NUSAP1 and PCLAF (KIA0101) Downregulation by Neoadjuvant Therapy is Associated with Better Therapeutic Outcomes and Survival in Breast Cancer.

Purpose: To evaluate whether changes in genomic expression that occur beginning with breast cancer (BC) diagnosis and through to tumor resection after neoadjuvant chemotherapy (NCT) reveal biomarkers that can help predict therapeutic response and survival. Materials and Methods: We determined gene expression profiles based on microarrays in tumor samples from 39 BC patients who showed pathologic complete response (pCR) or therapeutic failure (non-pCR) after NCT (cyclophosphamide-doxorubicin/epirubicin). Based on unsupervised clustering of gene expression, together with functional enrichment analyses of differentially expressed genes, we selected NUSAP1, PCLAF, MME, and DST. We evaluated the NCT response and the expression of these four genes in BC histologic subtypes. In addition, we study the presence of tumor-infiltrating lymphocytes. Finally, we analyze the correlation between NUSAP1 and PCLAF against disease-free survival (DFS) and overall survival (OS). Results: A signature of 43 differentially expressed genes discriminated pCR from non-pCR patients (|fold change >2|, false discovery rate <0.05) only in biopsies taken after surgery. Patients achieving pCR showed downregulation of NUSAP1 and PCLAF in tumor tissues and increased DFS and OS, while overexpression of these genes correlated with poor therapeutic response and OS. These genes are involved in the regulation of mitotic division. Conclusions: The downregulation of NUSAP1 and PCLAF after NCT is associated with the tumor response to chemotherapy and patient survival.

Genetic alterations of triple negative breast cancer (TNBC) in women from Northeastern Mexico.

Triple negative breast cancer (TNBC) is a subtype of breast cancer of heterogeneous nature that is negative for estrogen receptor (ER), progesterone receptor (PR) and growth factor human epidermal 2 (HER2) following immunohistochemical analysis. TNBC is frequently characterized by relapse and reduced survival. To date, there is no targeted therapy for this type of cancer. Chemotherapy, radiotherapy, and surgery remain as the standard treatments options. The lack of a target therapy and the heterogeneity of TNBC highlight the need to seek new therapeutic options. In this study, fresh tissue samples of TNBC were analyzed with a panel of 48 driver genes (212 amplicons) that are likely to be therapeutic targets. We found intron variants, missense, stop gained and splicing variants in TP53, PIK3CA and FLT3 genes. Interestingly, all the analyzed samples had at least two variants in the TP53 gene, one being a drug response variant, rs1042522, found in 94% of our samples. We also found seven additional variants not previously reported in the TP53 gene, to the best of our knowledge, with probable deleterious characteristics of the tumor suppressor gene. We found four genetic variants in the PIK3CA gene, including two missense variants. The rs2491231 variant in the FLT3 gene was identified in 84% (16/19) of the samples, which not yet reported for TNBC, to the best of our knowledge. In conclusion, genetic variants in TP53 were found in all TNBC tumors, with rs1042522 being the most frequent (94% of TNBC biopsies), which had not been previously reported in TNBC. Also, we found two missense variants in the PIK3CA gene. These results justify the validation of these genetic variants in a large cohort, as well as the extensive study of their impact on the prognosis and therapy management of TBNC.

A New Gene Expression Signature for Triple Negative Breast Cancer Using Frozen Fresh Tissue before Neoadjuvant Chemotherapy.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer tumors. Comparisons between TNBC and non-triple negative breast cancer (nTNBC) may help to differentiate key components involved in TNBC neoplasms. The purpose of the study was to analyze the expression profile of TNBC versus nTNBC tumors in a homogeneous population from northeastern Mexico. A prospective study of 50 patients was conducted (25 TNBC and 25 nTNBC). Clinic parameters were equally distributed for TNBC and nTNBC: age at diagnosis (51 vs 47 years, p=0.1), glucose levels (107 mg/dl vs 104 mg/dl, p=0.64), and body mass index (28 vs 29, p=0.14), respectively. Core biopsies were collected for histopathological diagnosis and gene expression analyses. Total RNA was isolated and expression profiling was performed. 40 genes showed differential expression pattern in TNBC tumors. Among these, 9 over-expressed genes (PRKX/PRKY, UGT8, HMGA1, LPIN1, HAPLN3, and ANKRD11), and one under-expressed (ANX9) gene are involved in general metabolism. Based on this biochemical peculiarity, and the over-expression of BCL11A and FOXC1 (involved in tumor growth and metastasis, respectively) we validated by qPCR the expression profile of 7 genes out of the signature. In this report, a new gene signature for TNBC is proposed. To our knowledge, this is the first TNBC signature which describes genes involved in general metabolism. The findings may be pertinent for Mexican patients and require to be evaluated in further ethnic groups and populations.