Predictive Value of ABCC2 and UGT1A1 Polymorphisms on Irinotecan-Related Toxicities in Patients with Cancer.

Background: There is extensive interindividual variability in response and tolerance to anticancer drugs. This heterogeneity provides a major limitation to the "rational" use of cytotoxic drugs, and it becomes a major problem in oncology giving a narrow therapeutic window with a vital risk. Among these anticancer drugs, irinotecan can cause dose-limiting toxicities, commonly diarrhea and neutropenia. Interaction among pathways of activation/inactivation (UGT1A1) and hepatobiliary transport of irinotecan and its metabolites could, in part, explain its interindividual variability. The objective of this study was to perform an exploratory analysis to evaluate the correlation between the genetic polymorphisms of UGT1A1 and ABCC2 with the different toxicities associated with irinotecan treatment. Materials and Methods: Seventy-five patients with solid cancers were included, all were administered an irinotecan-based regimen in both Mission Bay Medical Center; and Zuckerberg San Francisco General Hospital from May 2016 to December 2016. The patients' genotyping was performed for both the UGT1A1*28 polymorphism, and the ABCC2 - 1549G>A, and ABCC2 - 1249G>A single nucleotide polymorphism. Comparisons among qualitative data were assessed using the χ2-test, and Fisher's exact test in the case of small group sizes. Results: Diarrhea was observed in 40 patients (53.3%), among them only 9 patients had high grades diarrhea (grades III and IV). Grades III/IV of nausea were more frequently associated with the ABCC2-1549 AA genotype (83.3% p = 0.004) in patients with colorectal cancer. In pancreatic cancer, a significant absence of diarrhea grades III-IV was noted in patients with the ABCC2 1249 GG genotype compared to the other ABCC2 1249 genotypes.

Levels of mercury in Moroccan breast milk and the affecting factors: CONTAMILK study.

This study aims to evaluate the level of mercury in the breast milk of Moroccan mothers and its association with several maternal parameters and habits, and to estimate the daily intake of the newborns. Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the concentrations of mercury in 70 colostrum samples. Indeed, a structured questionnaire was administrated during milk collection to report data concerning the maternal socioeconomic and anthropometric parameters, as well as dietary habits and smoking habits in the family, etc. The median of mercury in breast milk was 3,56 µg/L (range 1.64-124 µg/L) and exceeded normal levels of 1.7 µg/l, suggested by the World health organization in 99% of milk samples. Significant associations were found between mercury levels and the occurrence of previous miscarriages, anemia before pregnancy and vitamin & mineral supplementation during pregnancy, as well the frequency of consumption of cereals and the use of lipstick. The estimated daily intake was higher than the tolerable daily intake of the World health organization and the European food safety authority in 30% of newborns. These results need to be confirmed by multicenter studies to investigate the levels of mercury in the breast milk of the Moroccan population.

Correlation of immunohistochemical expression of HIF-1alpha and IDH1 with clinicopathological and therapeutic data of moroccan glioblastoma and survival analysis.

INTRODUCTION: Glioblastomas are aggressive primary intracranial tumours of the central nervous system causing significant mortality and morbidity worldwide. OBJECTIVE: This study aims to evaluate the prognostic value of tissue expression by immunostaining of hypoxia-inducible factor (HIF-1α), isocitrate dehydrogenase 1 (IDH1), and tumour protein p53 in glioblastoma in Moroccan patients. The association of HIF-1α, IDH1, and p53 expression with the clinicopathological data and overall patient survival (OS) was also evaluated. MATERIALS AND METHODS: Confirmed glioblastomas were included in this study. Twenty-two tissue samples were obtained by neurosurgical intervention resulting from total resection, and subtotal resection or biopsy. Karnofsky index, histological type of tumour, and the status of IDH1, p53 protein, and HIF-1α expression by immunostaining were reported. RESULTS: The majority of the patients were males (64%) with a sex ratio of 1.75. The average age was 54 ± 13. Median follow-up was 10.10 months and median overall survival was 10 months. The expression of HIF-1α was high in 10 samples (45%) and low in 12 (55%). There was a statistically significant difference in OS of 85% at 12 months for the subgroup of patients "HIF-1α negative IDH1 positive" p = 0.038, the unadjusted analysis showed that the group "HIF-1α positive, IDH1 positive" was a poor prognostic factor, the HR was 0.08 (95% CI: 0.009-0.756, p = 0.027). CONCLUSION: Patients with negative HIF-1α expression and positive IDH1 expression have a better prognosis, suggesting that these two biomarkers may be useful in the search for new approaches for targeted therapy in glioblastoma.

Lead concentrations in breast milk of Moroccan nursing mothers and associated factors of exposure: CONTAMILK STUDY.

The aim of CONTAMILK study was to estimate levels of contamination of breast milk (BM) of Moroccan nursing mothers by some xenobiotics including, lead (Pb), to identify associated factors of exposure and to determine the daily intake of newborns. Lead concentrations were determined in 70 samples of colostrum by ICPMS and a structured questionnaire was filled during milk collection to report participants' data. The median lead concentration was 908 µg/L (range 1.38-515,39 µg/L) and in 79 % of samples, levels were higher than the normal range reported by the World Health Organization (WHO) in BM (2-5 µg/L). Indeed, preterm delivery, frequency of use of cosmetic powders and lipsticks were significantly associated with the level of lead in BM. The estimated daily intake was greater than the tolerable daily intake (TDI) of the European food safety authority (0.5 µg/kg/day) for 39 babies and 6 babies according to the WHO (3.6 µg/kg/day).

Clinicopathological, Treatment and Event-Free Survival Characteristics in a Moroccan Population of Triple-Negative Breast Cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) is a group of breast carcinoma characterized by the lack of expression of estrogen and progesterone hormone receptors (ER, PgR) and HER2. This form is also characterized by its aggressiveness, a low survival rate, and the absence of targeted therapies. This study was planned to evaluate the clinical features, treatment, and prognosis characteristics of TNBC in a population of Moroccan patients. METHODS: In this retrospective study, a total of 905 patients diagnosed with breast cancer at the National Institute of Oncology in Rabat, Morocco, have been included. Based on molecular subtype, patients were divided into 2 categories: TNBC and non-TNBC patients. Data were recorded from patients' medical files and analyzed using SPSS 13.0 software (IBM). RESULTS: Overall, 17% of the patients had TNBC. At diagnosis, the median age of TNBC cases was 47 years, with extreme ages of 40 and 55 years. The median follow-up time was 30 months (10-53 months) and the 3-year survival rate was 76%. No significant difference was observed among the patients in terms of age at diagnosis, age at menarche, age at the time of first birth, nulliparity, oral contraception, and family history of breast cancer. Menopausal status and the number of pregnancy were significantly higher in the non-TNBC group. The percentage of grade 3 (G3) tumors was higher in the TNBC group (P < .001). Using neoadjuvant, adjuvant chemotherapy and radiotherapy, a net benefit in the event-free survival was registered for the 2 groups. CONCLUSIONS: This retrospective study was very informative and showed that women with TNBC had a less favorable prognosis than non-TNBC cases. Clinical data demonstrated that risk factors including age, premenopausal status, parity, hormonal contraceptive use, advanced disease, and a high histologic grade were independently associated with TNBC. However, large tumors and high Scarff-Bloom and Richardson grade prevail in TNBC cases with a higher incidence of lymph node metastases.

Therapeutic Characteristics, Chemotherapy-Related Toxicities and Survivorship in Colorectal Cancer Patients.

BACKGROUND: Colorectal Cancer (CRC) is a major health problem around the globe. In Morocco, the disease ranks third after breast and lung cancers. This study is the first in Morocco to investigate epidemiological, clinical and therapeutic features while exhaustively describing toxic side-effects to chemotherapy of CRC and studying the 3-years survivorship. METHODS: This is a descriptive and analytical retrospective study of about 290 patients with CRC enrolled during the period of January-December 2013. Statistical analysis was performed to correlate clinicopathological data with chemotherapy toxicity and survivorship in patients, by Chi2 test. Overall Survival (OS) rate has been calculated by the Kaplan-Meier method and compared using Log-rank test. RESULTS: Fifty-five percent had a tumor localized in rectum, and 42,8% in colon. Mean age of these patients at diagnosis was 56,16 ± 14,6. incidence rate of adverse events (grade I to IV) was 85,6%. Diarrhea was the predominant toxicity (4.6%) occurring at a high grade (grade III-IV).The 3-years OS rate of patients with CRC was 71%. OS decreased by age, and patients with age subgroup between 40 to 59 years had a better OS than the other age subgroups (60 to 79 years and >80 years) with a p-value of 0.0001. Occurence of toxicity (all grades and types) was linked to a higher survival rates compared to the group who had no toxicity noticed (p-value of 0.001). CONCLUSION: Our study shows that patients who had a polychemotherapy had a better OS than those who had monotherapy (p-value of 0.002).

Cadmium Contamination in Breast Milk of Moroccan Lactating Women and the Associated Factors: CONTAMILK Study.

The objectives of this study were to assess levels of contamination of breast milk (BM) by cadmium (Cd) among lactating mothers from Rabat, Morocco, and to investigate its association with several maternal habits, parameters, and factors. In addition, to estimate the daily intake of the newborns. Cd concentrations were measured by inductively coupled plasma-mass spectrometry (ICP-MS) in 70 human milk samples collected between the 2nd and 5th day postpartum. Accuracy of the analysis was checked by various methods including the use of reference material. A structured questionnaire was filled during the collection of milk reporting data concerning anthropometric, sociodemographic parameters, dietary and cosmetic habits, etc. The median (range) of Cd in human milk was 0.49 µg/L (range 0.013-95.19 µg/L) respectively. In 21 (30%) of 70 samples, Cd levels were higher than the normal reported by the World Health Organization (WHO) in BM (< 1 µg/L). Indeed, several factors affect significantly Cd levels in BM of the mothers such as low maternal education level, preterm delivery, cesarean delivery, and area of residence. Also, the frequency of consumption of milk and dairy products as well dried fruits and wheat bread and the frequency of use of cosmetic powders. However, the daily intake of cadmium by the newborns was lower than tolerable daily intake of the WHO for 97% of them. Our results revealed low cadmium concentrations in human milk samples from Moroccan lactating mothers living in Rabat, also the association of some factors with the levels of contamination found in this population.

BRCA1 c.68_69delAG (exon2), c.181T>G (exon5), c.798_799delTT and 943ins10 (exon11) mutations in Burkina Faso.

The worldwide variation of BRCA mutations is well known. The c.68_69delAG, c.181T>G, c.798_799delTT mutations in BRCA1 were observed in Moroccan, Algerian and Tunisian Breast Cancer families and were described founder mutation in Northern Africa. The 943ins10 is also recognized a founder mutation in West Africa. To our knowledge no study has been published on BRCA1/2 germline mutations and hereditary breast cancer (HBC) in population of Burkina Faso. The aim of the present study (first in Burkina Faso) was to screen for these four mutations in 15 unrelated patients with HBC. Mutation analysis was performed by Sanger sequencing of coding exon2, Exon5 and exon11A sequences of the BRCA1 gene. Blood specimens of 15 patients from Burkina Faso, with HBC were collected at the University Hospital Yalgado OUEDRAOGO (CHU-YO) of Ouagadougou in Burkina Faso. c.68_69delAG (exon2), c.181T>G (exon5), c.798_799delTT and 943ins10 (exon11) mutations were not detected in any of the 15 women diagnosed with family breast cancer history. Genetic analysis in this study, we show that targeting relevant exons in BRCA1 genes did not allow detection of mutations in the population of Burkina Faso. Therefore, such an approach may be of interest to perfom a complete sequencing of BRCA1 and BRCA2 genes in families at a high risk of developing breast cancer in Burkina Faso.

Outcome of inflammatory breast cancer in Moroccan patients: clinical, molecular and pathological characteristics of 219 cases from the National Oncology Institute (INO).

BACKGROUND: Usually misdiagnosed, Inflammatory Breast Cancer (IBC) is the most aggressive form of non-metastatic breast cancer. This orphan disease is more frequent in North Africa. Despite intensive treatment, the survival rate remains very low. METHODS: We have retrospectively studied all breast cancer cases diagnosed at the National Oncology Institute (INO), Rabat between 2005 and 2010. We have collected 219 cases of women with metastatic and non-metastatic IBC. Data have been obtained from patients' personal medical files over a follow-up period of 5 years. We have described IBC's clinicopathological features and analyzed its clinical outcome using SPSS software. HR (hazard Ratio) was calculated using Cox regression analysis. RESULTS: The frequency of IBC cases is 4.05%. The majority of our patients (65.3%) were under 50 years old. The most prevalent molecular subtype was Luminal A (38.7%) followed by Luminal B HER2+ (27.9%) and Triple negative (21.6%). During the follow-up period, 72 patients (32.9%) had recurrence and 40 patients (18.3%) died. The 3-year OS (Overall Survival) and EFS (Event Free Survival) of non-metastatic patients were 70.4 and 46.5% respectively, while in the metastatic disease, the 3-year OS was only 41.9%. In non-metastatic women, we observed a higher rate of EFS associated to Selective estrogen receptor modulation treatment (p = 0.01), and a lower rate EFS in triple negative breast cancer patients (p = 0.02). In univariate analysis, we found that EFS rate is lower in patients presenting Triple Negative tumors when compared to other molecular subtypes (HR: 3.54; 95%CI: 1.13-11.05; p = 0.02). We also found that Selective estrogen receptor modulation treatment is associated with higher EFS rate (HR: 0.48; 95%CI: 0.07-0.59; p = 0.01). CONCLUSIONS: IBC in Morocco shows similar characteristics to those in North African countries; however, survival rates are still the highest when compared with neighboring countries. Collaborative studies with prospective aspects are warranted to establish the epidemiological profile and understand the high frequencies of IBC in North Africa. More studies on molecular markers are also needed to improve IBC patients' management and eventually their survival rate.

Outcome of Breast Cancer in Moroccan Young Women Correlated to Clinic-Pathological Features, Risk Factors and Treatment: A Comparative Study of 716 Cases in a Single Institution.

BACKGROUND: Breast cancer in young women is quite uncommon and shows more aggressive characteristics with major disparities between worldwide populations. Prognosis and outcome of breast cancer in young patients are widely studied, but still no consensus is available. METHODS: We retrospectively included 716 cases of breast cancer women diagnosed in 2009 at the National Institute of Oncology of Rabat. Patients were divided into two groups according to their age: women aged ≤40 years (Group 1) and women aged >40 years (Group 2). Data were recorded from patients' medical files and analyzed using SPSS 13.0 software (IBM). RESULTS: Young patients represent 24.9% of all patients with breast cancer. The comparison between the two groups displayed significant differences regarding nulliparity (p = 0.001) and progesterone receptor negativity (p = 0.01). Moreover, more progression (Metastases/Relapse) was registered in young women as compared to older women with breast cancer (p = 0.03). The estimated median follow-up period was 31 months. The 5-years Event-Free Survival (EFS) of patients with local disease was 64.6% in young women and 71.5% in older women with breast cancer (p = 0.04). Multivariate analysis in young women showed that nulliparity (HR: 7.2; 95%CI: 1.16-44.54; p = 0.03), T3 tumors (HR: 17.39; 95%CI: 1.74-173.34; p = 0.01) and negative PgR status (HR: 19.85; 95%CI: 1.07-366.54; p = 0.04) can be considered as risk factors for poorer event free survival while hormone therapy was associated with better EFS (HR: 0.11; 95%CI: 0.00-0.75; p = 0.03). In Group 2, multivariate analysis showed that patients with inflammatory breast cancer, N+ status, absence of radiotherapy, absence of chemotherapy, and absence of hormone therapy are at increased risk of recurrence. CONCLUSIONS: In Morocco, breast cancer is more frequent in young women as compared to western countries. Breast cancer in young women is more aggressive and is diagnosed late, leading to an intensive treatment. Moreover, the main factors associated with breast cancer development in young women would be hormonal and reproductive status. Analysis of other genetic biomarkers is needed to explain the high prevalence of breast cancer in young women to improve breast cancer management in Morocco.

Recent Progress in Triple Negative Breast Cancer Research.

Triple-negative breast cancer (TNBC) is defined as a type of breast carcinoma that is negative for expression of oestrogene and progesterone hormone receptors (ER, PR) and HER2. This form of breast cancer is marked by its aggressiveness, low survival rate and lack of specific therapies. Recently, important molecular characteristics of TNBC have been highlighted and led to the identification of some biomarkers that could be used in diagnosis, as therapeutic targets or to assess the prognosis. In this review, we summarize recent progress in TNBC research focusing on the genetic and epigenetic alterations of TNBC and the potential use of these biomarkers in the targeted therapy for better management of TNBC.

Breast cancer in Morocco: a literature review.

In Morocco, breast cancer is the most prevalent cancer in women and a major public health problem. Several Moroccan studies have focused on studying this disease, but more are needed, especially at the genetic and molecular levels. It is therefore interesting to establish the genetic and molecular profile of Moroccan patients with breast cancer. In this paper, we will highlight some pertinent hypotheses that may enhance breast cancer care in Moroccan patients. This review will give a precise description of breast cancer in Morocco and propose some new markers for detection and prediction of breast cancer prognosis.

Detection of MMTV-Like sequences in Moroccan breast cancer cases.

INTRODUCTION: The mouse mammary tumor virus (MMTV) like sequences have been reported to be present in some human breast cancers, but their association with breast cancer development is still controversial. METHODS: In this retrospective study, we investigated the status of MMTV-like in 42 tumor biopsies and 18 paired normal tissues from Moroccan patients with breast cancer. MMTV-like env sequences were identified by PCR and confirmed by direct DNA sequencing. RESULTS: Specific MMTV-like env sequences were found in 24 (57.14%) cases of breast carcinomas, and 6 (33.3%) cases of matched normal breast tissues. Comparison to sociologic and clinicopathological parameters showed no significant association between the presence of MMTV-like sequences and age, menopausal status, histological subtype, histological grade, tumor size and the expression of hormone receptors (estrogen ER and/or progesterone PgR) and Her 2. However, a significant correlation was found between MMTV-like presence and parity (p = 0.024). CONCLUSIONS: This present study confirms the presence of MMTV-like env sequences in breast cancer in Moroccan women, prompting further evaluation, on large sampling, to elucidate the probable causal roles of MMTV-like in breast cancer development.