RAS activation and CDKN2A deletion to predict prognosis in cancer of unknown primary.

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e13026 Background: Cancer of unknown primary (CUP) denotes a malignancy with histologically confirmed metastatic spread while the primary tumor remains elusive. Given the typically dismal response to empiric chemotherapy, the deciphering of molecular profiles holds a particular promise for targeted therapy. Here, we address the prognostic implications of mutations and copy number variations (CNVs) detected in tumor tissue in the context of a comprehensive clinical risk assessment. Methods: We performed targeted panel sequencing in a series of 252 CUP patients. Median age was 60.3 years and 59.1% were female. 71.2% of patients had unfavorable CUP. Lymph nodes, bone marrow, lung, peritoneum and pleura were the most frequent metastatic sites. Among histologic subtypes, adeno- (74.7%) and squamous cell carcinomas (13.7%) prevailed. DNA was extracted from micro-dissected formalin-fixed, paraffin-embedded tissue samples. For library preparation mostly multiplex PCR-based Ion Torrent AmpliSeq technology (Life Technologies) with Oncomine comprehensive assays v1 and v3 was used. Results: The prevailing genetic alterations were deletions in tumor suppressor genes TP53 (49.6%), CDKN2A (19.0%) and NOTCH1 (14.1%) as well as oncogenic activation of KRAS (23.4%), FGFR4 (14.9%) and PIK3CA (10.7%). KRAS activation was predominantly found in adenocarcinomas (p = 0.01) and PIK3CA activation in squamous cell carcinomas (p = 0.03). Regarding prognosis, male sex, high ECOG score, unfavorable CUP subtype, a higher number of involved organs as well as RAS activation predicted decreased event-free and overall survival in multivariate analysis. Deletions in CDKN2A were a poor prognostic factor regarding overall survival. Markedly, TP53 mutations did not significantly influence prognosis. Since July 2015, 17/198 (8.6%) patients received a recommendation for molecularly guided therapy. However, due to lack of coverage by insurers or rapid clinical deterioration only 7 of these patients (3.5%) actually received targeted treatment. Conclusions: Besides offering targets for therapy, targeted panel sequencing in CUP is prognostically relevant, with RAS activation and CDKNA2 deletion emerging as independent risk factors in a comprehensive assessment with clinical risk factors.