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PURPOSE: Tissue-derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology-agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset in which this was validated lacked colorectal cancers (CRC), and there is limited evidence for immunotherapy benefits in CRC using this threshold. PATIENTS AND METHODS: CO.26 was a randomized phase II study of 180 patients, comparing durvalumab and tremelimumab (D + T, n = 119 patients) versus best supportive care (BSC; n = 61 patients). ctDNA sequencing was available for 168 patients (n = 118 D + T; n = 50), of whom 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on OS were determined using a minimal P value approach. This report includes the final OS analysis. RESULTS: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D + T compared with BSC in microsatellite stable (MSS) metastatic CRC [HR, 0.71 (95% CI, 0.28-1.80); P = 0.47]. No tissue TMB threshold could identify a high TMB group that benefited from ICI. By contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D + T [HR, 0.34 (95% CI, 0.13-0.85); P = 0.022], as was clonal pTMB ≥10.6 mutations/Mb [HR, 0.10 (95% CI, 0.014-0.79); P = 0.029] and subclonal pTMB ≥25.9/Mb [HR, 0.20 (95% CI, 0.061-0.69); P = 0.010]. Higher pTMB was associated with length of time on cytotoxic agents (P = 0.021) and prior anti-EGFR exposure (P = 2.44 × 10-06). CONCLUSIONS: pTMB derived from either clonal or subclonal mutations may identify a group likely to benefit from immunotherapy, although validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial.
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Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais , Neoplasias Colorretais , Mutação , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais/genética , Feminino , Masculino , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Idoso de 80 Anos ou mais , Metástase NeoplásicaRESUMO
Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.
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Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Neoplasias/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Idoso , Mutação em Linhagem Germinativa , Adulto , Idoso de 80 Anos ou maisRESUMO
PURPOSE: Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left- and right-sided colorectal cancer is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC. EXPERIMENTAL DESIGN: Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wild-type (WT) mCRC from CO.17 and KRAS WT mCRC from CO.20 were analyzed according to location. RESULTS: A total of 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best supportive care (BSC) for overall survival [OS; median, 5.9 vs. 2.1 months; HR, 0.63; 95% confidence interval (CI), 0.28-1.42; P=0.26] and progression-free survival (PFS; median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26-1.28; P=0.16). Analyzing exclusively patients randomized to cetuximab, right-sided and transverse had comparable outcomes for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50-1.34; P=0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49-1.26; P=0.31). Patients with left-sided mCRC had superior outcomes with cetuximab compared with transverse for OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27-0.67; P=0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0,49; 95% CI, 0.31-0.76; P=0.001). Location was not prognostic in patients treated with BSC alone. CONCLUSIONS: Transverse mCRC has comparable prognostic and predictive features with right-sided mCRC.
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Colo Transverso , Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Colo Transverso/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias Retais/tratamento farmacológico , Biomarcadores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.
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Variações do Número de Cópias de DNA , Perfilação da Expressão Gênica , Neoplasias , Humanos , Criança , Neoplasias/genética , Neoplasias/terapia , Feminino , Adolescente , Masculino , Pré-Escolar , Prognóstico , Perfilação da Expressão Gênica/métodos , Lactente , Transcriptoma , Adulto Jovem , Sequenciamento Completo do Genoma , Mutação em Linhagem Germinativa , Mutação , Genoma Humano/genética , Predisposição Genética para DoençaRESUMO
Immune checkpoint inhibitors (ICI) are highly effective in specific cancers where canonical markers of antitumor immunity are used for patient selection. Improved predictors of T cell-inflammation are needed to identify ICI-responsive tumor subsets in additional cancer types. We investigated associations of a 4-chemokine expression signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) with metrics of antitumor immunity across tumor types. Across cancer entities from The Cancer Genome Atlas, subgroups of tumors displayed high expression of the c-Score (c-Scorehi) with increased expression of immune checkpoint (IC) genes and transcriptional hallmarks of the cancer-immunity cycle. There was an incomplete association of the c-Score with high tumor mutation burden (TMB), with only 15% of c-Scorehi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Scorehi tumors had a longer median time to progression (103 versus 72 days, P = 0.012) and overall survival (382 versus 196 days, P = 0.038) following ICI therapy initiation, compared to patients with low c-Score expression. We also found c-Score stratification to outperform TMB assignment for overall survival prediction (HR = 0.42 [0.22-0.79], P = 0.008 versus HR = 0.60 [0.29-1.27], P = 0.18, respectively). Assessment of the c-Score using the TIDE and PredictIO databases, which include ICI treatment outcomes from 10 tumor types, provided further support for the c-Score as a predictive ICI therapeutic biomarker. In summary, the c-Score identifies patients with hallmarks of T cell-inflammation and potential response to ICI treatment across cancer types, which is missed by TMB assignment.
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There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated with BRCA1/2 mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. Regression analyses examined the association between HRD and time to progression on platinum (TTPp). We included 223 patients with GI (n = 154) or thoracic (n = 69) malignancies. TTPp was associated with SBS3 (p < 0.01) but not HRD score in patients with GI malignancies, whereas neither was associated with TTPp in thoracic malignancies. Tumors with gBRCA1/2 mutations and a somatic second alteration exhibited high SBS3 and HRD scores, but these signatures were also present in several tumors with germline but no somatic second alterations, suggesting silencing of the wild-type allele or BRCA1/2 haploinsufficiency. Biallelic inactivation of an HR gene, including loss of XRCC2 and BARD1, was identified in BRCA1/2 wild-type HRD tumors and these patients had prolonged response to platinum. Thoracic cases with high HRD score were associated with high RECQL5 expression (p ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD and BRCA status in identifying patients who benefit from platinum therapy.
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Importance: Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). Objective: To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. Design, Setting, and Participants: In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Intervention: Durvalumab plus tremelimumab or best supportive care. Main Outcomes and Measures: Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Results: Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. Conclusions and Relevance: In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Retais , Idoso , Feminino , Humanos , Masculino , Biomarcadores Tumorais/análise , Canadá , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Intervalo Livre de Progressão , Neoplasias Retais/tratamento farmacológico , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Tumor mutation burden (TMB) is a key characteristic used in a tumor-type agnostic context to inform the use of immune checkpoint inhibitors (ICI). Accurate and consistent measurement of TMB is crucial as it can significantly impact patient selection for therapy and clinical trials, with a threshold of 10 mutations/Mb commonly used as an inclusion criterion. Studies have shown that the most significant contributor to variability in mutation counts in whole genome sequence (WGS) data is differences in analysis methods, even more than differences in extraction or library construction methods. Therefore, tools for improving consistency in whole genome TMB estimation are of clinical importance. METHODS: We developed a distributable TMB analysis suite, TMBur, to address the need for genomic TMB estimate consistency in projects that span jurisdictions. TMBur is implemented in Nextflow and performs all analysis steps to generate TMB estimates directly from fastq files, incorporating somatic variant calling with Manta, Strelka2, and Mutect2, and microsatellite instability profiling with MSISensor. These tools are provided in a Singularity container downloaded by the workflow at runtime, allowing the entire workflow to be run identically on most computing platforms. To test the reproducibility of TMBur TMB estimates, we performed replicate runs on WGS data derived from the COLO829 and COLO829BL cell lines at multiple research centres. The clinical value of derived TMB estimates was then evaluated using a cohort of 90 patients with advanced, metastatic cancer that received ICIs following WGS analysis. Patients were split into groups based on a threshold of 10/Mb, and time to progression from initiation of ICIs was examined using Kaplan-Meier and cox-proportional hazards analyses. RESULTS: TMBur produced identical TMB estimates across replicates and at multiple analysis centres. The clinical utility of TMBur-derived TMB estimates were validated, with a genomic TMB ≥ 10/Mb demonstrating improved time to progression, even after correcting for differences in tumor type (HR = 0.39, p = 0.012). CONCLUSIONS: TMBur, a shareable workflow, generates consistent whole genome derived TMB estimates predictive of response to ICIs across multiple analysis centres. Reproducible TMB estimates from this approach can improve collaboration and ensure equitable treatment and clinical trial access spanning jurisdictions.
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Biomarcadores Tumorais/genética , Mutação , Neoplasias/genética , Sequenciamento Completo do Genoma/métodos , Humanos , Estimativa de Kaplan-Meier , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Neoplasias/metabolismo , Neoplasias/terapia , Seleção de Pacientes , Modelos de Riscos Proporcionais , Reprodutibilidade dos TestesRESUMO
Tumor mutation burden (TMB) is a measure to predict patient responsiveness to immune checkpoint immunotherapy because with increased mutation frequency, the likelihood of a greater neoantigen burden is increased. Although neoantigen prediction tools exist, tumor neoantigen burden has not been adopted as a measure to predict immunotherapy response. With both measures, current guidelines are limited to the coding regions, but ectopic expression of sequences in the noncoding space may potentially be a source of neoantigens. A pan-cancer cohort of 574 advanced disease stage patients with whole genome and transcriptome sequencing was analyzed to report mutation burden and neoantigen counts within the coding and noncoding regions. The efficacy of tumor neoantigen burden, reported as tumor neoantigen count (TNC), including neoantigens derived from the expression of noncoding regions, compared with TMB as a predictor of response to immunotherapy for 80 patients who had received treatment, was evaluated. TMB was found to be the best predictor of response to immunotherapy, whereas expression-derived TNC from the noncoding regions did not improve prediction of response. Therefore, there is minimal benefit in extending the calculation of TNC to the noncoding space for the purposes of predicting response. However, it is likely that there is a wealth of neoantigens derived from the noncoding space that may impact patient outcomes and treatments.
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Antígenos de Neoplasias , Neoplasias , Antígenos de Neoplasias/genética , Biomarcadores Tumorais , Humanos , Imunoterapia , Mutação , Neoplasias/genética , Neoplasias/terapia , Sequenciamento do ExomaRESUMO
Uveal melanoma is the most common intraocular malignancy and has a poor prognosis compared to other melanoma subtypes with a median overall survival of 6-10 months. With immune checkpoint inhibitor therapy, either PD-1 inhibitor alone or combination ipilimumab/nivolumab (anti-CTLA-4/anti-PD-1), responses are rare and often not durable. We present a case report of a now 66-year-old woman with diffuse metastatic uveal melanoma previously treated with a combination of ipilimumab/nivolumab, followed by maintenance nivolumab. Almost complete resolution of all sites of metastatic disease was observed except for one liver metastasis which regressed partially on immunotherapy. Notably, the patient had a significantly elevated BMI and developed widespread vitiligo on treatment. Whole-genome and transcriptome analysis was performed on the residual liver biopsy and molecular markers that may have contributed to the exceptional response were investigated. Several alterations were observed in genes involved in T-cell responses. Estimates of tumour infiltrating immune cells indicated a high level of plasma cells compared to other uveal melanoma cases, a finding previously associated with indolent disease. The patient also carried several germline SNPs that may have contributed to her treatment response as well as widespread vitiligo. Whole-genome and transcriptome sequencing have provided insight into potential molecular underpinnings of an exceptional treatment response in a tumour type typically associated with poor prognosis. Immunological findings suggest a role for plasma cells in the tumour microenvironment. Elevated BMI and the development of vitiligo may be clinically relevant factors for predicting response to immune checkpoint inhibitor therapy, warranting further studies in patients with uveal melanoma.
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Melanoma , Segunda Neoplasia Primária , Neoplasias Cutâneas , Vitiligo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Genômica , Humanos , Inibidores de Checkpoint Imunológico , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Melanoma/patologia , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Microambiente Tumoral , Neoplasias UveaisRESUMO
Oncogenic KRAS mutations are absent in approximately 10% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and may represent a subgroup of mPDAC with therapeutic options beyond standard-of-care cytotoxic chemotherapy. While distinct gene fusions have been implicated in KRAS wildtype mPDAC, information regarding other types of mutations remain limited, and gene expression patterns associated with KRAS wildtype mPDAC have not been reported. Here, we leverage sequencing data from the PanGen trial to perform comprehensive characterization of the molecular landscape of KRAS wildtype mPDAC and reveal increased frequency of chr1q amplification encompassing transcription factors PROX1 and NR5A2. By leveraging data from colorectal adenocarcinoma and cholangiocarcinoma samples, we highlight similarities between cholangiocarcinoma and KRAS wildtype mPDAC involving both mutation and expression-based signatures and validate these findings using an independent dataset. These data further establish KRAS wildtype mPDAC as a unique molecular entity, with therapeutic opportunities extending beyond gene fusion events.
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Adenocarcinoma , Neoplasias dos Ductos Biliares , Carcinoma Ductal Pancreático , Colangiocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos , Carcinoma Ductal Pancreático/patologia , Colangiocarcinoma/genética , Humanos , Mutação , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/genética , Neoplasias PancreáticasRESUMO
The global impact of somatic structural variants (SVs) on gene regulation in advanced tumors with complex treatment histories has been mostly uncharacterized. Here, using whole-genome and RNA sequencing from 570 recurrent or metastatic tumors, we report the altered expression of hundreds of genes in association with nearby SV breakpoints, including oncogenes and G-protein-coupled receptor-related genes such as PLEKHG2. A significant fraction of genes with SV-expression associations correlate with worse patient survival in primary and advanced cancers, including SRD5A1. In many instances, SV-expression associations involve retrotransposons being translocated near genes. High overall SV burden is associated with treatment with DNA alkylating agents or taxanes and altered expression of metabolism-associated genes. SV-expression associations within tumors from topoisomerase I inhibitor-treated patients include chromatin-related genes. Within anthracycline-treated tumors, SV breakpoints near chromosome 1p genes include PDE4B. Patient treatment and history can help understand the widespread SV-mediated cis-regulatory alterations found in cancer.
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Regulação Neoplásica da Expressão Gênica/genética , Variação Estrutural do Genoma/genética , Recidiva Local de Neoplasia/genética , Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Bases de Dados Genéticas , Rearranjo Gênico/genética , Genoma Humano , Genômica , Humanos , Oncogenes , Análise de Sequência de RNA/métodos , Translocação Genética/genética , Sequenciamento do Exoma/métodos , Sequenciamento Completo do Genoma/métodosRESUMO
BACKGROUND: Single-arm trials are common in precision oncology. Owing to the lack of randomized counterfactual, resultant data are not amenable to comparative outcomes analyses. Difference-in-difference (DID) methods present an opportunity to generate causal estimates of time-varying treatment outcomes. Using DID, our study estimates within-cohort effects of genomics-informed treatment versus standard care on clinical and cost outcomes. METHODS: We focus on adults with advanced cancers enrolled in the single-arm BC Cancer Personalized OncoGenomics program between 2012 and 2017. All individuals had a minimum of 1-year follow up. Logistic regression explored baseline differences across patients who received a genomics-informed treatment versus a standard care treatment after genomic sequencing. DID estimated the incremental effects of genomics-informed treatment on time to treatment discontinuation (TTD), time to next treatment (TTNT), and costs. TTD and TTNT correlate with improved response and survival. RESULTS: Our study cohort included 346 patients, of whom 140 (40%) received genomics-informed treatment after sequencing and 206 (60%) received standard care treatment. No significant differences in baseline characteristics were detected across treatment groups. DID estimated that the incremental effect of genomics-informed versus standard care treatment was 102 days (95% CI: 35, 167) on TTD, 91 days (95% CI: -9, 175) on TTNT, and CAD$91,098 (95% CI: $46,848, $176,598) on costs. Effects were most pronounced in gastrointestinal cancer patients. CONCLUSIONS: Genomics-informed treatment had a statistically significant effect on TTD compared to standard care treatment, but at increased treatment costs. Within-cohort evidence generated through this single-arm study informs the early-stage comparative effectiveness of precision oncology.
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Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão/economia , Análise de Sequência de DNA , Neoplasias da Mama , Custos e Análise de Custo , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Estudo de Associação Genômica Ampla , Genômica/economia , Genômica/métodos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neoplasias/patologia , Medicina de Precisão/métodos , Estudos Retrospectivos , Resultado do Tratamento , Suspensão de TratamentoRESUMO
Poorly differentiated chordoma (PDC) is a recently recognized subtype of chordoma characterized by expression of the embryonic transcription factor, brachyury, and loss of INI1. PDC primarily affects children and is associated with a poor prognosis and limited treatment options. Here we describe the molecular and immune tumour microenvironment profiles of two paediatric PDCs produced using whole-genome, transcriptome and whole-genome bisulfite sequencing (WGBS) and multiplex immunohistochemistry. Our analyses revealed the presence of tumour-associated immune cells, including CD8+ T cells, and expression of the immune checkpoint protein, PD-L1, in both patient samples. Molecular profiling provided the rationale for immune checkpoint inhibitor (ICI) therapy, which resulted in a clinical and radiographic response. A dominant T cell receptor (TCR) clone specific for a brachyury peptide-MHC complex was identified from bulk RNA sequencing, suggesting that targeting of the brachyury tumour antigen by tumour-associated T cells may underlie this clinical response to ICI. Correlative analysis with rhabdoid tumours, another INI1-deficient paediatric malignancy, suggests that a subset of tumours may share common immune phenotypes, indicating the potential for a therapeutically targetable subgroup of challenging paediatric cancers.
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PURPOSE: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors with dramatic and durable responses seen across multiple tumor types. However, identifying patients who will respond to these drugs remains challenging, particularly in the context of advanced and previously treated cancers. EXPERIMENTAL DESIGN: We characterized fresh tumor biopsies from a heterogeneous pan-cancer cohort of 98 patients with metastatic predominantly pretreated disease through the Personalized OncoGenomics program at BC Cancer (Vancouver, Canada) using whole genome and transcriptome analysis (WGTA). Baseline characteristics and follow-up data were collected retrospectively. RESULTS: We found that tumor mutation burden, independent of mismatch repair status, was the most predictive marker of time to progression (P = 0.007), but immune-related CD8+ T-cell and M1-M2 macrophage ratio scores were more predictive for overall survival (OS; P = 0.0014 and 0.0012, respectively). While CD274 [programmed death-ligand 1 (PD-L1)] gene expression is comparable with protein levels detected by IHC, we did not observe a clinical benefit for patients with this marker. We demonstrate that a combination of markers based on WGTA provides the best stratification of patients (P = 0.00071, OS), and also present a case study of possible acquired resistance to pembrolizumab in a patient with non-small cell lung cancer. CONCLUSIONS: Interpreting the tumor-immune interface to predict ICI efficacy remains challenging. WGTA allows for identification of multiple biomarkers simultaneously that in combination may help to identify responders, particularly in the context of a heterogeneous population of advanced and previously treated cancers, thus precluding tumor type-specific testing.
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Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Tomada de Decisão Clínica , Feminino , Seguimentos , Testes Genéticos/métodos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/mortalidade , Seleção de Pacientes , Medicina de Precisão/métodos , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Inherited genetic variation has important implications for cancer screening, early diagnosis, and disease prognosis. A role for germline variation has also been described in shaping the molecular landscape, immune response, microenvironment, and treatment response of individual tumors. However, there is a lack of consensus on the handling and analysis of germline information that extends beyond known or suspected cancer susceptibility in large-scale cancer genomics initiatives. As part of the Personalized OncoGenomics program in British Columbia, we performed whole-genome and transcriptome sequencing in paired tumor and normal tissues from advanced cancer patients to characterize the molecular tumor landscape and identify putative targets for therapy. Overall, our experience supports a multidisciplinary and integrative approach to germline data management. This includes a need for broader definitions and standardized recommendations regarding primary and secondary germline findings in precision oncology. Here, we propose a framework for identifying, evaluating, and returning germline variants of potential clinical significance that may have indications for health management beyond cancer risk reduction or prevention in patients and their families.
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Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.
Assuntos
Epigenoma/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Transcriptoma/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Adulto , Idoso , Metilação de DNA/genética , Feminino , Humanos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Uganda , Regulação para Cima/genéticaRESUMO
Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2 Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.
Assuntos
Biologia Computacional/métodos , Proteínas de Ligação a DNA/genética , Retrovirus Endógenos/genética , Metástase Neoplásica/genética , Proteínas Proto-Oncogênicas/genética , Linhagem Celular Tumoral , Dioxigenases , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metástase Neoplásica/imunologia , RNA Viral/genética , Análise de Sequência de RNA , Análise de Sobrevida , Regulação para CimaRESUMO
Advanced and metastatic tumors with complex treatment histories drive cancer mortality. Here we describe the POG570 cohort, a comprehensive whole-genome, transcriptome and clinical dataset, amenable for exploration of the impacts of therapies on genomic landscapes. Previous exposure to DNA-damaging chemotherapies and mutations affecting DNA repair genes, including POLQ and genes encoding Polζ, were associated with genome-wide, therapy-induced mutagenesis. Exposure to platinum therapies coincided with signatures SBS31 and DSB5 and, when combined with DNA synthesis inhibitors, signature SBS17b. Alterations in ESR1, EGFR, CTNNB1, FGFR1, VEGFA and DPYD were consistent with drug resistance and sensitivity. Recurrent noncoding events were found in regulatory region hotspots of genes including TERT, PLEKHS1, AP2A1 and ADGRG6. Mutation burden and immune signatures corresponded with overall survival and response to immunotherapy. Our data offer a rich resource for investigation of advanced cancers and interpretation of whole-genome and transcriptome sequencing in the context of a cancer clinic.
Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.