The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated the success story of targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy in patients with NSCLC with sensitizing EGFR mutations, as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs, and as adjuvant therapy for patients with early stage resected NSCLC, harboring EGFR mutations. Despite durable responses in patients with advanced NSCLC, resistance to osimertinib, similar to other targeted therapies, inevitably develops. Understanding the mechanisms of resistance, including both EGFR-dependent and -independent molecular pathways, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Interestingly, differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting, indicating the importance of selection pressure and clonal evolution of tumor cells. Standard therapeutic approaches after progression to osimertinib include other targeted therapies, when a targetable genetic alteration is detected, and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Deciphering the when and how to use immunotherapeutic agents in EGFR-positive NSCLC is a current challenge in clinical lung cancer research. Emerging treatment options after progression to osimertinib involve combinations of different therapeutic approaches and novel EGFR-TKI inhibitors. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib.

Immune checkpoint inhibitors are novel agents that have been proved efficacious in a variety of cancer types, but they are associated with a unique set of organ-specific, immune-related adverse events. Among them, immune-related pneumonitis requires special attention because it is difficult to diagnose and potentially lethal. Accumulating real-world epidemiological data suggest that immune-related pneumonitis is more frequent than previously reported. Its diagnosis requires exclusion of other causes and assessment of radiographic features on high-resolution CT of the chest. Management of immune-related pneumonitis is based on the use of immunosuppressants. Future research should be focused on finding predictive biomarkers for immune-related pneumonitis as well as optimizing its management.

Tumor dormancy refers to a critical stage of cancer development when tumor cells are present, but cancer does not progress. It includes both the concept of cellular dormancy, indicating the reversible switch of a cancer cell to a quiescent state, and that of tumor mass dormancy, indicating the presence of neoplastic masses that have reached cell population equilibrium via balanced growth/apoptosis rates. Tumor dormancy provides the conceptual framework, potentially explaining a major challenge in clinical oncology, tumor recurrence, which may occur years after cancer diagnosis. The mechanisms by which tumors are kept dormant, and what triggers their reawakening, are fundamental questions in cancer biology. It seems that a plethora of intracellular pathways and extracellular factors are involved in this process, rewiring the cells to plastically alter their metabolic and proliferative status. This phenomenon is highly dynamic in space and time. Mechanistic insights into both cellular and tumor dormancy have provided the rationale for targeting this otherwise stable period of cancer development, in order to prevent recurrence and maximize therapeutic benefit.

The expression of estrogen receptors (ERs) in breast cancer (BC) represents a strong prognostic and predictive biomarker and directs therapeutic decisions in early and advanced stages. ER-low-positive BC, defined by the immunohistochemical (IHC) expression of ERs from 1% to 9%, constitutes a distinct subset of total BC cases. Guidelines recommend that a low expression of ERs be reported in pathology reports since the benefit of endocrine therapy in patients with ER-low-positive BC is uncertain. Recently, several cohorts, mostly of a retrospective nature, have been published, reporting the clinicopathological characteristics and outcomes of ER-low-positive BC. However, the majority of the data focus on early-stage BC and the use of (neo)adjuvant therapy, and there is a significant lack of data regarding metastatic ER-low-positive BC. Further factors, including tumor heterogeneity as well as the potential loss of ER expression due to endocrine resistance, should be considered. Including patients with ER-low-positive BC in clinical trials for triple-negative breast cancer (TNBC) might improve the understanding of this entity and allow novel therapeutic approaches. The design and conduction of randomized clinical trials regarding this subgroup of patients are greatly anticipated.