Avaliação prospectiva da correlação entre células tumorais circulantes e controle da doença encefálica após radioterapia focal de metástases encefálicas de câncer da mama / Prospective assessment of the correlation between circulating tumor cells and control of brain disease after focal radiotherapy of breast cancer brain metastases

RESUMO

Introdução: Predizer o risco de progressão encefálica distante (PED) precoce é um recurso útil e premente para a decisão terapêutica em pacientes candidatas ao tratamento local de metástases encefálicas. Este estudo tem como objetivo analisar a correlação entre células tumorais circulantes (CTCs) e controle da doença encefálica após radioterapia estereotática/radiocirurgia (RTE) de metástases encefálicas de câncer da mama (ME). Métodos: Avaliação prospectiva de CTC antes (CTC1) e 4­5 semanas após (CTC2) a RTE de ME e suas relações com o número de lesões sugestivas de ME (NL). As CTCs foram isoladas e quantificadas pelo método ISET (Rarecells, França) e analisadas por imunocitoquímica para avaliar a expressão das proteínas COX2, EGFR, ST6GALNAC5, NOTCH1 e HER2. Sobrevida livre de progressão encefálica distante (SLPED), o objetivo primário, sobrevida livre de progressão encefálica com envolvimento difuso (SLPED-ED), definida como progressão com mais de 4 novas ME ou carcinomatose meníngea, e sobrevida global (SG) foram estimadas pelo estimador de Kaplan-Meier. Testes de log-rank foram aplicados a fim de comparar as curvas de sobrevida. Para análise multivariada dos fatores prognósticos que afetaram a SPED e SG, foi ajustado o modelo proporcional de Cox. Análise de risco competitivo para SLPED na presença do óbito foi realizada. Resultados: Foram incluídas 39 pacientes entre novembro de 2016 e fevereiro de 2018. A idade mediana no momento da RTE foi 54 (34-70) anos e a avaliação prognóstica graduada doença-específica (DS-GPA) foi 1,5­2 em 17,5% e 2,5­4 em 82,5% das pacientes. CTCs foram detectadas em todas as 39 pacientes antes da RTE e a CTC1 mediana foi 2 CTC/mL. Após a RTE, CTCs foram detectadas em 34 das 35 pacientes (4 mortes entre CTC1 e CTC2) e a CTC2 mediana foi 2,33 CTC/mL. Após seguimento mediano de 16,6 (IC95% 14,8­18,4) meses, 15 pacientes evoluíram com PED, sendo 6 com progressão encefálica distante com envolvimento difuso (PED-ED), e 16 pacientes faleceram. A SLPED, SLPED-ED e SG mediana foram 15,3, 14,1 e 19,5 meses, respectivamente. A incidência cumulativa, com a morte como risco competitivo, de PED em 6 meses foi 40% nas pacientes com CTC1 ≤ 0,5 e 8,82% nas pacientes com CTC1 > 0,5 CTC/mL (p = 0,007) e a de PED-ED em 6 meses foi 40% nas pacientes com CTC1 ≤ 0.5 e 0 nas pacientes com CTC1 > 0,5 CTC/mL (p = 0,005) e 25% nas pacientes com NL/CTC1 > 6,8 e 2,65% com NL/CTC1 ≤ 6,8 (p = 0,063). Na análise mutivariada, a SLPED foi inferior nas pacientes com CTC1 ≤ 0,5 CTC/mL (HR 8,27, IC95%2,12­32,3; p = 0,002) e superior nas pacientes com imunofenótipo HER2-positivo (HR 0,128, IC95%0,025­0,534; p = 0,013), a SLPED-ED foi inferior nas pacientes com CTC1 ≤ 0,5 CTC/mL (HR 10,22, IC95%1,99­52,41; p = 0,005) e a SG foi superior nas pacientes com imunofenótipo HER2-positivo (HR 0,073, IC95%0,018-0,288; p < 0,0001) e luminal B (HR 0,224, IC95%0,062­0,816; p = 0,023) e nas pacientes com NL/CTC1 ≤ 2,2 (HR 0,159, 95% CI 0,05­0,505; p = 0,002). Não houve associação entre a expressão das proteínas nas CTCs e PED e SG. Conclusões: CTC1 foi um fator prognóstico independente de SLPED e SLPED-ED e NL/CTC1 foi um fator prognóstico independente de SG e um potencial fator prognóstico de PED-ED em 6 meses. Estes dados sugerem que CTC1 e NL/CTC1 podem ter um papel como biomarcador da PED-ED precoce, auxiliando a definir o momento e o tipo da radioterapia de resgate a fim de otimizar o controle das ME

ABSTRACT

Introduction: Predicting the risk of early distant brain failure (DBF) is a useful and demanding resource for management decisions in patients who are candidates to local treatment of brain metastasis. This study aims to analyze the correlation between circulating tumor cells (CTCs) and brain disease control after stereotactic radiotherapy/radiosurgery (SRT) for breast cancer brain metastasis (BM). Methods: Prospective assessment of CTCs before (CTC1) and 4­5 weeks after (CTC2) SRT for BM and its relations with the number of suggestive lesions of BM (NL). CTCs were isolated and quantified by the ISET method (Rarecells, France) and analyzed by immunocytochemistry to evaluate the expression of the proteins COX2, EGFR, ST6GALNAC5, NOTCH1 e HER2. Distant brain failure-free survival (DBFFS), the primary endpoint, diffuse distant brain failure-free survival (D-DBFFS), defined as progression with more than 4 new BM or meningeal carcinomatosis, and overall survival (OS) were estimated by Kaplan-Meier estimator. Log-rank tests were applied in order to compare the survival curves. For multivariate analysis of prognostic factors that affected DBFFS and OS, the Cox proportional model was adjusted. Competing risk analysis for DBFFS in the presence of death was performed. Results: 39 patients were included between November 2016 and February 2018. The median age at SRT was 54 (34-70) years and the diagnosis-specific graded prognostic assessment (DS-GPA) was 1.5­2 in 17.5% and 2.5­4 in 82.5% of them. CTCs were detected in all 39 patients before SRT and the median CTC1 was 2 CTC/mL. After SRT, CTCs were detected in 34 of 35 patients (4 deaths between CTC1 and CTC2) and the median CTC2 was 2.33 CTC/mL. After a median follow-up of 16.6 (95% CI 14.8­18.4) months, there were 15 patients with DBF, being 6 with diffuse distant brain failure (D-DBF), and 16 deaths. The median DBFFS, D-DBFFS and OS were 15.3, 14.1 and 19.5 months, respectively. The cumulative incidence, with death as competing risk factor, of DBF at 6 months was 40% in patients with CTC1 ≤ 0.5 and 8.82% in patients with CTC1 > 0.5 CTC/mL (p = 0.007) and of D-DBF at 6 months was 40% in patients with CTC1 ≤ 0.5 and 0 in patients with CTC1 > 0.5 CTC/mL (p = 0.005) and 25% in patients with NL/CTC1 > 6.8 and 2.65% with NL/CTC1 ≤ 6.8 (p = 0.063). On multivariate analysis, DBFFS was inferior in patients with CTC1 ≤ 0.5 CTC/mL (HR 8.27, 95% CI 2.12­32.3; p = 0.002) and superior in patients with immunophenotype HER2-positive (HR 0.128, 95% CI 0.025­0.534; p = 0.013), D-DBFFS was inferior in patients with CTC1 ≤ 0.5 CTC/mL (HR 10.22, 95% CI 1.99­52.41; p = 0.005) and OS was superior in patients with immunophenotype HER2-positive (HR 0.073, 95% CI 0.018-0.288; p < 0.0001) and luminal B (HR 0.224, 95% CI 0.062­0.816; p = 0.023) and in patients with NL/CTC1 ≤ 2.2 (HR 0.159, 95% CI 0.05­0.505; p = 0.002). There was no association between protein expression in CTCs and DBF and OS. Conclusions: CTC1 was an independent prognostic factor of DBFFS and D-DBFFS and NL/CTC1 was an independent prognostic factor of OS and a potential prognostic factor of D-DBF at 6 months. These data suggest that CTC1 and NL/CTC1 may have a role as a biomarker of early D-DBF, helping define the timing and type of salvage radiotherapy in order to optimize the control of BM