Quantitative Measurement of HER2 Expression in Non-Small Cell Lung Cancer With a High-Sensitivity Assay.

Recently, low human epidermal growth factor receptor 2 (HER2) protein expression has been proposed as a predictive biomarker for response to the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in metastatic breast cancer. HER2 expression in non-small cell lung cancer (NSCLC) patients has never been carefully measured, and little is known about the frequency of cases with unamplified but detectable levels of the protein. Although some HER2-targeted therapies have been studied in NSCLC patients, they have been restricted to those with genomic ERBB2 gene alterations, which only represent relatively rare cases of NSCLC. Still, emerging investigations of T-DXd in NSCLC have shown promise in patients with unamplified HER2. Taken together, we hypothesize that there may be many cases of NSCLC with levels of HER2 protein expression comparable with levels seen in breast cancer that benefit from T-DXd. Here, we used a previously validated, analytic, quantitative immunofluorescence (QIF) assay that is more sensitive than legacy clinical HER2 immunohistochemistry assays. We measured HER2 protein levels in NSCLC cases to determine the proportion of cases with detectable HER2 expression. Using cell line calibration microarrays alongside our QIF method enabled us to convert HER2 signal into units of attomoles per mm2. We found that over 63% of the 741 analyzed NSCLC cases exhibited HER2 expression above the limit of detection, with more than 17% of them exceeding the lower limit of quantification. Although the threshold for response to T-DXd in breast cancer is still unknown, many cases of NSCLC have expression in a range comparable to breast cancer cases with immunohistochemistry scores of 1+ or 2+. Our assay could potentially select NSCLC cases with a detectable target (ie, HER2) that might benefit from HER2 antibody-drug conjugates, irrespective of ERBB2 genomic alterations.

The safety and potential efficacy of exosomes overexpressing CD24 (EXO-CD24) in mild-moderate COVID-19 related ARDS.

INTRODUCTION: EXO-CD24 are exosomes genetically manipulated to over-express Cluster of Differentiation (CD) 24. It consists of two breakthrough technologies: CD24, the drug, as a novel immunomodulator that is smarter than steroids without any side effects, and exosomes as the ideal natural drug carrier. METHODS: A randomized, single blind, dose-finding phase IIb trial in hospitalized patients with mild to moderate Coronavirus disease 2019 (COVID-19) related Acute Respiratory Distress Syndrome (ARDS) was carried out in two medical centers in Athens. Patients received either 109 or 1010 exosome particles of EXO-CD24, daily, for five consecutive days and monitored for 28 days. Efficacy was assessed at day 7 among 91 patients who underwent randomization. The outcome was also compared in a post-hoc analysis with an income control group (n = 202) that fit the inclusion and exclusion criteria. RESULTS: The mean age was 49.4 (± 13.2) years and 74.4% were male. By day 7, 83.7% showed improved respiratory signs and 64% had better oxygen saturation (SpO2) (p < 0.05). There were significant reductions in all inflammatory markers, most notably in C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, fibrinogen and an array of cytokines. Conversely, levels of the anti-inflammatory cytokine Interleukin-10 (IL-10) were increased (p < 0.05). Of all the documented adverse events, none were considered treatment related. No drug-drug interactions were noted. Two patients succumbed to COVID-19. Post-hoc analysis revealed that EXO-CD24 patients exhibited greater improvements in clinical and laboratory outcomes compared to an observational income control group. CONCLUSIONS: EXO-CD24 presents a promising therapeutic approach for hyper-inflammatory state and in particular ARDS. Its unique combination of exosomes, as a drug carrier, and CD24, as an immunomodulator, coupled with inhalation administration, warrants further investigation in a larger, international, randomized, quadri-blind trial against a placebo.

Neoadjuvant Capecitabine Plus Temozolomide in Atypical Lung NETs.

Neoadjuvant and adjuvant treatment in lung neuroendocrine tumors (NETs) is a field that has not been explored in-depth, with little information on the impact on disease-free survival. This case study highlights the effectiveness of neoadjuvant treatment with capecitabine plus temozolomide (CAPTEM) in a woman with well-differentiated atypical carcinoid. The patient was asymptomatic at diagnosis and was referred to the outpatient NET clinic at Sotiria Hospital in Athens, following an incidental finding on a chest x-ray. 18F-fluorodeoxyglucose (FDG) PET/CT and 68Ga-Dotatoc PET/CT revealed another mass in the pancreas, with avidity in both imaging studies. The patient underwent treatment for 6 months with CAPTEM with a response in the lung NET and mediastinal lymph nodes. However, the mass in the pancreas slightly increased and was removed with a central pancreatectomy. The patient continued treatment with CAPTEM for 6 more months. There was further response according to RECIST 1.1 criteria (partial response in the mediastinal lymph nodes and a 21% regression in the primary tumor size). Pathology report after lobectomy with lymph node dissection showed a pathologic complete response in the mediastinal lymph nodes. Twenty-four months after surgery, the patient remains disease-free and has a good quality of life. Although large clinical trials are needed, this case study underlines the value of preoperative chemotherapy in atypical carcinoids.

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes.

The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer.

Kirsten rat sarcoma virus (KRAS) is the most frequently found oncogene in human cancers, including non-small-cell lung cancer (NSCLC). For many years, KRAS was considered "undruggable" due to its structure and difficult targeting. However, the discovery of the switch II region in the KRAS-G12C-mutated protein has changed the therapeutic landscape with the design and development of novel direct KRAS-G12C inhibitors. Sotorasib and adagrasib are FDA-approved targeted agents for pre-treated patients with KRAS-G12C-mutated NSCLC. Despite promising results, the efficacy of these novel inhibitors is limited by mechanisms of resistance. Ongoing studies are evaluating combination strategies for overcoming resistance. In this review, we summarize the biology of the KRAS protein and the characteristics of KRAS mutations. We then present current and emerging therapeutic approaches for targeting KRAS mutation subtypes intending to provide individualized treatment for lung cancer harboring this challenging driver mutation.

The Gap of Health Inequalities Amongst Lung Cancer Patients of Different Socioeconomic Status: A Brief Reference to the Greek Reality.

Lung cancer treatment and patient care are constantly improving, but it remains doubtful whether this applies equally to all socioeconomic groups. It is nowadays well established that there are socioeconomic inequalities regarding lung cancer incidence, screening, effective treatment, overall survival, and prognosis. One of the key contributing factors to low socioeconomic status is low education. Low educational level is correlated with several factors, such as smoking habits, bad lifestyle behaviors, lower paid and unhealthier occupations, polluted neighborhoods, and genetic-familial risk, that lead to increased lung cancer incidence. The disparities regarding lung cancer care are further enhanced by stigma. On this basis and inspired by the gap in health equality among the Greek population, the Greek Society of Lung Cancer initiated a campaign, "MIND THE GAP", to help increase awareness and minimize the gap associated with lung cancer, both in Greece and across Europe. The aim of this review is to explore the gap of health inequalities regarding lung cancer incidence and prognosis between patients of different SES and its root of causality. Key pivotal actions towards bridging this gap are reviewed as well.

Triple-Negative Breast Cancer and Emerging Therapeutic Strategies: ATR and CHK1/2 as Promising Targets.

Worldwide, breast cancer is the most frequently diagnosed malignancy in women, with triple-negative breast cancer (TNBC) being the most aggressive molecular subtype. Due to the dearth of effective therapeutic options for TNBC, novel agents targeting key mechanisms and pathways in cancer cells are continuously explored; these include ATR inhibitors, which target the ATR kinase involved in the DNA damage response (DDR) pathway, and CHK1/2 inhibitors, which target the Checkpoint Kinase 1/2 (CHK1/2) involved in cell cycle arrest and DNA repair. ATR and CHK1/2 inhibitors show potential as prospective treatments for TNBC by focusing on the DDR and interfering with cell cycle regulation in cancer cells. Preliminary preclinical and clinical findings suggest that when combined with chemotherapy, ATR and CHK1/2 inhibitors demonstrate significant anti-proliferative efficacy against TNBC. In this article, we introduce ATR and CHK1/2 inhibitors as promising therapeutic approaches for the management of TNBC. Preclinical and clinical studies performed evaluating ATR and CHK1/2 inhibitors for the treatment of TNBC and associated challenges encountered in this context to date are reviewed.

Robotic Bronchoscopy in Lung Cancer Diagnosis.

BACKGROUND: The widespread use of chest CT has increased the number of detected pulmonary nodules. Nodules with intermediate risk of malignancy warrant further evaluation with PET-CT or sampling. Although sampling with conventional bronchoscopy presents lower complication rates compared to transthoracic needle biopsy (TTNB), it is limited by the inability to reach distal airways. To overcome this shortcoming, a new bronchoscopic technique named robotic bronchoscopy (RB) has emerged. METHODS: A literature review was used to clarify the rationale behind RB emergence, describe RB procedure, and summarize data regarding its efficacy and safety. RESULTS: The FDA has approved three RB platforms for clinical use. RB is safe, presenting a mortality and complication rate of 0% and 0-8.1%, respectively. Common complications include pneumothorax (0-5.7%) and minor bleeding (0-3.2%). However, its diagnostic yield remains lower than that of TTNB. CONCLUSIONS: RB is a promising bronchoscopic technique that aims to overcome the limitations of conventional bronchoscopy and improve upon the current techniques of guided bronchoscopy for the investigation of pulmonary nodules. Despite the lower complication rate, current evidence suggests a lower diagnostic yield compared to TTNB. Additional studies are required to adequately evaluate the role of RB in the diagnosis of pulmonary nodules.

Molecular Diagnostics and Treatment Patterns in Metastatic Non-small Cell Lung Cancer Patients: Real World Evidence from Greece: LACHESIS Study.

BACKGROUND/AIM: Lung cancer, primarily non-small cell lung cancer (NSCLC), is the leading cause of cancer deaths globally. In Greece in 2020, 8,960 new cases were reported. NSCLC's 5-year survival rates range from 54% (stage I) to less than 2% (stage IV); however, innovative therapies like immune check points inhibitors (ICIs) and targeted treatments have notably enhanced outcomes. The aim of this study was to assess the 1st and 2nd line treatment patterns with the introduction of new treatment modalities. Additionally, we evaluated biomarker testing approaches in NSCLC. PATIENTS AND METHODS: LACHESIS was a retrospective multinational study, collecting and analyzing data from adult patients from Russia, Bulgaria, and Greece with metastatic NSCLC either newly diagnosed or relapsed from earlier stages, who had the option to undergo biomarker testing (genetic alterations/programmed death-ligand 1 protein expression levels, PD-L1), and who received 1st line treatment for squamous (SQ) or non-squamous (N-SQ) NSCLC. Subsequent lines of therapy were also reported. RESULTS: The Greek site registered retrospective data from 250 NSCLC patients, of whom 206 were newly diagnosed (ND) metastatic NSCLC patients and 44 were patients relapsed from earlier stages. Seventy-two had SQ NSCLC and 169 had N-SQ NSCLC. For these patients, treatment patterns including immunotherapy±chemotherapy combinations were recorded. Biomarker testing patterns, including genetic alterations and PD-L1 expression levels were also documented. CONCLUSION: LACHESIS provides treatment patterns and biomarker testing data. Greek patients were treated according to international guidelines, with immunotherapy as a viable option, particularly for PD-L1 levels over 50%. Biomarker testing, crucial for non-squamous (N-SQ) cases, should yield timely results for driver mutations, prioritizing patient benefits.

Biological and therapeutic implications of the cancer-related germline mutation landscape in lung cancer.

Although smoking is the primary cause of lung cancer, only about 15% of lifelong smokers develop the disease. Moreover, a substantial proportion of lung cancer cases occur in never-smokers, highlighting the potential role of inherited genetic factors in the cause of lung cancer. Lung cancer is significantly more common among those with a positive family history, especially for early-onset disease. Therefore, the presence of pathogenic germline variants might act synergistically with environmental factors. The incorporation of next-generation sequencing in routine clinical practice has led to the identification of cancer-predisposing mutations in an increasing proportion of patients with lung cancer. This Review summarises the landscape of germline susceptibility in lung cancer and highlights the importance of germline testing in patients diagnosed with the disease, which has the potential to identify individuals at risk, with implications for tailored therapeutic approaches and successful prevention through genetic counselling and screening.

Endocrine Immune-Related Adverse Events Are Independent Predictors of Survival in Patients with Lung Cancer.

Lung cancer (LC) is a serious health problem worldwide. Survival outcomes have improved over time due to the widespread use of novel therapeutic agents, including immune checkpoint inhibitors (ICIs). Endocrine immune-related adverse events (e-irAEs) are common in LC patients treated with ICIs. We performed a retrospective study of patients with LC who received treatment with ICIs at a tertiary referral center between January 2014 and October 2023. In total, 983 LC patients were included in the study. E-irAEs presented at a median time of 4.1 months and included hypothyroidism (15.6%), hyperthyroidism (4.3%), adrenal insufficiency (0.4%), hypophysitis (0.4%), and diabetes mellitus (0.2%). These toxicities were not related to the duration of treatment or the type of ICIs. Most (97.6%) e-irAEs were mild (grade 1-2). Median overall survival (OS) was higher in LC patients who experienced e-irAEs (31.6 months) compared to those who did not (10.8 months). The difference remained statistically significant in the 3-month (HR: 0.42) and 6-month landmark analysis (HR: 0.51). The OS advantage was observed in both patients with NSCLC (HR: 0.36) and SCLC (HR: 0.27). Additional research is needed to validate the role of e-irAEs as an independent predictor of survival outcomes in patients with LC.

Lung Cancer Related Thrombosis (LCART): Focus on Immune Checkpoint Blockade.

Cancer-associated thrombosis (CAT) is a common complication in lung cancer patients. Lung cancer confers an increased risk of thrombosis compared to other solid malignancies across all stages of the disease. Newer treatment agents, including checkpoint immunotherapy and targeted agents, may further increase the risk of CAT. Different risk-assessment models, such as the Khorana Risk Score, and newer approaches that incorporate genetic risk factors have been used in lung cancer patients to evaluate the risk of thrombosis. The management of CAT is based on the results of large prospective trials, which show similar benefits to low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in ambulatory patients. The anticoagulation agent and duration of therapy should be personalized according to lung cancer stage and histology, the presence of driver mutations and use of antineoplastic therapy, including recent curative lung surgery, chemotherapy or immunotherapy. Treatment options should be evaluated in the context of the COVID-19 pandemic, which has been shown to impact the thrombotic risk in cancer patients. This review focuses on the epidemiology, pathophysiology, risk factors, novel predictive scores and management of CAT in patients with active lung cancer, with a focus on immune checkpoint inhibitors.

Lung Cancer Proteogenomics: Shaping the Future of Clinical Investigation.

BACKGROUND: Lung cancer is associated with a high incidence of mortality worldwide. Molecular mechanisms governing the disease have been explored by genomic studies; however, several aspects remain elusive. The integration of genomic profiling with in-depth proteomic profiling has introduced a new dimension to lung cancer research, termed proteogenomics. The aim of this review article was to investigate proteogenomic approaches in lung cancer, focusing on how elucidation of proteogenomic features can evoke tangible clinical outcomes. METHODS: A strict methodological approach was adopted for study selection and key article features included molecular attributes, tumor biomarkers, and major hallmarks involved in oncogenesis. RESULTS: As a consensus, in all studies it becomes evident that proteogenomics is anticipated to fill significant knowledge gaps and assist in the discovery of novel treatment options. Genomic profiling unravels patient driver mutations, and exploration of downstream effects uncovers great variability in transcript and protein correlation. Also, emphasis is placed on defining proteogenomic traits of tumors of major histological classes, generating a diverse portrait of predictive markers and druggable targets. CONCLUSIONS: An up-to-date synthesis of landmark lung cancer proteogenomic studies is herein provided, underpinning the importance of proteogenomics in the landscape of personalized medicine for combating lung cancer.

Utilizing nullomers in cell-free RNA for early cancer detection.

Early detection of cancer can significantly improve patient outcomes; however, sensitive and highly specific biomarkers for cancer detection are currently missing. Nullomers are the shortest sequences that are absent from the human genome but can emerge due to somatic mutations in cancer. We examine over 10,000 whole exome sequencing matched tumor-normal samples to characterize nullomer emergence across exonic regions of the genome. We also identify nullomer emerging mutational hotspots within tumor genes. Finally, we provide evidence for the identification of nullomers in cell-free RNA from peripheral blood samples, enabling detection of multiple tumor types. We show multiple tumor classification models with an AUC greater than 0.9, including a hepatocellular carcinoma classifier with an AUC greater than 0.99.