Waree Rinsurongkawong

Mortality in the Randomized, Controlled Lung Intergroup Trial of Isotretinoin

In 2001, we reported that mortality may have been higher with isotretinoin (30 mg/d for 3 years) than with placebo in the subgroup of current smokers among the 1,166 patients with definitively resected early-stage non–small cell lung cancer who participated in the randomized, controlled Lung Intergroup Trial. We report the overall and cause (cancer, cardiovascular disease, or other)-specific mortality associated with long-term isotretinoin after an extended median follow-up of 6.2 years that included the capture of cause-of-death data from 428 deceased patients. Overall mortality was 36.7% in each of the two trial arms, about two thirds related to cancer and one third to other or unknown causes. Overall and cancer deaths increased in current smokers in the isotretinoin arm during the treatment and the extended follow-up period. No mortality end point increased among never smokers and former smokers taking isotretinoin, and cancer deaths decreased marginally in this combined subgroup. Isotretinoin also increased deaths from cardiovascular disease in current smokers. The present analysis supports the safety of protracted isotretinoin use in the combined group of never smokers and former smokers, which has important public health implications, for example, for treating acne in young people. The increased mortality in current smokers in this study is further evidence of the multifaceted danger of active smoking. The overall indications of this study have public health implications for treating acne in young people and other uses of retinoids in smokers. Cancer Prev Res; 3(6); 738–44. ©2010 AACR.

Building networks with microarray data.

This chapter describes methods for learning gene interaction networks from high-throughput gene expression data sets. Many genes have unknown or poorly understood functions and interactions, especially in diseases such as cancer where the genome is frequently mutated. The gene interactions inferred by learning a network model from the data can form the basis of hypotheses that can be verified by subsequent biological experiments. This chapter focuses specifically on Bayesian network models, which have a level of mathematical detail greater than purely conceptual models but less than detailed differential equation models. From a network learning perspective the most severe problem with microarray data is the limited sample size, since there are usually many plausible networks for modeling the system. Since these cannot be reliably distinguished using the number of samples found in current microarray data sets, we describe robust network learning strategies for reducing the number of false interactions detected. We perform preliminary clustering using co-expression network analysis and gene shaving. Subsequently we construct Bayesian networks to obtain a global perspective of the relationships between these gene clusters. Throughout this chapter, we illustrate the concepts being expounded by referring to an ongoing example of a publicly available breast cancer data set.

Targeted Tissue and Cell-Free Tumor DNA Sequencing of Advanced Lung Squamous-Cell Carcinoma Reveals Clinically Significant Prevalence of Actionable Alterations

Background: Major guidelines do not recommend routine molecular profiling of lung squamous‐cell carcinoma (LUSC) because the prevalence of actionable alterations is thought to be low. Increased utilization of next‐generation sequencing (NGS), particularly with cell‐free circulating tumor DNA, facilitates reevaluation of this premise. Patients and Methods: We retrospectively evaluated the prevalence of actionable alterations in 2 distinct LUSC cohorts totaling 492 patients. A total of 410 consecutive patients with stage 3B or 4 LUSC were tested with a targeted cell‐free circulating DNA NGS assay, and 82 patients with LUSC of any stage were tested with a tissue NGS cancer panel. Results: In the overall cohort, 467 patients (94.9%) had a diagnosis of LUSC, and 25 patients (5.1%) had mixed histology with a squamous component. A total of 10.5% of the LUSC subgroup had somatic alterations with therapeutic relevance, including in EGFR (2.8%), ALK/ROS1 (1.3%), BRAF (1.5%), and MET amplification or exon 14 skipping (5.1%). Sixteen percent of patients with mixed histology had an actionable alteration. In the LUSC subgroup, 3 evaluable patients were treated with targeted therapy for an actionable alteration; all of them experienced partial response. Conclusion: In this large, real‐world LUSC cohort, we observed a clinically significant prevalence of actionable alterations. Accurate local histopathologic assessment in advanced‐stage LUSC can be challenging. Further evaluation of the genomic landscape in this setting is warranted to potentially identify underappreciated treatment options.