ABSTRACT
HER2+ breast cancer (BC) is an aggressive subtype genetically and biologically heterogeneous. We evaluate the predictive and prognostic role of HER2 protein/gene expression levels combined with clinico-pathologic features in 154 HER2+ BCs patients who received trastuzumab-based neoadjuvant chemotherapy (NACT). The tumoral pathological complete response (pCR) rate was 40.9%. High tumoral pCR show a scarce mortality rate vs subjects with a lower response. 93.7% of ypT0 were HER2 IHC3+ BC, 6.3% were HER2 IHC 2+/SISH+ and 86.7% of ypN0 were HER2 IHC3+, the remaining were HER2 IHC2+/SISH+. Better pCR rate correlate with a high percentage of infiltrating immune cells and right-sided tumors, that reduce distant metastasis and improve survival, but no incidence difference. HER2 IHC score and laterality emerge as strong predictors of tumoral pCR after NACT from machine learning analysis. HER2 IHC3+ and G3 are poor prognostic factors for HER2+ BC patients, and could be considered in the application of neoadjuvant therapy. Increasing TILs concentrations, lower lymph node ratio and lower residual tumor cellularity are associated with a better outcome. The immune microenvironment and scarce lymph node involvement have crucial role in clinical outcomes. The combination of all predictors might offer new options for NACT effectiveness prediction and stratification of HER2+ BC during clinical decision-making.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Neoadjuvant Therapy , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Trastuzumab/therapeutic use , Lymphocytes, Tumor-Infiltrating , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Treatment Outcome , Tumor MicroenvironmentABSTRACT
BACKGROUND: Polymorphisms in the excision repair cross-complimentary group 1 (ERCC1) gene have been involved in the prognosis of various cancers. In the present study, we evaluated the prognostic role of the two most common ERCC1 polymorphisms in patients with T4 breast cancer receiving platinum-based chemotherapy. METHODS: A total of 47 patients with T4 breast cancer undergoing treatment with a platinum-based regimen were collected and followed up (median 159 months; range, 42-239 months). ERCC1 C8092A (rs3212986) and T19007C (rs11615) polymorphisms were genotyped, using an automated sequencing approach. The same series was screened for BRCA1/2 mutations by DHPLC analysis and DNA sequencing. RESULTS: Among the tested patients, 16 (34%) and 25 (53%) presented the 8092A (homo-zygosity A/A or heterozygosity A/C) and the 19007C (homozygosity C/C or heterozygosity C/T) genotypes, respectively. The 8092A and 19007C genotypes in ERCC1 were significantly associated with overall survival in T4 breast cancer patients treated with chemotherapy containing platinum (p-values = 0.036 and 0.004, respectively). Univariate and multivariate Cox regression analyses showed that combination of 8092A and 19007C genotypes acts as a significant prognostic factor in women with T4 breast cancer receiving platinum-based chemotherapy (p-values = 0.022 and 0.049, respectively). Two (4.3%) out of 47 cases were found to carry BRCA1/2 mutations; they presented the highest overall survival rates into the series. CONCLUSIONS: The ERCC1 8092A and 19007C genotypes or their combination may predict a favorable prognosis in T4 breast cancer patients undergoing a platinum-based treatment. Further large-scale, prospective studies are needed to validate our findings.
