NKX2­1 copy number alterations are associated with oncogenic, immunological and prognostic remodeling in non­small cell lung cancer.

NK2 homeobox 1 (NKX2-1) copy number alterations (CNAs) are frequently observed in lung cancer. However, little is known about the complete landscape of focal alterations in NKX2-1 copy number (CN), their clinical significance and their therapeutic implications in non-small cell lung cancer (NSCLC). The correlations between NKX2-1 expression and EGFR driver mutations and programmed death ligand 1 (PD-L1) co-expression were studied using immunohistochemistry and PCR from the tumors of recruited Filipino patients (n=45). Clinical features of NSCLC with NKX2-1 CNAs were resolved at the tumor and clonal levels using the molecular profiles of patients with lung adenocarcinoma and lung squamous cell carcinoma from The Cancer Genome Atlas (n=1,130), and deconvoluted single-cell RNA-seq data from the Bivona project (n=1,654), respectively. Despite a significant and positive correlation between expression and CN (r=0.264; P<0.001), NKX2-1 CNAs exerted a stronger influence on the combined EGFR and PD-L1 status of NSCLC tumors than expression. NKX2-1 CN gain was prognostic of favorable survival (P=0.018) and a better response to targeted therapy. NKX2-1 CN loss predicted a worse survival (P=0.041). Mutational architecture in the Y-chromosome differentiated the two prognostic groups. There were 19,941 synonymous mutations and 1,408 genome-wide CN perturbations associated with NKX2-1 CNAs. Tumors with NKX2-1 CN gain expressed lymphocyte markers more heterogeneously than those with CN loss. Higher expression of tumor-infiltrating lymphocyte gene signatures in CN gain was prognostic of longer disease-free survival (P=0.005). Tumors with NKX2-1 CN gain had higher B-cell (P<0.001) and total T-cell estimates (P=0.003). NKX2-1 CN loss was associated with immunologically colder tumors due to higher M2 macrophage infiltrates (P=0.011) and higher expression of immune checkpoint proteins, CD274 (P=0.025), VTCN1 (P<0.001) and LGALS9 (P=0.002). In conclusion, NKX2-1 CNAs are associated with tumors that exhibit clinically diverse characteristics, and with unique oncogenic, immunological and prognostic signatures.

The differential prognostic implications of PD-L1 expression in the outcomes of Filipinos with EGFR-mutant NSCLC treated with tyrosine kinase inhibitors.

Background: The tumor immune microenvironment influences tumor evolution in non-small cell lung cancer (NSCLC). Yet, the prognostic value of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor (EGFR)-mutant NSCLC remains controversial. Additionally, prognostic studies in Filipinos with EGFR-mutant NSCLC remain unexplored to this day. Methods: We prospectively studied the outcomes of EGFR-mutant NSCLC in Filipino cohort, and retrospectively verified the survival trend using The Cancer Genome Atlas (TCGA) cohort. Kaplan-Meier method and generalized linear regression were used to assess survival. Expression and DNA methylation of cluster of differentiation 274 (CD274, gene that codes for PD-L1) were examined from TCGA tumor profiles. Pearson's correlation was used to correlate PD-L1 expression with outcomes associated with occurrence of EGFR mutations, tyrosine kinase inhibitor (TKI) types, and programmed cell death protein 1 (PD-1) expression. Proteome network analysis was used to examine the correlation between drug resistance and PD-L1. Results: PD-L1 positivity was associated with significantly longer progression-free survival (PFS; P=0.0096) but had a significantly contrasting influence in the overall survival (OS; P=0.0011). PD-L1 positivity (in both protein and RNA) was associated with longer median OS (mOS) in exon21 L858R, whereas, negativity was associated with longer mOS in exon19 deletion (exon19del). Stratification (high, low, negative) of PD-L1 expression lacked significant prognostic value (all P>0.05). PD-L1/CD274 expression (P<0.05) and DNA methylation (P<0.001) vary significantly among NSCLC subtypes and in different disease stages. Erlotinib treatment produced the longest median progression-free survival (mPFS; 874 days) relative to other EGFR-TKIs (137-311 days). PD-L1 lacked a significant correlation with EGFR-TKIs. Consistent with the immune-regulation activities of PD-1, higher expression leads to relatively shorter mOS. PD-1 correlated positively with PD-L1 expression and occurrence of exon21 L858R. Conclusions: PD-L1 differentially influenced the outcomes of Filipinos with EGFR-mutant NSCLC. NSCLC subtypes, disease stage, and PD-1 expression may impact the collective outcomes associated with PD-L1 and EGFR-sensitizing mutations.

Expression landscapes in non-small cell lung cancer shaped by the thyroid transcription factor 1.

TTF-1-expressing non-small cell lung cancer (NSCLC) is one of the most prevalent lung cancer types worldwide. However, theparadoxical activity of TTF-1 in both lung carcinogenesis and tumor suppression is believed to be context-dependentwhich calls for a deeper understanding about the pathological expression of TTF-1. In addition, the expression circuitry of TTF-1-target genes in NSCLC has not been well examined which necessitates to revisit the involvement of TTF-1- in a multitude of oncologic pathways. We used RNA-seq and clinical data of patients from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), including ChIP-seq data from different NSCLC cell lines, and mapped the proteome of NSCLC tumor. Our analysis showed significant variability in TTF-1 expression among NSCLC,and further clarified that this variability is orchestrated at the transcriptional level. We also found that high TTF-1 expression could negatively influence the survival outcomes of stage 1 LUAD which may be attributed to growth factor receptor-driven activation of mitogenic and angiogenic pathways. Mechanistically, TTF-1 may also control the genes associated with pathways involved in acquired TKI drug resistance or response to immune checkpoint inhibitors. Lastly, proteome-based biomarker discovery in stage 1 LUAD showed that TTF-1 positivity is potentially associated with the upregulation of several oncogenes which includes interferon proteins, MUC1, STAT3, and EIF2AK2. Collectively, this study highlights the potential involvement of TTF-1 in cell proliferation, immune evasion, and angiogenesis in early-stage NSCLC.

Quality of life and nutritional status among cancer patients on chemotherapy.

OBJECTIVES: Malnutrition is prevalent among cancer patients, and maybe correlated with altered quality of life. The objective of this study is to determine wether quality of life among cancer patients on chemotherapy at the National Kidney and Transplant Institute- Cancer Unit differs from patients with normal nutrition based on the Subjective Global Assessment scale. METHODS: A cross sectional study was conducted among cancer patients admitted for chemotherapy at the National Kidney and Transplant Institute-Cancer Unit from January to May 2011. Demographic profile, performance status by Eastern Cooperative Oncology Group performance scale, nutritional status assessment by Subjective Global Assessment, and quality of life assessment by the European Organization for Research and Treatment of Cancer QoL-30 core module were obtained. Descriptive statistics and ANOVA were performed for analysis of quality of life parameters and nutritional status. RESULTS: A total of 97 subjects were included in this study, 66 subjects (68.04%) were females and 31 (31.96%) were males. Mean age was 54.55 ± 11.14 years, while mean performance status by the Eastern Cooperative Oncology Group classification was 0.88 ± 0.83 with a range of 0-3. According to the Subjective Global Assessment, there were 58 patients with SGA A, classified to have adequate nutrition, and 39 patients (40.21%) were considered malnourished. Among these 39 patients, 32 were classified SGA-B (moderately malnourished) and 7 were classified SGA C (severely malnourished) mean global quality of life was 68.73 ± 19.05. Results from ANOVA test revealed that patients were statistically different across the Subjective Global Assessment groups according to global quality of life (p<0.001), physical (p<0.001), role (p<0.001), emotional (p<0.001), and cognitive functioning (p<0.001); fatigue (p<0.001), nausea and vomiting (p<0.001), pain (p<0.001), insomnia (p<0.001), and appetite loss (p<0.001). CONCLUSION: GLOBAL QUALITY OF LIFE AND ITS PARAMETERS: physical state, role, emotional state, cognitive functioning, cancer fatigue, nausea and vomiting, pain, insomnia, and loss of appetite were statistically different across all Subjective Global Assessment groups. Moreover, there was no difference between financial difficulties, social functioning, constipation and diarrhea among the Subjective Global Assessment groups.

Anticancer immune reactivity and long-term survival after treatment of metastatic ovarian cancer with dendritic cells.

Hematopoietic stem cells collected by leukapheresis of a patient with metastatic ovarian carcinoma (OVCA) were induced into dendritic cell (DC) differentiation and fused with liposomal constructs of autologous and allogeneic ovarian carcinoma antigens (DC-OVCA). The proliferation of autologous T cells induced by DCs was determined by [(3)H]-thymidine uptake. Maximal T-cell proliferation was observed in co-cultures of DCs fused with liposomal OVCA constructs compared with intact autologous OVCA cells. The combination of autologous and allogeneic liposomal OVCA constructs induced greater T-cell proliferation than either alone. The cytotoxicity of DC-activated T cells against various target cells were analyzed by a (51)Cr-release assay. The combination of autologous and allogeneic liposomal OVCA constructs showed the highest stimulation of T cell-mediated cytotoxicity against OVCA cells, but had minimal cytotoxicity against normal fibroblasts or leukemia cells. The liposomal preparations of DC-OVCA were injected monthly into a patient with metastatic ovarian carcinoma whose tumors progressed following multiple courses of chemotherapy. DCs analyzed from the patient post-immunization showed 2- to 3-fold greater OVCA cytotoxicity compared to pre-immunization DCs. Immunoblots using the patient's serum showed reactivity with a number of proteins from ovarian cancer extracts, but not in normal fibroblasts and breast cancer. Following the DC-OVCA treatment, the metastatic lesions progressively decreased in size to the point of being undetectable by serial CAT scans. Seven years following the initial diagnosis, the patient continues to be free of cancer. This report described the anticancer immune reactivity and anti-tumor response induced by DCs sensitized with liposomal constructs of OVCA antigens. Immune cell therapy may therefore be a useful adjunct to surgery and chemotherapy for the treatment of ovarian cancer.

Socioeconomic impact of cancer in member countries of the Association of Southeast Asian Nations (ASEAN): the ACTION study protocol.

Cancer can be a major cause of poverty. This may be due either to the costs of treating and managing the illness as well as its impact upon people's ability to work. This is a concern that particularly affects countries that lack comprehensive social health insurance systems and other types of social safety nets. The ACTION study is a longitudinal cohort study of 10,000 hospital patients with a first time diagnosis of cancer. It aims to assess the impact of cancer on the economic circumstances of patients and their households, patients' quality of life, costs of treatment and survival. Patients will be followed throughout the first year after their cancer diagnosis, with interviews conducted at baseline (after diagnosis), three and 12 months. A cross-section of public and private hospitals as well as cancer centers across eight member countries of the Association of Southeast Asian Nations (ASEAN) will invite patients to participate. The primary outcome is incidence of financial catastrophe following treatment for cancer, defined as out-of-pocket health care expenditure at 12 months exceeding 30% of household income. Secondary outcomes include illness induced poverty, quality of life, psychological distress, economic hardship, survival and disease status. The findings can raise awareness of the extent of the cancer problem in South East Asia and its breadth in terms of its implications for households and the communities in which cancer patients live, identify priorities for further research and catalyze political action to put in place effective cancer control policies.