Exosomes in breast cancer management: Where do we stand? A literature review.

BACKGROUND: Exosomes constitute cellular molecular fingertips that participate in intercellular communication both in health and disease states. Hence, exosomes emerge as critical mediators of cancer development and progression, as well as potential biomarkers and novel therapeutic targets. OBJECTIVE: To review literature data regarding applications of circulating exosomes in breast cancer management. METHODS: This is a literature review of relevant published studies until April 2020 in PubMed and Google Scholar databases. Original papers in the English language concerning exosome related studies were included. RESULTS: Exosomes represent molecular miniatures of their parent cells. Several homeostatic mechanisms control exosomal secretion and synthesis. Exosomal exchange among cells creates an intricate intercellular crosstalk orchestrating almost every tissue process, as well as carcinogenesis. Available data highlight exosomes as major mediators of cancer development and progression. The secretion of specific exosomal molecules, particularly miRNAs, correlates with the underlying processes and can be used as a means of tumor detection and prognostic assessment. CONCLUSIONS: Exosomal miRNAs expression profiles and levels closely relate to cancer extent, type and prognosis. Deep comprehension of such correlations and systematization of experimental outcomes will offer a novel approach in cancer detection and management.

PD-L1 Gene Polymorphisms rs822336 G>C and rs822337 T>A: Promising Prognostic Markers in Triple Negative Breast Cancer Patients

Background and Objectives: Triple-negative breast cancer (TNBC) is a highly heterogeneous subtype that is associated with unresponsiveness to therapy and hence with high mortality rates. In this study we aimed to investigate the prognostic role of the rs822336 G>C and rs822337 T>A polymorphisms of the PD-L1 (Programmed Death-Ligand 1) in TNBC patients. Materials and methods: Formalin-fixed paraffin-embedded tissues from 114 TNBC patients and blood samples from 124 healthy donors were genotyped, and subsequently extensive statistical analysis was performed in order to investigate the clinical value of these polymorphism in TNBC. Results: Regarding rs822336 G>C, we found that the CG genotype was the most common among women that harbored Stage IV breast tumors (81.8%; p = 0.022), recurred (38.9%; p = 0.02) and died (66.7%; p = 0.04). Similarly, the rs822337 T>A genotype AA is associated with worse prognosis, since it was the most common genotype among stage IV tumors (72.7%; p = 0.04) and in TNBC patients that relapsed (75%; p = 0.021) and died (81.5%; p = 0.004). Our statistical analysis revealed that the rs822336 G>C genotype CG and the rs822337 T>A allele AA are strongly associated with inferior DFS and OS intervals. Moreover, it was revealed that women harboring mutated genotypes of both SNPs had shorter disease-free (Kaplan−Meier; p = 0.037, Cox analysis; p = 0.04) and overall (Kaplan−Meier; p = 0.025, Cox analysis; p = 0.03) survival compared to patients having normal genotype of at least one SNP. Multivariate analysis also showed that the presence of mutated genotypes of both SNPs is a strong and independent marker for predicting shorter DFS (p = 0.02) and OS (p = 0.008). Conclusion: Our study revealed that PD-L1 rs822336 G>C and rs822337 T>A polymorphisms were differentially expressed in our cohort of TNBC patients, and that this distribution was associated with markers of unfavorable prognosis and worse survival.

Trastuzumab administration during pregnancy: an update.

BACKGROUND: Over than one third (28-58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2) expression. Trastuzumab anti-HER2 monoclonal antibody is still the benchmark treatment of HER2-positive breast tumors. However, FDA has categorized Trastuzumab as a category D drug for pregnant patients with breast cancer. This systemic review aims to synthesize all currently available data of trastuzumab administration during pregnancy and provide an updated view of the effect of trastuzumab on fetal and maternal outcome. METHODS: Eligible articles were identified by a search of MEDLINE bibliographic database and ClinicalTrials.gov for the period up to 01/09/2020; The algorithm consisted of a predefined combination of the words "breast", "cancer", "trastuzumab" and "pregnancy". This study was performed in accordance with the PRISMA guidelines. RESULTS: A total of 28 eligible studies were identified (30 patients, 32 fetuses). In more than half of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration during gestation was 15.7 weeks (SD: 10.8; median: 17.5; range: 1-32). Oligohydramnios or anhydramnios was the most common (58.1%) adverse event reported in all cases. There was a statistically significant decrease in oligohydramnios/anhydramnios incidence in patients receiving trastuzumab only during the first trimester (P = 0.026, Fisher's exact test). In 43.3% of cases a completely healthy neonate was born. 41.7% of fetuses exposed to trastuzumab during the second and/or third trimester were born completely healthy versus 75.0% of fetuses exposed exclusively in the first trimester. All mothers were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months). Of note, there were three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy. CONCLUSIONS: Overall, treatment with trastuzumab should be postponed until after delivery, otherwise pregnancy should be closely monitored.

Germline mutations in a clinic-based series of pregnancy associated breast cancer patients.

BACKGROUND: Pregnancy-associated breast cancer (PABC) defined as breast cancer diagnosed during gestation, lactation or within 1 year after delivery, represents a truly challenging situation with significantly increasing incidence rate. The genomic background of PABC has only recently been addressed while the underlying mechanisms of the disease still remain unknown. This analysis aims to further elucidate the frequency of PABC cases attributable to genetic predisposition and identify specific cancer susceptibility genes characterizing PABC. METHODS: A comprehensive 94-cancer gene panel was implemented in a cohort of 20 PABC patients treated in our clinic and descriptive correlation was performed among the results and the patients' clinicopathological data. RESULTS: In the present study, 35% of PABC patients tested carried pathogenic mutations in two known cancer predisposition genes (BRCA1 and CHEK2). In total, 30% of the patients carried BRCA1 pathogenic variants. An additional 5% carried pathogenic variants in the CHEK2 gene. Variants of unknown/uncertain significance (VUS) in breast cancer susceptibility genes BRCA2, CHEK2 and BRIP1 were also identified in three different PABC patients (15%). Not all patients carrying germline mutations reported known family history of cancer. CONCLUSIONS: Genetic testing should be considered as an option for PABC patients since the disease is highly associated with genetic susceptibility among other predisposing factors. Germline mutation identification may further modify PABC management approach and improve the prognostic outcome.

Update Overview of the Role of Angiopoietins in Lung Cancer.

Angiogenesis is a biological process that involves the formation of new blood vessels from the existing vasculature, and it plays a fundamental role in the development and progression of several types of cancer, including lung cancer. The angiopoietin/Tie2 ligand/receptor system orchestrates vascular integrity. In particular, Angiopoietin-1 activates the endothelial cell (EC)-specific receptor tyrosine kinase,Tie2,which is essential for preserving endothelial quiescence. On the other hand, Angiopoietin-2 acts as an inhibitor of the Angiopoietin-1/Tie2 signaling pathways, thus facilitating the destabilization of quiescent endothelium in cases of inflammation and cancer. Clinical studies have proven that high levels of Angiopoietin-2 indicate the development of non-small-cell lung carcinomas (NSCLC), while high levels of Angiopoietin-2 are strongly related to tumor angiogenesis, lymphangiogenesis, metastasis, and poor prognosis. Interestingly, the association of Angiopoietin-2 levels with the type of surgical approach makes Angiopoietin-2 a valuable factor in selecting the most suitable therapeutic strategy for lung cancer patients. The role of the Angiopoietin-1 and Angiopoietin-4 levels in NSCLC development requires further investigation. The present review focuses on the clinical impact of the Angiopoietin-1, Angiopoietin-2, and Angiopoietin-4 levels in patients diagnosed with NSCLC, emphasizing the interaction between them, and how they affect the development, progression, and metastasis of lung disease. Finally, it estimates the role of angiopoietins levels in the effective therapy of lung cancer patients.

RANKL, OPG, TRAIL, KRas, and c-Fos expression in relation to central lymph node metastases in papillary thyroid carcinoma.

PURPOSE: RANKL, OPG and TRAIL have long been pursued in cancer. Mutated KRas proteins and c-Fos overexpression - well-recognized oncogenic events - have been conceived as coordinators of RANKL, OPG and TRAIL pathways. Considering the paucity in the relevant literature, the purpose of the present study was to investigate whether the expression of these molecules configures a distinct papillary thyroid carcinoma (PTC) subgroup with adverse clinicopathological characteristics. METHODS: RANKL, OPG, TRAIL, KRas, and c-Fos immunohistochemical expression in relation to clinicopathological characteristics of PTC was assessed retrospectively in paraffin-embedded PTC specimens from 114 patients who underwent total thyroidectomy with simultaneous central lymph node dissection (CLND). RESULTS: Expression of RANKL, OPG, TRAIL, Kras and c- Fos was revealed in 78.6, 63.2, 61.4, 47.4, and 73.7% of PTC, respectively. As predominant KRas-expressing PTC histotype emerged the classical PTC (cPTC), comprising 66.7% of PTC. A significant correlation was demonstrated of RANKL, OPG, and TRAIL expression with central lymph node metastasis CLNM (p=0.007, p<0.001, and p=0.002, respectively), concerning especially cPTC as regards to RANKL (p=0.027) and OPG (p=0.006), and both cPTC (p=0.043) and follicular variant of PTC (FVPTC) (p=0.049) with regard to TRAIL. OPG expression associated significantly with multifocality (p=0.045). Multivariable-adjusted logistic regression models characterized TRAIL as independent predictor of CLNM (OR=10.335, 95% CI: 1.23-86.87). CLNM correlated significantly with six pairs of coexpressions: TRAIL-KRas (p=0.011), TRAIL-c-Fos (p=0.006), OPG-c-Fos (p=0.024), RANKL-TRAIL (p<0.001), RANKL-OPG (p<0.001), TRAIL- OPG (p<0.001). CONCLUSION: The present study suggested for the first time that OPG, RANKL, TRAIL expressions, either alone or in concert involving c-Fos and KRas expression, are related to CLNM. Further research is warranted to elucidate whether the examined molecules can be endorsed as indicators of aggressive PTC behavior and guide a personalized therapeutic intervention.

Oral SERDs alone or in combination with CDK 4/6 inhibitors in breast cancer: Current perspectives and clinical trials.

Over the past few decades, first-line therapy for treating advanced and metastatic HR+/HER2-breast cancer has transformed due to the introduction of adjuvant endocrine therapy with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). However, there is an unmet need for novel classes of endocrine therapy with superior efficacy to improve treatment outcomes and overcome CDK4/6i resistance. New generation selective estrogen receptor degraders (SERDs), orally administered and with higher bioavailability, could potentially be the novel compounds to meet this emerging need. In this paper, we review accredited clinical studies on the combining effects of CDK4/6 inhibitors and oral SERDs, report efficacy of treatment data when available, and provide a framework for future research focusing on these promising agents.

Predictive tissue markers in testicular germ cell tumors: Immunohistochemical expression of MLH1 and REV-7 proteins.

PURPOSE: Testicular Germ Cell Tumors (TGCTs) are the most frequent solid malignancies in young adult men. Regardless of differences in their cell of origin, all TGCTs are considered highly curable malignancies. However, approximately 3-5% of all TGCTs do not respond to platinum-based chemotherapies. The purpose of our paper is to investigate whether immunohistochemical expression of MLH1 and REV-7 can be used as predictive tissue markers for TGCTs. MATERIAL AND METHODS: The main demographic and clinicopathological characteristics of 64 male patients with TGCTs who underwent orchiectomy from 2007 to 2022 were retrospectively obtained from two large Oncology Clinics in Greece. Both patients with chemosensitive and chemoresistant disease were included. Immunohistochemical staining for MLH1 and REV-7 proteins was applied in specimens of these patients. RESULTS: 31 seminomas and 33 non-seminomas were included. 48 patients had chemosensitive disease, while 16 had chemoresistant disease. 53 specimens showed preserved MLH1 expression, while 11 specimens had lost MLH1 expression. Expression of MLH1 was only significantly associated with patients' age. 16 specimens showed positive REV-7 expression, while 48 specimens were REV-7 negative. Interestingly, 50% of patients with chemoresistant disease and 16,7% of patients with chemosensitive disease were REV-7 positive. This difference was statistically significant. Moreover, REV-7 positivity was significantly associated with chemoresistance, various clinicopathological parameters and patients' prognosis and survival. CONCLUSION: Loss of MLH1 expression was only found to be significantly associated with lower patients' age. Positive immunohistochemical REV-7 expression was significantly associated with various clinicopathological parameters, while it was also associated with significantly lower survival and greater hazard. REV-7 positive percentages were significantly higher in patients with chemoresistant disease. Our findings imply that immunohistochemical staining for REV-7 could potentially be used as a predictive tissue marker for TGCT tumors. Moreover, targeting of REV-7 protein, could represent a potential therapeutic strategy for chemoresistant TGCT cases. The implementation of well-designed studies on a larger scale is of utmost importance, in order to draw safer conclusions. Additional studies are needed so as to draw safer conclusions.

Expression of DNA Repair Genes in Ewing Sarcoma.

Background/Aim: Ewing sarcoma is an aggressive mesenchymal malignancy commonly affecting children and young adolescents. The molecular basis of this neoplasia is well reported with the formation of the EWSR1/FLI1 fusion gene being the most common genetic finding. However, this fusion gene has not been targeted therapeutically nor is being used as a prognostic marker. Its relevance regarding the molecular steps leading to Ewing sarcoma genesis are yet to be defined. The generation of the oncogenic EWSR1/FLI1 fusion gene, can be attributed to the simultaneous introduction of two DNA double-strand breaks (DSBs). The scope of this study is to detect any association between DNA repair deficiency and the clinicopathological aspects of Ewing's sarcoma disease. Patients and Methods: We have conducted an expression analysis of 35 patients diagnosed with Ewing sarcoma concerning the genes involved in non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways. We have analyzed the expression levels of 6 genes involved in NHEJ (XRCC4, XRCC5, XRCC6, POLλ, POLµ) and 9 genes involved in HR (RAD51, RAD52, RAD54, BRCA1, BRCA2, FANCC, FANCD, DNTM1, BRIT1) using real time PCR. Age, sex, location of primary tumor, tumor size, KI67, mitotic count, invasion of adjacent tissues and treatment were the clinicopathological parameters included in the statistical analysis. Results: Our results show that both these DNA repair pathways are deregulated in Ewing sarcoma. In addition, low expression of the xrcc4 gene has been associated with better overall survival probability (p=0.032). Conclusion: Our results, even though retrospective and in a small number of patients, highlight the importance of DSBs repair and propose a potential therapeutic target for this type of sarcoma.

The Immunohistochemical Expression of REV-7 in Various Human Cancer Pathology Specimens: A Systematic Review.

The purpose of this systematic review is to summarize all existing evidence, regarding the immunohistochemical expression of REV-7 in different human cancer pathology specimens. Moreover, the association of REV-7 expression with disease severity (clinical course), patients' survival, prognosis, and response to various treatments, such as chemotherapy and irradiation, was investigated. Three databases (PubMed, Scopus, and Cochrane) were systematically screened, from inception to September 2, 2023, as suggested by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Only studies using immunohistochemical staining for REV-7 in paraffin-embedded cancer tissues were included. Nine studies met the inclusion criteria and were included in the final qualitative synthesis. All nine studies were retrospective and non-comparative ones. Selected studies reported immunohistochemical expression of REV-7 in different types of cancer, including testicular cancer, ovarian cancer, esophagus squamous cell carcinoma, prostate cancer, colorectal cancer, diffuse large B-cell lymphoma, breast cancer, lung cancer, and skin cancer. High REV-7 expression was associated with faster disease progression, resistance to available treatment options, and worse prognosis in the majority of included studies. These results indicate that immunohistochemical staining of REV-7 protein could potentially be used as a predictive tissue marker in certain cases. Promising results, arising from REV-7 inactivation experiments, render REV-7 targeting a potential therapeutic strategy for future cancer management, especially in the cases of chemoresistant or radioresistant disease.

Prognostic Value of Circulating Tumor DNA (ctDNA) in Oncogene-Driven NSCLC: Current Knowledge and Future Perspectives.

As we enter an unprecedented era of personalized medicine, molecular targeted therapies have the potential to induce improved survival outcome in patients with non-small cell lung cancer (NSCLC). However, a significant percentage of oncogene-driven NSCLC patients will relapse even after definitive treatment, whereas chronic and durable response to targeted therapies is a less common event in advanced-stage lung cancer. This phenomenon could be attributed to minimal residual disease (MRD), defined as a population of disseminated tumor cells that survive during the course or after treatment, eventually leading to recurrence and limiting patient survival. Circulating tumor DNA (ctDNA) is a powerful biomarker for MRD detection and monitoring and is a non-invasive approach of treating cancer, and especially NSCLC, based on a real-time assessment of the tumor genomic landscape. In this review, we present the key findings of studies that have used ctDNA with regard to its prognostic value and in respect to the most common druggable driver mutations of genes in NSCLC, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), B-Raf proto-oncogene (BRAF), and mesenchymal epithelial transition factor receptor (MET).

MicroRNAs as therapeutic targets in breast cancer metastasis.

Breast cancer is a complex disease with multiple risk factors involved in its pathogenesis. Among these factors, microRNAs are considered for playing a fundamental role in the development and progression of malignant breast tumors. In recent years, various studies have demonstrated that several microRNAs exhibit increased or decreased expression in metastatic breast cancer, acting as indicators of metastatic potential in body fluids and tissue samples. The identification of these microRNA expression patterns could prove instrumental for the development of novel therapeutic molecules that either mimic or inhibit microRNA action. Additionally, an efficient delivery system mediated by viral vectors, nonviral carriers, or scaffold biomaterials is a prerequisite for implementing microRNA-based therapies; therefore, this review attempts to highlight essential microRNA molecules involved in the metastatic process of breast cancer and discuss recent advances in microRNA-based therapeutic approaches with potential future applications to the treatment sequence of breast cancer.

Circulating miRNA Expression Profiling in Breast Cancer Molecular Subtypes: Applying Machine Learning Analysis in Bioinformatics.

BACKGROUND/AIM: Breast cancer is a leading worldwide cause of female cancer-related morbidity and mortality. Since molecular characteristics increasingly guide disease management, demystifying breast tumor miRNA signature emerges as an essential step toward personalized care. This study aimed to investigate the variations in circulating miRNA expression profiles between breast cancer subtypes and healthy controls and to identify relevant target genes and molecular functions. MATERIALS AND METHODS: MiRNA expression was tested by miScript™ miRNA PCR Array Human Cancer Pathway Finder kit, and subsequently, a machine learning approach was applied for miRNA profiling of the various breast cancer molecular subtypes. RESULTS: Serum samples from patients with primary breast cancer (n=66) and healthy controls (n=16) were analyzed. MiR-21 was the single common molecule among all breast cancer subtypes. Furthermore, several miRNAs were found to be differentially expressed explicitly in the different subtypes; luminal A (miR-23b, miR-142, miR-29a, miR-181d, miR-16, miR-29b, miR-155, miR-181c), luminal B (miR-148a, let-7d, miR-92a, miR-34c, let-7b, miR-15a), HER2+ (miR-125b, miR-134, miR-98, miR-143, miR-138, miR-135b) and triple negative breast cancer (miR-17, miR-150, miR-210, miR-372, let-7f, miR-191, miR-133b, miR-146b, miR-7). Finally, miRNA-associated target genes and molecular functions were identified. CONCLUSION: Applying a machine learning approach to delineate miRNA signatures of various breast cancer molecular subtypes allows further understanding of molecular disease characteristics that can prove clinically relevant.

Immunotherapy in HER2-Positive Breast Cancer: A Systematic Review.

Introduction: The clinical outcome of HER2-positive breast cancer patients changed with the use of anti-Her therapies, though it still remains an aggressive and fatal disease. Implementation of immune checkpoint inhibitors in HER2-positive Breast cancer is a concept supported by the reported biological and preclinical data. Methods: We conducted a systematic review of the current literature involving immune checkpoint inhibitors alone or in combination with targeted therapies or chemotherapy finalized or running in HER2-positive breast cancer. Results: Twelve clinical trials and 2 case reports were identified in our study. Conclusion: The reported clinical trials highlight that checkpoint inhibition seems to be promising in metastatic, neoadjuvant, and adjuvant settings of HER2-positive breast cancer.

Chasing Hippos: Implications of YAP1 and TAZ Expression in Pregnancy-associated Breast Cancer Tumorigenesis.

BACKGROUND/AIM: The Hippo pathway is a molecular pathway recently associated with tumorigenesis, metastasis, and drug resistance. Pregnancy-associated breast cancer (PABC) is the most common malignancy diagnosed during gestation; however, the molecular mechanisms underlying PABC are largely unknown. The aim of the present study was to evaluate Hippo pathway transducers TAZ and YAP1 expression in PABC in relation to the clinicopathological characteristics of the disease. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tissues from 21 PABC patients treated at Alexandra Hospital in Athens, Greece, were analyzed with immunohistochemistry. RESULTS: Strong nuclear TAZ/YAP1 stanning was found in 48% of the PABC patients analyzed. Hormone receptor negative patients had a statistically significant correlation with strong positive expression of TAZ/YAP1 co-transcription factors. No association was observed with overall and disease-free survival. CONCLUSION: The Hippo pathway is de-regulated in a subset of PABC patients, highlighting the complex molecular background of the disease, which certainly requires further investigation.

Multi-Gene Mutation Profiling by Targeted Next-Generation Sequencing in Premenopausal Breast Cancer.

Breast cancer has distinct etiology, prognoses, and clinical outcomes at premenopausal ages. Determination of the frequency of germline and somatic mutations will refine our understanding of the genetic contribution to premenopausal breast cancer susceptibility. We applied a comprehensive next generation sequencing-based approach to analyze blood and/or tissue samples of 54 premenopausal breast cancer patients treated in our clinic. Genetic testing results were descriptively analyzed in correlation with clinicopathological data. In the present study, 42.5% of premenopausal breast cancer patients tested carried pathogenic mutations in cancer predisposition genes (CHEK2, BRCA1, TP53, and MUTYH). Germline variants of unknown/uncertain significance (VUSs) in eight different cancer susceptibility genes, namely BRCA1, BRCA2, CHEK2, RAD51C, RAD51D, ATM, BRIP1, and PMS2, were also identified in 14 premenopausal patients (35%). Of the breast tumors tested, 61.8% harbored pathogenic somatic variants in tumor suppressor genes (TP53, NF1, RB), genes involved in DNA repair (BRCA1, BRCA2, ATM, RAD50), cell proliferation (PTEN, PIK3C FGFR3, AKT1, ROS1, ERBB2, NOTCH1), and cell adhesion (CTNNB1). This descriptive study employs the powerful NGS technology to highlight the high frequency of premenopausal cases attributable to genetic predisposition. Mutation identification in a larger cohort may further ensure that these patients receive tailored treatment according to their menopausal status.

Mutation Profile of HPV16 L1 and L2 Genes in Different Geographic Areas.

The causal relationship between HPV and cervical cancer in association with the high prevalence of high risk HPV genotypes led to the design of HPV vaccines based on the major capsid L1 protein. In recent years, capsid protein L2 has also become a focal point in the field of vaccine research. The present review focuses on the variability of HPV16 L1 and L2 genes, emphasizing the distribution of specific amino acid changes in the epitopes of capsid proteins. Moreover, a substantial bioinformatics analysis was conducted to describe the worldwide distribution of amino acid substitutions throughout HPV16 L1, L2 proteins. Five amino acid changes (T176N, N181T; EF loop), (T266A; FG loop), (T353P, T389S; HI loop) are frequently observed in the L1 hypervariable surface loops, while two amino acid substitutions (D43E, S122P) are adjacent to L2 specific epitopes. These changes have a high prevalence in certain geographic regions. The present review suggests that the extensive analysis of the amino acid substitutions in the HPV16 L1 immunodominant loops may provide insights concerning the ability of the virus in evading host immune response in certain populations. The genetic variability of the HPV16 L1 and L2 epitopes should be extensively analyzed in a given population.

Germline and somatic variants in ovarian carcinoma: A next-generation sequencing (NGS) analysis.

Background: Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers, while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations. Beyond these mutations, germline or somatic aberrations in genes of the homologous recombination (HR) pathway such as RAD51B/C/D, PALB2, ATM, BRIP1 may confer an HR deficiency in up to 50% of ovarian tumors. Next-generation sequencing (NGS) is a high-throughput massive parallel sequencing method that enables the simultaneous detection of several mutations in entire genomes. Methods: We performed NGS analysis in 86 patients with ovarian cancer treated in the Oncology Department of Alexandra University Hospital in order to identify the molecular landscape of germline and somatic mutations in ovarian cancer. Results: The genes with the highest number of pathogenic somatic mutations in high grade serous carcinoma (HGSC) patients were TP53 [68%; 34/50] and BRCA1 [22%; 11/50] followed by somatic mutations in RB1 [2%; 1/50], NF1 [2%; 1/50], BRCA2 [2%; 1/50], AKT1 [2%; 1/50], RAD50 [2%; 1/50], PIK3CA [2%; 1/50] genes. Of note, the most common TP53 genetic polymorphism was c.524G>A p.Arg175His in exon 5. Variants of unknown significance (VUS) detected in HGSC included ROS1 [26%; 13/50], RAD50 [6%; 3/50], BRCA2 [6%; 3/50], NOTCH1 [6%; 3/50], TP53 [6%; 3/50], AR [6%; 3/50]. As for germline mutations, BRCA1 [8/30; 27%] and BRCA2 [4/30; 13%] were the most common genes bearing pathogenic alterations in HGSC, while VUS germline mutations commonly affected HRR-related genes, including ATM (c.7816A>G), BRIP (c.2327 C>A), CHEK2 (c.320-5T>A). Conclusion: Overall, genetic testing should be offered in most patients with ovarian cancer to identify mutations in HRR genes and determine the population that would be susceptible to poly ADP ribose polymerase (PARP) inhibitors.

Baseline Ang-2 Serum Levels as a Predictive Factor for Survival in NSCLC and SCLC.

Angiopoietin-2 (Ang-2) has been implicated in the development of several types of cancer, including lung malignancy. In the present study, we examined the impact of Ang-2 serum concentration on the development, dissemination, and 5-year overall survival of NSCLC and SCLC. A total of 99 patients with lung cancer were tested. The OS of NSCLC and SCLC patients was estimated using Kaplan−Meier curves and compared through log-rank test. The median serum level of Ang-2 at baseline in both NSCLC and SCLC patients was significantly higher than that of controls (p < 0.0001). The Ang-2 serum concentration was not related to metastasis, neither in NSCLC nor in SCLC cases. The OS was found to be significantly shorter for stage IIIß NSCLC patients with a high baseline Ang-2 serum concentration (p = 0.012), while Cox regression analysis showed that Ang-2 is a significant independent factor for poor prognosis for stage IIIß NSCLC (hazard ratio = 2.97, 95% CI: 1.05−8.40, p = 0.04). The concentration of Ang-2 has no impact on the prognosis of SCLC. Ang-2 could be considered as a significant molecular marker that enables the prediction of NSCLC and SCLC development, and is involved in the poor prognosis of stage IIIß NSCLC.