Brief report: High prevalence of somatic oncogenic driver alterations in non-small cell lung cancer patients with Li-Fraumeni Syndrome
Actionable somatic molecular alterations are found in 15 to 20% of non-small cell lung cancer (NSCLC) in the Caucasians. NSCLC is a tumor observed in patients with germline-<I>TP53 </I>variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown. Retrospective study of clinical and molecular profile of NSCLC in patients with germline-TP53 variants. In 22 NSCLC patients with LFS (n=23 lung tumors), 64% were female, median age 51, 74% non-smokers, 73% with adenocarcinoma histology and 84% were diagnosed with advanced stage disease. These 22 patients harbor 16 distinct germline TP53 variants; the most common was p.R158H (5/22; 3 in the same family). Personal and familiar history of cancer was reported in 71% and 90% of patients, respectively. Lung cancer was in most of the cases (87%, 13/15) a late-onset diagnosis. Among the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19/21 (90%), 18 EGFR-mutations (exon-19 deletions in 12 cases, L858R in 3 cases and G719A, exon-20 insertion, missing mutation subtype, each in one case) and one case with ROS1 fusion. A PI3KCA mutation was concurrently detected at diagnosis in 3 EGFR exon 19 deletion tumors (3/12). The median OS was 37.3 months in 14 patients treated with EGFR-inhibitors; 7 developed resistance, 5 (71%) with acquired EGFR-T790M mutation and one with SCLC transformation. Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations but also one ROS1 fusion. The germline-TP53 variants and lung cancer carcinogenesis driven by oncogenic processes needs further evaluation.