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Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy. In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB–IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group. 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011). Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.

Topoisomerase IIα is not only a proliferation marker of tumor cells, but is also a target for anthracycline-based chemotherapy. Both in vitro and in vivo studies have shown that there is a relationship between topo IIα and chemosensitivity to anthracyclines, but the predictive role of topo IIα in breast cancer patients is still controversial. A meta-analysis based on published studies was performed to obtain an accurate assessment of the association between topo IIα and sensitivity to anthracycline-based chemotherapy. A total of 13 eligible studies, including 2,633 cases and 2,118 controls were identified. Topo IIα was associated with sensitivity to anthracyclines in locally advanced breast cancer patients who received neoadjuvant chemotherapy [five studies, including three using fluorescence in situ hybridization (FISH) and two using immunohistochemistry (IHC): relative risk (RR) = 1.93, 95% confidence interval (95% CI): 1.27-2.94, P = 0.002; two using FISH and three using IHC: RR = 1.98, 95% CI: 1.37-2.86, P0.001]. This association existed among three studies using FISH (RR = 2.03, 95% CI: 1.14-3.61, P = 0.017), but did not exist among three studies using IHC (P0.05). In early-stage breast cancer patients who received anthracycline-based adjuvant chemotherapy compared with non-taxane-based polychemotherapy, amplification [hazard ratio (HR) = 0.64, 95% CI: 0.49-0.83, P = 0.001; HR = 0.59, 95% CI: 0.35-1.01, P = 0.056] or deletion (HR = 0.82, 95% CI: 0.67-1.00, P = 0.051; HR = 0.58, 95% CI: 0.35-0.97, P = 0.036) of topo IIα was significantly associated with better recurrence-free survival and overall survival. In summary, the present meta-analysis suggests that topo IIα is a predictive factor for breast cancer patients who receive anthracycline-based chemotherapy. Larger and well-designed prospective studies are required to further evaluate the predictive role of topo IIα in clinical practice.

CD44+/CD24-/low tumor cells or aldehyde dehydrogenase 1 (ALDH1) positive tumor cells are considered cancer stem cells (CSCs) that possess the properties of self-renewal and tumorigenicity. However, their clinical value and significance in breast cancer remain controversial. A meta-analysis based on published studies was performed with the aim of obtaining an accurate evaluation of the association between the presence of CSCs in clinical samples and clinical outcome. A total of 12 eligible studies with 898 cases and 1,853 controls were included. CSC positive breast cancers, in particular those positive for ALDH1, were significantly associated with high histological grade, estrogen receptor (ER) negativity, progesterone receptor (PR) negativity, and human epidermal growth factor receptor type 2 (HER2) positivity. However, the presence of cancer stem cells was not associated with tumor size or nodal status. ALDH1 positive (RR = 2.83, 95% CI: 2.16-3.67, P < 0.001) and CD44+/CD24-/low tumor cells (RR = 2.32, 95% CI: 1.51-3.60, P < 0.001) were significantly associated with poor overall survival (OS). The stem cell markers are prognostic factors in breast cancer. Larger clinical studies are required to further evaluate the role of these markers in clinical practice.

The proper interaction between BRIP1/BACH1 and BRCA1 protein has been found to be crucial for BRCA1-mediated DNA double-strand break repair and BRIP1/BACH1 mutations were estimated to confer a relative risk for breast cancer of 2.0 in western populations. In Chinese population, BRCA1 mutations could explain a relatively large proportion of inherited breast cancer cases in comparison with BRCA2 mutations, which probably deduced a hypothesis that those genes involved in BRCA1-mediated DNA repair pathway might play a more significant role in the etiology of Chinese breast cancer. To investigate the contribution of BRIP1/BACH1 mutations to the predisposition of Chinese non-BRCA1/BRCA2 hereditary breast cancer, we screened all the coding exons and adjacent intronic splice junction regions of BRIP1/BACH1 in 357 Chinese women with early-onset breast cancer or affected relatives from five different breast disease clinical centers in China, using PCR-DHPLC and DNA sequencing analysis. Some genetic variants identified in the cases were then studied in 864 normal controls with no personal or family history of breast cancer. We found no protein-truncated mutations in our population, while a novel recurrent non-synonymous variant, Q944E, was detected in two independent families in contrast with none in the controls, interestingly, this alteration occurs in the BRCA1 binding domain of the BACH1 protein. Then a further study performed on the two mutation positive families revealed the partial co-segregation of this mutation allele with cancer. The novel alteration Q944E identified in our study possibly represents a rare disease-related allele, nevertheless functional analysis is still warranted to resolve the ability of this altered BACH1 protein to bind BRCA1. Altogether, the results of our study indicated that germline mutations in BRIP1/BACH were extremely rare in Chinese population and there was no evidence for the recommendation of BRIP1/BACH1 for genetic testing in Chinese.

PALB2 has been recently identified as breast cancer susceptibility gene in western populations. To investigate the contribution of PALB2 mutations to Chinese non-BRCA1/BRCA2 hereditary breast cancer, we screened all coding exons and intron-exon boundaries of PALB2 in 360 Chinese women with early-onset breast cancer or affected relatives from five breast disease clinical centers in China by utilizing PCR-DHPLC and DNA sequencing analysis. Some genetic variants identified in the cases were then studied in 864 normal controls with no personal or family history of breast cancer. Two protein-truncating PALB2 mutations, 751C>T and 1050_1051delAAinsTCT, were identified in three separate families, and 751C>T was a recurrent mutation. Neither of them, however, were present in the controls (P = 0.025). All the truncating mutations occured in exon 4 of PALB2, and there were still three unclassified variants were detected in the same fragment. We found that exon 4 accounted for 44.1% (15/34) of the person-times carrying with any variant in our study. PALB2 mutations were responsible for approximately 1% of Chinese women with early-onset breast cancer and affected relatives. Our results suggested that a detection of exon 4 before the assay of the whole PALB2 gene might be a cost-effective approach to the screening of Chinese population.

Certain rare germline mutations in the PALB2 gene have been confirmed to increase susceptibility to breast cancer in diverse populations, but it has not been very clear that whether some common polymorphic variants in PALB2 also increase breast cancer risk. We conducted a case-control study to validate the association of common variations in the PALB2 gene and breast cancer in eastern Chinese population. A total of six common single nucleotide polymorphisms (rs8053188, rs16940342, rs249954, rs447529, rs249935, and rs3096145), which tagged the known common variants (minor allele frequency >0.1) of PALB2, were genotyped among 660 cases and 756 cancer-free controls by SNPstream assay. Except rs3096145, other five SNPs passed the quality assessment criteria with genotyping call rate >95%. Genotype and allele frequencies were statistically different between cases and controls for PALB2 rs447529 and rs249935. PALB2 rs249935 G allele was related to a 1.21-fold (95% confidence interval = 1.02-1.43) increase in risk for each 'A' allele carried (P = 0.029). Based on the dominant inheritance model tests, we found that compared with rs447529 CC homozygotes, the variant homozygote GG and heterozygote GC carriers had a 0.43-fold decreased risk of breast cancer (95% confidence interval = 0.24-0.78, P = 0.005). Combined with the results of the former study, our findings further verified that some common PALB2 polymorphisms may contribute to the etiology of breast cancer in Chinese women, so other large studies are warranted to confirm these observations in different ethnic populations.

Germ line mutations in the tumor suppressor gene, p53, are known to cause Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (LFL). We sought to identify p53 germ line mutations in potential hereditary breast cancer patients without LFS/LFL phenotype, which will help us establish the genetic testing strategy for p53 in Chinese high-risk breast cancer families. We screened all coding exons and intron-exon boundaries of p53 in 240 women with early-onset breast cancer or affected relatives from four breast disease clinical centers in China by utilizing PCR-DHPLC and DNA sequencing analysis. Additionally, three cell lines (H1299, MCF-7, and MDA-MB-231) were transfected with pEGFP-N1-only or pEGFP-N1 vectors expressing either wild-type or two novel identified mutant p53. And then we performed flow cytometry analysis in the transfected cells to determine the status of cell apoptosis, and real-time PCR as well as western blot analysis to ascertain the expression of p53, p21, and p27. Two novel germ line mutations (563T > C and 643_660del18) were detected in two independent families. Neither of them, however, was present in the 768 normal controls. Functional assays revealed that the ability to trigger cell apoptosis and transcriptional activation of target gene under similar expression of p53 were lower in two mutants versus wild-type p53. Deleterious mutations of p53 seemed to be responsible for approximately 1% of non-BRCA1/BRCA2 hereditary breast cancer in Chinese population, and our findings suggested that p53 should be included in genetic testing of Chinese non-LFS/non-LFL high-risk breast cancer families.

Purpose To analyze the rule of recurrence risk for breast cancer patients after surgery in order to get characteristics for Chinese breast cancer. Methods We performed a retrospective study of 2,213 female unilateral breast cancer patients undergoing surgery in Cancer hospital of Fudan University, Shanghai, China. Survival curves were performed with Kaplan–Meier method and annual recurrence hazard was estimated by hazard function. Results Annual recurrence hazard curve for entire population showed a double-peaked pattern, with a first major recurrence surge reaching the maximum at the second year after surgery and a second recurrence peak near the 9.5th year. The analysis according to tumor size, axillary lymph node (ALN) status (T1 + T2 versus T3, node-positive versus node-negative) and menopausal status as well as hormone receptor (HR) status proved that the double-peaked pattern was present in each subgroup. Compared with ER-positive tumors, ER-negative breast cancers were more likely to recur early. As far as Her-2/neu status was concerned, Her-2/neu-positive patients exhibited a relatively pronounced and variable pattern and tended to have more relapse across all time periods (P < 0.05). Conclusions The double-peaked pattern observed in our patients gives further support to tumor dormancy hypothesis. It contributes to different treatment strategies (e.g. the type and timing of adjuvant therapy) for different patients, which provide the possibility to improve survival.