Patients with non-small cell lung cancer (NSCLC) develop bone metastasis (BoM) in more than 50% of cases during the course of the disease. This metastatic site can lead to the development of skeletal related events (SREs), such as severe pain, pathological fractures, spinal compression, and hypercalcemia, which reduce the patient’s quality of life. Recently, the treatment of advanced NSCLC has radically changed due to the advent of immunotherapy. Immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy have become the main therapeutic strategy for advanced or metastatic NSCLC without driver gene mutations. Since survival has increased, it has become even more important to treat bone metastasis to prevent SRE. We know that the presence of bone metastasis is a negative prognostic factor. The lower efficacy of immunotherapy treatments in BoM+ patients could be induced by the presence of a particular immunosuppressive tumor and bone microenvironment. This article reviews the most important pre-clinical and clinical scientific evidence on the reasons for this lower sensitivity to immunotherapy and the need to combine bone target therapies (BTT) with immunotherapy to improve patient outcome.

Serum and tissue markers in hepatocellular carcinoma and cholangiocarcinoma: clinical and prognostic implications

According to current guidelines, endocrine therapy (ET) is recommended as first-line treatment of luminal-like metastatic breast cancer (MBC), whereas chemotherapy (CT) should be considered in presence of life-threatening disease. In daily practice, CT is often used outside of this clinical circumstance. Factors influencing first-line choice and the relative impact on outcome are unknown. A consecutive series of luminal-like HER2-negative MBC patients treated from 2004 to 2014 was analyzed to test the association of disease- and patient-related factors with the choice of first-line treatment (ET vs. CT). A propensity score method was used to estimate impact of first-line strategy on outcome. Of 604 consecutive luminal-like MBC patients identified, 158 cases were excluded due to unknown or positive HER2-status. Among 446 HER2-negative cases, 171 (38%) received first-line CT. On multivariate analysis, the only factors significantly associated with lower CT use were old age (OR 0.25, 95%C.I. 0.13-0.49) or presence of bone metastases only (OR 0.26, 95%C.I. 0.13-0.53). In propensity score matched population, no differences were observed between CT and ET as first-line treatment either in terms of overall survival (37.5 months and 33.4 months respectively, log-rank test, P = 0.62) or progression-free survival (13.3 months and 9.9 months respectively, log-rank test, P = 0.92). High percentage of patients with luminal-like MBC received CT as first-line therapy in real-life. The choice was mainly driven by age and site of metastases. With the limitations of a non-randomized comparison, no differences on patients' outcome were observed depending on the first-line strategy.

Osimertinib is currently the preferred first-line therapy in patients with non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutation and the standard second-line therapy in T790M-positive patients in progression to previous EGFR tyrosine kinase inhibitor. Osimertinib is a highly effective treatment that shows a high response rate and long-lasting disease control. However, a resistance to the treatment inevitably develops among patients. Understanding the secondary mechanisms of resistance and the possible therapeutic options available is crucial to define the best management of patients in progression to osimertinib. We provide a comprehensive review of the emerging molecular resistance mechanism in EGFR-mutated NSCLC pre-treated with osimertinib and its future treatment applications.

Tissue biopsy is essential for NSCLC diagnosis and treatment management. Over the past decades, liquid biopsy has proven to be a powerful tool in clinical oncology, isolating tumor-derived entities from the blood. Liquid biopsy permits several advantages over tissue biopsy: it is non-invasive, and it should provide a better view of tumor heterogeneity, gene alterations, and clonal evolution. Consequentially, liquid biopsy has gained attention as a cancer biomarker tool, with growing clinical applications in NSCLC. In the era of precision medicine based on molecular typing, non-invasive genotyping methods became increasingly important due to the great number of oncogene drivers and the small tissue specimen often available. In our work, we comprehensively reviewed established and emerging applications of liquid biopsy in NSCLC. We made an excursus on laboratory analysis methods and the applications of liquid biopsy either in early or metastatic NSCLC disease settings. We deeply reviewed current data and future perspectives regarding screening, minimal residual disease, micrometastasis detection, and their implication in adjuvant and neoadjuvant therapy management. Moreover, we reviewed liquid biopsy diagnostic utility in the absence of tissue biopsy and its role in monitoring treatment response and emerging resistance in metastatic NSCLC treated with target therapy and immuno-therapy.