Sentinel node micrometastases in breast cancer do not affect prognosis: a population-based study

Sentinel node biopsy (SNB) for axillary staging in breast cancer allows the application of more extensive pathologic examination techniques. Micrometastases are being detected more often, however, coinciding with stage migration. Besides assessing the prognostic relevance of micrometastases and the need for administering adjuvant systemic and regional therapies, there still seems to be room for improvement. In a population-based analysis, we compared survival of patients with sentinel node micrometastases with those with node-negative and node-positive disease in the era after introduction of SNB. Data from the population-based Eindhoven Cancer Registry were used on all (n = 6803) women who underwent SNB for invasive breast cancer in the Southeast Region of The Netherlands in the period 1996–2006. In 451 patients (6.6%) a sentinel node micrometastasis (pN1mi) was detected and in 126 patients (1.9%) isolated tumor cells (pN0(i+)). Micrometastases or isolated tumor cells in the SNB did not convey any significant survival difference compared with node-negative disease. After adjustment for age, pT, and grade, still no survival difference emerged pN1mi: [HR 0.9 (95% CI, 0.6–1.3)] and pN0(i+): [HR 0.4 (95% CI, 0.14–1.3)] and neither was the case after additional adjustment for adjuvant systemic therapy. Our practice-based study showed that the presence of sentinel node micrometastases in breast cancer patients has hardly any impact on breast cancer overall survival during the first years after diagnosis.     

The prognostic role of circulating tumor cells (CTCs) detected by RT-PCR in breast cancer: a meta-analysis of published literature

The prognostic significance of circulating tumor cells (CTCs) in patients with breast cancer is controversial. We performed a meta-analysis of published literature to assess whether the detection of CTCs in patients diagnosed with primary breast cancer can be used as a prognostic factor. We searched Medline, Science Citation Index, and Embase databases as well as reference lists of relevant articles (including review articles) for studies that assessed the prognostic relevance of tumor cell detection in the peripheral blood (PB). A total of 24 eligible studies with 4,013 cases and 1,333 controls were included. Meta-analyses were performed using a random-effects model, using the hazard ratio (HR) and 95% confidence intervals (95% CIs) as effect measures. The positive detection of CTCs in patients was significantly associated with poor overall survival (OS) (HR = 3.00 [95% CI 2.29–3.94], n = 17, P < 0.0001) and recurrence-free survival (RFS) (HR = 2.67 [95% CI 2.09–3.42], n = 22, P < 0.0001). CTC-positive breast cancers were significantly associated with high histological grade (HR = 1.21 [95% CI 1.09–1.35], n = 34, P < 0.0001), tumor size (>2 cm) (HR = 1.12 [95% CI 1.02–1.22], n = 31, P = 0.01). and nodal status (≥1) (HR = 1.10 [95% CI 1.00–1.21], n = 32, P = 0.037), but cytokeratin-19 (CK-19) mRNA-positive CTCs were not associated with these clinicopathological parameters of breast cancer. Furthermore, the presence of CTCs was not associated with estrogen receptor (ER) negativity, progesterone receptor (PR) negativity, or human epidermal growth factor receptor type 2 (HER2) positivity. Detection of CTCs in the PB indicates poor prognosis in patients with primary breast cancer. Larger clinical studies are required to further evaluate the role of these markers in clinical practice.     

Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients.

PURPOSE: Early breast cancer presents with a remarkable heterogeneity of outcomes. Undetected, microscopic lymph node tumor deposits may account for a significant fraction of this prognostic diversity. Thus, we systematically evaluated the presence of lymph node tumor cell deposits相似文献   

Invasive ductal carcinoma of the breast with the “triple-negative” phenotype: prognostic implications of EGFR immunoreactivity

Invasive ductal carcinomas (IDC) of the breast with the triple negative phenotype (steroid hormone receptor absent, negative HER2 status) are characterized by poor clinical outcome. Additional tumor markers might allow identification of patients at higher risk. We evaluated clinical and biological features of 284 consecutive patients with pT1-3, pN1-3 M0 triple-negative IDC. Median follow-up was 70 months (interquartile range 59–94 months). Statistically significant worse disease-free and overall survival were observed in multivariate analysis, for patients with EGFR immunoreactivity in ≥50% invasive tumor cells (HR 2.39, 95% CI, 1.32–4.34, P = 0.004 for DFS; HR 2.34, 95% CI, 1.20–4.59 P = 0.01 for OS). Age ≥ 70 years and PVI were additional independent predictors of reduced overall survival. EGFR immunoreactivity significantly correlates with worse prognosis in patients with triple-negative IDC, supporting further studies on the correlation between the degree of EGFR expression and outcome of triple negative breast cancer.     

Serum neopterin levels in patients with breast cancer

The aim of this study was to determine the importance of serum neopterin level in female patients with breast cancer of various clinical stages. The study consisted of 75 female patients with breast cancer who were diagnosed and treated at the Gazi University Department of Medical Oncology. The patients were classified into three representative groups and a control group: group A (n = 26), patients with newly diagnosed primary breast cancer and without metastasis; group B (n = 33), patients with metastatic breast cancer who had undergone treatment for their diseases and on whom metastasis was detected during their follow-up; group C (n = 16), off-therapy patient whose cancer had been in remission for at least 5 years; group D (n = 20) healthy controls. The median serum neopterin levels of the 75 patients with breast cancer 11.0 (range, 0–23.6) nmol/L were significantly higher than those of controls (8.3 (range, 1.2–12.0) nmol/L). In group B patients, neopterin levels (12.6 (range, 0–23.6) nmol/L) were statistically significantly higher than those of controls, primary breast cancer patients, and off-therapy patients (P < .05). In group B, patients with visceral metastases had higher neopterin levels than did those with bone or local metastases; however, that difference was not statistically significant. The median serum neopterin levels of the primary breast cancer patients in group A (8.8 (range, 0–20) nmol/l) were not statistically significantly different from those in controls and off-therapy patients. Serum neopterin levels were significantly elevated in patients with metastatic breast cancer. Neopterin seems to be an indicator of metastatic cancer rather than a marker for local cancer. In patients with metastatic breast cancer, determining the serum neopterin levels may be useful in estimating survival; however, additional long-term follow-up will be needed.     

The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer

Increasing evidence has shown that chemokines and chemokine receptors are associated with tumor growth and metastasis. CCR4, an important chemokine receptor for regulating immune homeostasis, is thought to be involved in hematologic malignancies and has also recently implicated in some solid tumors, such as gastric cancer. The possible role of CCR4 in breast cancer has not been well elucidated. In this study, we show that CCR4 is differentially expressed in human breast cancer cell lines. Specifically, we find that CCR4 is overexpressed in breast cancer cell lines with high metastatic potential. More importantly, we used a combination of overexpression and RNA interference to demonstrate that CCR4 promotes breast tumor growth and lung metastasis in mice. Furthermore, we find that microvessel density is significantly increased in tumors formed by CCR4-overexpressing cells and decreased in those formed by CCR4-knockdown cells. We find that overexpression of CCR4 can enhance the chemotactic response of breast cancer cells to CCL17. However, the expression of CCR4 does not affect the proliferation of breast cancer cells in vitro. Furthermore, we show that CCR4 expression is positively correlated with HER2 expression, tumor recurrence and lymph node, lung and bone metastasis (P < 0.05). Multivariate analysis showed that CCR4 expression is a significant independent prognostic factor for overall survival (P = 0.036) but not for disease-free survival in patients with breast cancer (P = 0.071). Survival analysis indicated a strong association between CCR4 expression and lower overall survival (P = 0.0001) and disease-free survival (P = 0.016) in breast cancer.     

Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes

Insulin-like growth factor-1 receptor (IGF-1R) is expressed in normal and malignant breast tissue and has been implicated in cell survival and resistance to cytotoxic therapies. We sought to assess the prognostic impact of IGF-1R expression among patients with early breast cancer and among breast cancer subtypes. Patients with stages I–III breast cancer with archival tumor tissue were included. Paraffin tissue blocks were used to construct a tissue microarray that was stained for ER, PR, Ki-67, HER2, EGFR, and cytokeratins 5/6 to classify the breast subgroups and for expression of IGF-1R, p27, and Bcl2 by immunohistochemistry. Kaplan–Meier plots were created by subtypes. Associations between IGF-1R and prognostic variables were examined in multivariate analysis. Among 2,871 eligible women the prognostic cut point for IGF-1R expression for breast-cancer-specific survival (BCSS) was Allred score <7 versus ≥7. IGF-1R was ≥7 in 52% (LuminalA), 57.5% (LuminalB), 44.8% (LuminalHER2), 9.7% HER2-enriched, and 22.5% (Basal-like), P = 1.3 × 10⁻⁵². IGF-1R+ was associated with age ≥50, lower histopathology grade, ER+, HER2 negativity (−), high p27 and high Bcl2 score. IGF-1R ≥7 was associated with better BCSS among LuminalB patients, hazard ratio = 0.64 (0.49–0.84); P = 1.2 × 10^−3, and worse outcome in the HER2-enriched subtype, hazard ratio = 2.37 (1.21–4.64); P = 0.012. IGF-1R correlates with good prognostic markers among patients with early breast cancer and is differentially expressed with variable prognostic impact among breast cancer subtypes. Results may have relevance to the development of therapeutics targeting IGF-1R.     

Changes over time of extracellular domain of HER2 (ECD/HER2) serum levels have prognostic value in metastatic breast cancer

Background Blood levels of the extracellular domain of HER-2/neu (ECD/HER2) have been suggested to have potential as a tumor marker in breast cancer. Our aim was to assess the prognostic value of baseline levels of ECD/HER2, but more importantly changes in levels over time, in women with metastatic breast cancer. Methods Baseline and serial levels of ECD/HER2 were measured in 158 women with newly-diagnosed metastatic breast cancer, in whom we previously performed serial measurement of plasma osteopontin. ECD/HER2 was measured in 1,282 serum samples using a validated ELISA at baseline and every 3–12 weeks during and after therapy until death (median, n = 8 samples per patient). Multivariate time-dependent survival analyses were conducted using models that right-censored patient outcomes 3, 6 and 12 months after last known ECD/HER2 measurement. Results Thirty-four patients (22%) had elevated baseline ECD/HER2 (median 10.2 ng/ml: range 4.1–40.4 ng/ml). In univariate analysis, elevated baseline ECD/HER2 was associated with short survival (P = 0.001). In a multivariate model incorporating standard clinical prognostic factors, baseline ECD/HER2 was significantly associated with survival duration (RR 1.029; P = 0.020). Presence of visceral metastases and ECOG status 2–4 also retained significance. In a multivariate model incorporating standard prognostic factors and changes in sequential ECD/HER2 levels, an ECD/HER2 increase of >12 ng/ml at any time was the variable with most prognostic value for poor survival (RR 6.10; P = 0.0003); poor ECOG status also retained significance. Conclusion Increases over time of ECD/HER2 levels were strongly associated with poor survival in this cohort of women with metastatic breast cancer. An invited commentary to this article can be found at doi:.     

Telomere content correlates with stage and prognosis in breast cancer

SummaryPurpose To evaluate the hypothesis that telomere DNA content (TC) in breast tumor tissue correlates with TNM staging and prognosis.Experimental design Slot blot assay was used to quantitate TC in 70 disease-free normal tissues from multiple organ sites, and two independent sets of breast tumors containing a total of 140 samples. Non-parametric Rank–Sums tests, logistic regression and Cox proportional hazards models were used to evaluate the relationships between TC and tumor size, nodal involvement, TNM stage, 5-year survival and disease-free interval.Results TC in 95% of normal tissues was 75–143% of that in the placental DNA standard, whereas only 50% of tumors had TC values in this range. TC was associated with tumor size (p=0.02), nodal involvement (p<0.0001), TNM stage (p=0.004), 5-year overall survival (p=0.0001) and 5-year disease-free survival (p=0.0004). A multivariable Cox model was developed using age at diagnosis, TNM stage and TC as independent predictors of breast cancer-free survival. Relative to the high TC group (>123% of standard), low TC (<101% of standard) conferred an adjusted relative hazard of 4.43 (95% CI 1.4–13.6, p=0.009). Receiver operating characteristic curves using thresholds defined by the TC distribution in normal tissues predicted 5-year breast cancer-free survival with 50% sensitivity and 95% specificity, and predicted death due to breast cancer with 75% sensitivity and 70% specificity.Conclusions TC in breast cancer tissue is an independent predictor of clinical outcome and survival interval, and may discriminate by stage.Colleen A. Fordyce and Christopher M. Heaphy contributed equally to this study     

Outcome analysis of patients with well-differentiated oral cavity squamous cell carcinoma

The prognosis of well-differentiated oral cavity squamous cell carcinoma (OSCC) is better than less-well-differentiated neoplasms. The aim of this retrospective study was to identify prognostic factors in patients with well-differentiated OSCC. The 5-year outcomes of 467 patients with well-differentiated OSCC who underwent radical surgery and neck dissection were analyzed. In the entire cohort, the presence of pathological node metastases (pN+ vs. pN0) was an independent predictor of 5-year outcomes. In pN0 patients, tumor depth (?8 mm) was the only independently prognostic factor for 5-year survival rates on multivariable analysis (disease-free survival [DFS], P = 0.001, hazard ratio [HR] = 2.634, 95% confidence interval [95% CI] = 1.496–4.636; disease-specific survival [DSS], P < 0.001, HR = 6.794, 95% CI = 2.364–19.525). In pN+ patients, level IV/V neck nodal metastases (DFS, P < 0.001, HR = 47.483, 95% CI = 8.942–252.122; DSS, P < 0.001, HR = 14.301, 95% CI = 5.337–38.323), and ?3 positive nodes (DFS, P = 0.037, HR = 2.107, 95% CI = 1.047–4.242; DSS, P = 0.044, HR = 2.093, 95% CI = 1.020–4.295) were independently associated with 5-year outcomes. Our results suggest that a tailored treatment approach in well-differentiated OSCC patients should take into account the presence of either pN0 or pN+ disease.     

Circulating transforming growth factor-β-1 and breast cancer prognosis: results from the Shanghai Breast Cancer Study

Introduction Studies investigating the prognostic effect of circulating TGF-β-1 in breast cancer have given inconsistent findings. The purpose of this study is to evaluate whether circulating transforming growth factor beta 1 (TGF-β-1) is associated with overall and disease-free survival in a cohort of recently diagnosed breast cancer patients. Methods We measured TGF-β-1 levels in plasma samples of breast cancer patients in the Shanghai Breast Cancer Study, a population-based case–control study. We evaluated the relationship between TGF-β-1 levels and overall and disease-free survival. The median follow up time was 7.2 years. Results We observed that, compared with the patients with the lowest quartile of plasma TGF-β-1, patients with the highest quartile of plasma TGF-β-1 had significantly worse overall survival with hazards ratio (HR) = 2.78, with 95% confidence interval (CI): 1.34–5.79 and disease-free survival with HR = 2.49, 95% CI: 1.15–5.41, while the patients with the second and third quartiles of plasma TGF-β-1 did not have significantly different overall and disease-free breast cancer survival. The shape of association between plasma TGF-β-1 levels and breast cancer survival appears to be non-linear. Stratified analysis by stage of disease did not appreciably change the association pattern. Conclusions We conclude that the relationship between circulating levels of TGF-β-1 and prognosis in breast cancer is complex and non-linear. High levels of TGF-β-1 are associated with worse survival independent of stage of disease.     

Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups

The tumor suppressor gene TP53 and its regulator MDM2 are both important players in the DNA-damage repair “TP53 response pathway”. Common germline polymorphisms in these genes may affect outcome in patients with tumors characterized by additional somatic changes in the same or a related pathway. To evaluate this hypothesis, we determined the effect of the common germline TP53 R72P and MDM2 SNP309 polymorphisms on breast cancer survival in a consecutive cohort of breast cancer patients (age at diagnosis <53 years, n = 295) with gene expression data available. Patients were classified in subgroups according to their tumor TP53 mutation status and three gene expression profiles; a TP53 mutation status expression signature, a PTEN/PI3K pathway signature and the 70-gene prognosis profile. Survival analyses were performed using Cox regression models adjusting for clinico-pathological characteristics and treatment. An increase in breast cancer-specific mortality was observed for carriers of the germline MDM2 SNP309 rare GG-genotype (range hazard ratios: 2–3) or TP53 R72P heterozygous GC-genotype (range hazard ratios: 1–2) compared to those having the common genotypes within subgroups of tumors displaying a “more aggressive phenotype” gene expression profile. There was no evidence of such an effect on survival within the TP53-mutated tumor group for TP53 R72P carriers but a suggestion of an effect for MDM2 SNP309 carriers (GG vs. TT-genotype HR 2.99, P = 0.06). These results indicate that common polymorphisms in specific pathways may add to the worse prognosis of patients with tumors in which these pathways are affected by somatic alterations.     

Elevated plasma endoglin (CD105) predicts decreased response and survival in a metastatic breast cancer trial of hormone therapy

Background Endoglin (CD105) is a co-receptor for TGF-β, is expressed by human vascular endothelial cells, and plays a major role in angiogenesis. Materials and methods Pretreatment EDTA plasma from 224 metastatic breast cancer patients enrolled in a phase III 2nd-line hormone therapy trial and 50 control subjects were assayed for endoglin using an ELISA. Results The female control group (n = 50) plasma endoglin upper limit of normal was defined as the mean + 2 SD (8.7 ng/ml). The breast cancer patient plasma endoglin was 6.40 ± 2.23 ng/ml (range 3.00–19.79 ng/ml). Elevated plasma endoglin levels were detected in 26 of 224 patients (11.6%). Patients with elevated plasma endoglin had a reduced clinical benefit rate (CR + PR + Stable) (15 vs. 42%) (P = 0.01) to hormone therapy. TTP was shorter for patients with elevated plasma endoglin, but did not reach statistical significance (P = 0.2). Patients with elevated plasma endoglin had decreased overall survival (median 645 vs. 947 days) (P = 0.005). Conclusion Elevated pretreatment plasma endoglin levels predicted for decreased clinical benefit and a shorter overall survival in metastatic breast cancer patients treated with 2nd-line hormone therapy.     

Expression of Bmi-1 protein in tumor tissues is associated with favorable prognosis in breast cancer patients

Purpose Abnormal expression of the cell cycle regulatory protein Bmi-1 has been studied in breast cancer, but the clinical relevance has not been fully elucidated. We studied the expression of Bmi-1 protein in breast cancer patients to define its clinical significance in breast cancer. Experimental Design Tissue microarrays were performed to evaluate the expression of Bmi-1 by immunohistochemistry in tumor tissues from 960 patients with stage I–III breast cancer. We assessed the relationship between the expression of Bmi-1 and pathologic prognostic indices as well as clinical long-term follow up outcome. Results Bmi-1 was expressed in 53.2% of breast cancer patients by immunohistochemistry, and the expression of Bmi-1 was significantly correlated with favorable prognostic indices at diagnosis. In univariate analysis, patients with Bmi-1 expression showed favorable relapse-free survival (88.6 ± 2.7% vs. 72.3 ± 4.3%, P = 0.041) and favorable overall survival (93.5 ± 2.2% vs. 82.6 ± 3.5%, P < 0.001) than patients without Bmi-1 expression. According to multivariate analyses, Bmi-1 expression was identified as independent prognostic factor for overall survival with a statistical significance (hazard ratio of Bmi-1 (−) patients compared to Bmi-1 (+) patients, 1.744; 95% CI, 1.013–3.003; P = 0.045). This correlation of Bmi-1 expression with favorable overall survival was maintained in patients underwent uniform chemotherapy, regardless of undergoing adjuvant chemotherapy. In a subset analysis according to ER status, Bmi-1 expression associated with favorable overall survival only in ER-positive patients. Conclusions Bmi-1 expression assessed with Immunohistochemistry may be associated with favorable overall survival in breast cancer patients, especially in patients with ER-positive breast cancer. Young Jin Choi and Yoon La Choi contributed equally to this work as first authors. Presented in part at the 29th Annual San Antonio Breast Cancer Symposium December 14–17, 2006.     

Season of diagnosis and prognosis in breast and prostate cancer

Background  Patients with breast or prostate cancer diagnosed during the summer season have been observed to have better survival. The extent to which this is due to biological and/or health care system related factors is unclear. Methods  Using the Swedish Cancer Register and clinical databases, we analyzed overall survival by month of diagnosis among the incident cases of breast (n = 89,630) cancer and prostate (n = 72,375) cancer diagnosed from 1960 to 2004. We retrieved data on tumor stage from 1976 for breast cancer and 1997 for prostate cancer. Cox proportional hazards models were used to calculate relative risk of survival by the season of diagnosis. Results  There was a higher hazard ratio of death in men and women diagnosed with cancer in the summer with a relative hazard of 1.20 (95% confidence interval 1.15–1.25) for July for prostate cancer and 1.14 (95% confidence interval 1.09–1.19) for August for breast cancer when compared to being diagnosed in January. This difference coincided with a lower mean number of cases diagnosed per day, and a higher proportion of advanced cases diagnosed in the summer. This pattern of presentation was stronger in the later years. Conclusion  The difference in stage distribution explains the seasonal variation in prognosis seen in this study. The variation may be because of structure of the health care system and a strong tradition of vacationing from mid June to mid August. Thus, the health care infrastructure and the late presentation of symptomatic disease may influence cancer survival studied by season of diagnosis substantially.     

Validating the prognostic value of proliferation measured by Phosphohistone H3 (PPH3) in invasive lymph node-negative breast cancer patients less than 71 years of age

We validated and compared the prognostic value of the proliferation marker phosphohistone H3 (PPH3) with classical variables in 241 T_1–2N₀M₀ breast cancer patients less than 71 years old with long-term follow-up (median 117 months) and without adjuvant treatment. PPH3 was measured by automated digital image analysis. Thirty-seven patients (15%) developed distant metastases and 29 (12%) died. The previously established PPH3 prognostic threshold H3 <13 (n = 157; 65% of all cases) vs. ≥13 (n = 84; 35% of all cases) was the strongest prognostic threshold exceeding all other characteristics, with 10-year recurrence-free survival of distant metastases of 96 and 64%, respectively (P =  < 0.0001, hazard ratio = 7.8, 95% confidence interval = 3.4–17.9). PPH3 is robust as it showed high inter-observer reproducibility and was prognostic over wide range of thresholds around 13 and is the strongest prognostic variable in invasive node-negative breast cancer patients less than 71 years old.     

The effect of delays in treatment for breast cancer metastasis on survival

It is generally accepted that delay in receiving treatment for breast cancer results in adverse outcomes. The purpose of this study was to evaluate the impact of delay in treatment after the diagnosis of metastatic disease on survival measured from metastatic breast cancer diagnosis and from first treatment while controlling for immortal time effect among patients with metastatic breast cancer. A total of 553 patients with breast cancer metastasis diagnosis from one large urban practice have been followed between January 1, 1999 and June 30, 2008. Prognostic factors and outcomes of these patients were analyzed using log-rank test and Cox regression model. Backward stepwise selection of covariates was conducted to assess the association of treatment delay with survival. The median survival was 40 months (range 1–114 months), with 265 (47.9%) women alive and 288 (52.1%) having died at the end of the follow-up period. Treatment delays of more than 12 weeks had impact on poor survival from first treatment than the delays of 4–12 weeks with borderline significance level (HR 1.76, 95% CI 0.99–3.13, P = 0.056) in multivariate analysis, adjusted by BMI, history of hypertension, ER/PR status, HER2 status, number of metastatic sites, and liver metastasis. Moreover, the interval of 12–24 weeks, compared to the interval of 4–12 weeks was associated with greater risk of death from first treatment (HR 2.39, 95% CI 1.19–4.77, P = 0.014). The treatment delay interval of >12 weeks was not related with survival since metastatic breast cancer diagnosis, compared to the 4–12 weeks of treatment delays. This study demonstrated that delays of over 12 weeks in receiving treatment for metastatic breast cancer were related to adverse survival outcomes measured from initiation of first treatment. The findings of this study support targeted efforts to ensure prompt treatment initiation in patients diagnosed with metastatic breast cancer.