RESUMEN
BACKGROUND: Systemic inflammatory scores may aid prognostication and patient selection for trials. We compared five scores in advanced pancreatic adenocarcinoma (PDAC). METHODS: Unresectable/metastatic PDAC patients enrolled in the Comprehensive Molecular Characterisation of Advanced Pancreatic Ductal Adenocarcinoma for Better Treatment Selection trial (NCT02750657) were included. Patients had pre-treatment biopsies for whole genome and RNA sequencing. CD8 immunohistochemistry was available in a subset. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, Prognostic Nutritional Index, Gustave Roussy Immune Score (GRIm-S), and Memorial Sloan Kettering Prognostic Score (MPS) were calculated. Overall survival (OS) was estimated using Kaplan-Meier methods. Associations between inflammatory scores, clinical/genomic characteristics, and OS were analysed. RESULTS: We analysed 263 patients. High-risk NLR, GRIm-S and MPS were poorly prognostic. The GRIm-S had the highest predictive ability: median OS 6.4 vs. 10 months for high risk vs. low-risk (P < 0.001); HR 2.26 (P < 0.001). ECOG ≥ 1, the basal-like subtype, and low-HRDetect were additional poor prognostic factors (P < 0.01). Inflammatory scores did not associate with RNA-based classifiers or homologous recombination repair deficiency genotypes. High-risk MPS (P = 0.04) and GRIm-S (P = 0.02) patients had lower median CD8 + tumour-infiltrating lymphocytes. CONCLUSIONS: Inflammatory scores incorporating NLR have prognostic value in advanced PDAC. Understanding immunophenotypes of poor-risk patients and using these scores in trials will advance the field.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Pronóstico , Adenocarcinoma/genética , Adenocarcinoma/patología , Linfocitos/patología , Neutrófilos/patología , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.
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Carcinoma Ductal Pancreático/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Pancreáticas/genética , Reparación del ADN por Recombinación , Anciano , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Cisplatino/administración & dosificación , Proteínas de Unión al ADN/genética , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/genética , Femenino , Fluorouracilo/uso terapéutico , Inestabilidad Genómica , Mutación de Línea Germinal , Recombinación Homóloga , Humanos , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Oxaliplatino/uso terapéutico , Pancreatectomía , Neoplasias Pancreáticas/terapia , Pronóstico , Sensibilidad y Especificidad , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/genética , Secuenciación Completa del Genoma , GemcitabinaRESUMEN
BACKGROUND: Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at increased risk of developing PC. These high-risk individuals (HRIs) may benefit from PC surveillance. METHODS: A PC surveillance program was developed to evaluate the detection of premalignant lesions and early-stage PCs using biannual imaging and to determine whether locally advanced or metastatic PCs develop despite biannual surveillance. From January 2013 to April 2020, asymptomatic HRIs were enrolled and followed with alternating MRI and endoscopic ultrasound every 6 months. RESULTS: Of 75 HRIs, 43 (57.3%) had a germline mutation in a PC susceptibility gene and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 individuals (34.7%), but only 2 developed progressive lesions. One patient with Peutz-Jeghers syndrome (PJS) developed locally advanced PC arising from a BD-IPMN. Whole-genome sequencing of this patient's PC and of a second patient with PJS-associated PC from the same kindred revealed biallelic inactivation of STK11 in a KRAS-independent manner. A review of 3,853 patients from 2 PC registries identified an additional patient with PJS-associated PC. All 3 patients with PJS developed advanced PC consistent with the malignant transformation of an underlying BD-IPMN in <6 months. The other surveillance patient with a progressive lesion had FPC and underwent resection of a mixed-type IPMN that harbored polyclonal KRAS mutations. CONCLUSIONS: PC surveillance identifies a high prevalence of BD-IPMNs in HRIs. Patients with PJS with BD-IPMNs may be at risk for accelerated malignant transformation.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Carcinoma , Carcinoma Ductal Pancreático/patología , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Síndrome , Neoplasias PancreáticasRESUMEN
Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.
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Carcinogénesis/genética , Carcinogénesis/patología , Reordenamiento Génico/genética , Genoma Humano/genética , Modelos Biológicos , Mutagénesis/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Carcinoma in Situ/genética , Cromotripsis , Variaciones en el Número de Copia de ADN/genética , Progresión de la Enfermedad , Evolución Molecular , Femenino , Genes Relacionados con las Neoplasias/genética , Humanos , Masculino , Mitosis/genética , Mutación/genética , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Poliploidía , Lesiones Precancerosas/genéticaRESUMEN
BACKGROUND: Radiomic features in pancreatic ductal adenocarcinoma (PDAC) often lack validation in independent test sets or are limited to early or late stage disease. Given the lethal nature of PDAC it is possible that there are similarities in radiomic features of both early and advanced disease reflective of aggressive biology. PURPOSE: To assess the performance of prognostic radiomic features previously published in patients with resectable PDAC in a test set of patients with unresectable PDAC undergoing chemotherapy. METHODS: The pre-treatment CT of 108 patients enrolled in a prospective chemotherapy trial were used as a test cohort for 2 previously published prognostic radiomic features in resectable PDAC (Sum Entropy and Cluster Tendency with square-root filter[Sqrt]). We assessed the performance of these 2 radiomic features for the prediction of overall survival (OS) and time to progression (TTP) using Cox proportional-hazard models. RESULTS: Sqrt Cluster Tendency was significantly associated with outcome with a hazard ratio (HR) of 1.27(for primary pancreatic tumor plus local nodes), (Confidence Interval(CI):1.01 -1.6, P-value = 0.039) for OS and a HR of 1.25(CI:1.00 -1.55, P-value = 0.047) for TTP. Sum entropy was not associated with outcomes. Sqrt Cluster Tendency remained significant in multivariate analysis. CONCLUSION: The CT radiomic feature Sqrt Cluster Tendency, previously demonstrated to be prognostic in resectable PDAC, remained a significant prognostic factor for OS and TTP in a test set of unresectable PDAC patients. This radiomic feature warrants further investigation to understand its biologic correlates and CT applicability in PDAC patients.
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Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/tratamiento farmacológico , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/tratamiento farmacológico , Tomografía Computarizada por Rayos X/métodos , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Páncreas/diagnóstico por imagen , Pronóstico , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 'trios' of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity.
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Carcinoma Ductal Pancreático/genética , Genoma/genética , Modelos Biológicos , Neoplasias Experimentales/genética , Neoplasias Pancreáticas/genética , Animales , Investigación Biomédica/normas , Humanos , Páncreas/patologíaRESUMEN
Somatic mutations have been found in the mitochondria in different types of cancer cells, but it is not clear whether these affect tumorigenesis or tumor progression. We analyzed mitochondrial genomes of 268 early-stage, resected pancreatic ductal adenocarcinoma tissues and paired non-tumor tissues. We defined a mitochondrial somatic mutation (mtSNV) as a position where the difference in heteroplasmy fraction between tumor and normal sample was ≥0.2. Our analysis identified 304 mtSNVs, with at least 1 mtSNV in 61% (164 of 268) of tumor samples. The noncoding control region had the greatest proportion of mtSNVs (60 of 304 mutations); this region contains sites that regulate mitochondrial DNA transcription and replication. Frequently mutated genes included ND5, RNR2, and CO1, plus 29 mutations in transfer RNA genes. mtSNVs in 2 separate mitochondrial genes (ND4 and ND6) were associated with shorter overall survival time. This association appeared to depend on the level of mtSNV heteroplasmy. Non-random co-occurrence between mtSNVs and mutations in nuclear genes indicates interactions between nuclear and mitochondrial DNA. In an analysis of primary tumors and metastases from 6 patients, we found tumors to accumulate mitochondrial mutational mutations as they progress.
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Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , ADN Mitocondrial/genética , Mutación , Neoplasias Pancreáticas/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Factores de TiempoRESUMEN
We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10-6; exome-wide statistical significance threshold P < 2.5x10-6). Cases had more rare inactivating variants in DNA repair genes than controls, even after excluding 13 genes known to predispose to pancreatic cancer (adjusted odds ratio, 1.35; P = .045). At the suggestive threshold (P < .001), 6 genes were enriched for rare damaging variants (UHMK1, AP1G2, DNTA, CHST6, FGFR3, and EPHA1) and 7 genes had associations with pancreatic cancer risk, based on the sequence-kernel association test. We confirmed variants in BRCA2 as the most common high-penetrant genetic factor associated with pancreatic cancer and we also identified candidate pancreatic cancer genes. Large collaborations and novel approaches are needed to overcome the genetic heterogeneity of pancreatic cancer predisposition.
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Biomarcadores de Tumor/genética , Secuenciación del Exoma , Exoma , Variación Genética , Neoplasias Pancreáticas/genética , Proteína BRCA2/genética , Estudios de Casos y Controles , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Oportunidad Relativa , Neoplasias Pancreáticas/diagnóstico , Fenotipo , Medición de Riesgo , Factores de RiesgoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA-mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naïve to treatments; (2) stable-genome naïve to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Compuestos de Platino/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Animales , Carcinoma Ductal Pancreático/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Inestabilidad Genómica , Recombinación Homóloga , Humanos , Ratones , Mutación , Metástasis de la Neoplasia , Trasplante de Neoplasias , Neoplasias Pancreáticas/genética , Compuestos de Platino/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Pronóstico , Secuenciación Completa del GenomaRESUMEN
Gemcitabine is a potent inhibitor of DNA replication and is a mainstay therapeutic for diverse cancers, particularly pancreatic ductal adenocarcinoma (PDAC). However, most tumors remain refractory to gemcitabine therapies. Here, to define the cancer cell response to gemcitabine, we performed genome-scale CRISPR-Cas9 chemical-genetic screens in PDAC cells and found selective loss of cell fitness upon disruption of the cytidine deaminases APOBEC3C and APOBEC3D. Following gemcitabine treatment, APOBEC3C and APOBEC3D promote DNA replication stress resistance and cell survival by deaminating cytidines in the nuclear genome to ensure DNA replication fork restart and repair in PDAC cells. We provide evidence that the chemical-genetic interaction between APOBEC3C or APOBEC3D and gemcitabine is absent in nontransformed cells but is recapitulated across different PDAC cell lines, in PDAC organoids and in PDAC xenografts. Thus, we uncover roles for APOBEC3C and APOBEC3D in DNA replication stress resistance and offer plausible targets for improving gemcitabine-based therapies for PDAC.
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Carcinoma Ductal Pancreático , Citidina Desaminasa , Replicación del ADN , Desoxicitidina , Gemcitabina , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Citidina Desaminasa/metabolismo , Citidina Desaminasa/genética , Línea Celular Tumoral , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Ratones , Resistencia a Antineoplásicos/genética , Antimetabolitos Antineoplásicos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Sistemas CRISPR-CasRESUMEN
AIMS: The majority of pancreatic ductal adenocarcinomas (PDACs) harbour oncogenic mutations in KRAS with variants in TP53, CDKN2A and SMAD4 also prevalent. The presence of oncogenic fusions including NTRK fusions are rare but important to identify. Here we ascertain the prevalence of NTRK fusions and document their genomic characteristics in a large series of PDAC. METHODS: Whole genome sequencing and RNAseq were performed on a series of patients with resected or locally advanced/metastatic PDAC collected between 2008 and 2020 at a single institution. A subset of specimens underwent immunohistochemistry (IHC) analysis. Clinical and molecular characterisation and IHC sensitivity and specificity were evaluated. RESULTS: 400 patients were included (resected n=167; locally advanced/metastatic n=233). Three patients were identified as harbouring an NTRK fusion, two EML4-NTRK3 (KRAS-WT) and a single novel KANK1-NTRK3 fusion. The latter occurring in the presence of a subclonal KRAS mutation. Typical PDAC drivers were present including mutations in TP53 and CDKN2A. Substitution base signatures and tumour mutational burden were similar to typical PDAC. The prevalence of NTRK fusions was 0.8% (3/400), while in KRAS wild-type tumours, it was 6.25% (2/32). DNA prediction alone documented six false-positive cases. RNA analysis correctly identified the in-frame fusion transcripts. IHC analysis was negative in the KANK1-NTRK3 fusion but positive in a EML4-NTRK3 case, highlighting lower sensitivity of IHC. CONCLUSION: NTRK fusions are rare; however, with emerging therapeutic options targeting these fusions, detection is vital. Reflex testing for KRAS mutations and subsequent RNA-based screening could help identify these cases in PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Mutación , Proteínas de Fusión Oncogénica/genética , Proteínas del Citoesqueleto/genética , Proteínas Adaptadoras Transductoras de Señales , Neoplasias PancreáticasRESUMEN
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.
RESUMEN
Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions. SIGNIFICANCE: glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Platino (Metal)/farmacología , Platino (Metal)/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Mutación , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Neoplasias PancreáticasRESUMEN
AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.
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Oxadiazoles/química , Piridinas/química , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Animales , Sitios de Unión , Sistema Nervioso Central/diagnóstico por imagen , Evaluación Preclínica de Medicamentos , Células HEK293 , Semivida , Humanos , Marcaje Isotópico , Masculino , Microsomas/metabolismo , Oxadiazoles/síntesis química , Oxadiazoles/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Cintigrafía , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
Changes in metabolism are a hallmark of cancer, but molecular signatures of altered bioenergetics to aid in clinical decision-making do not currently exist. We recently identified a group of human tumors with constitutively reduced expression of the mitochondrial structural protein, Mic60, also called mitofilin or inner membrane mitochondrial protein (IMMT). These Mic60-low tumors exhibit severe loss of mitochondrial fitness, paradoxically accompanied by increased metastatic propensity and upregulation of a unique transcriptome of Interferon (IFN) signaling and Senescence-Associated Secretory Phenotype (SASP). Here, we show that an optimized, 11-gene signature of Mic60-low tumors is differentially expressed in multiple malignancies, compared to normal tissues, and correlates with poor patient outcome. When analyzed in three independent patient cohorts of pancreatic ductal adenocarcinoma (PDAC), the Mic60-low gene signature was associated with aggressive disease variants, local inflammation, FOLFIRINOX failure and shortened survival, independently of age, gender, or stage. Therefore, the 11-gene Mic60-low signature may provide an easily accessible molecular tool to stratify patient risk in PDAC and potentially other malignancies.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático/patología , Humanos , Interferones , Proteínas Mitocondriales/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias PancreáticasRESUMEN
Co-occurrent KRAS and TP53 mutations define a majority of patients with pancreatic ductal adenocarcinoma (PDAC) and define its pro-metastatic proclivity. Here, we demonstrate that KRAS-TP53 co-alteration is associated with worse survival compared with either KRAS-alone or TP53-alone altered PDAC in 245 patients with metastatic disease treated at a tertiary referral cancer center, and validate this observation in two independent molecularly annotated datasets. Compared with non-TP53 mutated KRAS-altered tumors, KRAS-TP53 co-alteration engenders disproportionately innate immune-enriched and CD8+ T-cell-excluded immune signatures. Leveraging in silico, in vitro, and in vivo models of human and murine PDAC, we discover a novel intersection between KRAS-TP53 co-altered transcriptomes, TP63-defined squamous trans-differentiation, and myeloid-cell migration into the tumor microenvironment. Comparison of single-cell transcriptomes between KRAS-TP53 co-altered and KRAS-altered/TP53WT tumors revealed cancer cell-autonomous transcriptional programs that orchestrate innate immune trafficking and function. Moreover, we uncover granulocyte-derived inflammasome activation and TNF signaling as putative paracrine mediators of innate immunoregulatory transcriptional programs in KRAS-TP53 co-altered PDAC. Immune subtyping of KRAS-TP53 co-altered PDAC reveals conflation of intratumor heterogeneity with progenitor-like stemness properties. Coalescing these distinct molecular characteristics into a KRAS-TP53 co-altered "immunoregulatory program" predicts chemoresistance in metastatic PDAC patients enrolled in the COMPASS trial, as well as worse overall survival.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/genética , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Humanos , Ratones , Mutación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Microambiente Tumoral , Proteína p53 Supresora de Tumor/genética , Neoplasias PancreáticasRESUMEN
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.
Asunto(s)
Adenocarcinoma , Neoplasias de los Conductos Biliares , Carcinoma Ductal Pancreático , Colangiocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/patología , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos , Carcinoma Ductal Pancreático/patología , Colangiocarcinoma/genética , Humanos , Mutación , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Transcripción/genética , Neoplasias PancreáticasRESUMEN
The immune contexture of pancreatic ductal adenocarcinoma (PDAC) is generally immunosuppressive. A role for immune checkpoint inhibitors (ICIs) in PDAC has only been demonstrated for the rare and hypermutated mismatch repair (MMR) deficient (MMR-d) subtype. Homologous recombination repair (HR) deficient (HR-d) PDAC is more prevalent and may encompass up to 20% of PDAC. Its genomic instability may promote a T-cell mediated anti-tumor response with therapeutic sensitivity to ICIs. To investigate the immunogenicity of HR-d PDAC, we used multiplex immunohistochemistry (IHC) to compare the density and spatial distribution of CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells (Tregs), and CD68+ tumor-associated macrophages (TAMs) in HR-d versus HR/MMR-intact PDAC. We also evaluated the IHC positivity of programmed death-ligand 1 (PD-L1) across the subgroups. 192 tumors were evaluated and classified as HR/MMR-intact (n=166), HR-d (n=25) or MMR-d (n=1) based on germline testing and tumor molecular hallmarks. Intra-tumoral CD8+ T-cell infiltration was higher in HR-d versus HR/MMR-intact PDAC (p<0.0001), while CD8+ T-cell densities in the peri-tumoral and stromal regions were similar in both groups. HR-d PDAC also displayed increased intra-tumoral FOXP3+ Tregs (p=0.049) and had a higher CD8+:FOXP3+ ratio (p=0.023). CD68+ TAM expression was similar in HR-d and HR/MMR-intact PDAC. Finally, 6 of the 25 HR-d cases showed a PD-L1 Combined Positive Score of >=1, whereas none of the HR/MMR-intact cases met this threshold (p<0.00001). These results provide immunohistochemical evidence for intra-tumoral CD8+ T-cell enrichment and PD-L1 positivity in HR-d PDAC, suggesting that HR-d PDAC may be amenable to ICI treatment strategies.
RESUMEN
Combination chemotherapy, either modified FOLFIRINOX (mFFX) or gemcitabine-nabpaclitaxel, are used in the treatment of most patients with advanced pancreatic ductal adenocarcinoma (PDAC), yet robust biomarkers of outcome are currently lacking to guide regimen selection. Here, we tested GATA6 immunohistochemistry (IHC) as a putative biomarker in advanced PDAC. GATA6 is a transcription factor in normal pancreas development. Two pathologists, blinded to clinical and molecular data, independently assessed GATA6 IHC in biopsy specimens of 130 patients with advanced PDAC, in 2 distinct phases (without and with computer assistance using the open source software QuPath). Low GATA6 IHC expression was associated with shorter overall survival [median OS 6.2 months for patients with GATA6 low tumors vs. 11.5 months for patients with GATA6 high tumors, HR 1.66 (95% CI 1.15-2.40), P = 0.007]. Progression appears to be higher in GATA6-low tumors compared to GATA6-high tumors in patients treated with mFFX (P = 0.024) but not in patients treated with gemcitabine regimens. GATA6 IHC expression was significantly associated with molecular subtypes (P = 0.0003). Digital assistance markedly improved interrater concordance (Cohen's kappa scores of 0.32 vs. 0.95). Our results provide strong evidence that GATA6 IHC can be used as a single biomarker in the clinic to predict clinical outcome in advanced PDAC, warranting further investigation in prospective clinical trials. These results provide the basis for an improved classification of PDAC and future biomarker design using digital pathology workflow.