To evaluate the therapeutic strategies commonly employed in the clinic for the management of brain metastases (BMs) and to correlate disease outcome with type of treatment and therapeutic resources available at the treating center.

Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context of EGFR mutant NSCLC and discuss its clinical and therapeutic implications. EGFR-dependent and independent molecular pathways have the potential to overcome or circumvent the activity of EGFR-targeted agents including the third-generation TKI, osimertinib, negatively impacting clinical outcomes. CNS metastases occur frequently in patients on EGFR-TKIs, due to the inability of first and second-generation agents to overcome both the BBB and the acquired resistance of cancer cells in the CNS. Newer-generation TKIs, TKIs targeting EGFR-independent resistance mechanisms, bispecific antibodies and antibody-drug conjugates or combinations of TKIs with other TKIs or chemotherapy, immunotherapy and Anti-Vascular Endothelial Growth Factors (anti-VEGFs) are currently in use or under investigation in EGFR mutant NSCLC. Liquid biopsies detecting mutant cell-free DNA (cfDNA) provide a window of opportunity to attack mutant clones before they become clinically apparent. Overall, EGFR TKIs-resistant NSCLC constitutes a multifaceted therapeutic challenge. Mapping its underlying mutational landscape, accelerating the detection of resistance mechanisms and diversifying treatment strategies are essential for the management of the disease.

Purpose: To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression.

Background: Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths worldwide. Epidermal Growth Factor Receptor (EGFR)-mutated patients usually benefit from TKIs treatment, but a significant portion show unresponsiveness due to primary resistance mechanisms. We investigated the role of TP53 mutations in predicting survival and response to EGFR-TKIs in EGFR-mutated NSCLC patients, to confirm, on an independent case series, our previous results. Methods: An independent retrospective cohort study was conducted, on a case series of 136 EGFR-mutated NSCLC patients receiving first or second generation TKIs as a first line therapy, and a smaller fraction of patients who acquired the T790M resistance mutation and were treated with third generation TKIs in the second or further line of treatment. TP53 mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) of the patients. Results: Forty-two patients (30.9%) showed a TP53 mutation. Considered together, TP53 mutations had no significant impact on time-to-event endpoints. Considering the different TP53 mutations separately, exon 8 mutations confirmed their negative effect on PFS (HR 3.16, 95% 1.59–6.28, p = 0.001). In patients who developed the T790M resistance mutation, treated with third generation TKIs, the TP53 exon 8 mutations predicted worse PFS (even though not statistically significant), and OS (HR 4.86, 95% CI: 1.25–18.90, p = 0.023). Conclusions: TP53 exon 8 mutations confirmed their negative prognostic impact in patients treated with first and second generation TKIs and demonstrated a role in affecting clinical outcome in patients treated with third generation TKIs.