Comprehensive genomic profiling of Finnish lung adenocarcinoma cohort reveals high clinical actionability and SMARCA4 altered tumors with variable histology and poor prognosis.

INTRODUCTION: Lung adenocarcinoma is the most common type of lung cancer and typically carries a high number of mutations. However, the genetic background of the tumors varies according to patients' ethnic background and smoking status. Little data is available on the mutational landscape and the frequency of actionable genomic alterations in lung adenocarcinoma in the Finnish population. MATERIALS AND METHODS: We evaluated the gene alteration frequencies of 135 stage I-IV lung adenocarcinomas operated at Turku University Hospital between 2004 and 2017 with a large commercial comprehensive genomic profiling panel. Additionally, we correlated the alterations in selected genes with disease outcomes in 115 stage I-III patients with comprehensive follow-up data. The genomic alterations in a sub-cohort of 30 never-smokers were assessed separately. RESULTS: Seventy percent of patients in the overall cohort and 77% in the never-smoker sub-cohort harbored an alteration or a genomic signature targetable by FDA and/or EMA approved drug for non-small cell carcinoma, respectively. In multivariable analysis for disease-specific survival, any alteration in SMARCA4 (DSS; HR 3.911, 95%CI 1.561-9.795, P=0.004) exhibited independent prognostic significance along with stage, tumor mutation burden, and predominant histological subtypes. CONCLUSIONS: Over two thirds of our overall cohort, and especially never-smokers had an actionable genomic alteration or signature. SMARCA4 alterations, detected in 7.4% of the tumors, independently predicted a shortened overall and disease-specific survival regardless of the alteration type. Most SMARCA4 alterations in our cohort were missense mutations associated with differentiated predominant histological subtypes and immunohistochemical SMARCA4/BRG1 and TTF-1 positive status.

High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study.

OBJECTIVES: Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines. MATERIALS AND METHODS: 176 surgically resected stage I-IV lung adenocarcinomas were histologically reclassified according to WHO 2015 guidelines. A modified classification subdividing the acinar subtype into classic acinar, complex glandular and cribriform subtypes was further applied and potentially prognostic histopathological characteristics such as tumor-infiltrating lymphocytes were evaluated. 148 patients with stage I-III tumors and complete follow-up data were included in the survival analyses. TMB was determined by a commercial next generation sequencing panel from 131 tumors, out of which 105 had survival data available. RESULTS: Predominant micropapillary, solid and complex glandular as well as nonpredominant cribriform histological subtypes were associated with significantly shorter survival. High TMB concentrated in micropapillary, solid and acinar predominant subtypes. Interestingly, TMB ≥ 14 mutations/MB conferred a stage- and histology-independent survival benefit compared to TMB < 14 in multivariable analysis for overall (HR 0.284, 95% CI 0.14-0.59, P=0.001) and disease-specific survival (HR 0.213, 95% CI 0.08-0.56, P=0.002). CONCLUSION: TMB was an independent biomarker of favorable prognosis in our cohort of lung adenocarcinoma despite being associated with predominant histological subtypes considered aggressive.

Retrospective Evaluation of Lung Adenocarcinoma Patients Progressing on 1st Line Chemotherapy.

Background and Objectives: Evaluation of data from electronic health care records could help in guiding towards more rational drug treatments. This single center study evaluated clinical characteristics that could be associated with disease progression. Methods: This was a real world data (RWD) study using existing data from the registries of a university hospital. Patients had lung adenocarcinoma and they had received 1st line treatment. Treatment patterns and survival parameters were characterized and clinical characteristics of the patients were evaluated together with their association with disease progression. Results: 80 stage III/IV patients fulfilling inclusion criteria were identified. Mean age was 62 years and 61% were men. In total, 65% were current smokers and 82% had performance status (ECOG) 0/1. Median progression free survival (mPFS) and median overall survival (mOS) for stage III and IV patients were 8.5 and 5.4 months, and 21.9 and 8.6 months, respectively. The study found that 69% of patients progressed within 9 months from the start of the 1st line treatment. Poor performance status (ECOG 3), male gender, and smoking suggested faster disease progression. Most had received cis/carboplatin-based treatment in the 1st line. Cisplatin regimens were associated with more complete responses and better PFS and OS than the carboplatin ones. Conclusions: By combining algorithmic and manual validation of electronic health care records, clinically valid characteristics and outcomes could be evaluated and presented. This approach forms a basis for tools such as quality registries that can guide treatment decisions.