Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20–50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/−3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/−22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.
Malignant pleural mesothelioma (MPM) is an incurable cancer with a dismal prognosis and few effective treatment options. Nonetheless, recent positive phase III trial results for immune checkpoint blockade (ICB) in MPM herald a new dawn in the fight to advance effective treatments for this cancer. Tumor mutation burden (TMB) has been widely reported to predict ICB in other cancers, but MPM is considered a low-TMB tumor. Similarly, tumor programmed death-ligand 1 (PD-L1) expression has not been proven predictive in phase III clinical trials in MPM. Consequently, the precise mechanisms that determine response to immunotherapy in this cancer remain unknown. The present review therefore aimed to synthesize our current understanding of the tumor immune microenvironment in MPM and reflects on how specific cellular features might impact immunotherapy responses or lead to resistance. This approach will inform stratified approaches to therapy and advance immunotherapy combinations in MPM to improve clinical outcomes further.
Background: Dumon silicone Y-stent is useful for releasing the tracheobronchial stenosis. We often encounter patients with tumors involving the carina between the bronchus to the right upper lobe and bronchus intermedius. However, there has not been ideal stenting for such cases, especially to maintain the patency of the right upper lobe bronchus. We investigated the clinical outcome in patients with malignant tracheobronchial stenosis, especially focused on the patency of right upper lobe bronchus after Y-stent placement. Method: From January 2012 until December 2018, 102 patients who had placed Y-stent on malignant tracheobronchial stenosis in our department were examined retrospectively. This study involved 73 male and 29 female. The mean age was 64 years (range, 30-91 years). Fifty-nine patients had lung cancer, 29 had esophageal cancer, and 14 had other carcinomas. All procedures were carried out in the operating room under general anesthesia, and the stents were implanted via rigid bronchoscopy. The patients were divided into two groups based on the patency of right upper bronchus: patency group (P group, n¼73) and stenosis /occlusion group (S group, n¼29). The clinicopathological features, clinical course, and the survival after stenting of the groups were compared. Result: Stents were implanted and symptoms were resolved in all cases. No operative death occurred. Stent indwelling types were only Y-stent in 69 patients and Y-stent with additional self-expanding metallic stent (SEMS) in 33. Although there was no difference between the two groups in age, gender, preoperative Hugh-Jones classification, hospitalization days, and size of Y-stent, esophageal cancer was significantly more frequent in P group. The total length of placed stent was significantly longer in S group (median 10.5cm) compared to P group (8cm) (p<0.01) and the postoperative Hugh-Jones classification (I or II) in S group (47%) was inferior compared to the P group (72%). After stent placement, 67% of the P group could be treated chemotherapy/radiotherapy to primary disease, while only 43% of the S group was received these because of their poor general condition (p ¼ 0.03).The median survival time (MST) and 1-year survival rate of the two groups was 7 months and 32% (P group), and 2 months and 17% (S group), respectively (p<0.01). Conclusion: The patency of right upper lobe bronchus after Y-stent placement affects not only the improvement of postoperative Hugh-Jones classification but also the administration of subsequent treatment to primary disease and associated to their clinical outcome.
e20534 Background: Targeting of the immune inhibitory PD1-PDL1 axis has proven clinically effective in mesothelioma, despite a low somatic mutation burden, and high rate of CDKN2A deletion. Tumour responses to anti PD1 or PDL1 immune checkpoint inhibition are heterogeneous, and the factors underpinning sensitivity remain poorly understood. We therefore addressed this knowledge gap through multi-omic interrogation of tumours from patients enrolled into arm 4 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST4), a multi-centre single arm phase IIA trial of atezolizumab and bevacizumab in patients with relapsed mesothelioma. Methods: Next generation sequencing of whole exomes (mesotheliomas and matched germline DNA), transcriptomes, and 16sRNA to profile gut microbiota were undertaken. Spatial phenotyping of the immune landscape employed multiplex immunofluorescence analysis using a 19x depth 4 panel detection. Tumour proportion score (TPS) for PDL1 was assessed using the 22C3 clone, and BAP1, p16ink4a assessed by immunohistochemistry. The MIST4 cohort was dichotomised by best tumour response (50:50) into those patients exhibiting any tumour reduction (R) versus those without (NR). Machine learning (boosting and bagging) was employed to decipher correlates of response. Results: Tumour responses correlated with progression-free survival (PFS, p = 0.0003). Neither PDL1 TPS or CDKN2A expression were predictive. The NR group exhibited a greater degree of genomic instability with higher somatic copy number burden (p = 0.02), homologous recombination deficiency (HRD, p = 0.03), and uniparental disomy (UPD, p = 0.01). Notably the burden of nonsynonymous mutations and neoantigens did not differ significantly between groups. The NR group was transcriptionally enriched for epithelial mesenchymal transition (p < 0.05). Conversely, 16s RNA sequencing revealed higher gut microbial diversity in the R group compared with NR (Shannon index p = 0.009) with R-group enrichment of the type 2 enterotype (provotella 33% vs 9%). R-group enriched genera comprised prevotella, butyricicoccus, bilophilla, Eubacterium ventriosum, whereas the NR group was enriched for erysipelatoclostidium. The log ratio of genera, ie. Log[GR/GNR] was 2-log higher for the R group (p < 0.0001) vs NR group, and was highly predictive of response (with an area under the receiver operator curve of 0.99). Log[GR/GNR] positively correlated with tumour CD8 T cell infiltration (r = 0.6, p = 0.05) and PFS (p = 0.04), but negatively with CD68 monocyte infiltration (p = 0.05), UPD (p = 0.008) and HRD (p = 0.05). Conclusions: We propose a model in which interacting tumour intrinsic and extrinsic factors correlate with response to PDL1-VEGF inhibition in patients with mesothelioma. Gut microbiota composition represents a new, potentially modifiable target with potential to improve immunotherapy outcomes in patients with mesothelioma. Clinical trial information: NCT03654833 .
8506 Background: Leveraging adaptive immunity to control mesothelioma is now a standard approach, however the factors that underpin clinical response are poorly understood. Here we report the final analysis of the CONFIRM trial (NCT03063450), a double-blind phase III randomized study of the PD-1 inhibitor nivolumab (N) versus placebo (P) in patients (pts) with unresectable mesothelioma. Genomic, transcriptomic and multiplex spatial phenotypic correlates were explored in mesotheliomas exhibiting either partial response or progressive disease as their best outcome. Methods: Pts with relapsed pleural or peritoneal mesothelioma with ECOG performance status 0–1 were randomized 2:1 to N (3 mg/kg) or P once every 2 weeks until progression, or a maximum of 12 months. Pts were stratified by epithelioid (E) vs non-epithelioid (NE) histology. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS); key secondary endpoints included best overall response, safety and tolerability. PD-L1 tumour proportion score (TPS, Dako22C3) was evaluated. To decipher correlates response to N, blinded multi-omic analysis was conducted in a subset of responders (R, n=16) versus progressors (NR, n=13). Whole exomes (WES) and transcriptomes were sequenced, with immune landscapes profiled by 19x depth 4-panel multiplex immunofluorescence. Acquired resistance was explored by WES in a biopsied responder at the time of progression. Results: Between April 2017-March 2020, 332 pts were randomised to N (n=221) or P (n=111). Median follow up was 37.2m. Baseline characteristics were balanced between arms. Histology: E 88.3%, 3rd line or greater 69.9%. PFS was longer for N vs P (events=324; median, 2.9 vs 1.6 months; HR 0.65; 95% CI, 0.51 – 0.82; P<0.001). Crossover from P was 18.0% (due to widespread availability of N during the covid19 pandemic). OS curves crossed at 32m; 9.5 vs 6.8 months; HR, 0.81; 95% CI, 0.64 – 1.04; P=0.096). Grade 3-4 treatment-related toxicity occurred in 20.4% vs 7.2% of pts; discontinuation occurred in 13.6% (N) versus 9.9%. PD-L1 TPS was not predictive of PFS or OS. The R-subgroup had longer PFS versus NR (319 versus 30 days, Hazard ratio, HR 0.02, p<0.001) and OS (670 vs 122 days HR 0.19, p<0.001). The R-group were enriched for BAP1 inactivation, CD8+ T-cell infiltration, T cell co-stimulation, cytolytic activity and mature tertiary lymphoid structures (TLSs). Conversely, the NR group had significantly more aneuploidy (notably uniparental disomy, UPD), and enrichment of epithelial mesenchymal transition, TGF beta signalling, and E2F transcription. Acquired resistance was associated with increased aneuploidy (UPD) and subclonal evolution including a new DNMT3A c2204A>G mutation. Conclusions: N met its co-primary endpoint of PFS with responding mesotheliomas harbouring a TLS enriched, inflamed tumour microenvironment and stable genome compared to non-responders. Clinical trial information: NCT03063450 .
Background: Mesothelioma, a cancer caused by asbestos is lethal and lacks molecularly targeted therapy. The tumor suppressor NF2 constitutes a frequent, positively selected somatic alteration warranting synthetic lethal approaches to target this driver. NF2 inactivation drives nuclearization of YAP to mediate TEAD dependent oncogenic transcriptional program. YAP is stabilized by CDK7 through phosphorylation of S169/S128/S90, inhibiting the E3 ligase complex CDL4DCAF12. We hypothesized that biallelic NF2 inactivation would be vulnerable to augmentation of CRL4DCAF12 through inhibition of CDK7. Methods: 50 Patients (the MEDUSA cohort) undergoing routine extended pleurectomy decortications consented to have multiregional sampling of their mesotheliomas at resection at 4-5 stereotyped locations, followed by multiregional whole exome sequencing (mWES 200x), phylogenetic deconvolution and transfer learning to examine evolutionary trajectories. Bulk RNA sequencing enabled gene set enrichment analysis, and spatial YAP phenotyping using tissue microarrays were conducted on the mWES profiled cohort. Primary cell lines were generated from a subset of mesotheliomas and whole exome sequenced. Results: NF2 exhibited biallelic inactivation involving copy number/mutation allelic heterogeneity in 42% of mesotheliomas. Double hits were predominantly clonal. Hippo signalosome exhibited additional clonal somatic alterations in 26% of mesotheliomas, with biallelic inactivation being observed in LATS2 (8%) and LATS1 (4%). Transfer learning identified NF2 inactivation as a predominantly secondary clonal event, constituting an evolutionary bottleneck. Random forest analysis revealed YAP dependent transcription, epithelial mesenchymal transition and spindle checkpoint transcriptional signature enrichments in NF2 double hit mesotheliomas. We conducted drug screening of NF2 wild type versus inactivated primary mesothelioma cell lines, which revealed selective sensitivity to CDK7 inhibitors THZ1 and YKL-5-124 in NF2 inactivated but not wild type MEDUSA cell lines. Conclusions: NF2 biallelic inactivation constitutes an evolutionary bottleneck during early mesothelioma evolution, associated with a specific vulnerability to CDK7 highlighting a potential path to clinical stratified therapy. Citation Format: Essa Y. Baitei, Min Zhang, Qianqian Sun, Jin-Li Luo, Philip Zhang, Tamihiro Kamata, James Harber, Aleksandra Bzura, Peter W. Jordan, Charlotte Poile, Alan Dawson, Apostolos Nakas, Cathy Richards, Hongji Yang, Ed Hollox, Dean A. Fennell. Clonal biallelic inactivation of NF2 is an evolutionary bottleneck that exposes a vulnerability to CDK7 inhibition in mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6086.
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