, TERT A1062T mutation is an independent negative prognostic factor in AML patients. Therefore, molecular testing for TERT A1062T mutation in patients with AML is recommended in order to delineate their prognostic status.