Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.

BACKGROUND:The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation. METHODS: The study investigated 78 EGFR-mutant patients who had undergone rebiopsy after TKI failure. The peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method was used in EGFR mutational analyses. Various patient characteristics and postprogression survivals (PPSs) after initial TKI failure were retrospectively compared in patients with and without T790M. RESULTS: The T790M mutation was identified in 4 (17%) of 24 central nervous system lesions, and in 22 (41%) of 54 other lesions (P 5.0417). No other characteristics had a statistical association with T790M prevalence. Median PPS was 31.4 months in 26 patients with T790M, and 11.4 months in 52 patients without T790M (P 5.0017). In the multivariate analysis, statistically significant factors for longer PPS included T790M-positive, good performance status, and no carcinomatous meningitis. CONCLUSIONS: The emergence of T790M in central nervous system lesions was rare, compared with other lesions. Patients with T790M after TKI failure appear to have better prognoses than those without T790M. TKI rechallenge or continuous administration beyond progression may be effective after initial TKI failure. Cancer 2013;119:4325-32.

CT-guided lung biopsy has a high diagnostic accuracy. Complication rates were acceptable and comparable to those of previous studies.

7528 Background: The secondary epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitors (TKI). A recent report has demonstrated the presence of T790M predicts a favorable prognosis and indolent progression, compared to the absence of T790M after TKI failure. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M. Methods: We investigated 73 patients harboring EGFR sensitive mutations who had undergone rebiopsy to confirm the emergence of T790M after TKI failure. The peptide nucleic acid-locked nucleic acid PCR clamp method was used in EGFR mutational analyses. Patient characteristics (age, gender, smoking history, performance status, EGFR mutation site, initial TKI, response to initial TKI, line of initial TKI, progression-free survival with initial TKI, and biopsy site) and postprogression survivals (PPS) after initial TKI failure, were retrospectively compared in patients with and without T790M. Results: We identified T790M in 2 (10%) of 21 central nervous system (CNS) (19 cerebrospinal fluid and 2 brain tissue) specimens, and in 20 (38%) of 52 other lesions (25 lung tissue, 24 pleural effusion, and 3 lymph node) (p = 0.0225). Other characteristics had no statistical association with the detection of T790M. Median PPS in patients with T790M was 34.0 months, and in those without T790M, 14.5 months (p = 0.0038). Although none of our patients received TKIs continuously after initial failure, 56 (77%) patients were re-administered TKIs. Regardless of T790M status, PPS in patients with TKI re-administration (23.4 months) was significantly longer than without re-administration (10.4 months) (p = 0.0085). Conclusions: The emergence of T790M in CNS is rare compared with other lesions. Patients with T790M after TKI failure have significantly better prognosis than those without T790M. The effectiveness of TKI re-administration or continuous administration beyond progression is suggested after initial TKI failure.

High-dose erlotinib suggested its efficacy and safety in some patients with refractory LM. It represents a potential therapeutic option against LM after failure of standard-dose EGFR-TKIs, especially to palliate LM-related neurological symptoms.