Overall Survival for HER2-Positive Breast Cancer Patients in the HER2-Targeted Era: Evidence From a Population-Based Study

BackgroundHER2-positive breast cancer is an aggressive tumor subtype and it is usually associated with worse clinical outcomes. Given the advances in HER2-targeted therapies, we hypothesized that HER2 amplification is no longer a marker of poor prognosis.MethodsWe conducted a population-based observational study employing two independent cohorts of patients with breast cancer. Samples from the METABRIC cohort were collected before clinical availability of HER2-targeted therapies, whereas samples from the SCAN-B cohort were collected afterward. The primary endpoint was overall survival (OS).ResultsA total of 5121 patients were included in the analyses. In both cohorts, HER2-positive tumors were more likely to be node-positive (P < .05) and high grade (P < .001). Before HER2-targeted agents, HER2 patients had a significantly worse 5-year OS than hormone receptor-positive (HR+) patients (63.4% vs. 83.0%, HR = 2.49, P < .001). In contrast, after HER2-targeted agents entered clinical practice, 5-year OS no longer differed (88.3% vs. 90.4%, HR = 1.24, P = .17). Additionally, in an exploratory analysis using PAM50 subtypes, we identified that, after HER2-targeted therapies were implemented, patients clinically HER2-negative but PAM50-HER2-enriched have a lower OS (HR = 1.99, P = .009) than those who are both HER2-positive and PAM50-HER2-enriched, since they have not benefitted from HER2-targeted therapies.ConclusionsHER2-targeted therapies dramatically altered the natural history of HER2-positive breast cancer, with overall survival approaching those of luminal subtype. HER2 positivity is no longer a marker of poor prognosis if access to HER2-targeted therapies is granted. Future trials should assess whether HER2-negative PAM50-HER2-enriched patients may also benefit from such therapies.     

Breast Cancer Subtype as a Predictor of Lymph Node Metastasis according to the SEER Registry

Purpose

Breast cancer subtype correlates with response to systemic therapy and overall survival (OS), but its impact on lymphatic spread is incompletely understood. In this study, we used the Surveillance, Epidemiology, and End Results registry to assess whether the subtype can predict the presence of nodal metastasis or advanced nodal stage in breast cancer.

Methods

A total of 7,274 eligible patients diagnosed with T1-3 infiltrating ductal carcinoma with known estrogen or progesterone hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, who underwent surgical excision of the primary tumor and pathologic lymph node evaluation, were included in this analysis. Patients were categorized into four breast cancer subtypes: HR+/HER2-; HR+/HER2+; HR-/HER2+; and HR-/HER2-. Binary logistic regression analysis was used to determine whether breast cancer subtype, tumor size, tumor grade, patient race, and patient age at diagnosis are independently predictive of lymph node positivity or advanced nodal stage. The Pearson chi-square test was used to determine whether progesterone receptor (PR) status had an impact on the incidence of lymph node positivity in estrogen receptor (ER) positive patients.

Results

Independent predictors of nodal positivity included breast cancer subtype (p=0.040), tumor size (p<0.001), tumor grade (p<0.001), and patient age (p<0.001), whereas only tumor size (p<0.001), grade (p=0.001), and patient age (p=0.005) predicted advanced nodal stage. Triple-negative cancers had a significantly lower risk of nodal positivity than the HR+/HER2- subtype (odds ratio, 0.686; p=0.004), but no other significant differences between subtypes were observed. There was also no difference in lymph node positivity between PR+ and PR- tumors amongst ER+/HER2- (p=0.228) or ER+/HER2+ tumors (p=0.713).

Conclusion

The HR+/HER2-breast cancer subtype has a higher rate of lymph node involvement at diagnosis than the triple-negative subtype. These findings may play a role in guiding regional management considerations if confirmed in further studies.     

Hypomethylation of the MMP7 promoter and increased expression of MMP7 distinguishes the basal-like breast cancer subtype from other triple-negative tumors

Identification of novel targets for the treatment of basal-like breast cancer is essential for improved outcomes in patients with this disease. This study investigates the association of MMP7 expression and MMP7 promoter methylation with subtype and outcome in breast cancer patient cohorts. Immunohistochemical analysis was performed on a breast cancer tissue microarray and validated in independent histological samples. MMP7 expression significantly correlated with patient age, tumor size, triple-negative (TN) status, and recurrence. Analysis of publically available datasets confirmed MMP7 gene expression as a prognostic marker of breast cancer metastasis, particularly metastasis to the brain and lungs. Methylation of the MMP7 promoter was assessed by methylation-specific PCR in a panel of breast cancer cell lines and patient tumor samples. Hypomethylation of the MMP7 promoter significantly correlated with TN status in DNA from patient tumor samples, and this association was confirmed using The Cancer Genome Atlas (TCGA) dataset. Evaluation of a panel of breast cancer cell lines and data from the Curtis and TCGA breast carcinoma datasets revealed that elevated MMP7 expression and MMP7 promoter hypomethylation are specific biomarkers of the basal-like molecular subtype which shares considerable, but not complete, overlap with the clinical TN subtype. Importantly, MMP7 expression was identified as an independent predictor of pathological complete response in a large breast cancer patient cohort. Combined, these data suggest that MMP7 expression and MMP7 promoter methylation may be useful as prognostic biomarkers. Furthermore, MMP7 expression and promoter methylation analysis may be effective mechanisms to distinguish basal-like breast cancers from other triple-negative subtypes. Finally, these data implicate MMP7 as a potential therapeutic target for the treatment of basal-like breast cancers.     

HER3 status by immunohistochemistry is correlated with poor prognosis in hormone receptor-negative breast cancer patients

Breast cancer is a highly heterogeneous malignancy. The triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2) breast cancer subtypes are highly aggressive and are associated with a poor prognosis. The therapeutic targets for TNBC remain undefined, and many patients with the HER2 subtype acquire resistance to therapy after prolonged treatment. The objective of this study was to evaluate the prognostic significance of HER3 expression in invasive breast carcinoma. We established matched tissue microarray (TMA) blocks and clinical data from 950 cases of invasive breast carcinoma with long-term clinical follow-up data (median 109.7 months). Using the TMAs, we characterized the expression of ER, PR, HER2, EGFR, and HER3 by immunohistochemistry. Each case was classified as one of four IHC-based subtypes based on the expression of hormonal receptor (HR) and HER2. The clinicopathological characteristics and survival of 950 patients were analyzed by subtype. In the TNBC subtype, the HER3(+) group showed poorer disease-free survival (DFS, P = 0.010) and overall survival (OS, P = 0.015) than the HER3(?) group. In the HER2 subtype, the HER3(+) group also showed poorer DFS (P = 0.022) and OS (P = 0.077) than the HER3(?) group. However, there was no difference in patients with HR-positive breast cancer. HER3 expression was associated with poor DFS in both the TNBC and HER2 subtypes and poor OS in the TNBC subtype. HER3 overexpression is an important prognostic marker in hormone receptor-negative breast cancer, and further study is needed to clarify the role of HER-3 targeted treatment.     

αB-Crystallin is a Novel Oncoprotein Associated with Poor Prognosis in Breast Cancer

Purpose

αB-crystallin, a small heat shock protein, is an anti-apoptotic protein associated with aggressive tumor behavior. A recent study revealed that αB-crystallin is overexpressed in a metastatic variant of the GI101A human breast carcinoma cell line. The purpose of this study was to investigate whether αB-crystallin is related to other breast tumor markers and can predict a breast cancer prognosis.

Methods

Eighty-two patients who underwent breast cancer surgery at Hallym Sacred Heart Hospital were enrolled. αB-crystallin expression was determined by immunohistochemical staining. Estrogen receptor, progesterone receptor (PR), human epidermal growth factor receptor, lymphovascular invasion, histological grade, other tumor markers and time to recurrence were compared with αB-crystallin expression.

Results

αB-crystallin expression in breast cancer tissues was associated with PR (p=0.030), the number of metastatic lymph nodes (pN) (p=0.020), lymphovascular invasion (p=0.022), histological grade (p=0.004) and triple negative breast cancer (TNBC) (p=0.004). αB-crystallin expression significantly decreased time to recurrence (p=0.039).

Conclusion

The results revealed a strong relationship between αB-crystallin and poor prognostic factors such as the number of metastatic lymph nodes (especially pN2), TNBC, and rapid time to recurrence. We believe that αB-crystallin could be a novel oncoprotein biomarker of a poor prognosis in breast cancer.     

Effects of trastuzumab on locoregional recurrence in human epidermal growth factor receptor 2-overexpressing breast cancer patients treated with chemotherapy and radiotherapy

Purpose

In the present study, the ability of adjuvant trastuzumab to reduce locoregional recurrence in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer receiving adjuvant chemotherapy and radiotherapy (RT) was investigated.

Materials and methods

We retrospectively included 520 patients with HER2-overexpressing breast cancer who received surgery followed by adjuvant RT and cytotoxic chemotherapy from 2003 to 2011. Adjuvant trastuzumab was administered to 286 patients. Propensity score matching was conducted to compare trastuzumab-treated and non-treated cohorts.

Results

Median follow-up duration was 7.1 years (range 1.1–14.1 years). Propensity score matching yielded 171 matched pairs of patients with no significantly different clinical factors. An improved 7-year locoregional control (LRC) rate was observed in the trastuzumab-treated cohort compared with the non-treated cohort (95.6% vs. 89.9%, p?=?0.014). Based on multivariate analysis, hormone receptor negativity (hazard ratio [HR]?=?5.348, p?=?0.007), positive lymph node ratio?>?0.25 (HR?=?2.549, p?=?0.040), and lack of adjuvant trastuzumab (HR?=?3.401, p?=?0.017) were identified as significant risk factors for poor LRC. Adjuvant trastuzumab significantly reduced the locoregional recurrence rate in patients with one or two risk factors (7-year LRC?=?95.0% vs. 84.2%, p?=?0.007); however, the benefit of adjuvant trastuzumab was non-significant in patients with no risk factors (7-year LRC?=?95.8% vs. 97.9%, p?=?0.75).

Conclusions

Adjuvant trastuzumab improved LRC in patients with HER2-overexpressing breast cancer receiving adjuvant RT and cytotoxic chemotherapy, especially in hormone receptor-negative, HER2-enriched subtype, and high positive lymph node ratio breast cancer.

     

Prognostic and Therapeutic Significance of Adhesion-regulating Molecule 1 in Estrogen Receptor-positive Breast Cancer

IntroductionAdhesion-regulating molecule 1 (ADRM1) is a polyubiquitin receptor on the 26S proteasome. ADRM1 is upregulated in many cancers. In this study, we evaluated the potential prognostic and predictive value of ADRM1 in breast cancer.Materials and MethodsIndividual and pooled survival analyses were performed on 19 independent breast cancer microarray datasets. Gene signatures enriched by ADRM1 were also analyzed in pooled datasets.ResultsGene set enrichment analysis revealed that high expression of ADRM1 was significantly associated with aggressive breast cancer. Our findings revealed that ADRM1 mRNA levels were significantly associated with estrogen receptor (ER) status, progesterone receptor status, tumor size, lymph node status, histologic grade, and molecular subtypes. We also found that higher mRNA ADRM1 expression was significantly correlated with poor survival in patients with breast cancer. The prognostic power of ADRM1 mRNA was similar to the 70-gene wound response genes and 21 gene recurrence score; it was superior to TNM staging. The prognostic value of ADRM1 was better in ER-positive (ER⁺) breast cancer cases than in ER-negative breast cancer cases. In cases involving stage II breast cancer, radiotherapy significantly reduced the relative risk of OS in the ADRM1-low subgroup.ConclusionADRM1 mRNA levels were significantly related to poor outcome in our breast cancer sample population. It could serve as a prognostic biomarker, especially in ER⁺ breast cancer and Luminal A breast cancer cases, as well as a predictive biomarker for ER⁺ breast cancer.     

脉管癌栓中间质细胞/癌细胞、巨噬细胞/癌细胞比值与pT1～4N1～3M0期乳腺癌患者临床病理特征及预后的关系

目的探讨脉管癌栓中间质细胞/癌细胞比值、巨噬细胞/癌细胞比值与pT_1～4N_1～3M₀期乳腺癌患者临床病理特征及预后的关系。 方法采用回顾性研究方法,选取2013年1月至2015年12月在中国医科大学附属第一医院及大连医科大学附属第一、二医院经系统治疗并有完整随访资料的167例pT_1～4N_1～3M₀期腋窝淋巴结阳性乳腺癌患者作为研究对象,中位随访55.2个月(16.8～69.6个月)。采用免疫组织化学染色方法分别检测脉管癌栓中间质细胞和巨噬细胞的数目,计算间质细胞/癌细胞比值及巨噬细胞/癌细胞比值,采用Ward法分别对间质细胞/癌细胞比值和巨噬细胞/癌细胞比值进行聚类,得到低比值和高比值两类。分别采用Kruskal-Wallis H检验、χ²检验分析该比值与患者临床病理特征的关系,并用log-rank检验分析该比值与患者预后的关系。 结果167例患者间质细胞/癌细胞、巨噬细胞/癌细胞比值的M(P₂₅～P₇₅)分别为0.025(0.015～0.063)和0.023(0.015～0.036)。间质细胞/癌细胞比值与患者的组织学分级、肿瘤大小、腋窝淋巴结转移状态、临床分期及脉管浸润有关(χ²＝10.210、6.210、64.315、56.901、19.771,P＝0.001、0.045及P均<0.001),但与ER、PR、HER-2、Ki67表达及神经侵犯无关(χ²＝3.148、2.260、3.187、0.145、1.384,P＝0.076、0.133、0.074、0.704、0.240);巨噬细胞/癌细胞比值与患者的肿瘤大小、ER表达、神经侵犯、组织学分级、腋窝淋巴结转移状态、临床分期、脉管浸润和HER-2表达有关(χ²＝7.487、6.680、8.439、13.002、25.856、31.394、19.771、27.921,P＝0.024、0.010、0.004及P均<0.001),但与PR、Ki67表达无关(χ²＝3.616、1.183,P＝0.057、0.277)。聚类后间质细胞/癌细胞比值与腋窝淋巴结转移状态及临床分期均有关系(χ²＝47.300,P<0.001;χ²＝14.260,P＝0.001),而巨噬细胞/癌细胞比值仅与ER表达有关(χ²＝5.136,P＝0.023)。间质细胞/癌细胞、巨噬细胞/癌细胞比值均与乳腺癌患者DFS率相关,比值越高者DFS率越低(预后越差)(χ²＝24.124、18.746,P均<0.001)。 结论脉管癌栓中间质细胞/癌细胞比值和巨噬细胞/癌细胞比值高的患者预后不良,此比值可作为评价pT_1－4N_1－3M₀期乳腺癌患者复发风险的参考指标。     

Nomogram for Predicting the Overall Survival of Patients With Breast Cancer With Pathologic Nodal Status N3

BackgroundPatients with breast cancer with pathologic N3 (pN3) lymph node status have been proven to have a poor prognosis. This study aimed to establish a nomogram to predict overall survival (OS) in patients with pN3 breast cancer.Materials and MethodsThe eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database were randomly divided into training and validation cohorts. χ² tests and survival curves were performed to define the consistency between these 2 cohorts. Univariate and multivariate logistic regressions were carried out to identify the independent clinicopathologic factors of patients with pN3 breast cancer. A nomogram was developed and validated internally and externally by a calibration curve and compared with the seventh edition American Joint Committee on Cancer TNM staging classification in discrimination ability.ResultsRace, age at diagnosis, marital status, grade, T stage, N stage, breast cancer subtype, surgery, radiotherapy, and chemotherapy were independent predictive factors of OS in pN3 breast cancer. We developed a nomogram to predict 1-, 3-, and 5-year OS and further validated it in both cohorts, demonstrating better prediction capacity in OS than that of the seventh edition American Joint Committee on Cancer TNM staging classification (area under the curve in the receiver operating characteristic curve, 0.745 and 0.611 in the training cohort and 0.768 and 0.624 in the validation cohort, respectively).ConclusionWe have developed and validated the first nomogram for predicting the survival of pN3 breast cancer. This nomogram accurately and reliably predicted the OS of patients with pN3 breast cancer. However, more prognostic factors need to be further explored to improve the nomogram.     

D-dimer as a possible prognostic marker of operable hormone receptor-negative breast cancer

BackgroundBreast cancer is the most common cause of death in women by neoplasia. The mechanisms related to recurrence are unclear, specially the hemostatic alterations that occur during the development of the disease. Plasma D-dimer is a hypercoagulability and fibrinolytic system marker and is increased in patients with various solid tumors. The purpose of this study was to evaluate the hemostatic status assessed by plasma D-dimer in operable breast cancer patients and to investigate its value as a prognostic marker.Materials and methodsThe study comprised 32 patients with operable hormone receptor-negative breast cancer and a control group with 43 healthy women. Variables included presence and absence of breast cancer, clinical and histopathology findings, and overall survival.ResultsPlasma D-dimer level was normal in the control group and significantly higher in breast cancer patients (P = 0.001), as well as in nonsurvivors compared with survivors (P = 0.025). The results showed that plasma D-dimer levels were not correlated with clinical and histopathology findings (P > 0.213).ConclusionsThe results taken together indicate the presence of a hypercoagulability state in women with operable hormone receptor-negative breast cancer given the increased levels of D-dimer in this group. Therefore, considering higher levels of D-dimer in patients with a poor outcome, its evaluation may be a promising tool for prognosis in women with operable hormone receptor-negative breast cancer.     

D2-40, Podoplanin,and CD31 as a Prognostic Predictor in Invasive Ductal Carcinomas of the Breast

Purpose

Distant metastasis and recurrence are major prognostic factors associated with breast cancer. Both lymphovascular invasion (LVI) and blood vessel invasion (BVI) are important routes for metastasis to regional lymph nodes and for systemic metastasis. Despite the importance of vascular invasion as a prognostic factor, application of vascular invasion as a histopathological criterion is controversial. The aim of this study was to distinguish LVI from BVI in prognosis and recurrence of breast cancer using an endothelial subtype specific immunohistochemical stain (podoplanin, D2-40, and CD31).

Methods

Sections from 80 paraffin-embedded archival specimens of invasive breast cancer were stained for podoplanin, D2-40, or CD31 expression. Immunohistochemical staining results were correlated with clinicopathological features, such as tumor size, status of lymph node metastases, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor-2 expression, and recurrence. Patients with ductal carcinoma in situ and stage IV breast cancer were excluded.

Results

A significant correlation was found between D2-40 LVI positivity and lymph node metastasis (p=0.022). We found a significant correlation between D2-40 LVI positivity and recurrence of breast cancer (p=0.014). However, no significant correlation was found between BVI and recurrence. A poorer disease free survival was shown for D2-40 positive LVI (p=0.003). In a multivariate analysis, the presence of D2-40 LVI positivity revealed a significant association with decreased disease-free survival.

Conclusion

D2-40 LVI positivity was a more prognostic predictor of breast cancer than BVI.     

Prognostic significance of molecular subtype in T1N0M0 breast cancer: Korean experience

Purpose

Gene expression profiling studies have identified several breast cancer subtypes associated with markedly different clinical outcomes. In general, patients with stage I breast cancer have excellent outcomes. We assessed the clinicopathological characteristics and outcomes of patients with T1N0M0 breast cancer according to molecular subtype.

Methods

Seven hundred and sixty-two T1N0M0 breast cancer patients undergoing curative surgery between January 1990 and December 2007 were analyzed. Subtypes were classified according to hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status as follows: HR+/HER2−, HR+/HER2+, HR−/HER2− (triple-negative, TN), and HR−/HER2+.

Results

The distribution of subtypes was HR+/HER2−, 56.6%; HR+/HER2+, 10.1%; TN, 20.1%; and HR−/HER2+, 13.3%. Marked differences were observed among subtypes in multifocality/multicentricity, histological grade, extensive intraductal components, p53 expression and the Ki-67 index. There were differences in recurrence-free survival and overall survival among patients with different molecular subtypes (log-rank p < 0.001 and 0.024, respectively). By multivariate analysis, lymphovascular invasion and classification of molecular subtype were independent predictors of recurrence (p = 0.003 and 0.043, respectively). The TN subtype showed significantly worse recurrence-free survival compared to the HR+/HER2− subtype (hazard ratio, 4.54; 95% confidence interval, 1.60-12.86; p = 0.004).

Conclusion

Patients with T1N0M0 breast cancer, a group with generally favorable clinical outcomes, had prognoses that were associated with the molecular subtype. The TN subtype was an independent predictor for recurrence in patients with T1N0M0 breast cancer.     

An optimized five-gene multi-platform predictor of hormone receptor negative and triple negative breast cancer metastatic risk

Introduction

Outcome predictors in use today are prognostic only for hormone receptor-positive (HRpos) breast cancer. Although microarray-derived multigene predictors of hormone receptor-negative (HRneg) and/or triple negative (Tneg) breast cancer recurrence risk are emerging, to date none have been transferred to clinically suitable assay platforms (for example, RT-PCR) or validated against formalin-fixed paraffin-embedded (FFPE) HRneg/Tneg samples.

Methods

Multiplexed RT-PCR was used to assay two microarray-derived HRneg/Tneg prognostic signatures IR-7 and Buck-4) in a pooled FFPE collection of 139 chemotherapy-naïve HRneg breast cancers. The prognostic value of the RT-PCR measured gene signatures were evaluated as continuous and dichotomous variables, and in conditional risk models incorporating clinical parameters. An optimized five-gene index was derived by evaluating gene combinations from both signatures.

Results

RT-PCR measured IR-7 and Buck-4 signatures proved prognostic as continuous variables; and conditional risk modeling chose nodal status, the IR-7 signature, and tumor grade as significant predictors of distant recurrence (DR). From the Buck-4 and IR-7 signatures, an optimized five-gene (TNFRSF17, CLIC5, HLA-F, CXCL13, XCL2) predictor was generated, referred to as the Integrated Cytokine Score (ICS) based on its functional pathway linkage through interferon-γ and IL-10. Across all FFPE cases, the ICS was prognostic as either a continuous or dichotomous variable, and conditional risk modeling selected nodal status and ICS as DR predictors. Further dichotomization of node-negative/ICS-low FFPE cases identified a subset of low-grade HRneg tumors with <10% 5-year DR risk. The prognostic value of ICS was reaffirmed in two previously studied microarray assayed cohorts containing 274 node-negative and chemotherapy naive HRneg breast cancers, including 95 Tneg cases where it proved prognostically independent of Tneg molecular subtyping. In additional HRneg/Tneg microarray assayed cohorts, the five-gene ICS also proved prognostic irrespective of primary tumor nodal status and adjuvant chemotherapy intervention.

Conclusion

We advanced the measurement of two previously reported microarray-derived HRneg/Tneg breast cancer prognostic signatures for use in FFPE samples, and derived an optimized five-gene Integrated Cytokine Score (ICS) with multi-platform capability of predicting metastatic outcome from primary HRneg/Tneg tumors independent of nodal status, adjuvant chemotherapy use, and Tneg molecular subtype.     

三阴性乳腺癌的临床病理特征及预后分析

目的探讨三阴性乳腺癌的临床病理特征及生存情况。方法收集2004年1月-2009年12月武汉大学中南医院及湖北省肿瘤医院确诊的乳腺癌患者560例,对比分析三阴性乳腺癌患者情况。结果三阴性乳腺癌多见于绝经前女性,肿瘤直径大,组织学分级高,淋巴结转移率高,5年无瘤生存率及总生存率均低于非三阴性乳腺癌,二者差别有统计学意义。绝经与否、肿瘤直径大小以及淋巴结有无转移与其预后相关。 结论三阴性乳腺癌是一类预后差的乳腺癌亚型。     

The PDGF pathway in breast cancer is linked to tumour aggressiveness,triple-negative subtype and early recurrence

Purpose

The platelet-derived growth factor (PDGF) signalling pathway is often dysregulated in cancer and PDGF-receptor expression has been linked to unfavourable prognostic factors in breast cancer (e.g. ER negativity, high Ki67 and high grade). This study aimed to evaluate the expression of PDGFRα, PDGFRβ and ligand PDGF-CC in breast cancer in relation to molecular subtypes and prognosis.

Methods

Protein expression of tumour and/or stromal cell PDGFRα, PDGFRβ and PDGF-CC was evaluated in primary tumours (N = 489), synchronous lymph node metastases (N = 135) and asynchronous recurrences (N = 39) using immunohistochemistry in a prospectively maintained cohort of primary breast cancer patients included during 1999–2003. Distant recurrence-free interval (DRFi) was the primary end-point.

Results

High expression of all investigated PDGF family members correlated to increasing Nottingham histopathological grade and high Ki67. Tumour cells displayed high expression of PDGFRα in 20%, and PDGF-CC in 21% of primary tumours, which correlated with the triple-negative subtype (TNBC). Patients with high PDGF-CC had inferior prognosis (P = 0.04) in terms of 5-year DRFi, whereas PDGFRα was up-regulated in lymph node metastasis and recurrences compared to primary tumours. High primary tumour PDGFRα was associated with increased risk of central nervous system (CNS) recurrence.

Conclusions

High PDGFRα and PDGF-CC expression were linked to breast cancer with an aggressive biological phenotype, e.g. the TNBC subtype, and high PDGF-CC increased the risk of 5-year distant recurrence. Tumour cell PDGFRα was significantly up-regulated in lymph node metastases and asynchronous recurrences. Our findings support an active role of the PDGF signalling pathway in tumour progression.

     

The prognostic analysis of clinical breast cancer subtypes among patients with liver metastases from breast cancer

Background

To determine whether the inferior outcome noted with triple-negative breast cancer (TNBC) reflects a higher risk population among patients with breast cancer liver metastases.

Methods

A total of 123 patients with breast cancer liver metastases diagnosed at Tianjin Medical University Cancer Hospital were included in this study. Breast cancer subtype was assigned using immunohistochemistry or fluorescence in situ hybridization: hormone receptor (HR) positive (+)/human epidermal growth factor receptor 2 (HER2) negative (?), HR+/HER2+, HR?/HER2+ and triple-negative subtype. Clinical features and survival were evaluated in different subtypes.

Results

The median age at breast cancer diagnosis was 47 years (range, 23–67 years). Breast cancer subtype was confirmed in all patients (39.8% with HR+/HER2?, 24.4% with HR+/HER2+, 15.3% with HR?/HER2+ and 20.3% with TNBC). The median overall survival after liver metastases was 29 months (range, 4–89 months), and the overall 1-, 2- and 3-year survival rate was 68.3, 48.0 and 34.1%, respectively. Survival was found to be impacted by breast cancer subtype (P = 0.001), and was shortest for patients with TNBC. Time to liver metastases (TTLM) less than 24 months and liver metastasis lesions ≥3 were found to be important predictors of poor survival after liver metastases (P = 0.009 and 0.001, respectively).

Conclusions

The results indicate that clinical breast cancer subtype remains an independent prognostic predictor among patients with breast cancer liver metastases. Liver metastases arising from TNBC confers the worst prognosis, and novel agents capable of controlling intrahepatic and extrahepatic TNBC are needed.     

Local-regional control according to surrogate markers of breast cancer subtypes and response to neoadjuvant chemotherapy in breast cancer patients undergoing breast conserving therapy

Introduction

Breast cancers of different molecular subtypes have different survival rates. The goal of this study was to identify patients at high risk for local-regional recurrence according to response to neoadjuvant chemotherapy and surrogate markers of molecular subtypes in patients undergoing breast conserving therapy (BCT).

Methods

Clinicopathologic data from 595 breast cancer patients who received neoadjuvant chemotherapy and BCT from 1997 to 2005 were identified. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression determined by immunohistochemistry were used to construct the following subtypes: ER+ or PR+ and HER2- (hormone receptor (HR)+/HER2-; 52%), ER+ or PR+ and HER2+ (HR+/HER2+; 9%), ER- and PR- and HER2+ (HR-/HER2+; 7%) and ER- and PR- and HER2- (HR-/HER2-; 32%). Actuarial rates were calculated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards models were used for multivariate analysis (MVA).

Results

After a median follow-up of 64 months, the five-year local-regional recurrence (LRR)-free survival rate for all patients was 93.8%. The five-year LRR-free survival rates varied by subtype: HR+/HER2- 97.0%, HR+/HER2+ 95.9%, HR-/HER2+ 86.5% and HR-/HER2- 89.5% (P = 0.001). In addition to subtype, clinical stage III disease (90% vs. 95% for I/II, P = 0.05), high nuclear grade (92% vs. 97% with low/intermediate grade, P = 0.03), presence of lymphovascular invasion (LVI) (89% vs. 95% in those without LVI, P = 0.02) and four or more positive lymph nodes on pathologic examination (87% vs. 95% with zero to three positive lymph nodes, P = 0.03) were associated with lower five-year LRR-free survival on univariate analysis. On MVA, HR-/HER2+ and HR-/HER2- subtypes and disease in four or more lymph nodes were associated with decreased LRR-free survival. A pathologic complete response (pCR) was associated with improved LRR-free survival.

Conclusions

Patients with HR+/HER2- and HR+/HER2+ subtypes had excellent LRR-free survival regardless of tumor response to neoadjuvant chemotherapy. Patients with HR-/HER2+ and HR-/HER2- subtypes with poor response to neoadjuvant chemotherapy had worse LRR-free survival after BCT. Additional study is needed to determine the impact of trastuzumab on local-regional control in HER2+ tumors. Our data suggest that patients with HR-/HER2- subtype tumors not achieving pCR may benefit from novel strategies to improve local-regional control.     

Clinical and pathological characteristics of intraductal proliferative lesions and coexist with invasive ductal carcinomas

Objective

The purpose of this study was to study the clinical and pathological characteristics of breast intraductal proliferative lesions (IDPLs) and associated with invasive breast cancer.

Methods

We reviewed 327 cases of breast intraductal proliferative lesions including 53 cases of usual ductal hyperplasia, 57 cases of atypical ductal hyperplasia, 89 cases of ductal carcinoma in situ, and 128 cases coexist with invasive ductal carcinomas. Cases of pure invasive cancer without intraductal proliferative lesions were excluded. The mult IDPLs biological parameters including the express of ER, PR, HER2, HIF-1α and Ki-67 detected by immunohistochemistry S-P method (n = 327) and the levels of CA153, TSGF, CA125 and CEA both in nipple discharge and serum (n = 179) measured with Electrochemiluminescence method and their relationship were studied, and 30 cases of normal pregnant women were compared with.

Results

A single histologic subtype was present in 49.85% (163/327) of the cases, two subtypes in 33.03% (108/327), and three in 17.13% (56/327). The most common subtypes present were cribriform (43.12%, 141/327) and solid (38.53%, 126/327), while the comedo (16.35%, 54/327), and micropapillary (12.84%, 42/327) subtypes were less common. Comedo and solid were frequently found together for coexpression as were micropapillary and papillary subtypes. However, Comedo subtype was much less likely to be found with papillary, cribriform or micropapillary subtypes. Additionally, comedo subtypes tend to be hormone receptor negative, Her2 positive and high-grade while the cribriform and solid subtype tends to be hormone receptor positive, Her2 negative and low grade. Papillary subtype was least likely to be associated with an invasive cancer. Furthermore, the nipple discharge and serum levels of CA153, TSGF, CA125 and CEA in coexist with invasive ductal carcinomas patients were significantly higher than those in the benign breast disease (pure intraductal proliferative lesions) and normal pregnant women (P < 0.01). Additionally, the levels of CA153, TSGF, CA125 and CEA in nipple discharge were significantly higher than in the serum (P < 0.01), and had a positive correlation with the Ki-67, grade, clinical stage, lymph node metastasis and tumor recurrence (P < 0.05), and negative correlation with the level of ER and PR (P < 0.05). The sensitivity of the four serum tumor markers in combination was only 69.77%, in contrast, the combined detection both in discharge and serum was 97.67%, and the negative predictive value was 99.03%. The sensitivity of combined detection both in nipple discharge and serum were significantly higher than other detection (P < 0.05).

Conclusion

IDPLs often present more than one histologic subtype and the most common subtypes are cribriform and solid, while comedo and micropapillary subtypes are less common. Our results suggest that the levels of CA153, TSGF, CA125 and CEA in nipple discharge were significantly higher than those in the serum, and is associated with HIF-1α. The aberration of HIF-1α may play a key role during oncogenesis and promote breast cellular transformation into malignancy, a finding useful for further understanding of tumorigenesis. Nipple discharge can be the earliest presenting symptom of breast cancer. The dynamic combined detection of the four tumor markers both in nipple discharge and serum are helpful to the stratification of preoperative patients and benefit to better prewarning markers for monitoring their recurrence and metastasis and clinical staging of tumors in clinic, but cannot increase the sensitivity of judging the patients with early breast cancer.