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Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.

Although the role of miR-200s in regulating E-cadherin expression and epithelial-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here, we use clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. MiR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.

AR gene aberrations are rare in prostate cancer prior to primary hormone treatment but emerge with castration resistance. To determine AR gene status using a minimally-invasive assay that could have broad clinical utility, we developed a targeted next-generation sequencing approach amenable to plasma DNA that covers all the AR coding bases and regions of the genome highly informative in prostate cancer. We here sequenced 274 plasma samples from 97 castration-resistant prostate cancer patients treated with abiraterone at two institutions. After controlling for the fraction of normal DNA in patients’ circulation, we quantified AR copy number state and point mutations. AR aberrations by the two mechanisms were inversely correlated, supported further by the enrichment of non-synonymous versus synonymous mutations in AR copy number normal as opposed to AR gain samples. While AR copy number was unchanged from pre-treatment to progression and no mutant AR alleles showed signal for acquired gain, we observed emergence of T878A or L702H AR amino acid changes in 13% at progression on abiraterone. Patients with AR gain or T878A or L702H pre-abiraterone (45%) were 4.9 times and 7.8 times less likely to have a decline in PSA by ≥50% or ≥90% respectively and had a significantly worse overall (HR 7.33, 95% CI 3.51-15.34) and progression-free (HR 3.73, 95% CI 2.17-6.41) survival. Evaluation of plasma AR using next-generation sequencing could identify cancers with primary resistance to abiraterone.

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Switching to anastrozole after the first 2 to 3 years of treatment is well tolerated and significantly improves event-free and recurrence-free survival in postmenopausal patients with early breast cancer.

The aim of this work was to validate a previously constructed prognostic score for terminally ill cancer patients in order to determine its value in clinical practice. The Palliative Prognostic Score (PaP Score) was tested on a population of 451 evaluable patients consecutively entered in the hospice programs of 14 Italian Palliative Care Centers. The score subdivided patients into three specific risk classes based on the following six predictive factors of death: dyspnea, anorexia, Karnofsky Performance Status (KPS), Clinical Prediction of Survival (CPS), total white blood count (WBC), and lymphocyte percentage. The performance of the PaP Score index in the training and testing sets was evaluated by comparing mortality rates in the 3 prognostic risk categories. The score was able to subdivide the validation-independent case series into three risk groups. Median survival was 76 days in group A (with a 86.6% probability of 30-day survival), 32 days in group B (with a 51.6% probability of 30-day survival), and 14 days in group C (with a 16.9% probability of 30-day survival). Survival medians were remarkably similar to those of the training set (64 days in group A, 32 days in group B, and 11 days in group C). In the complex process of staging terminally ill patients, the PaP Score is a simple instrument which permits a more accurate quantification of expected survival. It has been validated on an independent case series and is thus suitable for use in clinical practice.