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Purpose: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2) may be an alternative mechanism to HER2 activation and can affect the sensitivity toward HER2-targeted therapies. We aimed to investigate the prevalence, clinicopathologic characteristics, and functional relevance of novel HER2 mutations in breast cancer., Experimental Design: We performed Sanger sequencing of all exons of the HER2 gene in 1,248 primary tumors and 18 paired metastatic samples. Novel HER2 mutations were functionally characterized., Results: The total HER2 somatic mutation rate was 2.24% (28/1,248). Of the seven novel HER2 mutations, L768S and V773L were only detected in HER2-negative tumors, whereas K753E was found in HER2-positive disease. L768S and V773L mutations exhibited a significant increase in tyrosine kinase-specific activity and strongly increased the phosphorylation of signaling proteins in various cell lines. Xenograft experiments showed that NIH3T3 cells bearing the L768S and V773L mutations displayed more rapid growth. MCF10A, BT474, and MDA-MB-231 cells bearing the K753E mutation were resistant to lapatinib, but could be inhibited by neratinib. Finally, comparison of HER2 mutations in 18 pairs of primary and metastatic lesions revealed that the drug-resistant HER2 mutations (K753E and L755S) were enriched in metastatic lesions., Conclusions: HER2-negative breast cancer with activating mutations can benefit from HER2-targeted therapies. Meanwhile, mutations in the HER2 kinase domain might be a key mechanism of resistance to HER2-targeted therapy, and irreversible tyrosine kinase inhibitors such as neratinib may offer alternative treatment options. Clin Cancer Res; 22(19); 4859-69. ©2016 AACR., (©2016 American Association for Cancer Research.)

Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in ~ 10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.

Aims: To explore the clinical characteristics and prognostic value of malignant calcification in operable breast cancer., Methods: A total of 721 patients with invasive ductal carcinoma were divided into two groups based on whether malignant calcifications were observed on mammograms. The association of calcification with pathological features and survival were evaluated. The relative importance of each of the potential prognostic variables was tested using a Cox regression analysis., Results: Compared with tumors without calcification, those with calcification had a larger tumor size, more lymph node involvement, lower estrogen and progesterone receptor expression and higher human epithelial growth factor receptor 2 expression. The 8-year relapse-free survival was lower for patients with calcifications than for those without (77.5 vs 89.2%, P < 0.01). The 8-year overall survival for patients with calcifications was 82.2% compared with 91.9% for those without (P < 0.01). In multivariate analysis, node status, existence of calcification and tumor size were demonstrated to have a prognostic value for relapse-free survival. The node status, existence of calcifications and estrogen receptor status were also prognostic factors for overall survival., Conclusion: Mammographic calcification is a poor prognostic factor for patients with invasive ductal carcinoma. Its prognostic value is second only to axillary node status and greater than the other factors evaluated. Thus, breast cancers with calcifications should be regarded as high risk when determining adjuvant treatment., (© 2012 Wiley Publishing Asia Pty Ltd.)

Purpose: Pure mucinous breast carcinoma (PMBC) is a rare pathologic finding. Few studies have addressed the biologic features of PMBC and prognostic factors among patients with this disease. We performed a study to compare PMBC and invasive ductal carcinoma (IDC) by means of a large database to reliably assess the biologic phenotype and clinical behavior of PMBC., Methods: A total of 2,511 patients who met the inclusion criteria were identified from 1999 to 2010; 2,202 patients had pure IDC and 309 had PMBC. Clinical and biologic features, overall survival, and recurrence/metastasis-free survival (RFS) were compared for both groups., Results: PMBC had favorable characteristics including smaller size, lower rates of lymph node positivity, lower stage, higher expression of hormone receptors, and less HER2 overexpression. Patients with PMBC had better 10-year RFS (71 %) than patients with IDC (64 %). Multivariate analysis revealed that node status and tumor, node, metastasis system (TNM) stage were statistically significant prognostic factors for survival. RFS curves stratified for node status revealed a highly significant difference between node negative and node positive patients. Additionally, patients with PMBC underwent breast-conserving surgery (BCS) more frequently than patients with IDC, and the 5-year overall survival rate of the BCS group was not significantly different from the total mastectomy group., Conclusions: PMBC in Chinese women showed less aggressive behavior and had a better prognosis than IDC, and this favorable outcome was maintained after 10 years. Node status and TNM stage appeared to be the most significant predictors of worse prognosis. BCS should be preferred over mastectomy in the treatment of early-stage PMBC.

Background: We sought to compare the baseline demographics, standard pathologic factors and long-term clinical outcomes between ILC and infiltrating ductal carcinoma (IDC) using a large database., Methods: Clinicopathologic features, overall survival (OS), and recurrence/metastasis-free survival (RFS) were compared between 2,202 patients with IDC and 215 patients with ILC., Results: ILC was significantly more likely to be associated with a favorable phenotype, but the incidence of contralateral breast cancer was higher for ILC patients than for IDC patients (8.4% vs. 3.9%; P=0.001). The frequencies of recurrence/metastasis (P = 0.980) and death (P = 0.064) were similar among patients with IDC and patients with ILC after adjustment for tumor size and nodal status. The median follow-up was 42.8 months., Conclusions: Chinese women with ILCs do not have better clinical outcomes than their counterparts with IDC. Management decisions should be based on individual patient and tumor biologic characteristics, and not on lobular histology.

Background: Breast ductal carcinoma in situ with microinvasion (DCIS-Mi) is considered to be the interim stage in the progression from DCIS to invasive breast cancer (IDC). Cases that exceed DCIS-Mi but still do not fulfill the diagnostic criteria of IDC often are observed. We define those cases as DCIS with invasion component (DCIS-I), and attempt to study the differences of clinicopathological features and immunohistochemical-based subtypes among DCIS, DCIS-Mi, and DCIS-I., Methods: In this retrospective study, 550 consecutive DCIS patients were recruited, 271 (49.3%) cases were diagnosed as pure-DCIS, 67 as DCIS-Mi, and 212 as DCIS-I. They were categorized into four groups: luminal-A (ER+ and/or PR+, HER2-), luminal-B (ER+ and/or PR+, HER2+), ERBB2+ (ER-, PR-, HER2+), and basal-like (ER-, PR-, HER2-)., Results: DCIS-Mi and DCIS-I patients tended to have larger tumors with highly graded nuclear (P = 0.011 for size; P < 0.0001 for nuclear grade). The proportion of luminal-like tumors decreased, whereas ERBB2+ and basal-like tumors increased in DCIS-I/DCIS-Mi compared with pure-DCIS (P = 0.039). Although the HER2-positive tumors displayed a stable proportion among DCIS subgroups, the essences of them were varying. In pure-DCIS, luminal-B was the major subtype of HER2-positive tumors (luminal-B vs. ERBB2+, 19% vs. 14.6%), whereas in DCIS-I, the proportion of luminal-B decreased vastly (luminal-B vs. ERBB2+, 12.8% vs. 23.5%). DCIS-I had a worse relapse-free survival outcome compared with pure-DCIS., Conclusions: Different distribution of subtypes and distinctive characteristics among DCIS, DCIS-Mi, and DCIS-I indicate that they are distinct entities. Further studies with larger sample size are needed to replicate our observations.

The aims of this study are to describe tumor characteristics and treatment patterns of elder breast cancer patients and to determine the factors influencing local and systemic treatments. This retrospective cohort included 866 patients (>or=60 years) referred for surgery between January 2002 and December 2006. The patients were divided into four groups according to age. Elderly women had larger tumors at diagnosis with more mucinous carcinomas, more estrogen/progesterone-positive, lower Ki-67 labeling indices and less c-erbB2 positive tumors. Comorbidities were more often recorded for older patients. They were more likely to undergo simple mastectomy or breast-conserving surgery, less likely to receive adjuvant chemotherapy and radiotherapy, compared with their younger counterparts. Multinomial and binary logistic regression showed that age was independently associated with local and systemic treatments. Our data suggest that the tumors of elderly patients are biologically more favorable, and elderly women appear to receive less aggressive treatments.

Objective: To investigate the clinical response, pathological complete response (pCR), tumor resection rate and safety of neoadjuvant chemotherapy with docetaxel and epirubicin (ET) for locally advanced breast cancer (LABC)., Methods: From March to December 2001, 40 women with LABC, aged from 28-67 (medium 48) years were alloted. Twenty patients had clinical stage IIIa disease, 15 had stage IIIb disease and 5 stage IV patients who had ipsilateral sura-clavicular metastasis. The dose was: epirubicin (E) 60 mg/m2, docetaxel (T) 75 mg/m2 every 3 weeks, with G-CSF given preventively. After 2 cycles of ET, a pilot clinical response evaluation was performed by investigators for each patient to decide if she should receive another 1-2 cycles of ET before surgery or radiation therapy., Results: Thirty-eight patients received 2-3 cycles of ET regimen. The pCR, clinical complete response (cCR) and clinical partial response (cPR) rates were 15.0%, 20.0% and 52.5%, respectively. Tumor resection rate in this group was 92.5%. Incidence of III/IV Grade neutropenia was 8.4%/14.0% of cycles, and 3 patients suffered from neutropenia with fever. Non-hematological adverse events were alopecia, nausea, vomiting, fluid retention, myalgia, arthralgia and nail disorders, which were mild to moderate., Conclusion: Neo-adjuvant chemotherapy with a combination of docetaxel and epirubicin is effective and well tolerated by women with locally advanced breast cancer.

Objective: To demonstrate the impact of hypoxia on ER-alpha in both breast cancer tissue and cell line, and its relationship with hypoxia-related parameters., Methods: Expression of ER-alpha in 51 breast cancer patients with ER positive determined by ligand-binding assay was examined by immunohistochemistry and compared with CA-IX and Glut-1. Impact of hypoxia on breast cancer cell line MCF-7 (ER-alpha positive) was observed by Western Blot and RT-PCR., Results: Of 51 breast cancer patients, 49 were ER-alpha positive. Regional decrease of ER-alpha expression was consistently observed in peri-necrotic regions as compared to distant regions in both in-situ carcinomas (n=29, P <0.0001) and invasive carcinomas (n=20, P=0.0001), which was closely associated with the induction of CA-IX and Glut-1 in hypoxia (P <0.0001). The decreased expression of ER-alpha protein and mRNA in breast cancer cell lines were attributed to hypoxia and not to other stress factors, such as reduced glucose, low pH, and products released from necrotic or hypoxic cells. Chronic intermittent hypoxia could cause persistent down-regulation of ER-alpha in the MCF-7 breast cancer cell line., Conclusion: Regional hypoxia in breast cancer is associated with the reduced ER-alpha expression, and intermittent hypoxia can cause persistent down-regulation. Hypoxia may therefore contribute to the progression of ER-alpha negative status and potentially to the development of resistance to endocrine therapy.