Background/objectives: Non-small cell lung cancer and pleural mesothelioma are among the most lethal and therapy-resistant tumors in humans. These tumors are diagnosed late, frequently present pleural effusion and develop drug resistance, and the treatment is often inefficient and largely alliative. Therefore, there is an urgent need to refine the selection of drugs and patients for personalized treatment. Methods: To progress the field, we performed a systematic literature review in line with the PRISMA guidelines followed by a narrative synthesis approach to identify themes. Results: The literature to date shows, in general, a positive correlation between the drug-sensitivity of patient-derived cells ex vivo and the clinical outcome. However, only a handful of these studies show a numerical correlation. This, along with the vast diversity of correlated techniques and parameters makes it difficult to directly compare the findings. To build a common knowledge base for future studies, we therefore offer a comprehensive summary of the literature, identify gaps, and suggest future avenues for research. Conclusions: We present unified recommendations for the collection, preparation, and ex vivo sensitivity testing of samples for the future development of personalized medicine.

Background: Tumors of the pleura, such as metastatic lung cancer and mesothelioma, are amongst the most lethal and therapy-resistant tumors. The first manifestation of the disease is often pleural effusion, the first available material for diagnosis. The five-year survival rate is exceptionally low, around 10–20%, and only a small proportion of patients harbor mutations that allow targeted treatments. Almost all patients develop resistance to treatment, which is often palliative. There is therefore an urgent need to refine the selection of drugs and patients for personalized treatment. Methods: We isolated and cultured cells from pleural effusions in 3D cell aggregates and compared their drug sensitivity ex vivo to the clinical response to the same chemotherapeutic agents, combined with targeted sequencing and network analysis. Results: The ex vivo drug response showed a positive correlation with the treatment response and survival of patients in the clinic, with a stronger link to overall survival than to progression-free survival. Cryopreserved cells showed a similar response to freshly collected cells from the clinic. Conclusions: The findings advance the field of ex vivo screening and present an opportunity to combine strategies for functional precision medicine with comprehensive characterization of disease for improved treatment and future management of lung cancer.