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 AsuntoRESUMEN
Adjuvant chemotherapy with fluorouracil and folinic acid improves overall survival for resected carcinoma of the colon of Dukes' stage C by 10-12%. In metastatic disease, response rates with fluorouracil-based regimens are about 25%. Combination with newer agents such as irinotecan and oxaliplatin can improve response rates to more than 50% in selected patients. New treatments with novel molecular targets will soon be entering clinical use. Despite these improvements, many patients undergo chemotherapy for resistant cancer, thus incurring side-effects without benefit. Expression of particular genes can be tested at the protein or RNA level and can be correlated with response or resistance to particular systemic therapies. Thus, predictive-factor testing of tumour biopsy samples may allow us to select chemotherapy or immunotherapy treatments with a high likelihood of benefit for the individual patient.