RESUMO
PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved as maintenance therapy for patients with advanced pancreatic cancer (PC) and a germline BRCA1 or BRCA2 pathogenic variant (PV). This investigator-initiated, single-arm phase II study assessed the role of the PARPi rucaparib as maintenance therapy in advanced PC with germline or somatic PV in BRCA1, BRCA2, or PALB2. PATIENTS AND METHODS: Eligible patients had advanced PC; germline (g) or somatic (s) PVs in BRCA1, BRCA2, or PALB2, and received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance. Chemotherapy was discontinued and patients received rucaparib 600 mg orally twice a day until progression. The primary end point was the progression-free survival (PFS) rate at 6 months (PFS6). Secondary end points included safety, ORR, disease control rate, duration of response, and overall survival. RESULTS: Of 46 enrolled patients, 42 were evaluable (27 gBRCA2, seven gBRCA1, six gPALB2, and two sBRCA2). PFS6 was 59.5% (95% CI, 44.6 to 74.4), median PFS was 13.1 months (95% CI, 4.4 to 21.8), and median overall survival was 23.5 months (95% CI, 20 to 27). The PFS at 12 months was 54.8%. ORR of the 36 patients with measurable disease was 41.7% (3 complete responses; 12 partial responses; 95% CI, 25.5 to 59.2), and disease control rate was 66.7% (95% CI, 49.0 to 81.4). Median duration of response was 17.3 months (95% CI, 8.8 to 25.8). Responses occurred in patients with gBRCA2 (41%, 11 out of 27), gPALB2 (50%, 3 out of 6), and sBRCA2 (50%, 1 out of 2). No new safety signals were noted. CONCLUSION: Maintenance rucaparib is a safe and effective therapy for platinum-sensitive, advanced PC with a PV in BRCA1, BRCA2, or PALB2. The finding of efficacy in patients with gPALB2 and sBRCA2 PVs expands the population likely to benefit from PARPi beyond gBRCA1/2 PV carriers.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Indóis/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mutação em Linhagem Germinativa , Humanos , Indóis/efeitos adversos , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêuticoRESUMO
ABSTRACT Background: Hepatitis B virus (HBV) infection and diabetes mellitus are major health problems associated with significant morbidity and mortality. The published literature suggests an association of diabetes mellitus with liver disease. However, the role of HBV infection in diabetes aetiology is still controversial. The present study was conducted to explore the veracity of this enigmatic association among Pakistani subjects. Methodology: The blood samples and clinical information were collected from chronic HBV-positive patients Group 1 (n = 120), and their age and gender were matched with those of the healthy control subjects Group 2 (n = 120). Hepatitis B virus-positive patients were also subdivided into two groups; (Group 1a and Group 1b) with and without liver cirrhosis for evaluation of the prevalence of diabetes. Results: The study revealed that there were statistically significant differences in the biochemical parameters in the HBV-positive and control groups. There was no correlation between diabetes and HBV with the prevalence of diabetes mellitus being similar in subjects with and without HBsAg (11.7% in the positive group and 10% in the controls). Since there were a relatively large number (32.5%) of HBV-positive patients with liver cirrhosis, a comparison of biochemical parameters was also carried out to evaluate the extent of the liver damage and its association with diabetes. During the comparison of HBV patients with and without cirrhosis for the prevalence of diabetes, no aetiologic association was found with diabetes. Conclusion: Study revealed that there was no correlation between HBV infection and diaabetes despite the significantly different biochemical parameters in the HBV-infected group and control subjects.
RESUMEN Antecedentes: La infección por el virus de la hepatitis B (VHB) y la diabetes mellitus son problemas de salud importantes asociados con morbilidad y mortalidad significativas. La literatura publicada sugiere una asociación de la diabetes mellitus con las enfermedades hepáticas. Sin embargo, el papel de la infección por VHB en la etiología de diabetes sigue siendo contro-versial. El presente estudio fue conducido con el propósito de explorar la veracidad de esta enigmática asociación entre sujetos paquistaníes. Metodología: Se recogieron muestras de sangre e información clínica de pacientes crónicos VHB positivos Grupo 1 (n = 120), y su edad y género fueron comparados con los de los sujetos sanos del control Grupo 2 (n = 120). Los pacientes positivos al virus de la hepatitis B también se subdividieron en dos grupos, a saber, (Grupo 1a y Grupo 1b) con y sin cirrosis hepática en relación con la prevalencia de la diabetes. Resultados: El estudio reveló que hubo diferencias significativas en estos dos grupos en los parámetros bioquímicos entre el grupo de control y el grupo VHB positivo. En estos dos grupos no hubo correlación entre la diabetes y el VHB. Puesto que hubo un número relativamente grande (32.5%) de pacientes VHB positivos con cirrosis hepática, se realizó también una comparación de los parámetros bioquímicos a fin de comprender el grado del daño hepático y su asociación con la diabetes. Durante la comparación de los pacientes con VHB con y sin cirrosis en relación con la prevalencia de diabetes, no se halló asociación etiológica con la diabetes. Conclusión: Este estudio reveló que no hubo correlación entre la infección por VHB y la diabetes, a pesar de los parámetros bioquímicos significativamente diferentes entre el grupo infectado por el VHB y los sujetos del control.