EGFR, KRAS, BRAF and ALK gene alterations in lung adenocarcinomas: patient outcome, interplay with morphology and immunophenotype

Abstract

Numerous studies have been published on single aspects of pulmonary adenocarcinoma (ADC). To comprehensively link clinically relevant ADC characteristics, we evaluated established morphological, diagnostic and predictive biomarkers in 425 resected ADCs.Morphology was reclassified. Cytokeratin-7, thyroid transcription factor (TTF)1, napsin A, thymidylate synthase and excision repair cross-complementing rodent repair deficiency complementation group-1 expression, anaplastic lymphoma kinase rearrangements as well as epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) and v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) mutations were analysed. All characteristics were correlated with clinical and survival parameters.Morphological ADC subtypes were significantly associated with smoking history and distinct patterns of diagnostic biomarkers. KRAS mutations were prevalent in male smokers, while EGFR mutations were associated with female sex, nonsmoking and lepidic as well as micropapillary growth patterns. TTF1 expression (hazard ratio (HR) for overall survival 0.61, p50.021) and BRAF mutations (HR for disease-free survival 2.0, p50.046) were found to be morphology-and stage-independent predictors of survival in multivariate analysis. Adjuvant radio-/chemotherapy, in some instances, strongly impacted on the prognostic effect of both diagnostic and predictive biomarkers.Our data draw a comprehensive picture of the prevalence and interplay of established histological and molecular ADC characteristics. These data will help to develop time-and cost-effective diagnostic and treatment algorithms for ADC. @ERSpublications Morphological, diagnostic and predictive biomarkers, and clinical characteristics of pulmonary adenocarcinomas

Synergistic effects of crizotinib and radiotherapy in experimental EML4–ALK fusion positive lung cancer

“…Chromosomal rearrangements between Echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) are found in 3-7% of NSCLC patients [7,8]. EML4-ALK fusions are predominantly detected in adenocarcinomas of female light smokers (<10 pack years) or non-smokers at a younger age, and are mutually exclusive with epidermal growth factor receptor (EGFR) or KRAS mutations [9].…”

Diagnose, Prognose und Prädiktion nicht-kleinzelliger Lungenkarzinome

“…Hinzu kommt die Schwierigkeit, dass die Marker jeweils mit der zellulären Differenzierung assoziiert sind, d. h. bei morphologisch nicht klassifizierbaren Tumoren öfters nur fokal oder gar nicht mehr exprimiert sind. Dies zeigt sich exemplarisch in ADC, in welchen die Expression von TTF-1 und Napsin jeweils mit einem signifikant besseren Überleben assoziiert ist ( [33]; . Abb.…”

“…Dies erfordert die systematische Analyse großer Kohorten, um die prognostische Bedeutung im natürlichen Verlauf der Erkrankung zu untersuchen. Für ADC zeigte sich hierbei kein signifikanter prognostischer Effekt für KRAS-, EGFR-und ALK-, jedoch ein deutlich negativer Effekt für BRAF-Mutationen [33]. ROS1-Translokationen finden sich wiederum eher in gut differenzierten ADC und sind möglicherweise mit einer leicht besseren Prognose assoziiert [26].…”

“…Hierbei erscheint es unumgäng-lich, klinische, bildgebende, morphologische und molekulare Charakteristika integriert zu analysieren. Dies erfordert jedoch einerseits sehr große Kohorten, andererseits führen entsprechende Analysen unvermeidbar zu komplexen Assoziationen, welche bezüglich ihre prognostischen Bedeutung neu kategorisiert werden müssen ( [33], . Abb.…”

Predictive biomarkers in patients with resected non-small cell lung cancer treated with perioperative chemotherapy

“…The trials would require a large cohort and a long follow-up in order to come to any firm conclusions, and they must take into account the rarity of this abnormality (4-5% of metastatic NSCLC, with no data on its frequency in early-stage disease). Other rare mutation events, such as B-Raf mutations [19], could potentially also have their own targeted therapy and appear to have a predictive value for efficacy of the specific kinase inhibitors in preliminary phase I studies [20]; however, they only represent 1-2% of NSCLC, with no available data in stage I-II patients. Finally, all available molecular-targeted therapies have been developed in non-squamous NSCLC, predominantly adenocarcinoma, and there is currently no predictive marker for any drug in squamous cell carcinomas, which still represent 30% of NSCLC.…”