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.

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.

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.

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.

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.

Comparative Effectiveness of Robotic-Assisted Surgery for Resectable Lung Cancer in Older Patients.

BACKGROUND: Robotic-assisted surgery (RAS) is a novel surgical approach increasingly used for patients with non-small cell lung cancer (NSCLC). However, data comparing the effectiveness and costs of RAS vs open thoracotomy and video-assisted thoracoscopic surgery (VATS) for NSCLC are limited. METHODS: Patients > 65 years old with stage I to IIIA NSCLC treated with RAS, VATS, or open thoracotomy were identified from the Surveillance, Epidemiology, and End Results-Medicare database and matched according to age, sex, stage, and extent of resection. Propensity score methods were used to compare adjusted rates of postoperative complications, adequate lymph node staging, survival, and treatment-related costs. RESULTS: In this matched study cohort of 2,766 patients with resected NSCLC, RAS was associated with lower complication rates (OR, 0.57; 95% CI, 0.42-0.79) compared with open thoracotomy, and similar complication rates (OR, 1.02; 95% CI, 0.76-1.37) compared with VATS. Patients undergoing RAS were as likely to have adequate lymph node sampling as those undergoing open thoracotomy (OR, 1.28; 95% CI, 0.94-1.74) or VATS (OR, 0.88; 95% CI, 0.66-1.18). There was no significant difference in overall survival after RAS vs open thoracotomy (hazard ratio, 0.81; 95% CI, 0.63-1.04) or VATS (hazard ratio, 0.91; 95% CI, 0.70-1.18). Costs were similar for RAS ($54,702) vs open thoracotomy ($57,104; P = .08), and higher compared with VATS ($48,729; P = .02). CONCLUSIONS: RAS led to improved operative outcomes compared with open thoracotomy but may not offer an advantage over VATS. The comparative effectiveness of RAS should be further evaluated prior to widespread adoption.

Benefits and Challenges of Lung Cancer Screening in Older Adults.

PURPOSE: Lung cancer screening with low-dose computed tomography has been shown to significantly reduce lung cancer-related mortality in high-risk patients. However, patients diagnosed with lung cancer are typically older and often have multiple age- and smoking-related comorbidities. As a result, cancer screening in older adults remains a complex decision, requiring careful consideration of patients' risk characteristics and life expectancy to ensure that the benefits outweigh the risks of screening. In this review, we evaluate the evidence regarding lung cancer screening, with a focus on older patients. METHODS: PubMed was searched to identify relevant studies evaluating the clinical outcomes of lung cancer screening. The key words used in our search included non-small cell lung cancer (NSCLC), screening, older, comorbidities, computed tomography, and survival. While we primarily looked for articles specific to older patients, we also focused on subgroup analysis in older patients in larger studies. Finally, we reviewed all relevant guidelines regarding lung cancer screening. FINDINGS: Guidelines recommend that lung cancer screening be considered in adults aged 55 to 80 years who are at high risk based on smoking history (ie, 30-pack-year smoking history; having smoked within the past 15 years). Patients who fit these criteria have been shown to have a 20% reduction in lung cancer-related mortality with the use of low-dose computed tomography versus chest radiography. High rates of false-positive results and potential overdiagnoses were also observed. Therefore, screening is generally not recommended in adults with severe comorbidities or short life expectancy, who may experience limited benefit and higher risks with screening. However, several studies have shown a benefit with continued lung cancer screening with appropriate selection of older individuals at the highest risk and with the lowest comorbidities. IMPLICATIONS: Older patients experience the highest risk for lung cancer incidence and mortality, and stand to be the most likely to benefit from lung cancer screening. However, careful consideration must be given to higher rates of false-positives and overdiagnosis in this population, as well as tolerability of surgery and competing risks for death from other causes. The appropriate selection of older individuals for lung cancer screening can be greatly optimized by using validated risk-based targeting.

Outcomes after Stereotactic Body Radiotherapy versus Limited Resection in Older Patients with Early-Stage Lung Cancer.

BACKGROUND: Limited resection and stereotactic body radiotherapy (SBRT) have emerged as treatment options for older patients with early-stage non-small-cell lung cancer (NSCLC), who are not good candidates for lobectomy. METHODS: We used the Surveillance, Epidemiology and End Results-Medicare registry to identify patients older than 65 years with stage I to II NSCLC and negative lymph nodes treated with SBRT versus limited resection. We fitted a propensity score model predicting the use of SBRT and compared adjusted overall survival of patients treated with SBRT versus limited resection. Secondary analyses stratified the sample by type of limited resection (wedge versus segmentectomy), age (≤75 versus >75 years), and tumor size (<3 versus ≥3 cm). We also compared rates of surgical complications and SBRT-related toxicity in the two groups. RESULTS: We identified 2243 patients of which 362 (16%) patients received SBRT. SBRT-treated patients were older, had higher comorbidity scores, and had larger tumors (p < 0.001 for all comparisons). Adjusted analyses showed no differences in survival (hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.97-1.47) among patients treated with SBRT versus limited resection. Although survival of patients who underwent SBRT versus wedge resection was not different (HR, 1.22; 95% CI, 0.98-1.52), SBRT was associated with worse outcomes when compared with segmentectomy (HR, 1.55; 95% CI, 1.18-2.03). Adverse events were most often respiratory and more frequent in the patients treated with limited resection (28% versus 14%, p < 0.001). CONCLUSION: SBRT is better tolerated and associated with similar survival when compared with wedge resection but not with segmentectomy in older patients with node-negative NSCLC.

Limited Resection Versus Lobectomy for Older Patients With Early-Stage Lung Cancer: Impact of Histology.

PURPOSE: Limited resection has been increasingly used in older patients with stage IA lung cancer. However, the equivalency of limited resection versus lobectomy according to histology is unknown. METHODS: We identified patients older than 65 years with stage IA invasive adenocarcinoma or squamous cell carcinoma ≤ 2 cm who were treated with limited resection (wedge or segmentectomy) or lobectomy in the Surveillance, Epidemiology, and End Results-Medicare database. We estimated propensity scores that predicted the use of limited resection and compared survival of patients treated with limited resection versus lobectomy. Treatments were considered equivalent if the upper 95th percentile of the hazard ratio (HR) for limited resection was ≤ 1.25. RESULTS: Overall, 27% of 2,008 patients with adenocarcinoma and 32% of 1,139 patients with squamous cell carcinoma underwent limited resection. Survival analyses, adjusted for propensity score by using inverse probability weighting, showed that limited resection was not equivalent to lobectomy in patients with adenocarcinoma (HR, 1.21; upper 95% CI,1.34) or squamous cell carcinoma (HR, 1.21; upper 95% CI, 1.39). Although patients with adenocarcinomas treated with segmentectomy had equivalent survival rates to those treated with lobectomy (HR, 0.97; upper 95% CI, 1.07), outcomes of those treated with wedge resection (HR, 1.29; upper 95% CI, 1.42) did not. Among patients with squamous cell carcinoma, neither wedge resection (HR, 1.34; upper 95% CI, 1.53) nor segmentectomy (HR, 1.19; upper 95% CI, 1.36) were equivalent to lobectomy. CONCLUSION: We found generally that limited resection is not equivalent to lobectomy in older patients with invasive non-small-cell lung cancer ≤ 2 cm in size, although segmentectomy may be equivalent in patients with adenocarcinoma.

Adjuvant treatment for elderly patients with early-stage lung cancer treated with limited resection.

OBJECTIVES: Limited resection is commonly used for treating older patients with early-stage non-small cell lung cancer (NSCLC) who cannot tolerate lobectomy. However, parenchymal-sparing procedures leave patients at increased risk of recurrence. The role of postoperative radiotherapy (PORT) and chemotherapy after limited resection is not established. METHODS: We identified 1,929 patients with stage I-II (≤ 5 cm in size) NSCLC who underwent limited resection (wedge or segmentectomy) from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Using propensity score methods, we compared toxicity and survival of patients treated with limited resection alone, PORT, adjuvant chemotherapy, or PORT and chemotherapy. We conducted secondary analysis stratifying the sample by size (>2-5 cm), stage (IA vs. IB/IIA), and type of limited resection (wedge resection vs. segmentectomy). MEASUREMENTS AND MAIN RESULTS: Overall, 1,656 (85.8%), 159 (8.3%), 74 (3.8%), and 40 (2.1%) patients were treated with limited resection alone, PORT, adjuvant chemotherapy, or PORT and chemotherapy, respectively. Adjusted analysis using inverse probability weighting showed that PORT (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.45-1.69), adjuvant chemotherapy (HR, 1.48; 95% CI, 1.36-1.61), and PORT and chemotherapy (HR, 1.73; 95% CI, 1.61-1.86) were associated with worse survival compared with limited resection alone. Similar results were obtained in secondary analyses. Compared with limited resection alone, the adjusted odds ratios for toxicity were 1.97 (95% CI, 1.6-2.4), 3.15 (95% CI, 2.58-3.85), 2.59 (95% CI, 2.0-3.4) for PORT, chemotherapy, and PORT and chemotherapy, respectively. CONCLUSIONS: PORT and adjuvant chemotherapy are not beneficial and appear to be associated with increased toxicity and worse survival after limited resection in elderly patients with early-stage NSCLC. Alternative strategies should be explored to improve local control.