A germline SNP in BRMS1 predisposes patients with lung adenocarcinoma to metastasis and can be ameliorated by targeting c-fos.

About 50% of patients with early-stage, surgically resected lung cancer will develop distant metastasis. There remains an unmet need to identify patients likely to develop recurrence and to design innovative therapies to decrease this risk. Two primary isoforms of BRMS1, v1 and v2, are present in humans. Using next-generation sequencing of BRMS1 on matched human noncancerous lung tissue and non-small cell lung cancer (NSCLC) specimens, we identified single-nucleotide polymorphism (SNP) rs1052566 that results in an A273V mutation of BRMS1v2. This SNP is homozygous (BRMS1v2A273V/A273V) in 8% of the population and correlates with aggressive biology in lung adenocarcinoma (LUAD). Mechanistically, we show that BRMS1v2 A273V abolishes the metastasis suppressor function of BRMS1v2 and promotes robust cell invasion and metastases by activation of c-fos-mediated gene-specific transcriptional regulation. BRMS1v2 A273V increases cell invasion in vitro and increases metastases in both tail-vein injection xenografts and LUAD patient-derived organoid (PDO) intracardiac injection metastasis in vivo models. Moreover, we show that BRMS1v2 A273V fails to interact with nuclear Src, thereby activating intratumoral c-fos in vitro. Higher c-fos results in up-regulation of CEACAM6, which drives metastases in vitro and in vivo. Using both xenograft and PDO metastasis models, we repurposed T5224 for treatment, a c-fos pharmacologic inhibitor investigated in clinical trials for arthritis, and observed suppression of metastases in BRMS1v2A273V/A273V LUAD in mice. Collectively, we elucidate the mechanism of BRMS1v2A273V/A273V-induced metastases and offer a putative therapeutic strategy for patients with LUAD who have this germline alteration.

Postinduction therapy pulmonary function retesting is necessary before surgical resection for non-small cell lung cancer.

OBJECTIVE: Pretreatment-predicted postoperative diffusing capacity of the lung for carbon monoxide (DLCO) has been associated with operative mortality in patients who receive induction therapy for resectable non-small cell lung cancer (NSCLC). It is unknown whether a reduction in pulmonary function after induction therapy and before surgery affects the risk of morbidity or mortality. We sought to determine the relationship between induction therapy and perioperative outcomes as a function of postinduction pulmonary status in patients who underwent surgical resection for NSCLC. METHODS: We retrospectively reviewed data for 1001 patients with pathologic stage I, II, or III NSCLC who received induction therapy before lung resection. Pulmonary function was defined according to American College of Surgeons Oncology Group major criteria: DLCO ≥50% = normal; DLCO <50% = impaired. Patients were categorized into 5 subgroups according to combined pre- and postinduction DLCO status: normal-normal, normal-impaired, impaired-normal, impaired-impaired, and preinduction only (without postinduction pulmonary function test measurements). Multivariable logistic regression was used to quantify the relationship between DLCO categories and dichotomous end points. RESULTS: In multivariable analysis, normal-impaired DLCO status was associated with an increased risk of respiratory complications (odds ratio, 2.29 [95% CI, 1.12-4.49]; P = .02) and in-hospital complications (odds ratio, 2.83 [95% CI, 1.55-5.26]; P < .001). Type of neoadjuvant therapy was not associated with an increased risk of complications, compared with conventional chemotherapy. CONCLUSIONS: Reduced postinduction DLCO might predict perioperative outcomes. The use of repeat pulmonary function testing might identify patients at higher risk of morbidity or mortality.

Propensity-matched Analysis Demonstrates Long-term Risk of Respiratory and Cardiac Mortality After Pneumonectomy Compared With Lobectomy for Lung Cancer.

OBJECTIVE: We sought to quantify and characterize long-term consequences of pneumonectomy, with particular attention to nononcologic mortality. SUMMARY OF BACKGROUND DATA: Pneumonectomy is associated with profound changes in cardiopulmonary physiology. Studies of long-term outcomes after pneumonectomy typically report generalized measures, such as disease-free and overall survival. METHODS: Patients undergoing lobectomy or pneumonectomy for lung cancer at our institution from 2000 to 2018 were reviewed. Propensity-score matching was performed for 12 clinicopathologic factors. Ninety-day complications and deaths were compared. Five-year cumulative incidence of oncologic and nononcologic mortality were compared using competing risks approaches. RESULTS: From 3339 lobectomy and 355 pneumonectomy patients identified, we derived 318 matched pairs. At 90 days, rates of overall complications were similar (46% for pneumonectomy vs 43% for lobectomy; P = 0.40), but rates of major complications (21% vs 13%; P = 0.005) and deaths (6.9% vs 1.9%; P = 0.002) were higher the pneumonectomy cohort. The cumulative incidence of oncologic mortality was not significantly different between cohorts (P = 0.9584). However, the cumulative incidence of nononcologic mortality was substantially higher in the pneumonectomy cohort for both date of surgery and 1-year landmark analyses (P < 0.0001 and P = 0.0002, respectively). Forty-five pneumonectomy patients (18%) died of nononcologic causes 1-5 years after surgery; pneumonia (n = 21) and myocardial infarction (n = 10) were the most common causes. In pneumonectomy patients, preexisting cardiac comorbidity and low diffusion capacity of the lungs for carbon monoxide were predictive of nononcologic mortality. CONCLUSIONS: Compared to lobectomy, excess mortality after pneumonectomy extends beyond 1 year and is driven primarily by nononcologic causes. Pneumonectomy patients require lifelong monitoring and may benefit from expeditious assessment and intervention at the initial signs of illness.

The Emerging Importance of Tumor Genomics in Operable Non-Small Cell Lung Cancer.

During the last two decades, next-generation sequencing (NGS) has played a key role in enhancing non-small cell lung cancer treatment paradigms through the application of "targeted therapy" in advanced and metastatic disease. The use of specific tyrosine kinase inhibitors in patients with oncogenic driver alterations, such as EGFR, ALK, ROS1, BRAF V600E, MET, and NTRK mutations, among others, has changed treatment approaches and improved outcomes in patients with late-stage disease. Although NGS technology has mostly been used in the setting of systemic therapy to identify targets, response to therapy, and mechanisms of resistance, it has multiple potential applications for patients with earlier-stage disease, as well. In this review, we discuss the emerging role of NGS technologies to better understand tumor biology in patients with non-small cell lung cancer who are undergoing surgery with curative intent. In this patient cohort, we examine tumor heterogeneity, the underlying tumor genomics associated with lung adenocarcinoma subtypes, the prediction of recurrence after complete surgical resection, the use of plasma circulating tumor DNA for detection of early cancers and monitoring for minimal residual disease, the differentiation of separate primaries from intrapulmonary metastases, and the use of NGS to guide induction and adjuvant therapies.

Preoperative clinical and tumor genomic features associated with pathologic lymph node metastasis in clinical stage I and II lung adenocarcinoma.

While next-generation sequencing (NGS) is used to guide therapy in patients with metastatic lung adenocarcinoma (LUAD), use of NGS to determine pathologic LN metastasis prior to surgery has not been assessed. To bridge this knowledge gap, we performed NGS using MSK-IMPACT in 426 treatment-naive patients with clinical N2-negative LUAD. A multivariable logistic regression model that considered preoperative clinical and genomic variables was constructed. Most patients had cN0 disease (85%) with pN0, pN1, and pN2 rates of 80%, 11%, and 9%, respectively. Genes altered at higher rates in pN-positive than in pN-negative tumors were STK11 (p = 0.024), SMARCA4 (p = 0.006), and SMAD4 (p = 0.011). Fraction of genome altered (p = 0.037), copy number amplifications (p = 0.001), and whole-genome doubling (p = 0.028) were higher in pN-positive tumors. Multivariable analysis revealed solid tumor morphology, tumor SUVmax, clinical stage, SMARCA4 and SMAD4 alterations were independently associated with pathologic LN metastasis. Incorporation of clinical and tumor genomic features can identify patients at risk of pathologic LN metastasis; this may guide therapy decisions before surgical resection.

Intraoperative opioid exposure, tumour genomic alterations, and survival differences in people with lung adenocarcinoma.

BACKGROUND: Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and intra-tumoural opioid receptor gene alterations, but no study has investigated whether the tumour genome interacts with opioid exposure to affect survival. We sought to determine whether intraoperative opioid exposure is associated with recurrence-specific survival and overall survival in early-stage lung adenocarcinoma, and whether selected tumour genomics are associated with this relationship. Associations between ketamine and dexmedetomidine and outcomes were also studied. METHODS: Surgical patients (N=740) with pathological stage I-III lung adenocarcinoma and next-generation sequencing data were retrospectively reviewed from a prospectively maintained database. RESULTS: On multivariable analysis, ketamine administration was protective for recurrence-specific survival (hazard ratio = 0.44, 95% confidence interval 0.24-0.80; P=0.007), compared with no adjunct. Higher intraoperative oral morphine milligram equivalents were significantly associated with worse overall survival (hazard ratio=1.09/10 morphine milligram equivalents, 95% confidence interval 1.02-1.17; P=0.010). Significant interaction effects were found between morphine milligram equivalents and fraction genome altered and morphine milligram equivalents and CDKN2A, such that higher fraction genome altered or CDKN2A alterations were associated with worse overall survival at higher morphine milligram equivalents (P=0.044 and P=0.052, respectively). In contrast, alterations in the Wnt (P=0.029) and Hippo (P=0.040) oncogenic pathways were associated with improved recurrence-specific survival at higher morphine milligram equivalents, compared with unaltered pathways. CONCLUSIONS: Intraoperative opioid exposure is associated with worse overall survival, whereas ketamine exposure is associated with improved recurrence-specific survival in patients with early-stage lung adenocarcinoma. This is the first study to investigate tumour-specific genomic interactions with intraoperative opioid administration to modify survival associations.

Management of Synchronous Extrathoracic Oligometastatic Non-Small Cell Lung Cancer.

Stage IV non-small cell lung cancer (NSCLC) accounts for 35 to 40% of newly diagnosed cases of NSCLC. The oligometastatic state-≤5 extrathoracic metastatic lesions in ≤3 organs-is present in ~25% of patients with stage IV disease and is associated with markedly improved outcomes. We retrospectively identified patients with extrathoracic oligometastatic NSCLC who underwent primary tumor resection at our institution from 2000 to 2018. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Factors associated with EFS and OS were determined using Cox regression. In total, 111 patients with oligometastatic NSCLC underwent primary tumor resection; 87 (78%) had a single metastatic lesion. Local consolidative therapy for metastases was performed in 93 patients (84%). Seventy-seven patients experienced recurrence or progression. The five-year EFS was 19% (95% confidence interval (CI), 12-29%), and the five-year OS was 36% (95% CI, 27-50%). Factors independently associated with EFS were primary tumor size (hazard ratio (HR), 1.15 (95% CI, 1.03-1.29); p = 0.014) and lymphovascular invasion (HR, 1.73 (95% CI, 1.06-2.84); p = 0.029). Factors independently associated with OS were neoadjuvant therapy (HR, 0.43 (95% CI, 0.24-0.77); p = 0.004), primary tumor size (HR, 1.18 (95% CI, 1.02-1.35); p = 0.023), pathologic nodal disease (HR, 1.83 (95% CI, 1.05-3.20); p = 0.033), and visceral-pleural invasion (HR, 1.93 (95% CI, 1.10-3.40); p = 0.022). Primary tumor resection represents an important treatment option in the multimodal management of extrathoracic oligometastatic NSCLC. Encouraging long-term survival can be achieved in carefully selected patients, including those who received neoadjuvant therapy and those with limited intrathoracic disease.

KRAS G12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma.

PURPOSE: KRAS G12C is the most common KRAS mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of KRAS G12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRAS G12C-mutant lung adenocarcinoma. EXPERIMENTAL DESIGN: Patients who underwent resection of stage I-III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as KRAS wild-type (KRAS wt), G12C (KRAS G12C), or non-G12C (KRAS other). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed. RESULTS: In total, 604 patients were included: 374 KRAS wt (62%), 95 KRAS G12C (16%), and 135 KRAS other (22%). Three-year DFS was not different between KRAS-mutant and KRAS wt tumors. However, 3-year DFS was worse in patients with KRAS G12C than KRAS other tumors (log-rank P = 0.029). KRAS G12C tumors had more lymphovascular invasion (51% vs. 37%; P = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3-10.8) vs. 6.1 (3.5-9.7); P = 0.021], compared with KRAS other tumors. KRAS G12C mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort. CONCLUSIONS: KRAS G12C mutations are associated with worse DFS after complete resection of stage I-III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other KRAS-mutant tumors. We identified a high-risk group for whom KRAS G12C inhibitors may be investigated to improve survival.

A Genomic-Pathologic Annotated Risk Model to Predict Recurrence in Early-Stage Lung Adenocarcinoma.

Importance: Recommendations for adjuvant therapy after surgical resection of lung adenocarcinoma (LUAD) are based solely on TNM classification but are agnostic to genomic and high-risk clinicopathologic factors. Creation of a prediction model that integrates tumor genomic and clinicopathologic factors may better identify patients at risk for recurrence. Objective: To identify tumor genomic factors independently associated with recurrence, even in the presence of aggressive, high-risk clinicopathologic variables, in patients with completely resected stages I to III LUAD, and to develop a computational machine-learning prediction model (PRecur) to determine whether the integration of genomic and clinicopathologic features could better predict risk of recurrence, compared with the TNM system. Design, Setting, and Participants: This prospective cohort study included 426 patients treated from January 1, 2008, to December 31, 2017, at a single large cancer center and selected in consecutive samples. Eligibility criteria included complete surgical resection of stages I to III LUAD, broad-panel next-generation sequencing data with matched clinicopathologic data, and no neoadjuvant therapy. External validation of the PRecur prediction model was performed using The Cancer Genome Atlas (TCGA). Data were analyzed from 2014 to 2018. Main Outcomes and Measures: The study end point consisted of relapse-free survival (RFS), estimated using the Kaplan-Meier approach. Associations among clinicopathologic factors, genomic alterations, and RFS were established using Cox proportional hazards regression. The PRecur prediction model integrated genomic and clinicopathologic factors using gradient-boosting survival regression for risk group generation and prediction of RFS. A concordance probability estimate (CPE) was used to assess the predictive ability of the PRecur model. Results: Of the 426 patients included in the analysis (286 women [67%]; median age at surgery, 69 [interquartile range, 62-75] years), 318 (75%) had stage I cancer. Association analysis showed that alterations in SMARCA4 (clinicopathologic-adjusted hazard ratio [HR], 2.44; 95% CI, 1.03-5.77; P = .042) and TP53 (clinicopathologic-adjusted HR, 1.73; 95% CI, 1.09-2.73; P = .02) and the fraction of genome altered (clinicopathologic-adjusted HR, 1.03; 95% CI, 1.10-1.04; P = .005) were independently associated with RFS. The PRecur prediction model outperformed the TNM-based model (CPE, 0.73 vs 0.61; difference, 0.12 [95% CI, 0.05-0.19]; P < .001) for prediction of RFS. To validate the prediction model, PRecur was applied to the TCGA LUAD data set (n = 360), and a clear separation of risk groups was noted (log-rank statistic, 7.5; P = .02), confirming external validation. Conclusions and Relevance: The findings suggest that integration of tumor genomics and clinicopathologic features improves risk stratification and prediction of recurrence after surgical resection of early-stage LUAD. Improved identification of patients at risk for recurrence could enrich and enhance accrual to adjuvant therapy clinical trials.

Outcomes After Multidisciplinary Management of Primary Mediastinal Germ Cell Tumors.

OBJECTIVE: We examined management strategies, overall survival (OS), and progression-free survival (PFS) among patients with PMNSGCTs undergoing resection and multidisciplinary management at a high-volume institution. SUMMARY OF BACKGROUND DATA: Outcomes after resection of PMNSGCTs are not well-characterized, with limited data on factors associated with survival. METHODS: We reviewed patients with PMNSGCT who underwent resection between 1980 and 2019. Median follow-up was 3.4 years. Preoperative therapy (including use of bleomycin), surgical management, recurrence, and survival were examined. Factors associated with survival were analyzed using Cox regression. RESULTS: In total, 113 patients were included [median age, 28 years (range, 16-65)]. Preoperative serum tumor markers (STMs) normalized/decreased in 74% of patients. Pathology included necrosis only (25%), teratoma +/- necrosis (20%), viable nonteratomatous germ cell tumor +/- teratoma (41%), and secondary somatic-type malignancy +/- teratoma (20%). Bleomycin chemotherapy was not associated with pulmonary complications or 90-day mortality. Patients receiving second-line chemotherapy followed by resection had significantly worse OS and PFS than patients receiving first-line chemotherapy followed by resection. On multivariable analysis, R1/R2 resection (HR, 3.92; P < 0.001) and increasing postoperative STMs (HR, 4.98; P < 0.001) were associated with shorter PFS; necrosis on pathology (HR, 0.42, P = 0.043) was associated with longer PFS. CONCLUSIONS: In patients with PMNSGCT undergoing resection, completeness of resection, postoperative pathology, and postoperative STMs were associated with PFS. Induction bleomycin was not associated with pulmonary complications or mortality in patients undergoing resection. Patients undergoing second-line chemotherapy followed by resection have a poor prognosis, with long-term survival of 22%.

Thoracic Metastasectomy in Germ Cell Tumor Patients Treated With First-line Versus Salvage Therapy.

BACKGROUND: Outcomes after thoracic metastasectomy in patients with testicular germ cell tumors (GCTs) who received first-line chemotherapy alone versus salvage chemotherapy remain unexplored. METHODS: We conducted a retrospective review of patients who underwent thoracic metastasectomy for residual GCT between 1997 and 2019 at a single tertiary center. Factors associated with progression-free survival (PFS) and overall survival (OS) were assessed using multivariable Cox regression. RESULTS: Of 251 patients, 191 received only first-line chemotherapy (76%) and 60 received salvage chemotherapy (24%). Median follow-up was 3.45 years (interquartile range, 1-7.93 years). Among first-line patients without teratoma in the primary tumor, with necrosis in the retroperitoneal nodes and normalized or decreasing serum tumor markers, 17 of 20 had intrathoracic necrosis (85%). Among first-line and salvage patients, respectively, 5-year OS was 93% (95% confidence interval [CI], 89%-98%) versus 63% (95% CI, 51%-78%; P < .001), and 5-year PFS was 69% (95% CI, 62%-77%) versus 40% (95% CI, 29%-56%; P < .001). On multivariable analysis, multiple lung lesions (hazard ratio [HR] = 3.01; 95% CI, 1.50-6.05; P = .002) and brain metastasis (HR = 4.51; 95% CI, 2.34-8.73; P < .001) at diagnosis, salvage chemotherapy (HR = 1.85; 95% CI, 1.10-3.13; P = .021), teratoma (HR = 2.68; 95% CI, 1.50-4.78; P = .001), and viable malignancy (HR = 4.34; 95% CI, 2.44-7.71; P < .001) were associated with worse PFS. CONCLUSIONS: Although GCT patients treated with salvage chemotherapy followed by thoracic metastasectomy have more aggressive disease and poorer PFS, they can achieve encouraging OS. Our findings highlight the integral role of aggressive thoracic metastasectomy in the treatment of GCT patients with residual thoracic disease after first line-only or salvage chemotherapy.

Is Routine Chest Radiography Necessary After Endobronchial Ultrasound-guided Fine Needle Aspiration?

BACKGROUND: Chest radiography is routinely performed after endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) to detect clinically occult pneumothorax. Because the established rate of postprocedure pneumothorax is low, this study sought to determine whether routine chest radiography can be safely eliminated and to ascertain the potential cost reduction with its omission. METHODS: Patients who underwent EBUS-FNA between January 1, 2017 and December 31, 2018 at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively identified. Patient-related factors were summarized using descriptive statistics. Outcomes were compared using the χ2, Fisher exact, and analysis of variance tests. Univariate regression analysis was used to identify factors predictive of postprocedure pneumothorax. RESULTS: A total of 757 patients were included in the study: 72.4% (548 of 757) underwent routine chest radiography in the postanesthesia care unit. Clinically relevant or radiographically evident pneumothorax developed in 1.5% of patients (11 of 757). Of the patients who underwent chest radiography, 0.5% (3 of 548) required unplanned admission for postprocedure pneumothorax, and 0.2% (1 of 548) required tube thoracostomy. Of the 209 patients who did not undergo chest radiography, none experienced a clinically evident pneumothorax. In total, only 1 patient (0.1%) had symptomatic pneumothorax. The pneumothorax event rate was so low that no association with demographic or clinical factors and no predictive factors could be identified. The number of patients needed to be screened by chest radiography to identify 1 patient requiring deviation from routine management is 183. The potential total cost reduction if routine chest radiography had been eliminated was $33,950. CONCLUSIONS: The extremely low rate of postprocedure pneumothorax precluded informative statistical analysis. Routine chest radiography after EBUS-FNA may not be necessary, and its omission may confer a cost savings.

Intentional Segmentectomy for Clinical T1 N0 Non-small Cell Lung Cancer: Survival Differs by Segment.

BACKGROUND: Outcomes after segmentectomy compare favorably with those after lobectomy in patients with stage I non-small cell lung cancer (NSCLC). Whether long-term outcomes vary by segmentectomy location is unclear. We investigated whether disease-free survival (DFS) and overall survival (OS) differ by segmentectomy location after intentional segmentectomy for clinical T1 N0 M0 NSCLC. METHODS: Patients who received intentional segmentectomy for cT1 N0 M0 NSCLC from 2000 to 2018 were reviewed. Patients with prior lung cancer, forced expiratory volume in 1 second of less than 50%, or R1/R2 resection were excluded. Segmentectomy groups were left (L) basilar, L segment 6, L lingula, L trisegment; right (R): basilar (R_Bas), segment 6 (R_S6), and R upper. The 5- and 10-year DFS and OS were estimated using Kaplan-Meier and compared between groups using the log-rank test. Factors associated with DFS and OS were determined using Cox proportional hazards models. RESULTS: In total, 416 patients met the inclusion criteria. Segmentectomy groups differed with regard to surgical approach, mediastinal lymphadenectomy, lymphovascular invasion, tumor histology, margin distance, and adjuvant therapy. Long-term outcomes were worst after R_S6 resection (5-year DFS, 57.6% [95% confidence interval {CI}, 45.7%-72.7%]; OS, 66.3% [95% CI, 54.7%-80.3%]) and best after R_Bas resection (5-year DFS, 77.1% [95% CI, 59.2%-100%]; OS, 79.5% [95% CI, 60.9%-100%]). On multivariable analysis, R_S6 resection was independently associated with DFS vs R_Bas (hazard ratio, 2.89; 95% CI, 1.18-7.08; P = .02) and OS vs R_Bas (hazard ratio, 4.35; 95% CI, 1.61-11.76; P = .004). CONCLUSIONS: Resection of R_S6 is independently associated with worse DFS and OS in patients receiving intentional segmentectomy for cT1 N0 M0 NSCLC and may warrant more extensive resection, complete lymph node dissection, and closer postoperative surveillance.

The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma.

INTRODUCTION: The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD). METHODS: We identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic [LEP], acinar or papillary [ACI/PAP], and micropapillary or solid [MIP/SOL]). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection. RESULTS: MIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049). CONCLUSIONS: These results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.

Time-varying analysis of readmission and mortality during the first year after pneumonectomy.

OBJECTIVES: Mortality rates of 5% to 10% after pneumonectomy have remained constant during the last decade. To understand the patterns of outcomes after pneumonectomy, we investigated the time-varying risks of readmission and death during the first postoperative year and examined the contributions of specific causes to these patterns over time. METHODS: We retrospectively reviewed all pneumonectomies for lung cancer at our institution from 2000 to 2018. The time-varying instantaneous risk of all-cause readmission and mortality up to 1 year after pneumonectomy was estimated using parametric analyses and was repeated for each primary cause of readmission (oncologic, infectious, pulmonary, cardiac, or other) and death (oncologic or nononcologic). RESULTS: In our cohort of 355 patients who underwent pneumonectomy, risk of readmission was highest immediately after discharge and was halved by 14 days. This risk reached a nadir and remained constant from 4 to 8 months, after which it gradually increased. Pulmonary causes accounted for most readmissions within 90 days, after which oncologic causes predominated. Likewise, the overall risk of death was highest immediately after surgery, was halved by 7 days, reached a nadir at 90 days, and then increased throughout the remainder of the first year. All deaths during the first 90 days after surgery were due to nononcologic causes. CONCLUSIONS: Nononcologic causes of readmission and death predominate in the first 90 days after pneumonectomy, after which oncologic causes prevail. We also identify specific causes that pose the highest risk of readmission immediately after discharge. Efforts are warranted to define the effects of specific causes of readmission on overall mortality after pneumonectomy.

Prognostic factors following complete resection of non-superior sulcus lung cancer invading the chest wall.

OBJECTIVES: Locally advanced non-small-cell lung cancer (NSCLC) with chest wall invasion carries a high risk of recurrence and portends poor survival (30-40% and 20-50%, respectively). No studies have identified prognostic factors in patients who underwent R0 resection for non-superior sulcus NSCLC. METHODS: A retrospective review was conducted for all chest wall resections for NSCLC from 2004 to 2018. Patients with superior sulcus tumours, partial (<1 rib) or incomplete (R1/R2) resection or distant metastasis were excluded. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazards modelling was used to determine factors associated with DFS and OS. RESULTS: A total of 100 patients met inclusion criteria. Seventy-three (73%) patients underwent induction therapy, and all but 12 (16%) patients experienced a partial radiological response. A median of 3 ribs was resected (range 1-7), and 67 (67%) patients underwent chest wall reconstruction. The 5-year DFS and OS were 36% and 45%, respectively. Pathological N2 status [hazard ratio (HR) 3.12, confidence interval (CI) 1.56-6.25; P = 0.001], intraoperative blood transfusion (HR 2.24, CI 1.28-3.92; P = 0.005) and preoperative forced vital capacity (per % forced vital capacity, HR 0.97, CI 0.96-0.99; P = 0.013) were associated with DFS. Increasing pathological stage, lack of radiological response to induction therapy (HR 7.35, CI 2.35-22.99; P = 0.001) and cardiovascular comorbidity (HR 2.43, CI 1.36-4.36; P = 0.003) were associated with OS. CONCLUSIONS: We demonstrate that blood transfusion and forced vital capacity are associated with DFS after R0 resection for non-superior sulcus NSCLC, while radiological response to induction therapy greatly influences OS. We confirm that pathological nodal status and pathological stage are reproducible determinants of DFS and OS, respectively.

Analysis of Tumor Genomic Pathway Alterations Using Broad-Panel Next-Generation Sequencing in Surgically Resected Lung Adenocarcinoma.

PURPOSE: The majority of broad-panel tumor genomic profiling has used a gene-centric approach, although much of that data is unused in clinical decision making. We hypothesized that a pathway-centric approach using next-generation sequencing (NGS), combined with conventional clinicopathologic features, may better predict disease-free survival (DFS) in early stage lung adenocarcinoma. EXPERIMENTAL DESIGN: Utilizing our prospectively maintained database, we analyzed 492 patients with primary, untreated, completely surgically resected lung adenocarcinoma. Ten canonical pathways were analyzed using broad-panel NGS. The correlations of DFS and number (and type) of pathway (NPA) were analyzed using the Kaplan-Meier method and log-rank test. Associations between altered pathways and clinicopathologic variables, as well as identification of actionable therapeutic strategies were explored. RESULTS: Median NPA for the cohort was two (range, 0-5). Smoking status, solid morphologic appearance on preoperative CT, maximal standardized uptake value, pathologic tumor size, aggressive histologic subtype, lymphovascular invasion, visceral pleural invasion, and positive lymph nodes were significantly associated with NPA (P < 0.05). Of 543 actionable genetic alterations identified, 455 (84%) were within the RTK/RAS pathway. A total of 86 tumors had actionable therapeutic genomic alterations in >1 pathway. On multivariable analysis, higher NPA was significantly associated with worse DFS (HR, 1.31; P = 0.014). CONCLUSIONS: NPA and specific pathway alterations are associated with clinicopathologic features in patients with surgically resected lung adenocarcinoma. Cell cycle, Hippo, TGFß, and p53 pathway alterations are associated with poor DFS. Finally, NPA is an independent risk factor for poor DFS in our cohort.See related commentary by Blakely, p. 7269.