Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.

An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis.

Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.

Modulation of chemoimmunotherapy efficacy in non-small cell lung cancer by sex and histology: a real-world, patient-level analysis.

BACKGROUND: It has been postulated that patient's sex impacts response to immunotherapy. Sex modulation of immunotherapy benefit, however, has not yet been explored using patient-level data, where potential confounders, as well as histologic type, can be accounted for. Here we investigated the association between sex and chemoimmunotherapy efficacy for non-small cell lung cancer (NSCLC) using a large, nation-wide dataset. PATIENTS & METHODS: Stage IV NSCLC patients diagnosed in 2015 were identified in the National Cancer Database (NCDB). Patients were treated with either chemoimmunotherapy or chemotherapy alone. The efficacy of the addition of immunotherapy treatment by sex was investigated using both an adjusted Cox proportional hazards model and propensity-score matching, in both the overall cohort and stratified by histological subtype. RESULTS: 2064 (16%) patients received chemoimmunotherapy and10,733 (84%) received chemotherapy alone. Adjusted survival analysis in the overall cohort showed that both males (hazards ratio (HR)adj: 0.80, 95% CI: 0.74-0.87) and females (HRadj: 0.83, 95% CI: 0.76-0.90) had better OS when treated with chemoimmunotherapy than chemotherapy alone, with no statistically significant interaction between sex and receipt of immunotherapy (p = 0.63). Propensity matching confirmed these results. However, for those with squamous cell histology, male patients derived more benefit from chemoimmunotherapy treatment than females (HRadj: 0.73, 95% CI: 0.58-0.91 vs HRadj: 1.03, 95% CI: 0.76-1.38; p for interaction = 0.07). CONCLUSION: Male patients with squamous cell carcinoma may derive more benefit from chemoimmunotherapy treatment. Histology likely plays an important role in how sex modulates immunotherapy efficacy.

Analysis of Real-World Data to Investigate the Impact of Race and Ethnicity on Response to Programmed Cell Death-1 and Programmed Cell Death-Ligand 1 Inhibitors in Advanced Non-Small Cell Lung Cancers.

BACKGROUND: Racial disparities among clinical trial participants present a challenge to assess whether trial results can be generalized into patients representing diverse races and ethnicities. The objective of this study was to evaluate the impact of race and ethnicity on treatment response in patients with advanced non-small cell lung cancer (aNSCLC) treated with programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) inhibitors through analysis of real-world data (RWD). MATERIALS AND METHODS: A retrospective cohort study of 11,138 patients with lung cancer treated at hospitals within the Mount Sinai Health System was performed. Patients with confirmed aNSCLC who received anti-PD-1/PD-L1 treatment were analyzed for clinical outcomes. Our cohort included 249 patients with aNSCLC who began nivolumab, pembrolizumab, or atezolizumab treatment between November 2014 and December 2018. Time-to-treatment discontinuation (TTD) and overall survival (OS) were the analyzed clinical endpoints. RESULTS: After a median follow-up of 14.8 months, median TTD was 7.8 months (95% confidence interval, 5.4-not estimable [NE]) in 75 African American patients versus 4.6 (2.4-7.2) in 110 White patients (hazard ratio [HR], 0.63). Median OS was not reached (18.4-NE) in African American patients versus 11.6 months (9.7-NE) in White patients (HR, 0.58). Multivariable Cox regression conducted with potential confounders confirmed longer TTD (adjusted HR, 0.65) and OS (adjusted HR, 0.60) in African American versus White patients. Similar real-world response rate (42.6% vs. 43.5%) and disease control rate (59.6% vs. 56.5%) were observed in the African American and White patient populations. Further investigation revealed the African American patient group had lower incidence (14.7%) of putative hyperprogressive diseases (HPD) upon anti-PD-1/PD-L1 treatment than the White patient group (24.5%). CONCLUSION: Analysis of RWD showed longer TTD and OS in African American patients with aNSCLC treated with anti-PD-1/PD-L1 inhibitors. Lower incidence of putative HPD is a possible reason for the favorable outcomes in this patient population. IMPLICATIONS FOR PRACTICE: There is a significant underrepresentation of minority patients in randomized clinical trials, and this study demonstrates that real-world data can be used to investigate the impact of race and ethnicity on treatment response. In retrospective analysis of patients with advanced non-small cell lung cancer treated with programmed cell death-1 or programmed cell death-ligand 1 inhibitors, African American patients had significantly longer time-to-treatment discontinuation and longer overall survival. Analysis of real-world data can yield clinical insights and establish a more complete picture of medical interventions in routine clinical practice.

Chemotherapy in elderly patients with nonsmall cell lung cancer.

PURPOSE OF REVIEW: Using chemotherapy in elderly nonsmall cell lung cancer (NSCLC) patients is often challenging given concerns of treatment-related toxicity. However, data have demonstrated that chemotherapy can lead to improved survival in this age group. In this review, we summarize existing data and discuss the role of chemotherapy in elderly patients with localized, locally advanced, and metastatic NSCLC. RECENT FINDINGS: Clear evidence-based guidelines for chemotherapy management in elderly patients is lacking given the limited prospective data available. However, there are more clinical trials investigating optimal chemotherapy agents and dosing schedules specific to the elderly. Comprehensive geriatric assessment-directed interventions are also being prospectively investigated to improve treatment selection for elderly patients. SUMMARY: Chronological age should not be a limiting factor for chemotherapy use in elderly NSCLC patients. Several studies have demonstrated similar survival benefits than in younger patients when chemotherapy is given as adjuvant treatment for localized disease; part of definitive treatment with radiation in locally advanced disease; and palliative treatment for advanced NSCLC, however, at the cost of greater toxicity. Tolerability of chemotherapy in this heterogeneous group can be difficult to predict. Therefore, therapeutic decisions should be individualized based on performance status. Comprehensive geriatric assessment should be used to supplement performance status measures to minimize both under and overtreatment.

The global burden of lung cancer: current status and future trends.

Lung cancer is the leading cause of cancer-related death worldwide. However, lung cancer incidence and mortality rates differ substantially across the world, reflecting varying patterns of tobacco smoking, exposure to environmental risk factors and genetics. Tobacco smoking is the leading risk factor for lung cancer. Lung cancer incidence largely reflects trends in smoking patterns, which generally vary by sex and economic development. For this reason, tobacco control campaigns are a central part of global strategies designed to reduce lung cancer mortality. Environmental and occupational lung cancer risk factors, such as unprocessed biomass fuels, asbestos, arsenic and radon, can also contribute to lung cancer incidence in certain parts of the world. Over the past decade, large-cohort clinical studies have established that low-dose CT screening reduces lung cancer mortality, largely owing to increased diagnosis and treatment at earlier disease stages. These data have led to recommendations that individuals with a high risk of lung cancer undergo screening in several economically developed countries and increased implementation of screening worldwide. In this Review, we provide an overview of the global epidemiology of lung cancer. Lung cancer risk factors and global risk reduction efforts are also discussed. Finally, we summarize lung cancer screening policies and their implementation worldwide.

Outcomes Following SBRT vs. IMRT and 3DCRT for Older Patients with Stage IIA Node-Negative Non-Small Cell Lung Cancer > 5 cm.

BACKGROUND: To describe outcomes and compare the effectiveness of stereotactic body radiotherapy (SBRT) versus 3-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) in patients with stage IIA lymph node-negative (N0) non-small cell lung cancer (NSCLC) tumors > 5 cm. METHODS: We used the SEER-Medicare database (2005-2015) to identify patients > 65 years with stage IIA (AJCC TNM7) N0 NSCLC > 5 cm tumors who were treated with SBRT, IMRT, and 3DCRT. We used propensity score methods with inverse probability weighting to compare lung cancer-specific survival (LCSS), overall survival (OS), and toxicity. RESULTS: Of 584 patients, 88 (15%), 140 (24%), and 356 (61%) underwent SBRT, IMRT, and 3DCRT, respectively. The SBRT group was older (P = .004), had more comorbidities (P = .02), smaller tumors (P = .03), and more adenocarcinomas (P < .0001). We found a trend towards higher median unadjusted OS with SBRT compared to IMRT and 3DCRT (19 vs. 13 and 14 months, respectively, P = .37). In our propensity score-adjusted analyses, SBRT was significantly associated with better OS and LCSS compared to IMRT (HROS: 0.78, 95% CI: 0.68-0.89, HRLCSS: 0.70, 95% CI: 0.60-0.81) and 3DCRT (HROS: 0.81, 95% CI: 0.72-0.93, HRLCSS: 0.80, 95% CI: 0.68-0.93). SBRT-treated patients also had lower overall adjusted complication rates compared to IMRT (OR: 0.74, 95% CI: 0.55-0.99) and 3DCRT (OR: 0.53, 95% CI: 0.40-0.71). CONCLUSION: For patients with NSCLC tumors > 5 cm, SBRT trends towards fewer toxicities and improved survival compared to other forms of radiotherapy. Our findings support SBRT as an appropriate treatment strategy for older patients with larger inoperable NSCLC tumors.

The incorporation of cognitive-sparing techniques into prophylactic cranial irradiation in the management of small cell lung cancer.

The use of prophylactic cranial irradiation (PCI) remains an important component in the management of small cell lung cancer (SCLC). This is due to the high rates of subclinical brain metastases at the time of diagnosis. Following a response to initial treatment, PCI historically has been associated with improvements in overall survival and decreased development of brain metastases in patients with limited stage (LS-SCLC) and extensive stage (ES-SCLC) SCLC. However, PCI is commonly withheld in these settings in favor of observation, largely due to its association with cognitive sequelae following treatment. While randomized data has demonstrated that in patients with ES-SCLC, PCI may be withheld in favor of close MRI surveillance without a detriment in overall survival or cognitive functioning, these patients did not undergo formal neuropsychological assessments. In recent years, cognitive sparing techniques incorporated into whole brain radiation therapy and PCI, such as the addition of memantine and hippocampal avoidance, have demonstrated significant improvements in cognitive outcomes. As the overall survival in patients with SCLC continues to improve due to the incorporation of novel systemic therapies (e.g., immune checkpoint inhibitors), the role of PCI and maximizing quality of life remains a highly relevant topic. This article reviews the role of PCI and cognitive-sparing techniques in the management of SCLC.

Small cell lung cancer patients treated with immune checkpoint inhibitor: a systematic literature review of treatment efficacy, safety and quality of life.

BACKGROUND: This systematic literature review examines the current immune checkpoint inhibitors treatment paradigms, treatment gaps and unmet needs for treating SCLC with respect to efficacy, safety, health related quality of life (HRQoL) and cost-effectiveness. METHODS: A search strategy was developed and executed using the National Library of Medicine bibliographic database (PubMed), Cochrane Library, Embase and Google Scholar. Data regarding efficacy, safety, cost-effectiveness and HRQoL were extracted and entered in a data extraction sheet created a priori. RESULTS: A total of 4961 patients were comprised in all the 12 studies combined. All the studies focus on extensive stage SCLC (ES-SCLC) and not limited stage SCLC (LS-SCLC). All studies used an ICI as the intervention arm and chemotherapy as the control arm. A statistically significant increase in overall survival (OS) and progression free survival (PFS) was observed when ICIs were added to chemotherapy, especially atezolizumab and durvalumab. ICIs in SCLC resulted in immune-related toxicities that have been well-documented in prior immunotherapy trials; their addition to cytotoxic chemotherapy did not worsen chemotherapy-related toxicities. Out of 12 studies, only 3 (25%) included measures to assess the impact of immunotherapy on SCLC patients' HRQoL. Although domain level scores were limited, the addition of ICIs did not seem to worsen symptoms. Two studies conducted a cost-effectiveness analysis of the combination of atezolizumab plus chemotherapy vs. chemotherapy. The addition of atezolizumab to chemotherapy was not found to be cost-effective in either study. CONCLUSION: Combining ICIs with chemotherapy enhanced OS and PFS as well as not worsening HRQoL. Among all ICIs, PD-L1 inhibitors showed better effectiveness. Future studies should focus on real-world settings and more clinical trials using ICIs for not only ES-SCLC but also LS-SCLC.

Optimizing the use of adjuvant chemotherapy in non-small cell lung cancer patients with comorbidities.

Veterans with locoregional non-small cell lung cancer (NSCLC) may benefit from adjuvant chemotherapy. However, comorbidities and other factors may impact the harms and benefits of this treatment. Here, we identified the optimal indications for adjuvant chemotherapy in Veterans with NSCLC, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), and/or coronary artery disease (CAD). We used data from randomized controlled trials (RCTs) and Veterans Administration (VA) databases to enhance a simulation model. Then, we conducted in-silico RCTs comparing adjuvant chemotherapy vs observation among Veterans with stage II-IIIA NSCLC. Among Veterans without COPD or CKD, adjuvant chemotherapy was the optimal strategy regardless of the presence or absence of CAD except for patients >70 years with squamous cell carcinoma. Conversely, most veterans without COPD but with CKD were optimally managed with observation. Veterans with COPD but without CKD, benefited from adjuvant chemotherapy if they were ≤70 years with stage II-IIIA adenocarcinoma or <60 years with stage II-IIIA squamous cell carcinoma. Adjuvant chemotherapy was only beneficial for Veterans with both COPD and CKD among stage II-IIIA adenocarcinoma <60 years of age. Veterans with stages II-IIIA squamous cell carcinoma, COPD, and CKD were optimally managed with observation. Many Veterans with comorbidities are optimally managed with observation post-surgical resection. However, we also identified several groups of Veterans whom the benefits of adjuvant chemotherapy outweighed the risks of early toxicity. Our findings could inform patient-provider discussions and potentially reduce physicians' uncertainty about the role of adjuvant chemotherapy in this population.

Immunotherapy Outcomes in Individuals With Non-Small Cell Lung Cancer and Poor Performance Status.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) treated in real-world practice typically have worse performance status (PS) compared with clinical trial patients, and the effectiveness of immunotherapy in this population in unknown. In this study, we assessed the effectiveness of standard of care immunotherapy for the first-line treatment of stage IV patients with NSCLC with Eastern Cooperative Oncology Group (ECOG) PS greater than or equal to 2. METHODS: We selected ECOG PS greater than or equal to 2 patients from real-world oncology data from a deidentified database and included them if they were diagnosed with stage IV NSCLC and had documented Programmed death-ligand 1 [PD-(L)1] expression greater than 0. Patients with tumor PD-(L)1 expression of at least 50% treated with pembrolizumab monotherapy were compared with those who did not have any documented treatment. Patients with tumor PD-(L)1 expression less than 50% treated with pembrolizumab and chemotherapy were compared with those treated with pembrolizumab monotherapy and those without documented treatment. RESULTS: In our propensity score-adjusted analysis, patients with ECOG PS of at least 2 and tumor PD-(L)1 expression of at least 50% treated with pembrolizumab monotherapy had statistically significantly better real-world overall survival compared with those without documented treatment (adjusted hazard ratio [HR] = 0.39, 95% confidence internal [CI] = 0.32 to 0.47). For patients with tumor PD-(L)1 expression less than 50%, there was also a statistically significant real-world overall survival benefit for those who received treatment either with combination pembrolizumab plus chemotherapy (adjusted HR = 0.39, 95% CI = 0.32 to 0.46) or pembrolizumab monotherapy (adjusted HR = 0.55, 95% CI = 0.41 to 0.70) compared with patients receiving no documented treatment. CONCLUSIONS: Among a highly representative sample of patients with advanced NSCLC and poor PS, our findings suggest that immunotherapy may provide an important survival benefit in individuals with high PD-(L)1-expressing tumors and in conjunction with chemotherapy in tumors with low PD-(L)1 expression.

Real-World longitudinal practice patterns in the use of PD-1 and PD-L1 inhibitors as First-Line therapy in patients with Non-Small cell lung cancer in the United States.

BACKGROUND: Immune checkpoint inhibitors targeting the programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) axis (collectively referred to as PD[L]1i) have demonstrated clinical benefits in non-small cell lung cancer (NSCLC) patients. The purpose of this United States-based real-world study is to examine changes in the landscape of first-line therapies for NSCLC since the introduction of PD(L)1i. METHODS: Patients with NSCLC initiating first-line treatment between May 1, 2017, and October 31, 2020, were identified in the IBM MarketScan® database. Patients were assigned groups based on first-line therapy: PD(L)1i monotherapy, chemotherapy alone, PD(L)1i with chemotherapy, or targeted therapy for patients with actionable driver mutations. RESULTS: A total of 5431 patients with NSCLC starting first-line treatment were identified: chemotherapy alone 2568 (47%), PD(L)1i with chemotherapy 1364 (25%), PD(L)1i monotherapy 790 (15%), and targeted therapy 709 (13%). The use of PD(L)1i monotherapy and targeted therapy remained consistent, while the percentage of patients receiving PD(L)1i with chemotherapy more than doubled. Over a third of patients in 2019 and 2020 received chemotherapy alone. Patients aged ≥65 years (odds ratio [OR]: 0.80; 95% confidence interval [CI]: 0.68-0.95), females (OR: 0.86; 95% CI: 0.74-0.98), and those with respiratory (OR: 0.82; 95% CI: 0.71-0.94) or kidney (OR: 0.56; 95% CI: 0.40-0.77) disease were less likely to have received PD(L)1i with chemotherapy than patients that received chemotherapy alone. CONCLUSIONS: Since the approval of PD(L)1i for NSCLC, their use has significantly increased for first-line treatment, especially when used in combination with chemotherapy. A significant proportion of patients received chemotherapy alone.

The benefits and harms of adjuvant chemotherapy for non-small cell lung cancer in patients with major comorbidities: A simulation study.

BACKGROUND: Randomized controlled trials (RCTs) have demonstrated a survival benefit for adjuvant platinum-based chemotherapy after resection of locoregional non-small cell lung cancer (NSCLC). The relative benefits and harms and optimal approach to treatment for NSCLC patients who have major comorbidities (chronic obstructive pulmonary disease [COPD], coronary artery disease [CAD], and congestive heart failure [CHF]) are unclear, however. METHODS: We used a simulation model to run in-silico comparative trials of adjuvant chemotherapy versus observation in locoregional NSCLC in patients with comorbidities. The model estimated quality-adjusted life years (QALYs) gained by each treatment strategy stratified by age, comorbidity, and stage. The model was parameterized using outcomes and quality-of-life data from RCTs and primary analyses from large cancer databases. RESULTS: Adjuvant chemotherapy was associated with clinically significant QALY gains for all patient age/stage combinations with COPD except for patients >80 years old with Stage IB and IIA cancers. For patients with CHF and Stage IB and IIA disease, adjuvant chemotherapy was not advantageous; in contrast, it was associated with QALY gains for more advanced stages for younger patients with CHF. For stages IIB and IIIA NSCLC, most patient groups benefited from adjuvant chemotherapy. However, In general, patients with multiple comorbidities benefited less from adjuvant chemotherapy than those with single comorbidities and women with comorbidities in older age categories benefited more from adjuvant chemotherapy than their male counterparts. CONCLUSIONS: Older, multimorbid patients may derive QALY gains from adjuvant chemotherapy after NSCLC surgery. These results help extend existing clinical trial data to specific unstudied, high-risk populations and may reduce the uncertainty regarding adjuvant chemotherapy use in these patients.

Adverse Events Following Limited Resection versus Stereotactic Body Radiation Therapy for Early Stage Lung Cancer.

Rationale: Approximately a quarter of patients with early stage lung cancer are not medically fit for lobectomy. Limited resection and stereotactic body radiation therapy (SBRT) have emerged as alternatives for these patients. Given the equipoise on the effectiveness of the two treatments, treatment-related adverse events (AEs) could have a significant impact on patients' decision-making and treatment outcomes. Objectives: To compare the AE profile between SBRT versus limited resection. Methods: Data were derived from a prospective cohort of patients with stage I-IIA non-small cell lung cancer who were deemed as high-risk for lobectomy recruited from five centers across the United States. Propensity scores and inverse probability weighting were used to compare the rates of 30- and 90-day AEs among patients treated with limited resection versus SBRT. Results: Overall, 65% of 252 patients underwent SBRT. After adjusting for propensity scores, there was no significant difference in developing at least one AE comparing SBRT to limited resection (odds ratio [OR]: 1.00; 95% confidence interval [CI]: 0.65-1.55 and OR: 1.27; 95% CI: 0.84-1.91 at 30 and 90 days, respectively). SBRT was associated with lower risk of infectious AEs than limited resection at 30 days (OR: 0.05; 95% CI: 0.01-0.39) and 90 days posttreatment (OR: 0.41; 95% CI: 0.17-0.98). Additionally, SBRT was associated with persistently elevated risk of fatigue (OR: 2.47; 95% CI: 1.34-4.54 at 30 days and OR: 2.69; 95% CI: 1.52-4.77 at 90 days, respectively), but significantly lower risks of respiratory AEs (OR: 0.36; 95% CI: 0.20-0.65 and OR: 0.51; 95% CI: 0.31-0.86 at 30 and 90 days, respectively). Conclusions: Though equivalent in developing at least one AE, we found that SBRT is associated with less toxicity than limited resection in terms of infectious and respiratory AEs but higher rates of fatigue that persisted up to 3 months posttreatment. This information, combined with data about oncologic effectiveness, can help patients' decision-making regarding these alternative therapies.

Prognostic Value of the Tumor Immune Microenvironment for Early-stage, Non-Small Cell Lung Cancer.

INTRODUCTION: The role of specific immune cell types within the tumor immune microenvironment in non-small cell lung cancer survival is unclear. The potential of these immune cells to become predictive biomarkers of prognosis, and to define subpopulations who will benefit of additional treatment is urgently needed. METHODS: Stage I to IIIA non-small cell lung cancer patients who underwent surgical resection were queried from the Cancer Genome Atlas; RNAseq data as well as clinical information was extracted. Sample-specific scores for different immune cells were computed via xCell. The association between each cell type and survival was assessed with Cox regression, both unadjusted and adjusted for sex, stage, smoking status, and tumor purity. Models were stratified by lung adenocarcinoma and lung squamous cell carcinoma. RESULTS: There were 383 lung adenocarcinoma and 328 lung squamous cell carcinoma samples, and 161 (42%) and 124 (38%) deaths respectively. There was no association between any immune cell infiltrations and survival in the combined unadjusted Cox regression model. After adjustment, the presence of CD8+ cytotoxic T cells (adjusted hazard ratio [HRajd]: 0.84; 95% confidence interval [CI]: 0.71-0.99; P=0.03), CD4+ helper T cells (HRajd: 0.79; 95% CI: 0.66-0.95; P=0.01) and CD20+ B cells (HRajd: 0.80; 95% CI: 0.66-0.97; P=0.02) were significant predictors of decreased risk of death. CONCLUSIONS: This study shows that the adjustment for clinical characteristics is key when evaluating tumor immune infiltration and its association with cancer outcomes. Adjustment for confounding factors modified the prognostic significance of specific immune cell populations in early-stage surgically resected NSCLC cases; clinical attributes may have high relevance on immune infiltration composition.

KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing.

Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic driver in advanced non-small cell lung cancer, occurring in approximately 30% of lung adenocarcinomas. Over 80% of oncogenic KRAS mutations occur at codon 12, where the glycine residue is substituted by different amino acids, leading to genomic heterogeneity of KRas-mutant tumors. The KRAS glycine-to-cysteine mutation (G12C) composes approximately 44% of KRAS mutations in non-small cell lung cancer, with mutant KRasG12C present in approximately 13% of all patients with lung adenocarcinoma. Mutant KRas has been an oncogenic target for decades, but no viable therapeutic agents were developed until recently. However, advances in KRas molecular modeling have led to the development and clinical testing of agents that directly inhibit mutant KRasG12C. These agents include sotorasib (AMG-510), adagrasib (MRTX-849), and JNJ-74699157. In addition to testing for known actionable oncogenic driver alterations in EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, and NTRK and for the expression of programmed cell-death protein ligand 1, pathologists, medical oncologists, and community practitioners will need to incorporate routine testing for emerging biomarkers such as MET amplification, ERBB2 (alias HER2), and KRAS mutations, particularly KRAS G12C, considering the promising development of direct inhibitors of KRasG12C protein.

Post-anticoagulant D-dimer is a highly prognostic biomarker of COVID-19 mortality.

Clinical biomarkers that accurately predict mortality are needed for the effective management of patients with severe coronavirus disease 2019 (COVID-19) illness. In this study, we determine whether changes in D-dimer levels after anticoagulation are independently predictive of in-hospital mortality. Adult patients hospitalised for severe COVID-19 who received therapeutic anticoagulation for thromboprophylaxis were identified from a large COVID-19 database of the Mount Sinai Health System in New York City (NY, USA). We studied the ability of post-anticoagulant D-dimer levels to predict in-hospital mortality, while taking into consideration 65 other clinically important covariates including patient demographics, comorbidities, vital signs and several laboratory tests. 1835 adult patients with PCR-confirmed COVID-19 who received therapeutic anticoagulation during hospitalisation were included. Overall, 26% of patients died in the hospital. Significantly different in-hospital mortality rates were observed in patient groups based on mean D-dimer levels and trend following anticoagulation: 49% for the high mean-increase trend group; 27% for the high-decrease group; 21% for the low-increase group; and 9% for the low-decrease group (p<0.001). Using penalised logistic regression models to simultaneously analyse 67 clinical variables, the high increase (adjusted odds ratios (ORadj): 6.58, 95% CI 3.81-11.16), low increase (ORadj: 4.06, 95% CI 2.23-7.38) and high decrease (ORadj: 2.37; 95% CI 1.37-4.09) D-dimer groups (reference: low decrease group) had the highest odds for in-hospital mortality among all clinical features. Changes in D-dimer levels and trend following anticoagulation are highly predictive of in-hospital mortality and may help guide resource allocation and future studies of emerging treatments for severe COVID-19.

PD-L1 as a prognostic biomarker in surgically resectable non-small cell lung cancer: a meta-analysis.

BACKGROUND: PD-L1 tumor expression has been associated with poor prognosis in a variety of solid tumors, including lung cancer, and represents a validated target for immune checkpoint inhibition in advanced malignances. It remains unknown, however, if PD-L1 can be used to predict survival in early stage, surgically treated cancers. This meta-analysis compares PD-L1 tumor expression and long term survival after surgical resection in early non-small cell lung cancer (NSCLC). METHODS: PubMed was searched to identify eligible studies that compared survival of surgically resected stage I-III NSCLC patients according to PD-L1 tumor expression. Included studies were grouped according to measurement criteria of PD-L1 expression: 1%, 5%, 50% cutoffs or H-score. Meta-analysis was performed using a linear mixed-effects model to determine overall survival (OS). I2 was used as a measure of heterogeneity. RESULTS: There were 40 eligible studies, including 10,380 patients. Regardless of cut-off used, higher PD-L1 tumor expression was associated with worse OS [hazard ratio (HR)1%: 1.59, 95% confidence interval (CI), 1.17-2.17; HR5%: 1.44, 95% CI, 1.03-2.00; HR50%: 1.52, 95% CI, 1.02-2.25, HRH-score: 1.34, 95% CI, 1.04-1.73]. Study heterogeneity was low and not statistically significant under all PD-L1 cutoffs. CONCLUSIONS: PD-L1 expression is consistently associated with worse survival, regardless of how it is quantified. In addition to acting as a prognostic biomarker, PD-L1 may also be used in future as a predictive biomarker for patients most likely to benefit from adjuvant immunotherapy.