Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial.

BACKGROUND: Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC. METHODS: Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A). CONCLUSIONS: First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.

Expression of c-MET in Estrogen Receptor Positive and HER2 Negative Resected Breast Cancer Correlated with a Poor Prognosis.

Introduction: The mesenchymal-epithelial transition factor (c-MET) receptor is overexpressed in about 14−54% of invasive breast cancers, but its prognostic value in clinical practice is still unclear. Methods: In order to investigate the relationship between c-MET expression levels and prognosis, we retrospectively reviewed the clinical features and outcomes of 105 women with estrogen receptor positive HER2 negative (ER+/HER2-) resected breast cancer. We used the Kaplan Meier method to estimate Disease Free Survival (DFS) and Breast Cancer Specific Survival (BCSS) in the subgroups of patients with high (≥50%) and low (<50%) c-MET expression. Univariate and multivariate Cox proportional regression models were performed to assess the prognostic impact of clinicopathological parameters for DFS an BCSS. Results: High c-MET values significantly correlated with tumor size, high Ki67 and low (<20%) progesterone receptor expression. At a median follow up of 60 months, patients with high c-MET tumor had significantly worse (p = 0.00026) and BCSS (p = 0.0013). Univariate analysis showed a significant association between large tumor size, elevated Ki67, c-MET values and increased risk of recurrence or death. The multivariate COX regression model showed that tumor size and high c-MET expression were independent predictors of DFS (p = 0.019 and p = 0.022). Moreover, large tumor size was associated with significantly higher risk of cancer related death at multivariate analysis (p = 0.017), while a trend towards a poorer survival was registered in the high c-MET levels cohort (p = 0.084). Conclusions: In our series, high c-MET expression correlated with poor survival outcomes. Further studies are warranted to validate the clinical relevance and applicability of c-MET as a prognostic factor in ER+/HER2- early BC.

Prognostic Relevance of Progesterone Receptor Levels in Early Luminal-Like HER2 Negative Breast Cancer Subtypes: A Retrospective Analysis.

Introduction: In luminal-like early breast cancer (BC), the lack of Progesterone Receptor (PR) expression generally correlates with more aggressive behavior but the clinical validity of low PR levels remains a debated issue. Methods: The main aim of this retrospective analysis was to assess the survival outcome (Breast cancer specific survival, BCSS) in a cohort of 687 luminal-like HER2 negative early BC patients treated at our Institutions from January 2000 to December 2018, using a sub-classification of tumors in subgroup 1 (PR high/Ki67 low), subgroup 2 (PR high/Ki67 high), subgroup 3 (PR low/Ki67 low), subgroup 4 (PR low/Ki67 high) according to PR and Ki67 values. Results: At a median follow-up of 7 years, BCSS rates were 96.3%, 89%, 86.8% and 85% in the subgroup 1, 2, 3, 4 respectively. Overall, a statistically significant difference in BCSS rates was observed among the 4 subgroups (p=0.0036). On univariate analysis, post-menopause, older age (≥ 50 years), low PR and high Ki67 expression, poorly differentiated grade and size ≥ 2 cm as well as luminal B-like tumors (subgroups 2, 3, 4) were significantly associated with a worse BCSS. Multivariate analysis identified grade, size and subgroup classification of BC as independent prognostic markers of poorer outcome. In particular, subgroups 4, 3 and 2 displayed a significantly higher risk of BC-related death (HR=4.11; p=0.008; HR=3.43; p=0-007; HR=2.57; p=0.020, respectively) when compared to subgroup 1. Conclusions: Our results support the usefulness of PR and Ki67 levels as prognostic markers, corroborating their crucial role in the decision-making process of patients with luminal-like HER2 negative early BC. Clinical application of these parameters should be assessed prospectively.

Campora: a young genetic isolate in South Italy.

Genetic isolates have been successfully used in the study of complex traits, mainly because due to their features, they allow a reduction in the complexity of the genetic models underlying the trait. The aim of the present study is to describe the population of Campora, a village in the South of Italy, highlighting its properties of a genetic isolate. Both historical evidence and multi-locus genetic data (genomic and mitochondrial DNA polymorphisms) have been taken into account in the analyses. The extension of linkage disequilibrium (LD) regions has been evaluated on autosomes and on a region of the X chromosome. We defined a study sample population on the basis of the genealogy and exogamy data. We found in this population a few different mitochondrial and Y chromosome haplotypes and we ascertained that, similarly to other isolated populations, in Campora LD extends over wider region compared to large and genetically heterogeneous populations. These findings indicate a conspicuous genetic homogeneity in the genome. Finally, we found evidence for a recent population bottleneck that we propose to interpret as a demographic crisis determined by the plague of the 17th century. Overall our findings demonstrate that Campora displays the genetic characteristics of a young isolate.

A deformable grid-matching approach for microarray images.

A fundamental step of microarray image analysis is the detection of the grid structure for the accurate location of each spot, representing the state of a given gene in a particular experimental condition. This step is known as gridding and belongs to the class of deformable grid matching problems which are well known in literature. Most of the available microarray gridding approaches require human intervention; for example, to specify landmarks, some points in the spot grid, or even to precisely locate individual spots. Automating this part of the process can allow high throughput analysis. This paper focuses on the development of a fully automated procedure for the problem of automatic microarray gridding. It is grounded on the Bayesian paradigm and on image analysis techniques. The procedure has two main steps. The first step, based on the Radon transform, is aimed at generating a grid hypothesis; the second step accounts for local grid deformations. The accuracy and properties of the procedure are quantitatively assessed over a set of synthetic and real images; the results are compared with well-known methods available from the literature.