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Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA–IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D . After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40–10.3, P  = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4–2.0, P  = 1.2 × 10 –10 ). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.

Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA . Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1 /2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Purpose Erlotinib is active in advanced non-small cell lung cancer (aNSCLC) particularly in patients with EGFR -sensitizing mutations. The thymidylate synthase inhibitors are active in NSCLC, but capecitabine is not well studied. This study explored the safety and activity of this oral combination. Methods This phase Ib trial used a 3 + 3 escalation design with a combination of erlotinib (100 mg daily) with increasing doses of capecitabine (500, 750 and 1000 mg/m 2 BD, 14/21 days), in first- and second-line aNSCLC of adenocarcinoma histology. The DLT was any drug-induced toxicity ≥grade (G)2 causing dose interruption or dose delay during the first 2 cycles. Results Forty patients were recruited, and 1 patient had an EGFR mutation. Dose escalation stopped at capecitabine 1000 mg/m 2 with expansion to 6 patients due to unpredicted DLTs in 2/6 patients: G2 creatinine rise, G2 anaemia, G3 atrial fibrillation and G3 pneumonia. MTD was capecitabine 750 mg/m 2 . First-line dose escalation at the MTD led to unpredicted DLTs in 3/4 patients (G3 troponin rise, G2 rash and G2 hyperbilirubinaemia). MTD expansion in the second-line setting was well tolerated. The most common drug toxicities were gastrointestinal (35 %), followed by skin disorders (28 %). The response rate was 3 % with a disease control rate of 34 %. Median progressive-free survival was 1.6 months (95 % CI 1.4–3.5), and median overall survival was 6.1 months (95 % CI 5.1–10.1). Conclusion The MTD for the combination of capecitabine and erlotinib is 750 mg/m 2 BD, 14/21 days, and 100 mg daily, respectively, which is lower than predicted. Capecitabine did not improve the efficacy of erlotinib in aNSCLC unselected for EGFR mutation.