Inequalities in survival and care across social determinants of health in a cohort of advanced lung cancer patients in Quebec (Canada): A high-resolution population-level analysis.

BACKGROUND: Advanced lung cancer patients exposed to breakthrough therapies like EGFR tyrosine kinase inhibitors (EGFR-TKI) may experience social inequalities in survival, partly from differences in care. This study examined survival by neighborhood-level socioeconomic and sociodemographic status, and geographical location of advanced lung cancer patients who received gefitinib, an EGFR-TKI, as first-line palliative treatment. Differences in the use and delay of EGFR-TKI treatment were also examined. METHODS: Lung cancer patients receiving gefitinib from 2001 to 2019 were identified from Quebec's health administrative databases. Accounting for age and sex, estimates were obtained for the median survival time from treatment to death, the probability of receiving osimertinib as a second EGFR-TKI, and the median time from biopsy to receiving first-line gefitinib. RESULTS: Among 457 patients who received first-line treatment with gefitinib, those living in the most materially deprived areas had the shortest median survival time (ratio, high vs. low deprivation: 0.69; 95% CI: 0.47-1.04). The probability of receiving osimertinib as a second EGFR-TKI was highest for patients from immigrant-dense areas (ratio, high vs. lowdensity: 1.95; 95% CI: 1.26-3.36) or from Montreal (ratio, other urban areas vs. Montreal: 0.39; 95% CI: 0.16-0.71). The median wait time for gefitinib was 1.27 times longer in regions with health centers peripheral to large centers in Quebec or Montreal in comparison to regions with university-affiliated centers (95% CI: 1.09-1.54; n = 353). CONCLUSION: This study shows that real-world variations in survival and treatment exist among advanced lung cancer patients in the era of breakthrough therapies and that future research on inequalities should also focus on this population.

Advanced Lung Cancer Patients' Use of EGFR Tyrosine Kinase Inhibitors and Overall Survival: Real-World Evidence from Quebec, Canada.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are breakthrough palliative treatments for advanced lung cancer patients with tumors harboring mutations in the EGFR gene. Using healthcare administrative data, three cohorts were created to describe the use of three EGFR-TKIs that are publicly funded in Quebec for specific indications (i.e., 1st-line gefitinib, 1st-line afatinib, and post-EGFR-TKI osimertinib). The main objective was to compare overall survival (OS) among patients receiving these treatments to those in previous experimental and real-world studies. The patients who received EGFR-TKIs for indications of interest between 1 April 2001, and 31 March 2019 (or 31 March 2020, for post-EGFR-TKI osimertinib) were included to estimate the Kaplan-Meier-based median OS for each cohort. An extensive literature search was conducted to include comparable studies. For the gefitinib 1st-line (n = 457), the afatinib 1st-line (n = 80), and the post-EGFR-TKI osimertinib (n = 119) cohorts, we found a median OS (in months) of 18.9 (95%CI: 16.3-21.9), 26.6 (95%CI: 13.7-NE) and 19.9 (95%CI: 17.4-NE), respectively. Out of the 20 studies that we retained from the literature review and where comparisons were feasible, 17 (85%) had similar OS results, which further confirms the value of these breakthrough therapies in real-world clinical practice.

Stereotactic Ablative Radiation Therapy for the Treatment of Early-stage Non-Small-Cell Lung Cancer: CEPO Review and Recommendations.

BACKGROUND: Lung cancer is the second most diagnosed cancer and the leading cause of cancer-related mortality in Canada. Surgical resection is the treatment of choice for patients with stage I non-small-cell lung cancer (NSCLC). However, 20% to 30% of them are deemed medically inoperable and may be offered radiation therapy. Standard external-beam radiation therapy (EBRT) is associated with high rates of local recurrence and poor long-term survival. Stereotactic ablative radiation therapy (SABR) is increasingly being proposed for inoperable patients, and the use of this treatment modality for operable patients is also being contemplated. The objective of this guideline is to review the efficacy and safety of SABR in these two clinical situations and to develop evidence-based recommendations. METHOD: A review of the scientific literature published up to December 2013 was performed. A total of 44 publications were included. RECOMMENDATIONS: Considering the evidence available to date, the Comité de l'évolution des pratiques en oncologie recommends the following: (1) for medically operable patients with stage T1-2N0M0 NSCLC, surgery remains the standard treatment because comparative data regarding the efficacy of SABR and surgery are currently insufficient for SABR to be considered an equivalent alternative to surgery for these patients; (2) for medically inoperable patients with stage T1-2N0M0 NSCLC or medically operable patients who refuse surgery, SABR should be preferred to standard EBRT (grade B recommendation); (3) the biological equivalent dose (BED(10)) used for SABR treatment should be at least 100 Gy (grade B recommendation); (4) for patients with a central tumor, a large-volume tumor (large planning target volume) or severe pulmonary comorbidity, a risk-adaptive schedule should be used (dose reduction or increase in the number of fractions; grade B recommendation); (5) the choice of using SABR to treat NSCLC should be discussed within tumor boards; treatment with SABR (or with standard EBRT) should not be considered for patients whose life expectancy is very limited because of comorbidities (grade D recommendation).

Transarterial embolization therapies for the treatment of hepatocellular carcinoma: CEPO review and clinical recommendations.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most deadly cancers in the world and its incidence rate has consistently increased over the past 15 years in Canada. Although transarterial embolization therapies are palliative options commonly used for the treatment of HCC, their efficacy is still controversial. The objective of this guideline is to review the efficacy and safety of transarterial embolization therapies for the treatment of HCC and to develop evidence-based recommendations. METHOD: A review of the scientific literature published up to October 2013 was performed. A total of 38 studies were included. RECOMMENDATIONS: Considering the evidence available to date, the CEPO recommends the following: (i) transarterial chemoembolization therapy (TACE) be considered a standard of practice for the palliative treatment of HCC in eligible patients; (ii) drug-eluting beads (DEB)-TACE be considered an alternative and equivalent treatment to conventional TACE in terms of oncological efficacy (overall survival) and incidence of severe toxicities; (iii) the decision to treat with TACE or DEB-TACE be discussed in tumour boards; (iv) bland embolization (TAE) not be considered for the treatment of HCC; (v) radioembolization (TARE) not be considered outside of a clinical trial setting; and (vi) sorafenib combined with TACE not be considered outside of a clinical trial setting.

Adjuvant treatment for endometrial cancer: literature review and recommendations by the Comité de l'évolution des pratiques en oncologie (CEPO).

OBJECTIVE: Despite the very good prognosis of endometrial cancer, a number of patients with localized disease relapse following surgery. Therefore, various adjuvant therapeutic approaches have been studied. The objective of this review is to evaluate the efficacy and safety of neoadjuvant and adjuvant therapies in patients with resectable endometrial cancer and to develop evidence-based recommendations. METHODS: A review of the scientific literature published between January 1990 and June 2012 was performed. The search was limited to published phase III clinical trials and meta-analyses evaluating the efficacy of neoadjuvant or adjuvant therapies in patients with endometrial carcinoma or carcinosarcoma. A total of 23 studies and five meta-analyses were identified. RESULTS: The selected literature showed that in patients with a low risk of recurrence, post-surgical observation is safe and recommended in most cases. There are several therapeutic modalities available for treatment of endometrial cancers with higher risk of recurrence, including vaginal brachytherapy, external beam radiotherapy, chemotherapy, or a combination of these. CONCLUSIONS: Considering the evidence available to date, the CEPO recommends the following: (1)post-surgical observation for most patients with a low recurrence risk; (2)adjuvant vaginal brachytherapy for patients with an intermediate recurrence risk; (3)adjuvant pelvic radiotherapy with or without vaginal brachytherapy for patients with a high recurrence risk; addition of adjuvant chemotherapy may be considered as an option for selected patients (excellent functional status, no significant co-morbidities, poor prognostic factors); (4)adjuvant chemotherapy and pelvic radiotherapy with or without brachytherapy and para-aortic irradiation for patients with advanced disease;

Identification of a SIRT1 mutation in a family with type 1 diabetes.

Type 1 diabetes is caused by autoimmune-mediated ß cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to ß cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.

AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo.

AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.

Disruption of Igfbp1 fails to rescue the phenotype of Sirt1-/- mice.

Sirtuin 1 (SIRT1) is an NAD-dependent histone deacetylase (HDAC) whose activity is thought to forestall the onset of a variety of age-related diseases. Mice carrying null mutations of the Sirt1 gene suffer high rates of neonatal lethality and those that survive are sterile, growth retarded, lean and their livers express high levels of insulin-like growth factor binding protein-1 (IGFBP1). IGFBP1 binds and regulates the bioavailability of Igfs. Interestingly, Igfbp1 transgenic mice largely phenocopy Sirt1-/- mice, suggesting the possibility that the over-expression of IGFBP1 in Sirt1-/- mice might be responsible for many of their phenotypes. We interbred Sirt1 heterozygote mice to Igfbp1-deficient mice to test the hypothesis that the disruption of one or both alleles of Igfbp1 would rescue the phenotype of Sirt1-/- mice. We report that mono- or bi-allelic disruption of the Igfbp1 gene had no effect on the embryonic and neonatal lethality of Sirt1-/- mice. However, we show that mice lacking at least one allele of both Sirt1 and Igfbp1 genes have a much higher incidence of malocclusion.

sirt1-null mice develop an autoimmune-like condition.

The sirt1 gene encodes a protein deacetylase with a broad spectrum of reported substrates. Mice carrying null alleles for sirt1 are viable on outbred genetic backgrounds so we have examined them in detail to identify the biological processes that are dependent on SIRT1. Sera from adult sirt1-null mice contain antibodies that react with nuclear antigens and immune complexes become deposited in the livers and kidneys of these animals. Some of the sirt1-null animals develop a disease resembling diabetes insipidus when they approach 2 years of age although the relationship to the autoimmunity remains unclear. We interpret these observations as consistent with a role for SIRT1 in sustaining normal immune function and in this way delaying the onset of autoimmune disease.

SirT1 regulates energy metabolism and response to caloric restriction in mice.

The yeast sir2 gene and its orthologues in Drosophila and C. elegans have well-established roles in lifespan determination and response to caloric restriction. We have studied mice carrying two null alleles for SirT1, the mammalian orthologue of sir2, and found that these animals inefficiently utilize ingested food. These mice are hypermetabolic, contain inefficient liver mitochondria, and have elevated rates of lipid oxidation. When challenged with a 40% reduction in caloric intake, normal mice maintained their metabolic rate and increased their physical activity while the metabolic rate of SirT1-null mice dropped and their activity did not increase. Moreover, CR did not extend lifespan of SirT1-null mice. Thus, SirT1 is an important regulator of energy metabolism and, like its orthologues from simpler eukaryotes, the SirT1 protein appears to be required for a normal response to caloric restriction.

Connections between ETV6-modulated genes: identification of shared features.

Accumulating genetic and functional evidence point to ETV6 as being the tumour suppressor gene targeted by the deletions at chromosome 12p12-13 found in various cancers, particularly childhood leukemia. ETV6 is a ubiquitously expressed transcription factor (TF) of the ETS family with very few known targeted genes. We recently compiled a list of 87 ETV6-modulated genes that can be classified into a number of subgroups based on their coordinated expression patterns. In the present report, we hypothesized that genes presenting a similar profile of modulation could also share biological features, promoter sequence similarities and/or, common transcription factor binding sites (TFBSs). Using an exploratory approach based on hierarchical clustering of expression data, Gene Ontology (GO) terms, sequence similarity and evolutionary conserved putative TFBSs, we found that many genes presenting a similar expression profile also share biological features and/or conserved predicted TFBSs but rarely show detectable promoter sequence similarities. We also calculated the proportion of ETV6-modulated genes that have any conserved TFBSs of the Jaspar database in their regulatory sequence and compared these proportions to those calculated for two other gene lists, ETV6 non-modulated and ETS-regulated. We found that the NF-kB, c-REL and p65 TFBSs, which all bind TFs of the REL class, were under-represented among the ETV6-modulated genes compared to the ETV6-non-modulated genes, while the Broad-complex 1 TFBS appeared to be over-represented. NF-Y and Chop/cEBP TFBSs were over-represented in the promoters of ETV6-modulated genes compared to ETS-regulated genes. These analyses will help direct further studies intending to understand the role of ETV6 as a transcriptional regulator and aid in constructing the ETV6-regulatory gene network.

In vivo footprinting analysis of the Glypican 3 (GPC3) promoter region in neuroblastoma cells.

Glypican 3 (GPC3) is an X-linked gene that has its peak expression during development and is down-regulated in all studied tissues after birth. We have shown that GPC3 was expressed in neuroblastoma and Wilms' tumor. To understand the mechanisms regulating the transcription of this gene in neuroblastoma cells, we have focused our study on the identification of putative transcription factors binding the promoter. In this report we performed in vivo dimethylsulfate, UV type C irradiation and DNaseI footprinting analyses coupled with ligation-mediated PCR on nearly 1000 bp of promoter in two neuroblastoma cell lines, SJNB-7 (expressing GPC3) and SK-N-FI (not expressing GPC3). Nucleosome signature footprints were observed in the most distal part of the studied region in both cell lines. We detected eight large differentially protected regions, suggesting the presence of binding proteins in both cell lines but more DNA-protein interactions in GPC3-expressing cells. Sp1 was previously shown to be able to bind some of these regions. Here by combining electromobility shift assays and chromatin immunoprecipitations we showed that the transcription factor NFY was part of the DNA-protein complex found in footprinted regions upstream of the described minimal promoter. These studies performed on chromatin in situ suggest that NFY and yet unknown cell type-specific factors may play an important role in the regulation of GPC3.

Identification of transcripts modulated by ETV6 expression.

Deletions at chromosome 12p12-13 are observed in 26-47% of childhood pre-B acute lymphoblastic leukaemia (ALL) cases, suggesting the presence of a tumour suppressor gene (TSG). Accumulating genetic and functional evidence points to ETV6 as being the most probable TSG targeted by the deletions. ETV6 is a ubiquitously expressed transcription factor of the ETS family with very few known targets. To understand its function and to elucidate the impact of its absence in leukaemia, we conducted a study to identify targeted genes. Following the induction of ETV6 expression, global expression was evaluated at different time points. We identified 87 modulated genes, of which 10 (AKR1C1, AKR1C3, IL18, LUM, PHLDA1, PTGER4, PTGS2, SPHK1, TP53 and VEGF) were validated by real-time quantitative reverse transcription-polymerase chain reaction. To assess the significance of the validated candidate genes in leukaemia, their expression patterns were determined, as well as that of ETV6, in pre-B ALL patients. The expression of IL18, LUM, PTGER4, SPHK1 and TP53 was significantly correlated with that of ETV6, further suggesting that ETV6 could regulate the expression of these genes in leukaemia. This work constitutes another step towards the understanding of the functions of ETV6 and the impact of its inactivation in childhood leukaemia.

A detailed transcriptional map of the chromosome 12p12 tumour suppressor locus.

Loss of heterozygosity of the short arm of chromosome 12 is a frequent event in a wide range of haematological malignancies and solid tumours. In previous studies, the shortest commonly deleted region was delimited to a 750-kb interval, defined by the markers D12S89 and D12S358, in pre-B acute lymphoblastic leukaemia patients, suggesting the presence of a tumour suppressor locus. Here we report the construction of a transcriptional map that integrates the data obtained by genomic sequence analysis, EST database search, comparative analysis and exon amplification. We identified seven putative transcriptional units as well as six pseudogenes. Four of these candidate genes were already known: ETV6, encoding an ets-like transcription factor, LRP6, a member of the LDL receptor gene family, BCL-G, a recently identified pro-apoptotic gene and MKP-7, encoding a new member of the dual-specificity phosphatase family. The products encoded by the three new genes identified in this study, LOH1CR12, LOH2CR12 and LOH3CR12, have no clear homology to known proteins. The gene predictions were all confirmed by expression analysis using RT-PCR and Northern blot. This transcriptional map is a crucial step toward the identification of the tumour suppressor gene at 12p12.