Biological Pathways Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy: A Preliminary Study

Abstract

Radical hemithoracic radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of biological pathways, retrieved through whole exome sequencing (WES), possibly associated to the development of lung adverse effects in MPM patients treated with RHR. The study included individuals with MPM, treated with lung-sparing surgery and chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the strong impact of grade 3 pulmonary toxicities on the quality of life, compared with less serious adverse events, for genetic analyses, patients were divided into a none or tolerable pulmonary toxicity (NoSTox) group (grade ≤2) and a severe pulmonary toxicity (STox) group (grade = 3). Variant enrichment analysis allowed us to identify different pathway signatures characterizing NoSTox and Stox patients, allowing to formulate hypotheses on the protection from side effects derived from radiotherapy as well as factors predisposing to a worst response to the treatment. Our findings, being aware of the small number of patients analyzed, could be considered a starting point for the definition of a panel of pathways, possibly helpful in the management of MPM patients.

Immune marker expression of irradiated mesothelioma cell lines

“…The inflammatory cytokine profile and mechanisms of PD-L1 or MHC-I upregulation may also be of importance to predicting toxicities associated with delivering combined RT and ICI. A recent study of a small group of mesothelioma patients treated with radical hemithoracic RT showed that signaling pathways associated with inflammatory and fibrotic processes were upregulated in patients with no or low-grade toxicity following RT and ICI treatment, compared to those experiencing high grade toxicities ( 39 ). Overall, these results warrant further characterization of the role of these cytokines in tumor marker expression and particularly in antitumor immune responses in vivo .…”

The Genes–Stemness–Secretome Interplay in Malignant Pleural Mesothelioma: Molecular Dynamics and Clinical Hints

“…In this perspective, it has been reported that specific variants in three genes associated with iron metabolism, namely, ferritin, transferrin, and hephaestin, are significantly associated with protection against the development of MPM [ 26 , 27 ]. Moreover, different pathway signatures have been detected in MPM samples from patients in response to tissue damage after lung-sparing surgery, chemotherapy, and radical hemi-thoracic radiotherapy treatment with curative intent [ 28 ]. Due to their role in the inflammasome, polymorphisms of NLRP1 and NLRP3 genes have been hypothesized to be involved in determining genetic susceptibility to MPM [ 29 ].…”

Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers

“…In a previous study, we identified different pathway signatures associated with the development of pulmonary toxicity in mesothelioma patients treated with radical hemithoracic radiation therapy, using VEA. This allowed us to formulate some hypotheses on the protection from side effects derived from radiotherapy and on factors predisposing to a worst response to the treatment [ 32 ].…”