Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study.

Colorectal cancer is the second leading cause of cancer-related deaths in women and men in Algeria. Lynch syndrome (LS) is an autosomal dominant disease caused by heterozygous germline pathogenic variants in mismatch repair genes (MMR) and frequently predisposes to colorectal cancer. However, data about MMR germline pathogenic variants in Algerian patients are limited. This first nationwide study aims to describe clinicopathologic features and germline variants in MMR genes in Algerian families with suspected LS. Sixty-four (64) families with suspected LS were studied. Index cases with LS who fulfilled Amsterdam criteria were screened by PCR-direct sequencing for germline variants in MMR genes: MLH1 (exons 1, 9, 10, 13, 16), MSH2 (exons 5, 6, 7, 12), MSH6 (exons 4 and 8) and PMS2 (exons 6 and 10). We selected these specific risk exons genes since they have a higher probability of harboring pathogenic variants. In addition, two unrelated LS patients were screened by next-generation sequencing using a cancer panel of 30 hereditary cancer genes. Six germline pathogenic variants and one germline likely pathogenic variant were identified in 19 (29.68%) families (4 MLH1, 2 MSH2 and 1 MSH6). Of index cases and relatives who underwent genetic testing (n = 76), 30 (39.47%) had MMR pathogenic gene variants, one (0.13%) had MMR gene likely pathogenic variant and three had MMR variant of uncertain significance, respectively. Two novel germline pathogenic variants in MLH1 (2) and one germline likely pathogenic variant in MSH6 (1) never published in individuals with LS have been detected in the present study. The recurrent MLH1 germline pathogenic variant c.1546C>T has been found in nine LS families, six of them related with two large kindreds, from four North central provinces of Algeria. In addition, the common MSH2 germline pathogenic variant c.942+3A>T has been detected in five unrelated patients with a strong LS family history. The accumulative knowledge about clinicopathological and genetic characteristics of LS in Algerian patients will impact clinical management in the areas of both prevention and treatment.

Germline mutations of the adenomatous polyposis coli (APC) gene in Algerian familial adenomatous polyposis cohort: first report.

BACKGROUND: Familial adenomatous polyposis (known also as classical or severe FAP) is a rare autosomal dominant colorectal cancer predisposition syndrome, characterized by the presence of hundreds to thousands of adenomatous polyps in the colon and rectum from an early age. In the absence of prophylactic surgery, colorectal cancer (CRC) is the inevitable consequence of FAP. The vast majority of FAP is caused by germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene (5q21). To date, most of the germline mutations in classical FAP result in truncation of the APC protein and 60% are mainly located within exon 15. MATERIAL AND METHODS: In this first nationwide study, we investigated the clinical and genetic features of 52 unrelated Algerian FAP families. We screened by PCR-direct sequencing the entire exon 15 of APC gene in 50 families and two families have been analyzed by NGS using a cancer panel of 30 hereditary cancer genes. RESULTS: Among 52 FAP index cases, 36 had 100 or more than 100 polyps, 37 had strong family history of FAP, 5 developed desmoids tumors, 15 had extra colonic manifestations and 21 had colorectal cancer. We detected 13 distinct germline mutations in 17 FAP families. Interestingly, 4 novel APC germline pathogenic variants never described before have been identified in our study. CONCLUSIONS: The accumulating knowledge about the prevalence and nature of APC variants in Algerian population will contribute in the near future to the implementation of genetic testing and counseling for FAP patients.

Aberrant up-regulation of iNOS/NO system is correlated with an increased abundance of Foxp3+ cells and reduced effector/memory cell markers expression during colorectal cancer: immunomodulatory effects of cetuximab combined with chemotherapy.

Colorectal cancer (CRC) remains the most cancer type related to chronic inflammation; however, the mechanisms that link inflammation to CRC development and progression are still poorly understood. Our study aimed to investigate one of the prominent inflammatory response in cancers, iNOS/NO system. In this regard, we evaluated the link between the iNOS/NO system and CRC progression, its relation with the host immune responses and its response to cetuximab combined with chemotherapy. We found that the nitrite levels were nearly twice as high in metastatic CRC plasma and culture supernatants from PBMCs and tumor explants compared with those without metastases and healthy controls. Interestingly, we showed that the highest iNOS expression and NO levels are present in the damaged CRC tissues that have highest leukocyte infiltration. Our findings highlight the implication of iNOS/NO system in tissue alteration and leukocyte invasion. Thus, we observed imbalance between effector/memory T cell markers and Treg transcription factor (Foxp3). Accordingly, we detected higher IFNγ and T-bet expression levels in colorectal tumor tissues at early stage. In contrast, consistent with iNOS and Foxp3 expression, TGFß, CTLA-4 and IL-10 were significantly related to the tumor stage progression. Furthermore, our study revealed that Cetuximab combined with chemotherapy treatment markedly down-regulates iNOS/NO system as well as IL-10 and TGFß levels. Altogether, we conclude that cetuximab can potentiate the efficacy of chemotherapy, particularly by iNOS/NO system and immunosuppressive cytokines modulation. Thus, we suggest that iNOS/NO system may represent an attractive candidate biomarker for monitoring CRC progression, malignity and response to therapy.

All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-α and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer.

Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression.

Middle East and North Africa Registry to Characterize Rate of RAS Testing Status in Newly Diagnosed Patients with Metastatic Colorectal Cancer.

BACKGROUND: Rat sarcoma virus mutational status guides first-line treatment in metastatic colorectal cancer. This study was a multi center, multi-country ambispective, observational study in the Middle East and North Africa assessing regional rat sarcoma virus testing practices in newly diagnosed patients. METHODS: The retrospective arm (2011-2014) included adults with metastatic colorectal cancer who had initiated first-line therapy with ≥1 post-baseline visit and survival data. The prospective arm (2014-2019) enrolled newly diagnosed patients with histologically proven metastatic colorectal cancer with ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors, and tissue availability for biomarker analysis. Data look-back and follow-up were 2 years; the rate of RAS mutation was evaluated. RESULTS: RAS testing was ordered for patients in retrospective (326/417) and prospective (407/500) studies. In the former, testing was typically prescribed after first-line treatment initiation, significantly more in patients with stage IV disease (P < .005), resulting in the addition of targeted therapy (41.8% anti-epidermal growth factor receptor, 30.2% anti-vascular endothelial growth factor) in wild-type metastatic colorectal cancer, and significantly impacted the treatment of left-sided tumors (P = .037). In the latter, 58.4% were RAS wild-type; 41.6% were RAS mutant. Non-prescription of RAS testing was attributed to test unavailability, financial, or medical rea sons; predictors of testing prescription were older age, primary tumor in ascending colon, and high tumor grade. RAS status knowledge resulted in the addition of anti-vascular endothelial growth factor (20.4%) or anti-epidermal growth factor receptor therapy (21.2%). CONCLUSION: Before 2014, RAS testing in patients with colorectal cancer in the Middle East and North Africa was often performed after first-line treatment. Testing is more routine in newly diagnosed patients, potentially shifting early treatment patterns.

An Open-Label, Multinational, Multicenter, Phase IIIb Study with Subcutaneous Administration of Trastuzumab in Patients with HER2-Positive Early Breast Cancer to Evaluate Patient Satisfaction.

OBJECTIVE: This study was designed to investigate treatment satisfaction in patients and Health Care Professionals (HCP) and to evaluate the safety and tolerability of subcutaneous (SC) trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC). MATERIALS AND METHODS: Two-hundred and twenty-three patients with eBC were screened, of whom 173 patients met the eligibility criteria and received at least one dose of SC trastuzumab. The primary efficacy endpoint was to assess patient satisfaction via a questionnaire. RESULTS: The majority of patients (n = 166, 97.6%) reported satisfaction with the SC route. Patients and HCPs stated that SC trastuzumab was easy to use (93.5% and 62.5%, respectively) compared to the intravenous (IV) route and all HCPs (n = 16) expressed satisfaction with the SC route. Progression, disease recurrence or death was reported in 24 patients (13.8%) by two years of follow up. Four-year disease-free survival (DFS) and overall survival (OS) rates were 84.2% (±3.1) and 90.5% (±4.7), respectively. A total of 1299 adverse events (AEs) were recorded over 4-years follow-up, nearly 97% of which were judged non-serious. The most common AEs were arthralgia (n = 54, 4.2%), flu-like symptoms (n = 41, 3.2%) and nausea (n = 39, 3.0%). Fifty-four cardiac events, including left ventricular dysfunction, left ventricular failure and cardiotoxicity, were reported. Ejection fraction (EF) decrease [median decrease 3.5% (0.12-19.0)] was reported in 5.4% of cases. SC trastuzumab treatment was interrupted due to decreased EF in two cases. CONCLUSION: SC trastuzumab was widely acceptable to both patients and HCPs. The safety and tolerability of SC trastuzumab was consistent with the known safety profile of SC and IV administration.

Response to Induction Neoadjuvant Hormonal Therapy Using Upfront 21-Gene Breast Recurrence Score Assay-Results From the SAFIA Phase III Trial.

PURPOSE: Luminal, human epidermal growth factor receptor 2-negative breast cancer represents the most common subtype of breast malignancies. Neoadjuvant strategies of operable breast cancer are mostly based on chemotherapy, whereas it is not completely understood which patients might benefit from neoadjuvant hormone therapy (NAHT). MATERIALS AND METHODS: The SAFIA trial is a prospective multicenter, international, double-blind, neoadjuvant phase III trial, using upfront 21-gene Oncotype DX Breast Recurrence Score assay (recurrence score [RS] < 31) to select operable luminal human epidermal growth factor receptor 2-negative patients, for induction hormonal therapy HT (fulvestrant 500 mg with or without goserelin) before randomly assigning responding patients to fulvestrant 500 mg (with or without goserelin) plus either palbociclib (cyclin-dependent kinase 4/6 inhibitor) or placebo. The objectives of this interim analysis were to assess the feasibility of upfront RS determination on core biopsies in the Middle-East and North Africa region and evaluate the efficacy of induction NAHT in patients with an RS < 31. RESULTS: At the time of this interim analysis, 258 patients with relative risk were accrued, including 202 patients (RS < 31% to 78.3%) treated with induction NAHT and 182 patients evaluable so far for response. The feasibility of performing the Oncotype DX assays on core biopsy specimens was optimal in 96.4% of cases. Overall, 93.4% of patients showed hormone sensitivity and no difference in NAHT efficacy was noticed between RS 0-10, 11-25, and 26-30. Interestingly, patients with high RS (26-30) showed a trend toward a higher major response rate (P = .05). CONCLUSION: The upfront 21-gene assay performed on biopsies is feasible in our population and has allowed us to select patients with high hormone sensitivity (RS < 31). This approach could be an alternative to upfront surgery without significant risk of progression, particularly during pandemic times.

Incidence of lung cancer in males and females in Algeria: The lung cancer registry in Algeria (LuCaReAl).

BACKGROUND: Lung cancer is a major cause of death worldwide. However, few data on incidence, histologic types and mortality rates of lung cancer were available for Algeria. METHODS: LuCaReAl is an ongoing descriptive, non-interventional, national, multicenter, prospective and longitudinal study conducted in Algeria, among oncologists and pulmonologists in public community and university hospitals. Median and interquartile ranges are displayed. RESULTS: Between July 2016 and July 2017, 897 patients were included. Overall incidence of lung cancer was 3.4 [3.2;3.6] cases per 100,000 inhabitants; overall incidence by sex was 5.8 [5.4;6.2] for males and 1.0 [0.8;1.1] for females. Adenocarcinoma was the most common histologic type of cancer. Most tumors were diagnosed at Stage IV. CONCLUSION: The first results from the LuCaReAl study in Algeria showed that most patients are diagnosed with lung cancer at an advanced stage. The ongoing follow-up will next provide data on the survival and mortality rates.

Clinicopathological and Molecular Study of Triple-Negative Breast Cancer in Algerian Patients.

Triple-negative breast cancer (TNBC) is associated with aggressive tumor behavior, poor prognosis and BRCA1 mutations. There are limited data regarding TNBC among Algerian women. In this study, we sought to determine clinical and tumor characteristics associated with TNBC. We also screened for the prevalence of BRCA1 mutations in unselected cohort of TNBC patients. Clinical and tumor characteristics data of 877 breast cancer patients diagnosed between 2011 and 2015, were collected from cancer registry of public hospital of Rouiba. Patients were divided in two groups: those with TNBC and those with other breast cancer subtypes. Differences between the two groups with regard to clinical and tumor characteristics were compared using Fisher's exact test. BRCA1 mutations analysis was performed in unselected cohort of 103 women with TNBC, including all exons where a mutation was previously found in Algerian population (exons 2, 3, 5, 11). The median age at diagnosis for TNBC and non-TNBC patients was 47.4 years and 49.4 years, respectively. The proportion of TNBC was 19.95%. Our data showed significant differences in menopausal status, TNM stage, histological type, tumor histological grade, Ki67 expression and family history of breast cancer between TNBC and non-TNBC patients. Four distinct deleterious mutations in BRCA1 gene were detected in eight young TNBC patients. TNBC is associated with young age, poor histopathological characteristics and family history of breast cancer. BRCA1 mutations have been detected in young TNBC patients. TNBC phenotype should be added as criterion to screen for BRCA1 mutations in Algerian women.

Distribution of molecular breast cancer subtypes among Algerian women and correlation with clinical and tumor characteristics: a population-based study.

BACKGROUND: Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. Molecular classification of breast cancer is an important factor for prognosis and clinical outcome. There are limited data regarding molecular breast cancer subtypes among Algerian women. The objective of the present study was to analyze the proportion and distribution of molecular subtypes and to determine their associations with some clinical and tumor characteristics: age at diagnosis, menopausal status, histological type and histological grade. MATERIALS AND METHODS: The study population included 3014 female breast cancers. We analyzed breast cancers from cancer registries of academic medical oncology service of public hospital of Rouiba, anticancer center of Blida, and anticancer center of Batna. Breast cancers were diagnosed between 2008 and 2013. Molecular subtype classification was done based on immunohistochemical surrogates for ER (Estrogen receptor), PR (Progesterone receptor) and HER2 (human epidermal growth factor receptor-2) status obtained from medical records for 3014 breast cancer patients. Breast cancer subtypes definitions were as follow: Luminal A (ER+ and/or PR+, HER2-), Luminal B (ER+ and/or PR+, HER2+), TNBC (ER-, PR - , HER2-), HER2+ (ER-, PR-, HER2+). Molecular subtypes were correlated with the clinicopathological characteristics of the tumors. RESULTS: The mean age at diagnosis cancer was 48.5 years. Proportions of the luminal A, TNBC, luminal B and HER2+ breast cancer subtypes were 50.59%, 20.80%, 19.67% and 8.92%, respectively. We noted a significant difference in the distribution of age at diagnosis among the four cancer subtypes (P= 0.004). Luminal A, Luminal B, TNBC and HER2+ subtypes were significantly different by premenopausal and postmenopausal status (P= 0.01). Invasive Ductal Carcinoma was the most common histological type in all breast cancer subtypes. Tumors with histological grade 2 and 3 were more common in patients for the four breast cancer subtypes. CONCLUSIONS: For the first time, we report the distribution of molecular breast cancer subtypes and their associations with some clinicopathological characteristics in a large cohort of Algerian women. In our current study, the median age of diagnosis for all breast cancer subtypes was younger than the average age in Europe and America. Luminal A was the most common sub- type in our patients followed by TNBC. The proportion of luminal A subtype was lesser than reported in white women with breast cancer in Europe and America. The proportion of TNBC subtype in Algerian women was higher compared with Caucasian women of European ancestry. This study will contribute in developing optimal clinical trial protocols and personalized management strategies for Algerian breast cancer patients.