Abstract: Non-small cell lung cancer (NSCLC) constitutes 85% of lung cancer cases and represents a leading cause of cancer-related mortality globally. This significant prevalence underscores the importance of understanding the diverse molecular alterations associated with NSCLC. Gene fusions represent a specific type of molecular alteration resulting from chromosomal rearrangements or splicing errors during transcription. While anaplastic lymphoma kinase (ALK) rearrangements have been extensively studied, the post-progression management of patients with other gene fusions, such as ROS proto-oncogene 1 (ROS1), rearranged during transfection proto-oncogene (RET), or neurotrophic tyrosine receptor kinase (NTRK) remains an active research area. Resistance and subsequent disease progression necessitate thoroughly examining potential resistance mechanisms to develop targeted therapeutic interventions. Resistance to treatments targeting ROS1, RET, or NTRK fusions can arise from intrinsic and extrinsic alterations to these genes. In response to these different resistance mechanisms, specific therapies are being studied, such as the combination of tyrosine kinase inhibitors (TKIs) or novel molecular-targeted therapies. This review aims to evaluate the current understanding of genetic and non-genetic resistance mechanisms to TKIs in NSCLC with non-ALK gene fusions. Additionally, we highlight recently identified gene fusions and discuss their potential implications for future clinical practice, emphasizing the need for ongoing research to improve patient outcomes in this challenging and dynamic field of oncology.

Background and Objective: Neuregulin 1 (NRG1) is a small ligand of the tyrosine kinase receptors (TKRs) that was recently described as a new molecular trait of non-small cell lung cancer (NSCLC). NRG1 gene rearrangements mainly occur in the rare NSCLC subtype of lung invasive mucinous adenocarcinomas (IMAs), but are also reported with low frequency in non-IMA NSCLC and many other solid tumors. The NRG1 oncogenic fusions enhance the ectopic expression of the NRG1/ErbB3 receptor-ligand complex, thus inducing the activation of PIK3CA-AKT/MAPK pathways. The most recent scientific advances highlight the potential use of the NRG1 fusions as agnostic biomarkers and add support to the key role of NRG1/ErbB3 axis deregulation in NSCLC cancer onset and evolution. The aim of this narrative review was to give a concise overview of the current knowledge on the biology and the predictive/prognostic role of the NRG1 fusions, as well as to summarize and update the available detection methods and pharmacological approaches related to their role as prognostic and predictive marker in NSCLC.

: In the past decades, the technical achievements in radiotherapy treatment planning and delivery, such as the use of intensity-modulated radiotherapy or the use of image-guided radiotherapy, alongside with the significant developments in molecular imaging and especially the use of positron-emission tomography (PET) have significantly improved radiotherapy treatment precision. In non-small cell lung cancer (NSCLC), the use of 18F-fluoro-desoxy-glucose (18F-FDG) positron-emission tomography/computed tomography (18F-FDG-PET/CT) has a high accuracy for diagnostic workup, staging and response assessment but has been also implemented to optimize target volume concepts in NSCLC with high precision. These advances led, in the recent years, to an increased tumor control and improved outcomes. Especially in the context of emerging systemic treatments, such as immune checkpoint blockades (ICBs), the prevention of unnecessary irradiation of the lymphatic system might be very important. In the past years, several prospective randomized studies have been performed, aiming to optimize, standardize and develop new concepts in the target volume delineation especially in locally advanced NSCLC using different approaches. While the PET-Plan trial used a uniform target volume reduction based on the 18F-FDG-PET/CT signal in the experimental arm, the PET boost trial and the RTOG 1106 used the 18F-FDG-PET/CT information to define an additional boost volume for dose escalation. Within this mini-review, we provide an overview on the role of 18F-FDG-PET/CT, the challenges and the benefits, in radiotherapy of NSCLC.

Abstract: Radiation therapy (RT) is an essential treatment modality for cancer care and cure. Over the years, radiation treatments have become more complex and more computerized leading to highly precise treatment approaches maximising loco-regional control while minimizing toxicity. Safe and effective radiotherapy delivery however requires the implementation of adapted quality assurance (QA) programs and integral quality management (QM) systems, favouring continuous quality improvement. These improvements can arise within the local or departmental context, but they can also be favoured by national programs and incentives. The Belgian College of Physicians for Radiation Oncology Centres (‘the College’) is a federal entity—composed mainly of radiation oncologists, medical physicists, radiation therapists and quality managers—whose mission is to improve the quality of radiotherapy by organizing peer review activities. Throughout the past decades, the College has been the source of numerous national initiatives, which have fostered and accompanied radiotherapy departments in taking the steps towards increased quality of care. With this review, we aim to share these national quality-oriented projects instigated by the College. These include the introduction of peer-reviewed target volume contouring programs, the organisation of clinical audits and external beam dosimetry audits as well as the implementation of a national adverse event analysis system and the collection and analysis of RT-specific quality indicators.

The importance of standardized treatment planning and decision-making in radiation oncology for non-small-cell lung cancer—are current guidelines sufficiently strict for uniform target delineation?—a narrative literature review

Background: The discovery of BRAF mutations occurrence in non-small cell lung cancer (NSCLC) is enriching the knowledge of molecular biology of oncogene addicted disease. Their overall prevalence amounts until 3–5%, being the V600E the most frequent, and accounting for 1–2% of cases. The combination of Dabrafenib and Trametinib guarantees clinical responses in first and second line setting for V600E positive NSCLC and it offers a therapeutic opportunity for BRAF positive disease that is usually insensitive to platinum-based chemotherapy. Conversely, data regarding non-V600E mutations are limited. They represent a heterogeneous subgroup, and the mutational specificity correlates with sensitivity to BRAF inhibition. Case Description: We report the case of a patient treated at our center in third line setting for a metastatic chemotherapy resistant BRAF non-V600E NSCLC with the oral tyrosine kinase inhibitors (TKIs) Dabrafenib and Trametinib. The patient did not experience any benefit, and we hypothesize that BRAF G466R did not represent a therapeutic target. The biological implications of non-V600E BRAF mutations in the field of NSCLC are not fully described: BRAF promotes cell proliferations in some cases, and it does not in others. There is some evidence that a subset of BRAF mutations is not driver of cancer cells growth, and their inhibition does not exert antitumoral effect. The literature reports clinical outcomes of patients receiving oral TKIs for “uncommon” oncogene mutations, especially epidermal growth factor receptor (EGFR). Conversely, the investigation of the TKIs efficacy for V600E and non-V600E BRAF disease is limited by the rarity and the heterogeneity of BRAF mutations. Recent studies recently provided some robust evidence supporting the treatment with Dabrafenib and Trametinib for V600E positive cancer, but their effectiveness for non-V600E mutations is far from being examined. Conclusions: The present case report suggests that the clinicians should first analyze the biological significance of specific BRAF mutations before considering the combination TKI strategy for NSCLC treatment.

Background and Objective: The objectives are to identify potential differences in outcomes between males and females patients with oncogene-addicted non-small-cell lung cancer (NSCLC) treated with targeted agents. The discovery of driver oncogene alterations and the identification of their targeted inhibitors have dramatically improved the outcomes of patients with oncogene-addicted advanced NSCLC and the use of this class of drugs, in clinical practice, became the gold standard. Although gender is considered an independent prognostic factor and several studies showed some differences in terms of activation of metabolic pathways between sex, few data are available regarding potential differences in outcomes between males and females patients with oncogene-addicted NSCLC treated with targeted agents. Methods: Available data regarding potential differences in outcomes between males and females affected by oncogene-addicted NSCLC and treated with targeted agents are reported. The study was limited to published manuscripts in the English language using extended literature data collection starting from 2009 and was focused on phase 3 trials. Key Content and Findings: In most of the trials carried out in patients with oncogene-addicted NSCLC, women reported a better progression-free-survival than men. Conclusions: The existence of a targetable driver alteration is significantly more frequent in women than in men. The majority of trials evaluating activity and efficacy of target agents demonstrated that both men and women with addicted-NSCLC benefited from the use of these treatments, whatever the treatment line. Most of the trials reported a hazard ratio (HR) for progression-free survival (PFS) consistently in favour of female patients over male. Unfortunately, a few studies used sex as a stratification factor, although this might impact the final results. Prospective studies are warranted to draw definitive conclusions about this topic.

: Financial toxicity is a well-documented side effect of cancer treatment, and can be a lifelong burden for childhood cancer survivors (CCS). CCS have difficulty maintaining adequate health insurance and this results in decreased healthcare visits, reduced survivor-focused healthcare, and missed outpatient clinic appointments. For CCS transitioning into adult care, understanding health insurance—how to get it, keep it, and use it—is a key aspect of combatting financial toxicity and of maintaining ongoing survivorship care. Thus, there is a clear role for longitudinal education on health insurance for CCS. In the Childhood Cancer Survivor Program at the University of Minnesota, health insurance education and counseling delivered by social workers has been incorporated as a regular part of routine survivorship care visits. In this commentary we provide a rationale for why health insurance education is crucial for CCS, describe our existing program for delivering this education, and make recommendations for future programs and directions in the current healthcare landscape. We believe our experience incorporating insurance education into clinical care is unique, and in sharing it, we hope to raise awareness of the need for health insurance education as part of cancer survivorship care and also to springboard future research and collaborative efforts in this realm.