Longer Metastasis-free Survival Research Articles

Abstract P5-04-02: Tumor Associated High Endothelial Venules (HEV) Predict Lymphocyte Infiltration and Breast Cancer Patients Clinical Outcome

Abstract Even if lymphocyte presence within tumor tissues and its impact on cancer patient prognosis have been well documented past few years, the type of tumor vessels governing infiltration of effector cells into tumors remain to be determined. High endothelial venules (HEV) are specialized vessels for lymphocyte recruitment physiologically present in secondary lymphoidorgans also found in chronic inflammation that may impact lymphocyte recruitment and cancer patient's clinical outcome. We recently identified HEV like vessels in the peritumoral stroma of human solid tumors including melanomas, breast, colon, ovarian, and lung carcinomas. In order to better analyse the functional consequence of HEV presence within human solid tumors, we quantified HEV and tumor infiltrating lymphocytes by immunohistochemistry on serial tumor sections of 146 breast cancer patients. We demonstrate that HEV like vessels density within tumor stroma is an important predictor of CD3+, CD8+ T and B lymphocyte tumor infiltration suggesting an active role played by these vessels in peripheral blood lymphocyte migration into tumors. The breast tumor infiltrating lymphocyte phenotype associated with HEV presence was further characterized by large scale flow cytometry analysis in 30 freshly operated breast tumors. Breast tumors with a high density of HEV (HEVhi) have increased numbers of effector memory T cells (CD45RA-CD62L-) that display an activated mature phenotype (CD69+, Granzyme A+, Granzyme B+, perforin+). T cells with a naïve (CD45RA+CD62L+) and a central memory (CD45RA-CD62L+) phenotype are also specifically increased within HEVhi tumors as compared to HEVlo tumors. Finally, we analyzed the prognostic value of HEV in a retrospective cohort of 146 invasive breast cancer patients and demonstrate that HEV density within tumor stroma is an independent predictor of good clinical outcome. Indeed, HEVhi patients have a significantly longer metastasis free survival (MFS) (p< 0,004), disease free survival (DFS) (P<0,012) and overall survival (OS) (P<0,023) than HEVlo patients. HEV like vessels, through the recruitment of high number of T lymphocytes and B lymphocytes from the periphery could limit the dissemination of primary breast tumors and prevent metastatic recurrence. Therefore, signals and cells that stimulate HEV differentiation within tumor stroma represent important solid tumors therapeutic target to modulate immune infiltration and patient's clinical outcome. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-04-02.

Characterization of triple-negative breast cancer utilizing microarray-based gene-expression profiling

e22014 Background: Triple-negative breast cancer (TNBC) is characterized by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and HER-2. This makes it one of the most challenging subgroups for clinical decision-making. Methods: We analyzed gene-expression profiles of 200 node-negative breast cancer patients utilizing the Affymetrix HG-U133A array. After performing an unsupervised hierarchical cluster analysis using 2579 genes selected for variable expression within our dataset, we constructed metagenes for five dominant cluster (basal-like, luminal, proliferation, T-cell, B-cell). The interrelation of the median expression of these metagenes between TNBC and those cancer specimens expressing at least one of those receptors was analysed with the Wilcoxon-Mann-Whitney test. An intrinsic gene list was used to define basal-like breast cancer (BLBC). Sensitivity and specificity of TNBC to correctly classify BLBC was calculated. Metastasis-free survival (MFS) at 5 years was calculated according to Kaplan Meier. Results: Of the 200 node-negative breast cancer patients, 33 (16.5%) were triple-negative and 20 (10%) basal-like. Sensitivity of TNBC to correctly predict BLBC was 100%, specificity was 93.1%. TNBC showed an overexpression of the basal-like metagene (P=7.905e-13), an inverse relation with the luminal metagene (p=1.151e-12) and had higher proliferation and higher expression of T-cell (P=6.316e-5) and B-cell (P=3.551e-6) metagene. A higher expression of the B-cell metagene was associated with longer MFS in both TNBC (P=0.048) and BLBC (P=0.041). Conclusions: Characterization of TNBC reveals marked differences in gene-expression. Overexpression of mRNA transcripts related to the humoral immune system might serve as a protective factor in this particular subgroup. No significant financial relationships to disclose.

Luteinizing hormone receptor status and clinical, pathologic, and prognostic features in patients with breast carcinomas.

It has been established that pregnancy protects against breast carcinoma, and animal models have shown that human chorionic gonadotropin (hCG) mimics this effect by inhibiting the initiation and progression of experimental breast carcinoma. Luteinizing hormone (LH)/hCG receptors (LHR) have been characterized in several human breast carcinoma cell lines and in a limited number of breast carcinoma biopsy specimens. These observations led to the suggestion that hCG may be used as a means of prevention and possibly treatment in patients with breast carcinoma. The authors used immunocytochemistry to analyze tumors from 160 patients who were followed for a median of 2539 days. Using a cut-off value of 18% immunolabeled cells in each tumor, 72% of tumors were identified as LHR positive. The LHR-positive tumors were found more frequently in premenopausal women, who had tumors with greater cell differentiation and positive estrogen receptor alpha status. Infiltrating lobular carcinomas were positive for LHR more frequently compared with infiltrating ductal carcinomas. There was no correlation between LHR status and lymph node invasion, tumor size, or progesterone receptor status. Patients with LHR-positive tumors had a longer metastasis free survival, although the statistical significance was slight (P = 0.07), most likely due to the limited number of events in the patients studied. Conversely, there was no difference between patients with LHR-positive or LHR-negative tumors in the local recurrence free interval. LHR status seems to be related in part to the degree of differentiation in breast tumors, confirming experimental evidence of the effect of hCG on mammary tissue. The presence of LHR is a tumor characteristic that largely is independent of other clinical and pathologic tumor features. It may be of interest in the future to correlate the presence of LHR with a possible therapeutic response in individual patients to hCG.

Characteristics of Breast Cancer in Women Undergoing Hormone Replacement Therapy

Purpose: Hormone replacement therapy (HRT) has been associated with an increased risk for breast cancer. Cancers in women who undergo HRT are often less advanced, and a lower mortality has been reported in those who use HRT vice nonusers. We sought to explain this by a comparison of indicators of tumor aggressiveness in patients who received HRT with those in patients who did not. Methods: A population-based cohort of 370 postmenopausal women with breast cancer were interviewed for the use, type, and duration of HRT. Clinical variables and indicators of tumor aggressiveness (nuclear grade, hormone receptors, c-erb B2 overexpression, tumor size, lymph node) were analyzed. Results: Breast tumors from 268 HRT patients were smaller (P=0.001), had less involved axillary lymph nodes (P=0.0), and had a lower overexpression of c-erb B2 (P=0.047) than the tumors from 102 non-recipients. These differences persisted after adjustments for age at diagnosis and screening with mammography by multiple logistic regression. No significant differences were observed in estrogen (ER) or progesterone receptor content (PR) or, nuclear grade. Neither the type of HRT (estrogen versus combination of estrogen and progesterone), nor the duration of HRT was not associated with the tumor size or with the involvement of lymph nodes. The use of HRT was significantly associated with a longer metastasis free survival in women with breast cancer (P=0.028), but was not associated with longer overall survival. The use of HRT was not significantly associated with longer overall survival or with a longer metastasis free survival after adjustment for T-stage, N-stage, age at diagnosis or screening mammography. Conclusion: The results indicate that breast cancer in women who receive HRT is biologically less aggressive than those without previous HRT. This may at least partly explain why breast cancer in HRT users has a more favorable clinical course. (Journal of Korean Breast Cancer Society 2002;5:7-13)

Prognostic significance of Nm23/NDPK expression in breast carcinoma, assessed on 10-year follow-up by automated and quantitative immunocytochemical assays.

The Nm23 gene has been described as an antimetastatic gene; in some studies, disease progression in patients with solid tumours is related to Nm23 protein expression, which can be detected by immunohistochemical procedures. Detection of Nm23-H1 protein in breast cancer may be relevant for the monitoring of patient therapy, provided that the technical procedures are reliable and cost-effective. The aim of the present study was to determine the prognostic significance of Nm23, assessed by quantitative immunocytochemical assays (Nm23 ICAs), under optimal technical conditions. Nm23-H1 ICAs were performed on frozen sections, using an automated immunoperoxidase technique (Ventana) and computer-assisted analysis of digitized colour microscopic images (SAMBA), in a series of 168 breast carcinomas. The results of automated quantitative ICAs were correlated with patients' follow-up (129 months). Nm23-H1 immunocytochemical expression in histological sections of tumours in which more than 3 per cent of the surface area was positively stained was significantly (0.012) correlated with longer metastasis-free survival in both node-positive and node-negative groups of patients (P = 0.032 and P = 0.036, respectively) (Kaplan-Meier log-rank test, NCSS 6.0.1 software). Nm23 expression (cut-point 3 per cent) did not, however, correlate with overall survival, or with the recurrence-free survival. In multivariate analysis (proportional hazards regression, Cox model), the prognostic significance of Nm23 in terms of metastasis-free survival was independent of tumour size and grade, and of histological grade, in the entire cohort of patients. It is concluded that Nm23 immunodetection is only of limited practical clinical relevance in breast carcinoma, even when assessed under optimal technical conditions.