KRAS Mutation: Characterization and Its Impact on Survival Outcome of Patients with Metastatic Colorectal Cancer.

INTRODUCTION: Colorectal cancer (CRC) is one of the most common cancer types, with rising incidence due to imbalanced lifestyle and dietary habit. Association between CRC cases and KRAS mutation has been established recently. Brunei Darussalam, located within the Borneo island, is of diverse ethnicity which could represent the genome of Southeast Asia population. Our study, for the first time, determined the survival outcome of metastatic colorectal cancer (mCRC) and established the link with KRAS mutation by modelling the population in Brunei Darussalam. METHODS: We collected data of 76 metastatic CRC (mCRC) patients undergoing treatment at The Brunei Cancer Centre, the national centre for cancer treatment in Brunei. These patients were diagnosed with Stage 4 CRC between 1 January 2013 and 31 December 2017. Age, gender, ethnicity, date of diagnosis, site of primary tumour, metastatic sites and molecular analysis of KRAS mutation status (either KRAS mutated or KRAS wild-type) of tumour were recorded. The survival outcomes of these mCRC patients were analysed. RESULTS: The end of this study period recorded 73.1% deceased mutant KRAS mCRC patients and 46.0% deceased wild-type KRAS mCRC patients, contributing to death rates of 45.2% and 54.8%, correspondingly. Chi-squared analysis showed a significant difference between the survival outcomes of wild-type KRAS and mutant KRAS mCRC patients (p-value = 0.024). CONCLUSIONS: There is a significant difference between the survival outcomes of wild-type KRAS and mutant KRAS mCRC patients in the Brunei population. In addition, we found that mutations in codon 12 of KRAS gene on mutant KRAS mCRC patients have shorter survival median periods than those with mutations within codon 13 of KRAS gene. This is the first study in Brunei Darussalam to analyse both the survival outcomes of mCRC patients and those of mutant KRAS mCRC patients.

Incidence, Survival and Prognostic Factors of Oesophagogastric Cancer.

INTRODUCTION: Oesophagogastric cancer is one of the leading causes of cancer death worldwide due to its aggressive nature. Despite the high mortality rate, there is limited information regarding this cancer in Brunei. AIM: To estimate the incidence and survival duration of oesophagogastric cancer patients, to identify prognostic factors of oesophagogastric cancer and associated factors for late-stage oesophagogastric cancer detection. METHODS: A retrospective study on all oesophagogastric cancer patients registered in the population-based national cancer registry in Brunei from January 2010 to December 2018. Kaplan-Meier and Cox proportional hazard regression survival analyses and multiple logistic regression were applied. RESULTS: Sixty-eight oesophagogastric cancer patients' data were retrieved from the registry. The incidence was 2.75 cases per 100,000 adults per year. Median survival time was 1.18 years (95% CI: 0.77, 1.80) and the 3-year survival rate was 26.3%. Age (61-70 years) (adjusted HR = 0.38; 95% CI: 0.17, 0.89; p = 0.025) and those who have undergone chemotherapy (adj. HR = 0.40; 95% CI: 0.18, 0.90; p = 0.026) have a significantly lower mortality risk. Obesity (adj. HR = 11.94; 95% CI: 1.94, 73.36; p = 0.007), and stage 4 (advanced stage) cancer (adj. HR=4.11; 95% CI: 1.97, 8.58; p< 0.001) have a significantly higher mortality risk. Females have 3-time odds (adj. OR = 3.05; 95% CI: 1.09, 9.02; p = 0.038) of presenting with stage 4 cancer. Smokers have 13-time odds (Adj. OR=12.99; 95% CI: 1.92, 262.0; p = 0.025) of presenting with stage 4 cancer. CONCLUSION: Prognosis of oesophagogastric cancer remains poor. Addressing late detection and improve endoscopic surveillance and awareness of symptoms may help improve prognosis and mortality.

Integrated genomics point to immune vulnerabilities in pleural mesothelioma.

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.

Y disruption, autosomal hypomethylation and poor male lung cancer survival.

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.

A phase 1b trial of the combination of an all-oral regimen of capecitabine and erlotinib in advanced non-small cell lung cancer in Caucasian patients.

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.

A pilot study of a novel home telemonitoring system for oncology patients receiving chemotherapy.

We examined the accuracy and acceptability of a home telemonitoring system for patients receiving chemotherapy. Patients undergoing two cycles of chemotherapy (over six weeks) used the telemonitoring system to analyse their own blood (capillary) and to enter symptom and temperature data. The blood results obtained from self-testing were compared with those from a venous blood sample analysed in the hospital laboratory analyser (the gold standard). We also documented the number and type of alerts generated by the telemonitoring system. Acceptability (ease of use and patient satisfaction) was assessed using questionnaires. Ten patients (mean age 61 years, 60% female) provided 48-paired samples. None of the patients succeeded in obtaining all blood results within pre-defined limits of agreement (i.e. within 15% for haemoglobin, haematocrit, white cell count; and 20% for neutrophil count) during the study. However, the level of clinical agreement between the system and the laboratory standard was good; only three out of the 48 samples and two out of the 10 patients had differences in blood results that might have had clinical implications. The telemonitoring system correctly generated 42 alerts. The patients found the telemonitoring system easy to use. With further refinement this should become an acceptable component of routine clinical practice for monitoring patients receiving chemotherapy.