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.

High-throughput Proteomic Profiling of Male Breast Cancer Tissue.

BACKGROUND/AIM: Until now, little emphasis has been placed on the protein expression profile of male breast cancer (MBC) tumors, due to the rarity of the disease. The present study aimed to identify a proteomic pattern that is characteristic for malignant male breast tissue epithelium. MATERIALS AND METHODS: The protein content of four male breast tumors and corresponding adjacent healthy (control) tissues was analyzed by high-throughput nano-liquid chromatography-MS/MS technology. RESULTS: A total of 2,352 proteins were identified, that correspond to 1,249 single gene products, with diverse biological roles. Of those, a panel of 119 differentially expressed tissue proteins was identified in MBC samples compared to controls; 90 were found to be over-expressed in MBC tissues, while 29 were down-regulated. Concurrently, 844 proteins were detected only in MBC tumors and 197 were expressed exclusively in control mammary samples. CONCLUSION: Differential proteomic expression was found in MBC tissue, leading to improved understanding of MBC pathology and highlighting the need for personalized management of male patients.

MicroRNAs as Potential Predictors of Response to CDK4/6 Inhibitor Treatment.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as novel treatment options in the management of advanced or metastatic breast cancer. MicroRNAs are endogenous non-coding 19-22-nucleotide-long RNAs that regulate gene expression in development and tumorigenesis. Herein, we systematically review all microRNAs associated with response to CDK4/6 inhibitors in solid tumors and hematological malignancies. Eligible articles were identified by a search of the MEDLINE and ClinicalTrials.gov databases for the period up to1 January 2021; the algorithm consisted of a predefined combination of the words "microRNAs", "cancer" and "CDK 4/6 inhibitors". Overall, 15 studies were retrieved. Six microRNAs (miR-126, miR-326, miR3613-3p, miR-29b-3p, miR-497 and miR-17-92) were associated with sensitivity to CDK4/6 inhibitors. Conversely, six microRNAs (miR-193b, miR-432-5p, miR-200a, miR-223, Let-7a and miR-21) conferred resistance to treatment with CDK4/6 inhibitors. An additional number of microRNAs (miR-124a, miR9, miR200b and miR-106b) were shown to mediate cellular response to CDK4/6 inhibitors without affecting sensitivity to treatment. Collectively, our review provides evidence that microRNAs could serve as predictive biomarkers for treatment with CDK4/6 inhibitors. Moreover, microRNA-targeted therapy could potentially maximize sensitivity to CDK4/6 inhibition.

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.

Long-Term Neurodevelopmental Outcome of Children after in Utero Exposure to Chemotherapy.

Pregnancy-related cancer management represents a real challenge for both the patients and the physicians. The long-term neurodevelopmental outcome of children in utero exposed to chemotherapeutic agents has only recently been addressed. This review aims to systematically integrate and highlight all existing data from the literature regarding the effect of prenatal exposure to chemotherapy on fetal brain growth and child development. All eligible studies are based on validated neurodevelopmental testing scales (e.g., Bayley Scales of Infant Development, Wechsler Preschool and Primary Scale of Intelligence) and/or well-defined questionnaires. Our systematic review including 17 studies demonstrates that no major consequences on the neurodevelopment of children after in utero exposure to anti-cancer drugs have been reported; nevertheless, longer and more thorough follow-up with large-scale multicenter prospective studies is certainly required in order to draw firm conclusions.

The Genomic Profile of Pregnancy-Associated Breast Cancer: A Systematic Review.

Breast cancer is the most common malignancy diagnosed during pregnancy. Strong data on the genomic profile of pregnancy-associated breast cancer are lacking. This systematic review aims to integrate and analyze all existing data from the literature regarding the genomic background and the gene mutational patterns of pregnancy-associated breast cancer. Using various genomic analysis methods, multiple differentially expressed genes and numerous non-silent mutations have been detected. More particularly, our review demonstrates the aberrant expression of several oncogenes (e.g., MYC, SRC, FOS), tumor suppressor genes (e.g., TP53, PTEN, CAV1), apoptosis regulators (e.g., PDCD4, BCL2, BIRC5), transcription regulators (e.g., JUN, KLF1, SP110), genes involved in DNA repair mechanisms (e.g., Sig20, BRCA1, BRCA2, FEN1), in cell proliferation (e.g., AURKA, MKI67), in the immune response (e.g., PD1, PDL1), and in other significant biological processes (e.g., protein modification, internal cell motility). Further research on the genomic profile of pregnancy-associated breast cancer is urgently required in order to identify potential biomarkers facilitating early-stage diagnosis and individualized therapy.

Taxanes during pregnancy in cervical cancer: A systematic review and pooled analysis.

BACKGROUND: Cervical cancer is one of the most common malignancies diagnosed during pregnancy. Taxanes administration has been established as theurapetic regimen in non pregrant women. OBJECTIVES: This systemic review and meta-analysis aims to synthesize all available data from cervical cancer series in pregnant women and evaluate the efficacy and safety of taxanes during pregnancy. SEARCH STRATEGY: Eligible articles were identified by a search of ClinicalTrial.gov and MEDLINE databases for the period 01/01/2000 up to 31/11/2017; The algorithm consisted of a predefined combination of the words "cervical", "cancer", "taxanes" and "pregnancy". SELECTION CRITERIA: PRISMA guidelines were applied in this study. The literature search and data extraction from all studies that examined the efficacy and safety of taxanes in pregnancy, were done by two independent investigators. Quantitative synthesis of the published articles was performed. DATA COLLECTION AND ANALYSIS: Overall eight articles were retrieved. In all cases (14 pregnancies, 14 newborns) the use of taxanes in combination with platinum derivatives resulted in the birth of alive neonates, with not any miscarriage. The taxane derivative used in all cases was paclitaxel, combined with Cisplatin (13 pregnancies) and Carboplatin (one pregnancy). RESULTS: Complete and partial response was achieved in 7.2% and 92.9% of cervical cancer patients. In the majority of cases chemotherapy was well tolerated. The median progression-free survival was 48.5 months. CONCLUSION: Taxanes administration during the 2nd and 3rd trimester of pregnancy is a safe choice.

Outcomes after surgical coronary artery revascularisation in children with congenital heart disease.

OBJECTIVE: Surgical coronary revascularisation in children with congenital heart disease (CHD) is a rare event for which limited information is available. In this study, we review the indications and outcomes of surgical coronary revascularisation from the Pediatric Cardiac Care Consortium, a large US-based multicentre registry of interventions for CHD. METHODS: This is a retrospective cohort study of children (<18 years old) with CHD who underwent surgical coronary revascularisation between 1982 and 2011. In-hospital mortality and graft patency data were obtained from the registry. Long-term transplant-free survival through 2014 was achieved for patients with adequate identifiers via linkage with the US National Death Index and the Organ Procurement and Transplantation Network. RESULTS: Coronary revascularisation was accomplished by bypass grafting (n=72, median age 6.8 years, range 3 days-17.4 years) or other operations (n=65, median age 2.6 years, range 5 days-16.7 years) in 137 patients. Most revascularisations were related to the aortic root (61.3%) or coronary anomalies (27.7%), but 10.9% of them were unrelated to either of them. Twenty in-hospital deaths occurred, 70% of them after urgent 'rescue' revascularisation in association with another operation. Long-term outcomes were available by external linkage for 54 patients surviving to hospital discharge (median follow-up time 15.0 years, max follow-up 29.8 years) with a 15-year transplant-free survival of 91% (95% CI 83% to 99%). CONCLUSIONS: Surgical coronary revascularisation can be performed in children with CHD with acceptable immediate and long-term survival. Outcomes are dependent on indication, with the highest mortality in rescue procedures.