Alterations in driver genes are predictive of survival in patients with resected pancreatic ductal adenocarcinoma.

BACKGROUND: KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection. METHODS: Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genomic alterations were determined on the basis of MSK-IMPACT results from formalin-fixed, paraffin-embedded samples. Associations between genomic alterations and clinical outcomes were assessed. RESULTS: Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow-up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0-45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P = .043; median for TP53, 37.4 months [95% CI, 32.1-42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P = .035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3-45.5 months] vs 39.2 months [95% CI, 37.4-75.2 months]; P = .012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4-75.2 months] vs 33.9 months [95% CI, 24.0-39.0 months]; P = .020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6-44.2 months] vs 39.2 months [95% CI, 34.5-49.1 months]; P = .048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01-2.33; P = .042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0-49.8 months; P = .035). CONCLUSIONS: In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC.

Identifying a wide range of actionable variants using capture-based ultra-deep targeted sequencing in treatment-naive patients with primary lung adenocarcinoma.

Precision medicine requires accurate multi-gene clinical diagnostics. In current clinical practice, the minimum confidence threshold for variant calling of targeted next-generation sequencing (NGS) on surgical specimens is set to 2%-5%. However, few studies have been conducted to identify a wide range of actionable variants using capture-based ultra-deep targeted sequencing, which has limit of detection (LOD) of 1%. The AmoyDx® Essential NGS panel for capture-based ultra-deep targeted sequencing (dual-indexed sequencing adapters with UMIs) was performed on 372 surgical specimens obtained from treatment-naive patients with primary lung adenocarcinoma, to detect actionable somatic driver mutations associated with each patient. Single-nucleotide variants, insertion/deletion events, and rearrangements were reported. Amplification-refractory mutation system (ARMS) assay and fluorescence in situ hybridization (FISH) were performed for the validation of hotspot mutations in EGFR and ALK, ROS1, and RET fusions. Potentially actionable variants were identified in 80.5% (352/437) of the nonsynonymous variants that were able to be sequenced, and were most commonly found in EGFR mutations (59.7%, 261/437), followed by KRAS mutations (5.5%, 24/437), PIK3CA mutations (3.7%, 16/437), ALK rearrangements (3.4%, 15/437), BRAF mutations (2.7%, 12/437), ERBB2 mutations (2.5%, 11/437), and RET rearrangements (2.3%, 10/437). A total of 7.2% (28/372) of the samples had multiple actionable mutations. Among the 93 triple-negative cases, which did not harbor mutations in EGFR, KRAS, or BRAF, gene fusions were detected in 26 cases (28%). Of the 328 samples, concordance of EGFR between the ARMS assay and NGS was observed in 318 samples (97.0%), and among 32 samples, concordance between ARMS/FISH test and NGS for ALK/ROS1/RET fusion genes was observed in 30 samples (93.8%). Here, we demonstrated that the capture-based ultra-deep targeted sequencing method, which has a LOD of 1% to profile a wide range of actionable variants in surgical specimens of treatment-naive lung adenocarcinoma patients, highlights the need for treatment-naive patients to undergo genomic profiling.

Genetic alterations of driver genes as independent prognostic factors for disease-free survival in patients with resected non-small cell lung cancer.

OBJECTIVES: This study assessed the associations between the molecular signatures and clinical information in non-small cell lung cancer (NSCLC) patients with postoperative disease-free survival (p-dfs) to identify novel prognostic factors, focusing on associations with driver gene alterations. MATERIALS AND METHODS: Between February 2014 and September 2015, 242 patients with NSCLC, including 192 patients with adenocarcinoma (Ad) and 50 patients with squamous cell carcinoma (Sq), underwent surgery and were enrolled in this study. Surgically resected tissues were subjected to whole exome sequencing. Mt detected in 138 cancer-related genes were evaluated as driver mutations. A multivariate analysis using the multi-state model was used to establish the associations between co-variables and p-dfs. RESULTS: Postoperative recurrence (p-rec) was observed in 49 (20.2%) and 19 (7.9%) patients with Ad and Sq, respectively. The median (range) follow-up period for all the censored cases was 2.5 (2.0-3.5) years. The characteristics of the patients with postoperative recurrence were as follows: median age (range), 71 (50-87) years; male, 38 (56%); smoker, 51 (75%); p-stage (I/II/III), 30 (44%)/19 (28%)/19 (28%); histological type (Ad/Sq), 49 (72%)/19 (28%); adjuvant chemotherapy (yes/no), 30 (44%)/38 (56%); and driver gene alteration (presence/absence), 65 (96%)/3 (4%). In univariate analyses, age (<70/≧70 years), smoking history (yes/no), p-stage (I, II/III), histological type (Ad/Sq), and driver mutation (presence/absence) were favorable prognostic factors (P = .017, P = .048, P = .0002, P = .006, P = .029, respectively). A multivariate analysis also revealed a significant association between the driver mutation status and p-dfs (P = .046; odds ratio [OR], 2.86; 95% confidence interval [CI], 1.02-8.08), when adjusted according to histological type (P = .10), smoking status (P = .09), gender (P = .51), age (P = .008) and p-stage (P = .00003). CONCLUSION: The driver mutation status may be an independent prognostic factor of p-dfs in NSCLC.