Next Generation Sequencing of Advanced Non-Small Cell Lung Cancer: Utilization Based on Race and Impact on Survival.

BACKGROUND: Next generation sequencing (NGS) of tumor of patients with advanced non-small cell lung cancer (NSCLC) is now a standard of care that informs the clinician on the best therapeutic approach for their patients. The purpose of our study was to investigate the overall impact of NGS testing on survival as well as potential racial differences in utilization, therapeutic decision, and genomic alterations. METHOD: Using a large institutional database, 928 patients with stage IV NSCLC were identified. NGS testing using Foundation One platform was used. Clinical and genomic characteristics were compared by race. We used a propensity-modeling technique to compare groups that were sequenced or not in terms of overall survival. Time to event data was analyzed using Kaplan-Meier method and Cox model. RESULTS: A total of 295 patients underwent NGS. Patients undergoing NGS testing had significantly longer survival of 25.3 months versus those who did not undergo sequencing with a median survival of 14.6 months (P = .002) irrespective if they received targeted therapy or not. There was no difference in terms of NGS utilization based on race (P = .32). African American individuals had significantly higher rates of ALK rearrangements and mutations in PBRM1, SETD2, TSC2, and FBXW7. CONCLUSION: Our study demonstrates that within a large single institution there is no racial difference in NGS utilization and that NGS testing directly impacts survival. We identify a number of differences in genomic findings between African American and white individuals.

A detailed smoking history and determination of MYC status predict response to checkpoint inhibitors in advanced non-small cell lung cancer.

BACKGROUND: Although many studies have determined that PD-L1 expression by immunohistochemistry can be somewhat predictive of a response to checkpoint inhibitor the impact of specific genomic changes and smoking history in the context of PD-L1 expression is limited. This single-center study examined clinical and genomic factors beyond STK11 and EGFR in patients with advanced non-small cell lung cancer (NSCLC) to determine which patients benefit from therapy with immune checkpoint inhibitors (ICIs). METHODS: Clinical and genomic features of patients with NSCLC treated with immunotherapy were compiled into a database. Genomic information collected included gene mutations via next generation sequencing, tumor mutation burden (TMB), and PD-L1 tumor proportional scores. RESULTS: A total of 131 patients with advanced NSCLC treated with ICIs were examined. Race was not associated with response. A positive response to immunotherapy was associated with smoke year increase (P=0.042). KRAS mutation and MYC amplification were associated with a positive response to immunotherapy while EGFR, RB1, and NF1 mutations were associated with a lack of response. KRAS mutation (P=0.007) and high TMB (P=0.070) were positively associated with smoking history. EGFR mutation was negatively associated with smoking history (P=0.002) . In multivariate analysis controlling for age and smoking history, MYC amplification continued to be the only predictive genomic marker with a trend toward response to therapy (P=0.092) beyond the smoking history. CONCLUSIONS: Among the clinical and genomic factors examined in this study, smoking status is the most predictive of response to ICIs. Only MYC amplification continued to predict a trend toward response to immunotherapy when controlling for smoking history. Other genomic predictors such as EGFR and KRAS simply reflect their association with smoking. Detailed smoking history and MYC amplification alone can predict response to ICI.

Retinoblastoma mutation predicts poor outcomes in advanced non small cell lung cancer.

The retinoblastoma gene (RB1) encodes the retinoblastoma (RB) pocket protein that plays an important role in cell cycle progression. Here we determine the frequency and prognostic significance of RB1 mutation in non small cell lung cancer (NSCLC), restricting inclusion to Stage III and IV patients with linked genomic and clinical data. The primary outcome was median overall survival (OS). We identified RB1 mutation in 8.2% of NSCLC patients. The median OS for wild-type (wt) RB1 was 28.3 months vs 8.3 months for mutant RB1 (Hazard Ratio = 2.59, P = 0.002). Of special interest, RB1 mutation also correlated with lack of response to immunotherapy. Our study focused on RB1 mutation in locally advanced and advanced non small cell lung cancer to better facilitate comparisons with small cell lung cancer (SCLC). In our SCLC cohort, RB1 mutation was identified in 75% of patients and wt RB1 was associated with significantly shorter OS (P = 0.002). The different outcomes of RB1 mutation observed among lung cancer subtypes suggest a more complicated mechanism than simple regulation of cell cycle or response to chemotherapy.

KMT2D Mutation Is Associated With Poor Prognosis in Non-Small-Cell Lung Cancer.

BACKGROUND: Mixed-lineage leukemia protein 2 (MLL2 or KMT2D) is a histone methyltransferase whose mutation has been associated with a poor prognosis in cancer. We compared the characteristics and significance of KMT2D alterations in non-small-cell lung cancer (NSCLC) with those in small cell lung cancer (SCLC). PATIENTS AND METHODS: Tumors from 194 NSCLC patients with locally advanced or advanced disease and 64 SCLC patients underwent targeted-exome sequencing. The association of KMT2D mutation with overall survival (OS) and progression-free survival (PFS) was measured using Kaplan-Meier methods and further evaluated using multivariable Cox proportional hazards regression model adjusting for known clinical prognostic features. RESULTS: The KMT2D mutation rate was 17.5% (34 of 194) in NSCLC. Patients with mutant KMT2D had significantly lower median OS (9.97 vs. 30.2 months; P < .0001) and median PFS (8.46 vs. 24.1 months; P = .0004) compared with patients with wild-type KMT2D. The KMT2D mutation was significantly more common in females (P = .017). Using a multivariate Cox regression model, KMT2D mutation was one of the most significant prognostic factors in NSCLC: hazard ratio (HR) for OS, 2.79 (95% confidence interval [CI], 1.8-4.33; P < .0001) and HR for PFS, 1.99 (95% CI, 1.32-3.01; P = .001). In contrast, the KMT2D mutation rate in SCLC was 32.8% (21 of 64) and showed no sex bias (P = .874). No significant change was found in survival in association with the KMT2D mutation in SCLC (OS, P = .952; PFS, P = .744). CONCLUSION: The KMT2D mutation was associated with reduced survival in NSCLC but not in SCLC.

Reciprocal expression of INSM1 and YAP1 defines subgroups in small cell lung cancer.

The majority of small cell lung cancer (SCLC) patients demonstrate initial chemo-sensitivity, whereas a distinct subgroup of SCLC patients, termed chemo-refractory, do not respond to treatment. There is little understanding of how to distinguish these patients prior to disease treatment. Here we used gene expression profiling to stratify SCLC into subgroups and characterized a molecular phenotype that may identify, in part, chemo-refractive SCLC patients. Two subgroups of SCLC were identified in both cell lines and tumors by the reciprocal expression of two genes; INSM1, a neuroendocrine transcription factor, and YAP1, a key mediator of the Hippo pathway. The great majority of tumors expressed INSM1, which was prognostic for increased progression-free survival and associated with chemo-sensitivity in cell lines. YAP1 is expressed in a minority of SCLC tumors and was shown in cell lines to be downstream of the retinoblastoma protein (RB1) and associated with decreased drug sensitivity. RB1 expression in SCLC cell lines sensitizes them to CDK4/6 inhibitors. Wild-type RB1 mutation status, used as a surrogate marker of YAP1 expression, was prognostic for decreased patient survival and increased chemo-refractory tumor response. Thus, the reciprocal expression of INSM1 and YAP1 appears to stratify SCLC into distinct subgroups and may be useful, along with RB1 mutation status, to identify chemo-refractory SCLC patients.