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1.
Br J Cancer ; 126(2): 247-258, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34728791

RESUMEN

BACKGROUND: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer. METHODS: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures. RESULTS: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression. CONCLUSIONS: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming. TRIAL REGISTRATION: Not applicable (non-interventional study). CRUK Internal Database Number 14232.


Asunto(s)
Neoplasias de la Mama/inmunología , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Daño del ADN , Proteínas de la Membrana/metabolismo , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/inmunología , Nucleotidiltransferasas/metabolismo , Taxoides/uso terapéutico , Adulto , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana/genética , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Nucleotidiltransferasas/genética , Resultado del Tratamiento
2.
Gut ; 68(11): 1918-1927, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30852560

RESUMEN

OBJECTIVE: Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. DESIGN: Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025). CONCLUSION: The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.


Asunto(s)
Adenocarcinoma/inmunología , Adenocarcinoma/terapia , Antineoplásicos/uso terapéutico , Daño del ADN/inmunología , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/terapia , Esofagectomía , Terapia Neoadyuvante , Adenocarcinoma/mortalidad , Anciano , Antígeno B7-H1 , Linfocitos T CD8-positivos , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Neoplasias Esofágicas/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Tasa de Supervivencia , Resultado del Tratamiento
3.
Blood Cells Mol Dis ; 54(1): 123-31, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25128083

RESUMEN

DEK is important in regulating cellular processes including proliferation, differentiation and maintenance of stem cell phenotype. The translocation t(6;9) in Acute Myeloid Leukemia (AML), which fuses DEK with NUP214, confers a poor prognosis and a higher risk of relapse. The over-expression of DEK in AML has been reported, but different studies have shown diminished levels in pediatric and promyelocytic leukemias. This study has characterized DEK expression, in silico, using a large multi-center cohort of leukemic and normal control cases. Overall, DEK was under-expressed in AML compared to normal bone marrow (NBM). Studying specific subtypes of AML confirmed either no significant change or a significant reduction in DEK expression compared to NBM. Importantly, the similarity of DEK expression between AML and NBM was confirmed using immunohistochemistry analysis of tissue mircorarrays. In addition, stratification of AML patients based on median DEK expression levels indicated that DEK showed no effect on the overall survival of patients. DEK expression during normal hematopoiesis did reveal a relationship with specific cell types implicating a distinct function during myeloid differentiation. Whilst DEK may play a potential role in hematopoiesis, it remains to be established whether it is important for leukemagenesis, except when involved in the t(6;9) translocation.


Asunto(s)
Proteínas Cromosómicas no Histona/biosíntesis , Proteínas de Unión al ADN/biosíntesis , Bases de Datos Genéticas , Regulación Leucémica de la Expresión Génica , Hematopoyesis , Leucemia Mieloide Aguda/metabolismo , Proteínas Oncogénicas/biosíntesis , Animales , Proteínas Cromosómicas no Histona/genética , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 9/genética , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Estudios Multicéntricos como Asunto , Proteínas Oncogénicas/genética , Proteínas de Unión a Poli-ADP-Ribosa , Tasa de Supervivencia , Translocación Genética
4.
JCO Precis Oncol ; 7: e2300197, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37972336

RESUMEN

PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous disease. We previously showed that homologous recombination deficiency (HRD) and the DNA damage immune response (DDIR) signature are prognostic in TNBC. We hypothesized that these biomarkers reflect related but not completely interdependent biological processes, that their combined use would be prognostic, and that simultaneous assessment of the immunologic microenvironment and susceptibility to DNA damaging therapies might be able to identify subgroups with distinct therapeutic vulnerabilities. METHODS: We analyzed the dual DDIR/HRD classification in 341 patients with TNBC treated with adjuvant anthracycline-based chemotherapy on the SWOG S9313 trial and corroborated our findings in The Cancer Genome Atlas breast cancer data set. RESULTS: DDIR/HRD classification is highly prognostic in TNBC and identifies biologically and immunologically distinct subgroups. Immune-enriched DDIR+/HRD+ TNBCs have the most favorable prognosis, and DDIR+/HRD- and DDIR-/HRD+ TNBCs have favorable intermediate prognosis, despite the latter being immune-depleted. DDIR-/HRD- TNBCs have the worst prognosis and represent an internally heterogeneous group of immune-depleted chemoresistant tumors. CONCLUSION: Our findings propose DDIR/HRD classification as a potentially clinically relevant approach to categorize tumors on the basis of therapeutic vulnerabilities.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Humanos , Pronóstico , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Recombinación Homóloga/genética , Daño del ADN/genética , Inmunidad , Microambiente Tumoral
5.
Clin Cancer Res ; 27(1): 288-300, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33028592

RESUMEN

PURPOSE: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer. EXPERIMENTAL DESIGN: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer. RESULTS: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer. CONCLUSIONS: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bioensayo/métodos , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/terapia , Daño del ADN/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante/métodos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Daño del ADN/efectos de los fármacos , Análisis Mutacional de ADN , Femenino , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Perfilación de la Expresión Génica , Humanos , Leucovorina/farmacología , Leucovorina/uso terapéutico , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , Terapia Neoadyuvante/métodos , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/uso terapéutico , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto
6.
J Clin Oncol ; 37(36): 3484-3492, 2019 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-31657982

RESUMEN

PURPOSE: To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. METHODS: Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. RESULTS: Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated (r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively. CONCLUSION: The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/inmunología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunología , Adulto , Anciano , Ciclofosfamida/uso terapéutico , Daño del ADN , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Persona de Mediana Edad , Pronóstico , Transcriptoma , Neoplasias de la Mama Triple Negativas/mortalidad
7.
Eur Urol ; 72(4): 509-518, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28408174

RESUMEN

BACKGROUND: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. OBJECTIVE: To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis. RESULTS AND LIMITATIONS: A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation. CONCLUSIONS: The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential. PATIENT SUMMARY: The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population.


Asunto(s)
Biomarcadores de Tumor/genética , Escisión del Ganglio Linfático , Prostatectomía , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Transcriptoma , Análisis por Conglomerados , Predisposición Genética a la Enfermedad , Humanos , Análisis de los Mínimos Cuadrados , Escisión del Ganglio Linfático/efectos adversos , Metástasis Linfática , Masculino , Análisis Multivariante , Fenotipo , Modelos de Riesgos Proporcionales , Prostatectomía/efectos adversos , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
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