The mixed subtype has a worse prognosis than other histological subtypes: a retrospective analysis of 217 patients with metaplastic breast cancer.

OBJECTIVE: Metaplastic breast cancer (MpBC) is an aggressive subtype of all breast cancer. We aimed to investigate the clinicopathological features, treatments and prognoses of MpBC patients. METHODS: We collected the data from MpBC patients diagnosed at Tianjin Medical University Cancer Hospital from 2010 to 2017. Kaplan Meier curves and Cox regression model were used to evaluating clinical outcomes and prognostic factors. After removing baseline differences by propensity score matching (PSM), we analyzed the prognosis between MpBC patients and invasive ductal carcinomas of no special type (IDC-NST) patients. RESULTS: A total of 217 MpBC patients were subsumed. Of all histological subtypes, 45.1% were mixed subtypes, followed by with mesenchymal differentiation (27.2%), pure squamous (15.2%) and pure spindle (12.4%) subtypes. 69.6% of MpBC were triple-negative, 25.3% and 6.5% were HR-positive and HER2-positive. MpBC patients had worse survival compared to IDC-NST patients, with 5-year RFS of 73.8 and 83.6% (HR = 1.177 95%CI (1.171-2.676) P = 0.0068), and 5-year BCSS of 79.0% and 89.7% (HR = 2.187 95%CI (1.357-3.523) P = 0.0013). In the multivariate COX model, AJCC stage, mixed subtype and chemotherapy were independent prognostic factors. Mixed MpBC is more aggressive than pure and with heterologous mesenchymal differentiation subtypes. And whether squamous or spindle MpBC, mixed forms have shorter outcomes than pure forms. CONCLUSIONS: MpBCs are associated with poorer prognoses than IDC-NSTs. They are heterogeneous with different clinicopathological features and clinical outcomes between histological subtypes. Pure and with heterologous mesenchymal differentiation subtypes have more survival benefits than the mixed subtype.

Malignant phyllodes tumors of the breast: the malignancy grading and associations with prognosis.

PURPOSE: This study aimed to correlate clinicopathological parameters with survival outcomes in a cohort of patients diagnosed with malignant phyllodes tumors (MPTs). We also analyzed the malignancy grade of MPTs and investigated the prognostic significance of the malignancy grading system. METHODS: Clinicopathological parameters, malignancy grades, and clinical follow-up data of 188 women diagnosed with MPTs in a single-institution were analyzed. MPTs of the breast were grouped according to stromal atypia, stromal overgrowth, mitotic count, tumor differentiation, and necrosis. A Fleiss' kappa statistic was calculated to test the agreement between the pathologists for the grading of MPTs. Disease-free survival (DFS), distant metastasis-free survival (DMFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Cox regression was carried out to identify factors predictive of locoregional recurrence (LRR), distant metastasis (DM) and death. RESULTS: A total of 188 MPTs were classified according to the malignancy grading system: 88 (46.8%) as low grade, 77 (41%) as an intermediate grade, and 23 (12.2%) as high grade. Excellent agreement between pathologists for the grading of MPTs (Fleiss' kappa 0.807). In our study population, the occurrence of DM and death were associated with the malignancy grade of MPTs (P < 0.001). Based on the DFS curves, the presence of heterologous elements (P = 0.025) and younger age (P = 0.014) were independent prognostic indicators. Additionally, the malignancy grade retained independent prognostic significance for predicting DMFS and OS (P < 0.001 and P = 0.009). CONCLUSIONS: Higher malignancy grade, presence of heterologous elements, younger age, larger tumor size, and recent rapid tumor growth are poor prognostic factors for MPTs of the breast. The malignancy grading system may be generalized in the future.

Integrated Analyses Reveal the Multi-Omics and Prognostic Characteristics of ATP5B in Breast Cancer.

The beta subunit of F1Fo-ATP synthase (ATP5B) has been demonstrated to play an essential role in tumor progression and metastasis. However, there has been no comprehensive pan-cancer multi-omics analysis of ATP5B, while the clinical relevance of ATP5B and its potential mechanism in regulating breast cancer are still poorly understood. In this study, we demonstrated that ATP5B has a higher frequency of amplification than deletion in most cancer types, and the copy number variation (CNV) of ATP5B was significantly positively correlated with its mRNA expression level. DNA methylation analysis across pan-cancer also revealed a strong correlation between ATP5B expression and epigenetic changes. We identified 6 significant methylation sites involved in the regulation of ATP5B expression. Tissue microarrays (TMA) from 129 breast cancer samples, integrated with multiple additional breast cancer dataset, were used to evaluate the ATP5B expression and its correlation with prognosis. Higher levels of ATP5B expression were consistently associated with a worse OS in all datasets, and Cox regression analysis suggested that ATP5B expression was an independent prognostic factor. Gene enrichment analysis indicated that the gene signatures of DNA damage recognition, the E-cadherin nascent pathway and the PLK1 pathway were enriched in ATP5B-high patients. Moreover, somatic mutation analysis showed that a significant different mutation frequency of CDH1 and ADAMTSL3 could be observed between the ATP5B-high and ATP5B-low groups. In conclusion, this study reveals novel significance regarding the genetic characteristics and clinical value of ATP5B highlighted in predicting the outcome of breast cancer patients.

Retrospective study of malignant phyllodes tumors of the breast: Younger age, prior fibroadenoma surgery, malignant heterologous elements and surgical margins may predict recurrence.

PURPOSE: The potential recurrence rate of malignant phyllodes tumors (MPTs) of the breast is high, and the prognostic factors are still unclear. We therefore aim to study the factors affecting the outcome of MPTs. METHODS: A retrospective review of MPT patients treated from 2006 to 2020 at our institution was conducted. Univariate and multivariate Cox proportional hazard models were used to examine the influence of different variables on RFS. Moreover, significant prognostic factors were combined to construct the nomogram to predict the probability of relapse occurring in MPT patients. The 5-year and 10-year RFS rates were estimated using the Kaplan-Meier method. RESULTS: During the study period, 188 MPT patients were identified. The presence of malignant heterologous elements was observed in 23 (12.2%) patients with MPT, and the patients with malignant heterologous elements who received chemotherapy had longer RFS, which could reduce the risk of recurrence (p = 0.022). Recurrence occurred in 56/188 (29.8%) patients, of whom 47 experienced local recurrence and 11 experienced distant metastases. The 5-year and 10-year cumulative RFS rates were 77.5% and 70.1%, respectively. Age (p = 0.041), fibroadenoma surgery history (p = 0.004), surgical margins (p = 0.001) and malignant heterologous elements (p < 0.001) were independent risk factors for postoperative RFS. Subsequently, a nomogram was built, with a C-index of 0.64 (95% CI: 0.629-0.661), to predict the risk of recurrence. CONCLUSION: The results of this study showed that younger age, fibroadenoma surgery history, malignant heterologous elements and surgical margins <1 cm predict a higher incidence of recurrence in MPT patients. Patients with malignant heterologous elements treated with chemotherapy could have a reduced risk of recurrence.

Precise pathologic diagnosis and individualized treatment improve the outcomes of invasive micropapillary carcinoma of the breast: a 12-year prospective clinical study.

Invasive micropapillary carcinoma of the breast is a histologic subtype of breast cancer and associated with high incidence of lymphovascular invasion, lymph node metastasis and poor prognosis. The aim of this prospective study was to investigate the impact of precise pathologic diagnosis and individualized treatment on the outcomes of invasive micropapillary carcinoma of the breast. The study group included 2299 women with invasive micropapillary carcinoma diagnosed at Tianjin Medical University Cancer Institute and Hospital between January 2004 and December 2015. In the study group, specimens were examined with the method of whole-specimen orientation and serial sectioning, and patients received precise pathological diagnosis and individualized treatment. The control group of invasive micropapillary carcinoma consisted of 163 cases, identified through a retrospectively review of 9056 invasive carcinomas diagnosed at our institution between January 1989 and December 2003 using the standard pathology-evaluation method (i.e., not using the whole-specimen orientation and serial-sectioning method). The clinicopathological features, treatments and outcomes were compared between the two groups. The incidence of invasive micropapillary carcinoma in the study group was 6% (2299/39,714 cases), significantly higher than that of the control group (2%; 163/9056 cases). The 5-year disease-free survival in the study group was significantly higher than that in the control group (83.8 vs.45.4%; p < 0.05). The 5-year overall survival was significantly increased from 57.4% in the control group to 90.9% in the study group (p < 0.05). In the multivariate analysis, lymphovascular invasion, estrogen receptor status and lymph node metastasis were independent prognostic factors. Although invasive micropapillary carcinoma of the breast is associated with poor prognosis, precise pathologic diagnosis and individualized treatment improved the disease-free survival and overall survival of invasive micropapillary carcinoma patients. Precise pathological diagnosis is the premises for individualized treatments and for improving the outcomes of patients with invasive micropapillary carcinoma of the breast.

Dasatinib inhibits c-src phosphorylation and prevents the proliferation of Triple-Negative Breast Cancer (TNBC) cells which overexpress Syndecan-Binding Protein (SDCBP).

Triple negative breast cancer (TNBC) progresses rapidly but lacks effective targeted therapies. Our previous study showed that downregulating syndecan-binding protein (SDCBP) in TNBC inhibits the proliferation of TNBC cells. Dasatinib is a new small-molecule inhibitor of c-src phosphorylation. The aim of this study was to investigate if SDCBP is a potential marker to indicate whether a TNBC is suitable for dasatinib therapy. This study applied co-immunoprecipitation to identify the interaction between SDCBP and c-src in TNBC cell lines. In addition, immunohistochemistry was used to investigate SDCBP and tyrosine-419 phosphorylated c-src (p-c-src-Y419) expression in TNBC tissues. SDCBP-overexpressing MDA-MB-231 cells were then constructed to evaluate the effects of dasatinib on SDCBP-induced TNBC progression in vitro and tumor formation in nude mice. We found wild-type SDCBP interacted with c-src and promoted the phosphorylation of c-src; this phosphorylation was completely blocked by dasatinib. SDCBP lacking the PDZ domain had no such effect. Among the 52 consecutive random TNBC cases examined, the expression of SDCBP was consistent with that of p-c-src-Y419, and positively correlated with histological grading or Ki-67 levels. SDCBP overexpression significantly accelerated the proliferation and cell cycle progression of the TNBC cell line MDA-MB-231; these effects were prevented by dasatinib treatment. However, the subsequent inhibition of p27 expression partially restored the proliferation and viability of the TNBC cells. The results of this study suggest that SDCBP interacts with c-src, regulates G1/S in TNBC cells, and enhances tumor cell proliferation by promoting the tyrosine phosphorylation of c-src at residue 419. Dasatinib inhibits such phosphorylation and blocks SDCBP-induced cell cycle progression. Therefore, SDCBP might be an important marker for identifying TNBC cases that are suitable for dasatinib therapy.

Both high expression of pyruvate kinase M2 and vascular endothelial growth factor-C predicts poorer prognosis in human breast cancer.

Pyruvate kinase M2 (PKM2) and vascular endothelial growth factor-C (VEGF-C) have been known to play an important role in tumorigenesis and tumor progression in breast cancer. However, the association between PKM2 and VEGF-C in breast cancer remains unclear. In the present study, a total of 218 specimens from breast cancer patients and 26 paired breast tumors with adjacent normal tissues as well as two breast cancer cell lines were enrolled to investigate the correlation between PKM2 and VEGF-C. We found that PKM2 and VEGF-C mRNA levels were both significantly increasing in breast tumors compared with adjacent normal tissues. Knockdown of PKM2 mRNA expression resulted in VEGF-C mRNA and protein down-regulated as well as cell proliferation inhibited. A positive correlation between PKM2 and VEGF-C expression was identified by immunohistochemical analyses of 218 specimens of patients with breast cancer (P=0.023). PKM2 high expression was significantly correlated with histological grade (P=0.030), lymph node stage (P=0.001), besides VEGF-C high expression was significantly associated with lymphovascular invasion (P=0.012). While combined high expression of PKM2 and VEGF-C was found to be associated with worse histological grade, more lymph node metastasis, more lymphovascular invasion, shorter progression free survival (PFS), and poorer overall survival (OS) in human breast cancer. The results of the present study suggested that PKM2 expression was correlated with VEGF-C expression, and combination of PKM2 and VEGF-C levels had the better prognostic significance in predicting the poor outcome of patients with breast cancer.

Polymorphisms in poly (ADP-ribose) polymerase-1 (PARP1) promoter and 3' untranslated region and their association with PARP1 expression in breast cancer patients.

Within the past several years, inhibition of the PARP1 activity has been emerged as one of the most exciting and promising strategies for triple-negative breast cancer (TNBC) therapy. The purpose of this study is to assess PARP1 expression in TNBCs and to evaluate the association between polymorphisms in PARP1 promoter or 3' untranslated region (3'UTR) and PARP1 expression. It was found that PARP1 was overexpressed in nuclear (nPARP1), cytoplasm (cPARP1) and nuclear-cytoplasmic coexisting (coPARP1) of 187 TNBCs in comparison to that of 115 non-TNBCs (nPARP1, p<0.001; cPARP1, p<0.001; coPARP1, p<0.001). High expression of nPARP1 and cPARP1 in breast cancer was related to worse progression-free survival (nPARP1, p=0.007, cPARP1, p=0.003). Additionally, we identified seven published polymorphism sites in the promoter region and in 3'UTR of PARP1 by sequencing. rs7527192 and rs2077197 genotypes were found to be significantly associated with the cPARP1 expression in TNBC patients (rs7527192 AA+GA versus GG, p=0.014; rs2077197 AA+GA versus GG, p=0.041). These findings were confirmed in an independent validation set of 88 TNBCs (rs7527192 GG versus GA+AA, p=0.030; rs2077197 GG versus GA+AA, p=0.030). The PARP1 over-expression including nuclear, cytoplasm and nuclear-cytoplasmic coexisting is a feature of TNBCs and the assessment of its expression may help to predict the efficacy of chemotherapy with PARP1 inhibitor.

A MicroRNA Expression Signature In Taxane-anthracycline-Based Neoadjuvant Chemotherapy Response.

There is an unmet clinical need to identify biomarkers for breast cancer neoadjuvant chemotherapy. Here, using miRNA TaqMan Low-Density Arrays (TLDA), we analyzed the miRNA expression profile in pre-treatment needle aspiration tumor samples from patients who received taxane-anthracycline-based neoadjuvant chemotherapy. Although, in an unsupervised hierarchical cluster analysis, the total miRNA expression profile could not generate a tree with clear distinction between pathologic complete response (pCR) and non-pCR classes, we found that elevated expression of miR-125b and miR-141 was associated with non-pCR. In vitro experiments indicated that inhibition of miR-125b and miR-141 expression reduced cellular survival in response to taxane-anthracycline treatment. Furthermore, co-transfection with miR-125b and miR-141 mimics increased resistance of MCF7 and BT549 cells to taxane-anthracycline induced cytotoxicity. Pathway analyses indicated that many of the target proteins of miR-125b are involved in apoptotic pathways and cell cycle control. Together, we provide evidence that elevated miR-125b and 141 expression predicts a poor clinical responsiveness of taxane-anthracycline-based neoadjuvant chemotherapy.

Clinicopathological Features and Prognosis of Metaplastic Breast Carcinoma: Experience of a Major Chinese Cancer Center.

Metaplastic breast carcinoma (MBC) is a rare heterogeneous group of primary breast malignancies, with low hormone receptor expression and poor outcomes. To date, no prognostic markers for this tumor have been validated. The current study was undertaken to evaluate the clinicopathologic characteristics, the response to various therapeutic regimens and the prognosis of MBCs in a large cohort of patients from Tianjin Medical University Cancer Hospital in China. Ninety cases of MBCs diagnosed in our hospital between January 2000 and September 2014 were retrieved from the archives. In general, MBCs presented with larger size, a lower rate of lymph node metastasis, and demonstrated more frequent local recurrence/distant metastasis than 1,090 stage-matched cases of invasive carcinoma of no specific type (IDC-NST), independent of the status of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expressions. The five-year disease-free survival (DFS) of MBC was significantly worse than IDC-NST. Using univariate analysis, lymph node metastasis, advanced clinical stage at diagnosis, high tumor proliferation rate assessed by Ki-67 labeling, and epidermal growth factor receptor (EGFR) overexpression/gene amplification were associated significantly with reduced DFS, while decreased OS was associated significantly with lymph node metastasis and EGFR overexpression/gene amplification. With multivariate analysis, lymph node status was an independent predictor for DFS, and lymph node status and EGFR overexpression/gene amplification were independent predictors for OS. Histologic subtyping and molecular subgrouping of MBCs were not significant factors in prognosis. We also found that MBCs were insensitive to neoadjuvant chemotherapy, routine chemotherapy, and radiation therapy. This study indicates that MBC is an aggressive type of breast cancer with poor prognosis, and that identification and optimization of an effective comprehensive therapeutic regimen is needed.

Invasive micropapillary mucinous carcinoma of the breast is associated with poor prognosis.

Invasive micropapillary carcinoma of breast (IMpC) is a special type of breast cancer with frequent lymph node metastasis (LNM) and poor prognosis, while pure mucinous carcinoma of breast (PMC) is generally associated with infrequent LNM and better prognosis. A similar micropapillary epithelial growth pattern has been described in PMC that was named as invasive micropapillary mucinous carcinoma (IMpMC), but its prognostic significance is as yet not known. A retrospective review of 531 cases of PMC in 43,685 cases of breast cancer diagnosed over a 10-year period was conducted to assess the frequency of IMpMC and its prognostic implications. IMpMC was identified in 134 (25.2 %) of the 531 PMC cases. Compared to conventional PMC (cPMC), IMpMC was found more frequently in younger patients and in tumors with increased frequency of LNM and lymphovascular invasion, and higher HER2 expression. In stage-matched Kaplan-Meier analysis, patients with stage II-III IMpMC suffered a decreased overall survival and recurrence-free survival (RFS) than matched cPMC patients. Multivariate analysis confirmed the presence of IMpMC morphology was an independent unfavorable predictor for LNM and RFS of PMC. However, decreased LNM, lower nuclear grade, higher expression of ER and PR, less expression of HER2, and better prognosis were identified in IMpMC when compared with IMpC (n = 281). This is the first study to show the prognostic significance of IMpMC in a large cohort. IMpMC pursues a more aggressive clinical course than cPMC and should be managed differently; therefore, recognition of IMpMC and its accurate diagnosis are clinically important.

Absence of caveolin-1 expression in carcinoma-associated fibroblasts of invasive micropapillary carcinoma of the breast predicts poor patient outcome.

Caveolin-1 (Cav-1) expression in stromal carcinoma-associated fibroblasts (CAFs) has been associated with tumor progression and clinical outcome. This study was undertaken to assess its prognostic significance in invasive micropapillary carcinoma of the breast (IMPC), a tumor with abundant stromal CAFs and a high tendency for nodal metastasis and poor outcome. Cav-1 expression was studied by immunohistochemistry in a group of 86 cases of IMPC along with a control group of 105 cases of invasive ductal carcinoma, not otherwise specified (IDC-NOS). Our results indicate that absence of Cav-1 expression in CAFs of IMPC is more common than in IDC-NOS (57 %, 49/86 vs. 36 %, 38/105). The absence of expression was associated with larger tumor size and higher lymph node stage (P < 0.05) of IMPC. Univariate analysis suggested absence of Cav-1 in CAFs to be a candidate independent predictor of reduced progression-free survival (PFS) (HR = 3.945, 95 % CI = 1.717-9.063, P = 0.001), which was confirmed by multivariable analysis (P = 0.018). In patients with IMPC spreading to local lymph nodes, loss of stromal Cav-1 predicted a fourfold increase in risk for shortened PFS. In contrast, no significant difference of tumor epithelial Cav-1 expression was found between IMPC and IDC-NOS, and the expression of tumor Cav-1 was not significantly associated with the prognosis of patients with IMPC. Absence of Cav-1 expression in CAFs is a strong prognostic factor for IMPC patients, and it may further subgroup the patients with lymph node metastasis to guide clinical management.

Primary acinic cell carcinoma of the breast: a case report and review of the literature.

Acinic cell carcinoma (ACC) of the breast is a rare tumor that is listed in the 2003 World Health Organization (WHO) classification of tumors of the breast. Pure form ACC of the breast is even rarer. To date, only 12 cases have been reported in the English-language literature. A case of primary ACC of the breast in a 38-year-old woman is presented in this report. Histologically, the neoplastic cells are characterized by widespread acinci cell-like differentiation with a eosinophilic granular or clear cytoplasm, resembling acinic cells of the parotid gland. In addition, the neoplastic cells are positive for lysozyme, EMA, S-100, CD68 and GCDFP-15 and negative for α-anti-chymotrypsin, synaptophysin, ER, PR and Her-2/neu. This primary breast tumor was confirmed by clinical, morphological, and immunohistochemical studies. Characteristic features and differential diagnosis of this tumor were discussed in the light of pertinent literature.

MicroRNA-132 is frequently down-regulated in ductal carcinoma in situ (DCIS) of breast and acts as a tumor suppressor by inhibiting cell proliferation.

Ductal carcinoma in situ (DCIS) is the most common type of non-invasive breast cancer. The currently accepted step-wise model suggests that breast cancer progressed in the following manner: normal breast cell→usually ductal hyperplasia (UDH)→atypical ductal hyperplasia (ADH)→DCIS→invasive ductal carcinoma (IDC). Therefore, DCIS can serve as a good model to analyze the mechanism underlying invasive breast cancer occurrence. MicroRNAs (miRNAs) are a novel class of small non-coding RNAs (~22nt) involved in the regulation of various biological processes. Altered miRNA expression could also contribute to the origination of cancer, including breast cancer. Here, by using miRNA microarray and real time PCR, we analyzed the miRNA expression profile in 21 DCIS and the corresponding normal tissues. miR-10b, miR-125b, miR-132, miR-145, miR-154-3p, miR-382-5p and miR-409-3p were found to be significantly deregulated in DCIS. Results from CCK-8 assay showed that the overexpression of miR-132 could inhibit the proliferation of breast cancer cell line. High expression of miR-132 could also inhibit the colony formation. Our findings will lead to further understanding of the development of breast cancer.

Deep sequencing reveals small RNA characterization of invasive micropapillary carcinomas of the breast.

Invasive micropapillary carcinoma (IMPC) is an uncommon histological type of breast cancer. IMPC has a special growth pattern and a more aggressive behavior than invasive ductal carcinomas of no special types (IDC-NSTs). microRNAs are a large class of non-coding RNAs involved in the regulation of various biological processes. Here, we analyzed the small RNA transcriptomes of five formalin-fixed paraffin-embedded (FFPE) pure IMPC samples and five FFPE IDC-NSTs samples by means of next-generation sequencing, generating a total of >170,000,000 clean reads. In an unsupervised cluster analysis, differently expressed miRNAs generated a tree with clear distinction between IMPC and IDC-NSTs classes. Paired fresh-frozen and FFPE specimens showed very similar miRNA expression profiles. By means of RT-qPCR, we further investigated miRNA expression in more IMPC (n = 22) and IDC-NSTs (n = 24) FFPE samples and found let-7b, miR-30c, miR-148a, miR-181a, miR-181a*, and miR-181b were significantly differently expressed between the two groups. We also elucidated several features of miRNA in these breast cancer tissues including 5' variability, miRNA editing, and 3' untemplated addition. Our findings will lead to further understanding of the invasive potency of IMPC and gain an insight into the diversity and complexity of small RNA molecules in breast cancer tissues.

Peritumoral FOXP3⁺ regulatory T cell is sensitive to chemotherapy while intratumoral FOXP3⁺ regulatory T cell is prognostic predictor of breast cancer patients.

It has been reported that the prognostic significances of tumor-infiltrating FOXP3(+) regulatory T cells (Tregs) in breast carcinoma depend on their relative density and tissue locations. We here assessed the changes of Tregs before and after neoadjuvant chemotherapy (NC) and their relationships with tumor response and patient survival. Intratumoral and peritumoral infiltration of FOXP3(+) Tregs were evaluated by immunohistochemistry in 132 cases of invasive breast carcinomas before and after NC. After NC, the density of infiltrated Tregs within tumor bed remained stable, whereas it decreased significantly (P = 0.015) in the tissue surrounding tumor. The changes were significant in those tumors that usually response to NC, including the HER2-enriched and basal-like subtypes (P = 0.035; P = 0.004). Univariate and multivariate analyses identified the decreased peritumoral Tregs were an independent predictor for pathologic complete response (pCR), while the intratumoral Tregs after chemotherapy was proved to be associated with overall survival and progression-free survival of the patients. The findings of the study indicated that peritumoral Treg was sensitive to chemotherapy and associated with pCR, while intratumoral Treg was an independent prognostic predictor of breast cancer patients.

Lymph node ratio: a new feature for defining risk category of node-positive breast cancer patients.

St. Gallen 2005 expert consensus guideline modified its criteria for the risk category of breast cancer (BC) patients by integrating a combination of lymph nodes with metastasis (positive lymph nodes [PLNs]) and HER-2/neu status of tumor. Recently, some studies have shown that lymph node ratio (LNR), defined as the ratio of axillary lymph nodes with tumor metastasis to the total lymph nodes dissected, was a better independent prognostic indicator than PLN and should be considered as an alternative to the status of regional lymph nodes in the staging of breast cancer (pN). In the current study, the authors retrospectively reviewed 1095 primary BC patients with PLN and assessed the prognostic effect of LNR measured by relapse-free survival and overall survival to explore the feasibility of LNR and HER-2/neu status in stratifying the risk category of BC. Our results indicate that although by univariate analysis and when assessed as single covariate in multivariate analysis, both PLN and LNR were independent prognostic factors, PLN lost its significance when combined with LNR as covariates. A cutoff value of LNR = 0.30 was identified to show high accuracy in separating patients based on their survivals. The risk categories defined by LNR combined with HER-2/neu status were compatible to those defined by the PLN in combination with HER-2/neu status. LNR was a strong prognostic predictor of node-positive BC patients, superior to PLN. It should be considered as a new factor to couple with HER-2/neu status in defining risk category of BC patients.

Genetic heterogeneity of HER2 in breast cancer: impact on HER2 testing and its clinicopathologic significance.

In 2009, ASCO/CAP expanded its human epidermal growth factor receptor type 2 (HER2) testing guideline to define HER2 genetic heterogeneity (GH). However, the clinical significance of GH is unclear. We investigated the impact of HER2 GH on HER2 testing and studied its clinicopathologic significance. Paraffin-embedded tumor tissues of surgical resections of 617 non-consecutive breast carcinoma patients were studied by routine HER2 fluorescence in situ hybridization (FISH). HER2 GH was evaluated, and the results were correlated with HER2 protein expression by immunohistochemistry and HER2 gene amplification by FISH, and with various clinicopathologic parameters. HER2 GH was observed in 15.2 % (94/617) of the patients. It was associated with low-to-middle level of HER2 expression, and with none-to-low level of HER2 gene amplification. Among the 17 patients with equivocal HER2 FISH results, 35.3 % (6/17) of tumors displayed GH. In contrast with HER2-positive tumors without GH, tumors with HER2 GH demonstrated significant association with lower histologic grade, smaller tumor size, and proclivity to hormone receptor expression. HER2 GH is a substantial cause of equivocal HER2 testing results of breast cancer by FISH. Tumors with HER2 GH showed that biologic features resemble more of HER2-negative tumors than HER2-positive tumors without GH. The findings indicate a need of the guidelines to clarify whether tumors with HER2 GH truly benefit from HER2-targeted therapy of breast cancer.

Accessory breast cancer occurring concurrently with bilateral primary invasive breast carcinomas: a report of two cases and literature review.

The development of accessory breast tissue, which is found anywhere along the milk line, is attributed to the failure of milk line remnants to regress during embryogenesis. Primary tumors may arise from any ectopic breast tissue. Accessory breast cancer occurring concurrently with primary invasive breast cancer is extremely rare. Two such cases were reported in this article. One was a 43-year-old Chinese female who exhibited bilateral breast cancer (invasive ductal carcinoma, not otherwise specified, IDC-NOS) and an accessory breast carcinoma (IDC-NOS) incidentally identified in her left axilla. The ectopic breast tissue in her right axilla presented with adenosis. The patient was surgically treated, followed by postoperative docetaxel epirubicin (TE) chemotherapy. The second case was a 53-year-old Chinese female with bilateral breast cancer (apocrine carcinoma) accompanied by an accessory breast carcinoma (IDC-NOS) in her right axilla that was also incidentally identified. The patient was surgically treated after three doses of cyclophosphamide epirubicin docetaxel (CET) neoadjuvant chemotherapy, followed by adjuvant chemotherapy of the same regimen.