Lung cancer in young patients: tumour characteristics and treatment in an Irish population

Background: Lung cancer is the leading cause of cancer death in both sexes in Ireland. Studies suggest that lung cancer in younger patients has distinct characteristics. The aim of this study is to define the characteristics of lung cancer in patients 55-year-old or younger in an Irish population. Methods: Data was collected retrospectively from local medical records and the hospital electronic database regarding all patients diagnosed with lung cancer aged 55-year-old and younger, from 2010–2016. Information regarding patient demographics, smoking status, tumour histology, molecular analysis, stage and location, diagnostic modality and initial treatment choice was collected. In all cases the diagnosis of lung cancer was confirmed at the regional lung cancer multidisciplinary team (MDT) meeting. Results: In total, 8% (n=130) of all cases of lung cancer diagnosed from 2010 to 2016 in our center occurred in patients aged 55 years old or younger; 83% (n=108) were 45 to 55-year-old, 15% (n=19) were 35 to 44-year-old and 2% (n=3) were younger than 35-year-old; 88% (n=115) of patients reported a smoking history. There was a female preponderance (58%, n=76), higher rates of NSCLC non-squamous subtype (53%, n=69) and an upper lobe predominance (42%, n=54); 53% (n=68) of patients had IV or extensive disease at presentation. Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and Kirsten rat sarcoma oncogene (KRAS) mutation rates were 9% (n=4) and 3% (n=1) and 80% (n=4) respectively. Conclusions: Lung cancer in younger patients has distinct characteristics. This study suggests a female preponderance, high smoking rates and a predilection for the upper lobes. Further large-scale multicenter studies are required to verify these results and to clarify the responsible mechanisms

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes

BackgroundThe authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a singleâ arm, openâ label phase 2 study.MethodsEligible patients with platinumâ treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28â day cycles in a 3â stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.ResultsGenomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intentâ toâ treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of â ¤15%). All patients experienced â ¥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (doseâ normalized maximum serum concentration [Cmax] after TIW dosing of 0.2 ng/mL/mg).ConclusionsTo the authorsâ knowledge, the current study represents the first clinical trial using genomicâ based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.After the genomicâ based selection of patients with urothelial cancer with inactivating mutations/deletions in the histone acetyltransferase genes CREBBP and/or EP300, singleâ agent mocetinostat appears to be associated with significant toxicities that limit drug exposure. This may have contributed to the limited activity noted in the current phase 2 study (response rate of 11%) among heavily pretreated patients with platinumâ refractory disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147860/1/cncr31817_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147860/2/cncr31817.pd

DNA copy number analysis of metastatic urothelial carcinoma with comparison to primary tumors

Background: To date, there have been no reports characterizing the genome-wide somatic DNA chromosomal copy-number alteration landscape in metastatic urothelial carcinoma. We sought to characterize the DNA copy-number profile in a cohort of metastatic samples and compare them to a cohort of primary urothelial carcinoma samples in order to identify changes that are associated with progression from primary to metastatic disease. Methods: Using molecular inversion probe array analysis we compared genome-wide chromosomal copy-number alterations between 30 metastatic and 29 primary UC samples. Whole transcriptome RNA-Seq analysis was also performed in primary and matched metastatic samples which was available for 9 patients. Results: Based on a focused analysis of 32 genes in which alterations may be clinically actionable, there were significantly more amplifications/deletions in metastases (8.6% vs 4.5%, p < 0.001). In particular, there was a higher frequency of E2F3 amplification in metastases (30% vs 7%, p = 0.046). Paired primary and metastatic tissue was available for 11 patients and 3 of these had amplifications of potential clinical relevance in metastases that were not in the primary tumor including ERBB2, CDK4, CCND1, E2F3, and AKT1. The transcriptional activity of these amplifications was supported by RNA expression data. Conclusions: The discordance in alterations between primary and metastatic tissue may be of clinical relevance in the era of genomically directed precision cancer medicine. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1192-2) contains supplementary material, which is available to authorized users

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening