RESUMO
Platinum-based chemoradiotherapy (CRT) is a preferred standard of care for locally advanced head and neck cancer (HNC). However, survival benefit is small, with substantial toxicity and biomarkers of CRT resistance that could guide treatment selection and spare morbidity. Increased DNA repair in solid tumors may contribute to cancer cells' ability to survive in genotoxic stress environments afforded by therapy. We assessed mRNA expression levels of DNA repair-related genes BRCA1, RAP80, 53 binding protein 1 (53BP1), mediator of DNA damage checkpoint 1 (MDC1), and RNF8. We correlated our findings with response and overall survival in 72 head and neck patients treated with weekly carboplatin AUC 2 and radiotherapy. Complete response (CR) to CRT was 50 % in patients with low levels of 53BP1 compared to 6.3 % in patients with high levels (p = 0.0059). Of high BRCA1 mRNA expressors, 41.2 % had CR compared to 29.4 % of low expressors (p = 0.72). For a small group of patients with low 53BP1 and either high BRCA1 or RAP80, CRs were 66.7 and 71.4 %, respectively. A trend for better overall survival (OS) was found for patients with low 53BP1 (15 vs 8 m; p = 0.056). Our findings highlight the potential usefulness of 53BP1 mRNA as a predictive biomarker of response and overall survival in HNC patients treated with chemoradiotherapy. Those with high 53BP1 expression could derive only a meager benefit from treatment. Analysis of BRCA1 and RAP80 could further reinforce the predictive value of 53BP1. Although this was a retrospective study with small sample size, it could inform larger translational studies in HNC.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Quimiorradioterapia , Enzimas Reparadoras do DNA/genética , Neoplasias de Cabeça e Pescoço/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Proteína BRCA1/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/genética , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Taxa de Sobrevida , Transativadores/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína LigasesRESUMO
BACKGROUND: In a Spanish Lung Cancer Group (SLCG) phase II trial, the combination of BRCA1 and receptor-associated protein 80 (RAP80) expression was significantly associated with outcome in Caucasian patients with nonsmall-cell lung cancer (NSCLC). The SLCG therefore undertook an industry-independent collaborative randomized phase III trial comparing nonselected cisplatin-based chemotherapy with therapy customized according to BRCA1/RAP80 expression. An analogous randomized phase II trial was carried out in China under the auspices of the SLCG to evaluate the effect of BRCA1/RAP80 expression in Asian patients. PATIENTS AND METHODS: Eligibility criteria included stage IIIB-IV NSCLC and sufficient tumor specimen for molecular analysis. Randomization to the control or experimental arm was 1 : 1 in the SLCG trial and 1 : 3 in the Chinese trial. In both trials, patients in the control arm received docetaxel/cisplatin; in the experimental arm, patients with low RAP80 expression received gemcitabine/cisplatin, those with intermediate/high RAP80 expression and low/intermediate BRCA1 expression received docetaxel/cisplatin, and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone. The primary end point was progression-free survival (PFS). RESULTS: Two hundred and seventy-nine patients in the SLCG trial and 124 in the Chinese trial were assessable for PFS. PFS in the control and experimental arms in the SLCG trial was 5.49 and 4.38 months, respectively [log rank P = 0.07; hazard ratio (HR) 1.28; P = 0.03]. In the Chinese trial, PFS was 4.74 and 3.78 months, respectively (log rank P = 0.82; HR 0.95; P = 0.82). CONCLUSION: Accrual was prematurely closed on the SLCG trial due to the absence of clinical benefit in the experimental over the control arm. However, the BREC studies provide proof of concept that an international, nonindustry, biomarker-directed trial is feasible. Thanks to the groundwork laid by these studies, we expect that ongoing further research on alternative biomarkers to elucidate DNA repair mechanisms will help define novel therapeutic approaches. TRIAL REGISTRATION: NCT00617656/GECP-BREC and ChiCTR-TRC-12001860/BREC-CHINA.