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MS 05 - Tumor Heterogeneity (ID 23)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
MS05.03 - Genomic Evolution and Tumor Heterogeneity (ID 1866)
14:15 - 15:45 | Author(s): W. Westra
Adenocarcinomas represent the most frequent subtype of lung cancer, and they are usually discovered late in the course of the disease even in the setting of vigilant radiographic and cytologic screening. Despite improvements in molecular diagnosis and targeted therapies, the average 5 year-survival rate for lung adenocarcinoma remains only 15%. Novel strategies based on the detection of genetic markers offer new hope for improved risk assessment, early cancer detection, therapeutic intervention and tumor surveillance, but the impact of these strategies has been limited by an incomplete understanding of the biology of lung cancer, particularly in its early developmental stages. Disappointingly, relatively few genetic alterations critical to the development of lung adenocarcinomas are currently recognized, and the timing and manner by which these alterations initiate and drive glandular neoplasia remains to be delineated. Recent refinements in the histologic classification of lung adenocarcinomas provide greater resolution of the sequential steps of glandular lung neoplasia. Atypical adenomatous hyperplasia (AAH) is a microscopic discrete focus of cytologically atypical type II pneumocytes and/or Clara cells[5-6]. Once dismissed as a reactive change, AAH is now regarded as the first histologic step in a morphologic continuum culminating in the fully malignant adenocarcinoma. The link between AAH and invasive adenocarcinoma is strong and compelling: 5-20% of lungs resected for primary adenocarcinomas also harbor AAH, and AAH harbors some of the same genetic and epigenetic alterations found in adenocarcinomas including KRAS mutations, EGFR mutations, loss of heterozygosity at 9q and 16p, TP53 mutations, and epigenetic alterations in the WNT pathway. Like AAH, adenocarcinoma in situ (AIS) (formerly known as bronchioloalveolar carcinoma, BAC) is recognized as a non-invasive form of glandular neoplasia, but one that exhibits increased size, cellularity and morphologic atypia. In effect, it represents a next step in the continuum towards malignant adenocarcinoma. Minimally-invasive adenocarcinoma (MIA) is defined as a small adenocarcinoma (≤ 3cm) with a predominantly lepidic pattern and invasion of 5 mm or less in any one focus. Invasive growth is present, albeit so limited that these carcinomas have been associated with 100% disease free survival[7,8]. This enhanced delineation of early glandular neoplasia provides a rational histologic framework for studying the timing of genetic alterations driving the early stages of lung tumorigenesis. “Branched evolutionary tumor growth” is the concept that cancers evolve by a repetitive process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. In this study, to determine whether this phenomenon is operational during early stages of tumor progression, we evaluated lung glandular neoplasms spanning the full spectrum of early histologic progression using next generation sequencing (NGS) of coding regions from 125 well-characterized cancer-driving genes. We specifically targeted multifocal AAHs and advancing zones of histologic progression within individual AISs and MIAs. This multi-region sequencing revealed that clonal expansion is an early event that can be confirmed even in the earliest recognized step in glandular neoplasia. Moreover, the identification of significant genetic alterations such as KRAS mutations, loss of P53 activity and EGFR activation points to the presence of functionally relevant “drivers” that empower territorial expansion of subclones en route to malignancy. Importantly, these driver alterations are potentially measurable in clinical samples. Using ultra-sensitive droplet digital PCR (ddPCR), mutant DNA associated with early lesions was detected in a patient’s plasma and sputum providing proof of principle that even the earliest stages of glandular neoplasia can be detected via analysis of circulating DNA (circDNA). Our study provides the unique insight into the genetic alterations that initiate and drive the progression of lung glandular neoplasia and underlines the need for precise definition of these events to improve proper diagnosis and early detection of tumors. 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Histologic features are important prognostic indicators in early stages lung adenocarcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20, 233-241, doi:10.1038/modpathol.3800734 (2007). 9. Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306-313, doi:10.1038/nature10762 (2012).
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