Identification of a DNA Methylation-Based Prognostic Signature for Patients with Triple-Negative Breast Cancer.

BACKGROUND Aberrant DNA methylation is an important biological regulatory mechanism in malignant tumors. However, it remains underutilized for establishing prognostic models for triple-negative breast cancer (TNBC). MATERIAL AND METHODS Methylation data and expression data downloaded from The Cancer Genome Atlas (TCGA) were used to identify differentially methylated sites (DMSs). The prognosis-related DMSs were selected by univariate Cox regression analysis. Functional enrichment was analyzed using DAVID. A protein-protein interaction (PPI) network was constructed using STRING. Finally, a methylation-based prognostic signature was constructed using LASSO method and further validated in 2 validation cohorts. RESULTS Firstly, we identified 743 DMSs corresponding to 332 genes, including 357 hypermethylated sites and 386 hypomethylated sites. Furthermore, we selected 103 prognosis-related DMSs by univariate Cox regression. Using a LASSO algorithm, we established a 5-DMSs prognostic signature in TCGA-TNBC cohort, which could classify TNBC patients with significant survival difference (log-rank p=4.97E-03). Patients in the high-risk group had shorter overall survival than patients in the low-risk group. The excellent performance was validated in GSE78754 (HR=2.42, 95%CI: 1.27-4.59, log-rank P=0.0055). Moreover, for disease-free survival, the prognostic performance was verified in GSE141441 (HR=2.09, 95%CI: 1.28-3.44, log-rank P=0.0027). Multivariate Cox regression analysis indicated that the 5-DMSs signature could serve as an independent risk factor. CONCLUSIONS We constructed a 5-DMSs signature with excellent performance for the prediction of disease-free survival and overall survival, providing a guide for clinicians in directing personalized therapeutic regimen selection of TNBC patients.

Somatic mutations of the HER2 in metastatic breast cancer.

Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the full length of HER2 in 198 metastatic breast cancers (MBC) as well as 34 other epithelial cancers (bladder, prostate, and colorectal cancers) and compared the mutational status with clinic pathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 11.6 % (23 of 198) of MBC and were absent in other types of cancers. HER2 mutations were located in exon 15 and the in-frame insertions in exon 20 with corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in patient after the administration of trastuzumab (34.8 %, 8 of 23; P = 0.02). Mutations in exon 15 and 20 were more potent than wild-type HER2 in associating with activating signal transducers and inducing survival, invasiveness, and tumorigenicity.

Design of p53-derived peptides with cytotoxicity on breast cancer.

The tumor suppressor p53 plays essential role in conserving stability by preventing genome mutation, which is inactivated naturally by its negative regulator MDM2. Thus, targeting p53-MDM2 protein-protein interaction has been raised as a new cancer therapy in the medicinal community. In the current study, we report a successful application of an integrative protocol to design novel p53-derived peptides with cytotoxicity on human breast cancer cells. A quantitative structure-activity relationship-improved statistical potential was used to evaluate the binding potency of totally 24,054 single- and dual-point mutants of p53 peptide to MDM2 in a high-throughput manner, from which 46 peptide mutants with high predicted affinity and typical helical feature were involved in a rigorous modeling procedure that employed molecular dynamics simulations and post-binding energy analysis to systematically investigate the structural, energetic and dynamic aspects of peptide interactions with MDM2. Subsequently, a biological analysis was performed on a number of promising peptide candidates to determine their cytotoxic effects on human breast cancer cell line MDF-7. Six dual-point mutants were found to have moderate or high activities with their IC50 values ranging from 16.3 to 137.0 µM, which are better than that of wild-type p53 peptide (IC50 = 182.6 µM) and close to that of classical anticancer agent cis-platin (IC50 = 4.3 µM). Further, the most active peptide ETFSDWWKLLAE was selected as parent to further derive new mutants on the basis of the structural and energetic profile of its complex with MDM2. Consequently, three triple-point mutants (LTFSDWWKLLAE, ESFSDWWKLLAE and ETFADWWKLLAE) were obtained, and their biological activities (IC50 = 15.1, 27.0 and 8.7 µM, respectively) were determined to be comparable or better than the parent (IC50 = 16.3 µM).

Omitting ALND Is Not Safe for a Cohort of Early-Stage Breast Cancer Patients with 1-2 SLNs Macro-Metastases and Breast-Conserving Therapy: A Single-Center Retrospective Study.

BACKGROUND: Omitting axillary lymph node dissection (ALND) is recommended for early-stage breast cancer patients with 1-2 sentinel lymph nodes (SLNs) macro-metastases and breast-conserving therapy. However, it is not safe for part of patients, so it is significant to find risk factors and develop a predictive model of non-SLNs metastases in breast cancer patients with 1-2 SLNs macro-metastases and breast-conserving therapy. METHODS: This retrospective study enrolled 228 breast cancer patients with 1-2 SLNs macro-metastases who underwent ALND and breast-conserving surgery between Jan 2012 and Dec 2017 at Cancer Hospital Chinese Academy of Medical Sciences. Chi-square test and backward stepwise binary logistic regression were used to find factors that influenced non-SLN metastases, then a predictive model was formulated and obtained its area under the curve. RESULTS: Tumor pathologic invasion size, number of positive SLNs and ALN status on imaging was associated with non-SLNs metastases. The predictive model was also formulated based on these three factors to assess and the area under the curve of model was 0.708. CONCLUSION: We developed a predictive model to assess the high-risk cohort of patients of non-SLNs metastases which can be an auxiliary tool for doctors.

Treatment outcomes of occult breast carcinoma and prognostic analyses.

BACKGROUND: The surgical management of occult breast cancer is controversial. We compared the outcomes of different treatments of occult breast cancer and evaluated the potential prognostic factors for overall survival and recurrence. METHODS: We retrospectively reviewed 77 patients who presented to our hospital from 1968 to 2011 with a diagnosis of occult breast cancer. Patients were divided into three groups: 42 patients (63%) were treated with modified radical mastectomy+axillary lymph node dissection (ALND), 16 patients (24%) were treated with ALND + postoperative radiotherapy, and 9 patients (13%) with only ALND. Survival analyses were undertaken to compare the efficacy of these three treatments. RESULTS: Of the 77 patients with occult breast cancer, 2 patients were lost to follow-up and 8 patients refused surgical treatment: 67 patients (90.4%) were included in this analysis. The median follow-up was 62.2 (0.6-328.0) months. Kaplan-Meier analyses showed no significant difference in overall survival and recurrence-free survival between the three groups (P = 0.494 and 0.397, respectively). The prevalence of local recurrence was 11.9% for the mastectomy + ALND, 18.8% for ALND + radiotherapy, and 11.1% for ALND-only groups, and those for distant recurrence were 2.4%, 12.5%, and 11.1%, respectively. Compared with progesterone receptor-negative subjects, progesterone receptor-positive patients had better overall survival and lower recurrence rates (P = 0.057 and 0.062, respectively). CONCLUSIONS: There was no significant difference in outcomes between mastectomy and breast-preserving surgery. Expression of the progesterone receptor should be taken into account when evaluating the prognosis of occult breast cancer.