RESUMO
AIMS: Basal-like breast cancer (BLBC) is characterized by aggressive behaviour; its genesis is the perturbation of DNA repair as a consequence of BRCA1 methylation or mutation. We comparatively evaluated alterations of DNA repair proteins and p53 between BLBC and non-BLBC cases. METHODS AND RESULTS: Tumour sections from 104 BLBC and 89 non-BLBC patients were immunostained for hMLH1, hMSH2, MGMT, BRCA1 and p53. Methylation status of DNA repair genes was analysed by methylation-specific PCR, and p53 mutation was examined by direct sequencing. Immunoreactive levels of hMLH1 and MGMT were lower in BLBC, whereas the levels of hMSH2 and p53 were higher, compared to non-BLBC (P ≤ 0.014). Reduced expression of hMLH1 [hazard ratio (HR) 5.26, P = 0.001] and preserved expression of MGMT (HR 2.58, P = 0.039) proved to be independent predictors of poor survival in BLBC patients. DNA repair genes were methylated in approximately 20-40% of BLBCs without a significant relationship between their methylation and p53 mutation. BRCA1 methylation was associated with the loss of its protein expression (P = 0.004). MGMT methylation was linked to larger tumour size (P < 0.001). CONCLUSIONS: Perturbations of the DNA repair system might be different between BLBC and non-BLBC. Alterations of hMLH1 and MGMT appear important for tumour progression and survival in BLBC patients.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteína BRCA1/genética , Neoplasias da Mama/genética , Carcinoma Basocelular/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/mortalidade , Carcinoma Basocelular/patologia , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Análise Mutacional de DNA , Enzimas Reparadoras do DNA/metabolismo , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Nucleares/metabolismo , Prognóstico , Taxa de Sobrevida , Proteínas Supressoras de Tumor/metabolismoRESUMO
PURPOSE: To evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) in patients with locally advanced basal-like breast cancers (BLBCs). PATIENTS AND METHODS: Thirty-two BLBC patients receiving NACT with an anthracycline-based regimen plus taxane were included in this study. The immunoreactivities of MGMT, MLH1, MSH2 and BRCA1 before and after NACT were evaluated. RESULTS: A pCR was obtained in 10 of 32 cases (31%). Cancer-related (P = 0.013) and disease-free (P = 0.023) survival rates were significantly higher in the pCR group than in the non-pCR group. In biopsy samples before NACT, attenuated expression of MGMT, MLH1, MSH2 and BRCA1 was observed in 12/32 (38%), 0/32 (0%), 5/32 (16%) and 28/32 (88%) cases, respectively. On evaluation of pCR, patients' characteristics (patients' age, menopausal status, or clinical and pathological stages) and immunohistochemical patterns, attenuated expression of MGMT was only found to be significantly predictive of a pCR (P = 0.018). Paired biopsy sample before NACT and a surgical tumor material after NACT were available for 19 cases of non-pCR. In these cases, decrease in expression during NACT were more frequently observed for MGMT as compared to MLH1, MSH2 or BRCA1 (P = 0.021). CONCLUSIONS: MGMT status is a predictive factor for pCR with neoadjuvant anthracycline-based plus taxane combination chemotherapy, which may be helpful in the selection of appropriate NACT for Japanese patients with BLBC.
