Triple Negative Breast Cancer (TNBC) is an aggressive neoplasia with median Overall Survival (OS) less than two years. Despite the availability of new drugs, the chance of survival of these patients did not increase. The combination of low doses of drugs in a metronomic schedule showed efficacy in clinical trials, exhibiting an anti-proliferative and anti-tumour activity. In Victor-2 study we recently evaluated a new metronomic combination (mCHT) of Capecitabine (CAPE) and Vinorelbine (VNR) in breast cancer patients showing a disease control rate with a median Progression-Free Survival (PFS) of 4.7 months in 28 TNBC patients.Here in Victor-0 study, we examined the effect of mCHT vs standard (STD) schedule of administration of different combinations of 5-Fluorouracil (5FU), the active metabolite of CAPE, and VNR in TNBC cell lines MDA-MB-231 and BT-549. A significant anti-proliferative activity was observed in cells treated with metronomic vs STD administration of 5FU or VNR alone. Combination of the two drugs showed an additive inhibitor effect on cell growth in both cell lines. Moreover, after exposure of cells to 5FU and VNR under mCHT or conventional schedule of administration we also observed a downregulation of chemoresistance factor Bcl-2, changes in pro-apoptotic protein Bax and in cleaved effector caspase-3 and increased expression of LC3A/B autophagy protein.Our results therefore suggest that molecular mechanisms implicated in apoptosis and autophagy as well as the cross-talk between these two forms of cell death in MDA-MB-231 and BT-549 cells treated with 5FU and VNR is dose- and schedule-dependent and provide some insights about the roles of autophagy and senescence in 5FU/VNR-induced cell death.

Background Angiogenesis has an important role in thymic epithelial tumors (TETs). Regorafenib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet‐derived growth factor receptor β (PDGFR‐β), and fibroblast growth factor receptors (FGFRs). This study explored the activity of regorafenib as monotherapy in patients with advanced or recurrent B2‐B3 thymoma (T) and thymic carcinoma (TC) previously treated with platinum‐containing chemotherapy. Methods A Fleming single‐arm, single‐stage, phase 2 trial to evaluate the activity of regorafenib (160 mg once a day by mouth for 3 weeks on/1 week off) was planned. The study was designed to reject the null hypothesis of an 8‐week progression‐free survival (PFS) rate ≤25% with a type I error of 0.10 and a statistical power of 80% at the alternative hypothesis of an 8‐week PFS rate of ≥50% (≥8 of 19 evaluable patients progression‐free at 2 months). Results From June 2016 to November 2017, 19 patients were enrolled (11T/8TC). We observed partial response (PR) in 1 patient (1T) (5.3%), stable disease (SD) in 14 patients (9T/5TC) (73.7%), and progressive disease in 2 patients (1T/1TC) (10.5%), with a disease control rate of 78.9%. According to Choi‐criteria, 13 patients (68.4%) achieved PR, and 2 patients SD (10.5%). The median PFS was 9.6 months whereas median overall survival was 33.8 months. The 8‐week PFS rate was 78.9% (15 of 19 patients). Grade 3‐4 treatment‐related adverse events were observed in 10 patients (52.6%). Conclusions The primary end point of this study was reached. The high rate of PR (Choi‐criteria) suggests antitumor activity of regorafenib in TETs. On the basis of survival outcomes, the efficacy of regorafenib should be further evaluated in larger studies.

The all-oral metronomic combination of vinorelbine and capecitabine had an acceptable efficacy profile and appears to be better tolerated than standard treatment schedules in elderly metastatic breast cancer patients (age ≥70 years).

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Thymic epithelial tumours (TETs) are rare tumours originating from the thymus. Considering the rarity of this disease, the management of TETs is still challenging and difficult. In fact, all the worldwide clinical practice guidelines are based on data from retrospective analyses, prospective single arm trials or experts’ opinions. The results of combined modality therapy (chemotherapy, surgery, radiotherapy) in thymic malignancies are reasonably good in less advanced cases whereas in case of advanced (unsuitable for surgery) or metastatic disease, a platinum-based chemotherapy is considered standard of care. Unfortunately, chemotherapy in the palliative setting has modest efficacy. Moreover, due to the lack of known oncogenic molecular alterations, no targeted therapy has been shown to be efficient for these tumours. In order to offer the best diagnostic and therapeutic tools, patients with TETs should be managed with a continuous and specific multidisciplinary expertise at any step of the disease, especially in the era of a novel coronavirus disease (COVID-19). Current evidences show that cancer patients might have more severe symptoms and poorer outcomes from COVID-19 infection than general population. With the exception of the patients carrying a Good’s syndrome, there is no evidence that patients with TETs present a higher risk of infection compared with other cancer patients and their management should be the same. The aim of this review is to summarize the existing literature about systemic treatments for TETs in all clinical setting (local and locally advanced/metastatic disease) exploring how these therapeutic strategies have been managed in the COVID-19 era.

Colorectal rhabdoid carcinomas (CRbCs) are very rare and aggressive cancers. The BRAF mutation and CpG island methylator phenotype have been reported to be common features of CRbCs. This study reviews the literature about CRbCs and analyzes the clinicopathological and molecular profiles of seven CRbCs characterized by large discohesive cells with abundant eosinophilic cytoplasm, showing hyaline inclusions and large rounded to bean-shaped nuclei. For comparison, we included four poorly differentiated medullary carcinomas (PDMCs) with focal aspects mimicking rhabdoid features. Overall survival was poor in both subsets, with 78% of patients dying of disease within 2–11 months. The main features of CRbCs were: Loss of/reduced SMARCB1/INI expression, intense vimentin immunostaining, and dense neutrophilic infiltration. The PDMCs were positive for pancytokeratin but negative for vimentin and showed moderate peritumoral/intratumoral CD8+ lymphocytes. All PDMCs showed SMARCB1(INI-1) expression. The coexistence of BRAF and TP53 mutations was observed in 80% of CRbCs and PDMCs. PDMCs always showed microsatellite instability and CpG island methylator phenotype (CIMP), while CRbCs were CIMP negative and exhibited microsatellite instability (MSI) in two out of seven cases. CRbCs are characterized by BRAF and TP53 mutations. Loss/reduced expression of nuclear SMARCB1/INI, intense vimentin immunostaining, dense neutrophilic infiltration, and low frequency of CIMP are useful markers to recognize these rare aggressive tumors.

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The main hypothesis of this study is that gene expression profiles (GEPs) integrating both tumor antigenicity and a pre-existing adaptive immune response can be used to generate distinct immune-related signatures of BRAF mutant colorectal cancers (BRAF-CRCs) to identify actionable biomarkers predicting response to immunotherapy. GEPs of 89 immunotherapy-naïve BRAF-CRCs were generated using the Pan-Cancer IO 360 gene expression panel and the NanoString nCounter platform and were correlated with microsatellite instability (MSI) status and with CD8+ tumor-infiltrating lymphocyte (TIL) content. Hot/inflamed profiles were found in 52% of all cases, and high scores of Tumor Inflammation Signature were observed in 42% of the metastatic BRAF-CRCs. A subset of MSI tumors showed a cold profile. Antigen Processing Machinery (APM) signature was not differentially expressed in MSI tumors compared with MSS cases. By contrast, the APM signature was significantly upregulated in CD8+ BRAF-CRCs versus CD8− tumors. Our study demonstrates that a significant fraction of BRAF-CRCs may be a candidate for immunotherapy and that the simultaneous analysis of MSI status and CD8+ TIL content increases accuracy in identifying patients who can potentially benefit from immune checkpoint inhibitors. GEPs may be very useful in expanding the spectrum of patients with BRAF-CRCs who can benefit from immune checkpoint blockade.