Increasing sTILs in TNBCs improves the likelihood of a pCR. However, inter-observer agreement is such that H&E-based assessment is not sufficiently reproducible for clinical application. Other methodologies should be explored, but may be at the cost of ease of application.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.

Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83–9.71) and 2.55- (95%CI 1.52–4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis.

The frequency of interval cancers (IC) can be an indicator inversely related to the quality of a breast screening programme. The objectives were to estimate the frequency of IC, to classify IC by posterior radiological review, and to describe the prognostic factors of these IC. The setting was the Sabadell-Cerdanyola Breast Cancer Screening Programme, in Northeast Spain. We developed a population-based study of the IC occurring in the first three rounds (1995-2001). The indicators used were the incidence rate of invasive IC per 10 000 women screened and the proportional incidence, stratified by age group, type of screening and the round, and the time elapsed since the last screening mammogram. A radiological informed consensus review was used to classify the IC. No specific pattern of incidence rates was evident with respect to age, type of screening, or round, although screening was generally more sensitive in women aged 60-69 years. The proportional incidence for the period 0-11 months was always under 30%. Twenty-one percent of 38 IC evaluated (95% CI: 8.0-34.0) were attributed to errors in the screening process (false negatives). No major differences in the prognostic factors of the 57 IC were identified on examining the radiological type or the time since the last screening mammogram. We observed a high frequency of IC from 12 months after screening. It is necessary to reach a consensus regarding the definition and the analysis of IC and to establish mechanisms that would allow all the malignant tumours diagnosed in the target population to be identified.

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