Purpose To assess the benefit from adjuvant systemic tamoxifen therapy in breast cancer risk groups identified by the previously established prognostic 76-gene signature. Methods In 300 lymph ...node-negative (LNN), estrogen receptor-positive (ER+) breast cancer patients (136 treated with adjuvant tamoxifen, 164 having received no systemic adjuvant therapy), distant metastasis-free survival (DMFS) as a function of the 76-gene signature was determined in a multicenter fashion. Results In 136 tamoxifen-treated patients, the 76-gene signature identified a group of patients with a poor prognosis hazard ratio (HR), 4.62; P = 0.0248. These patients showed a 12.3% absolute benefit of tamoxifen in 10-year DMFS (HR, 0.52; P = 0.0318) compared with untreated high-risk patients. This represented a 71% increase in relative benefit compared with the 7.2% absolute benefit observed for all 300 patients without using the gene signature. In the low-risk group there was no significant 10-year DMFS benefit of tamoxifen. Conclusions The 76-gene signature defines high-risk patients who benefit from adjuvant tamoxifen therapy. Although we did not study the value of chemotherapy in this study, low-risk patients identified by the 76-gene signature have a prognosis good enough that chemotherapy would be difficult to justify. The prognosis of these patients is sufficiently good, in fact, that a disease-free benefit for tamoxifen therapy is difficult to prove, though benefits in terms of loco-regional relapse and a reduction in risk for contralateral breast cancer might justify hormonal therapy in these patients.
TMPRSS2:ERG gene aberration may be a novel marker that improves risk stratification of prostate cancer before definitive cancer therapy, but studies have been inconclusive.
The study cohort consisted ...of 202 operable prostate cancer Slovenian patients who underwent laparoscopic radical prostatectomy. We retrospectively constructed tissue microarrays of their prostatic specimens for fluorescence in situ hybridization, with appropriate signals obtained in 148 patients for subsequent statistical analyses.
The following genetic aberrations were found: TMPRSS2:ERG fusion, TMPRSS2 split (a non-ERG translocation) and ERG split (an ERG translocation without involvement of TMPRSS2). TMPRSS2:ERG gene fusion happened in 63 patients (42 %), TMPRSS2 split in 12 patients and ERG split in 8 patients. Association was tested between TMPRSS2:ERG gene fusion and several clinicopathological variables, i.e., pT stage, extended lymph node dissection status, and Gleason score, correcting for multiple comparisons. Only the association with pT stage was significant at p = 0.05: Of 62 patients with pT3 stage, 34 (55 %) had TMPRSS2:ERG gene fusion. In pT3 stage patients, stronger (but not significant) association between eLND status and TMPRSS2:ERG gene fusion was detected. We detected TMPRSS2:ERG gene fusion in 64 % of the pT3 stage patients where we did not perform an extended lymph node dissection.
Our results indicate that it is possible to predict pT3 stage at final histology from TMPRSS2:ERG gene fusion at initial core needle biopsy. FISH determination of TMPRSS2:ERG gene fusion may be particularly useful for patients scheduled to undergo a radical prostatectomy in order to improve oncological and functional results.
CD10 antigen is a 100-kDa-cell surface zinc metalloendopeptidase expressed in a variety of normal and neoplastic lymphoid and nonlymphoid tissues including melanomas. It was recently shown that ...metastatic melanomas express more CD10 than primary tumors. We evaluated CD10 expression in tumor and stromal cells in 70 biopsies with primary and 28 with metastatic malignant melanomas. Ki-67, Bcl-2, and Bax were also examined to investigate whether CD10 expression is associated with tumor proliferation index or factors of apoptosis. Formalin-fixed/paraffin-embedded tissues were studied by immunohistochemistry. More advanced primary tumors had higher CD10 expression in the tumor cells (r=0.27, P=0.03 for Clark levels and r=0.29, P=0.02 for Breslow) and higher Ki-67 proliferation fraction (r=0.32, P=0.007 for Clark levels and r=0.32, P=0.001 for Breslow). Similarly, CD10 expression in the intratumoral stromal cells was also higher in primary tumors with higher Clark level (P=0.04, linear-by-linear association) and tumor thickness according to Breslow (r=0.33, P=0.01). The presence of CD10+ peritumoral stromal cell cuffs was also positively associated with tumor thickness according to Breslow (r=0.27, P=0.05). Also, expression of CD10 and Ki-67 were significantly higher in metastatic than in primary tumors (P=0.01 and 0.02 respectively), but Bcl-2 expression was higher in primary melanomas (P=0.02). We conclude that CD10 expression in malignant melanoma is associated with tumor progression.
The number of mitoses and, thus, the proliferative capacity of a tumor is one of the most crucial variables for tumor grading. The Ki-67 nuclear antigen may be considered as an alternative to mitotic ...counts in grading schemes and as a single parameter that can be used in fine-needle aspirates and small biopsies.
Immunohistochemistry using the anti-Ki-67 antibody MIB-1 was performed on 434 breast carcinoma specimens from the International Breast Cancer Study Group (formerly Ludwig) Trial V. Three groups based on Ki-67 percent were used to replace the mitotic counts component in the Nottingham grade (NHG) to produce the Nottingham/Ki-67 grade (NKG) and to assess Ki-67 as a single parameter.
In both the lymph node positive subgroup and the lymph node negative subgroup, the NKG and Ki-67 group was correlated significantly with Bloom-Richardson grade (BRG), NHG, and Nottingham type. Tumor size in the lymph node negative cohort and estrogen receptor status, progesterone receptor status, and c-erbB-2 expression in the lymph node positive cohort also were correlated significantly with NKG. Ki-67 percentage was correlated significantly with c-erbB-2 expression in the lymph node positive cohort only. NKG was similar to BRG and NHG when it was evaluated for prognostic significance. Patients with higher categoric Ki-67 percentages had worse overall and disease free survival in all groups except for the untreated, lymph node negative group.
Ki-67 detection represents a valuable tool and is a good objective substitute for mitotic counts when used in a grading system. When it is used alone, Ki-67 detection provides valuable information, although it is necessary to combine this with other parameters in the study of core biopsies and fine-needle aspirates.
Cathepsin X, a recently discovered lysosomal cysteine protease, shares common structural features and activity properties with cysteine protease cathepsin B. Based on its widespread mRNA distribution ...in primary tumors and tumor cell lines, a redundant function in tumor progression has been proposed. In this study, we have shown that these two related proteases exhibit different profiles with respect to their protein distribution in cells and tissues and to their possible roles in malignancy. Protein level of cathepsin X did not differ significantly between matched pairs of lung tumor and adjacent lung tissue obtained from patients with lung cancer whereas that of cathepsin B was 9.6-fold higher in tumor compared to adjacent lung tissue. Immunohistochemical analysis of lung tumor cathepsin X revealed very faint staining in tumor cells but positive staining in infiltrated histiocytes, alveolar macrophages, bronchial epithelial cells, and alveolar type II cells. Cathepsin X stained positive also in CD68
+ cells in germinal centers of secondary follicles in lymph nodes, corresponding to tingible body macrophages. Two cell lines with proven invasive behavior, MCF-10A neoT and MDA-MB 231, showed positive staining for cathepsin B, but negative for cathepsin X. We showed that the invasive potential of MCF-10A neoT cells can be impaired by specific inhibitor of cathepsin B but not by that of cathepsin X. Cathepsin X was found in large amounts in the pro-monocytic U-937 cell line, in monocytes and in dendritic cells, generated from monocytes in vitro. Our results show that cathepsin X is not involved in degradation of extracellular matrix, a proteolytic event leading to tumor cell invasion and metastasis. Its expression, restricted to immune cells suggests a role in phagocytosis and the regulation of immune response.
Introduction
We recently found that DNA methylation of
S100A2
,
spleen tyrosine kinase
(
SYK
), and
Stathmin-1
(
STMN1
) correlates with response to tamoxifen therapy in metastatic breast cancer. In ...this retrospective study, we investigated immunohistochemically whether these three markers are predictors of relapse in early breast cancer (EBC) patients treated with adjuvant tamoxifen alone.
Methods
Immunohistochemical staining was performed for S100A2, SYK and STMN1 on a tissue microarray containing ER-positive invasive breast carcinomas from a study cohort of 215 operable breast cancer patients, who underwent radical local therapy and who were treated with adjuvant tamoxifen monotherapy. Cox regression was used to correlate staining intensity of the three markers with main endpoints in our study; disease-free survival (DFS), and disease-specific survival (DSS).
Results
In univariate analysis, only
STMN1
staining intensity strongly correlated with DFS (
P
= 0.014) and DSS (
P
= 0.002). In the groups of low and high
STMN1
intensity, DFS was 84% and 63%, and DSS was 89% and 70%.
STMN1
retained its prognostic value for DFS (
P
= 0.002) and DSS (<0.001) in the multivariate model together with lymph node status. We found also a trend to better DFS in patients with low STMN1 intensity in both lymph node-positive (
P
= 0.001) and -negative patients (
P
= 0.065). As the tumour cells did not express S100A2 (except in one case) the potential prognostic value of this marker was not evaluated.
Conclusions
Staining intensity of
STMN1
, but not SYK, predicted outcome in our collective of ER- positive tamoxifen treated EBC patients.
The aim of the study was to determine optimal hydrolysis time for the Feulgen DNA staining of archival formalin fixed paraffin-embedded surgical samples, prepared as single cell suspensions for image ...cytometric measurements. The nuclear texture features along with the IOD (integrated optical density) of the tumor nuclei were analysed by an automated high resolution image cytometer as a function of duration of hydrolysis treatment (in 5 N HCl at room temperature). Tissue blocks of breast carcinoma, ovarian serous carcinoma, ovarian serous tumor of borderline malignancy and leiomyosarcoma were included in the study. IOD hydrolysis profiles showed plateau between 30 and 60 min in the breast carcinoma and leiomyosarcoma, and between 40 and 60 min in the ovarian serous carcinoma and ovarian serous tumor of borderline malignancy. Most of the nuclear texture features remained stable after 20 min of hydrolysis treatment. Our results indicate that the optimal hydrolysis time for IOD and for nuclear texture feature measurements, was between 40 and 60 min in the cell preparations from tissue blocks of three epithelial and one soft tissue tumor.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The expressions of different markers have been immunohistochemically studied in various types of the Ewing's sarcoma family of tumors, especially for diagnostic purposes. However, little is known ...about their prognostic value in combination with the clinicopathological data of such patients.
This retrospective study investigated the immunohistochemical expressions of NSE, TdT, EMA, S-100, CK MNF116, p53, bcl-2, CD99, and CD117 on formalin-fixed paraffin-embedded material of 72 patients (age range: 2-59 years) with various types of Ewing's sarcoma family of tumors using the tissue microarray method. The immunohistochemical results were compared with clinicopathological features using survival analysis (Cox regression).
CD99 expression was detected in 90%, CD117 in 75.8%, bcl-2 in 70.1%, NSE in 66.6%, p53 in 66.6%, EMA in 26%, S-100 in 25.4%, TdT in 22.1%, and CK MNF116 in 10.2% of the cases. No immunoreactivity was observed in the normal tissue around the tumors.
The expressions of EMA (p=0.107), NSE (p=0.126), CD99 (p=0.14), TdT (p=0.198), bcl-2 (p=0.382), p53 (p=0.54), CD117 (p=0.612), S-100 (p=0.867), and CK MNF116 (p=0.934) had no statistically significant impact on survival. Patient age at the time of diagnosis (p=0.008) and the presence of tumor necrosis (p=0.033) were the only significant prognostic factors in this study. Tumor location was an insignificant prognostic factor (p=0.38).
Thirty-six cases of synovial sarcoma (13 biphasic and 23 monophasic) were subjected to a clinicopathologic study that included electron microscopy and immunohistochemistry. The group consisted of 21 ...males and 15 females ranging in age from 2 to 63 years. The majority of tumors (27 cases) were found in the hip and lower extremity. Immunohistochemical study revealed that keratin, which was detected in 92% of the biphasic and 57% of the monophasic tumors, was a more sensitive marker of epithelial differentiation than EMA or CEA. The overall 5-year survival of the patients was 64%. Male sex, older age, presence of tumor necrosis, monophasic pattern, and absence of keratin positivity had an unfavourable effect on survival but lacked statistical significance. Survival was significantly lower in patients with tumors exhibiting more than 15 mitoses per 10 HPF (P less than .02) and in those with tumors showing necrosis and a mitotic rate greater than 5 mitoses per 10 HPF (P less than .005).
Byline: Rastko Golouh (1), Tanja Cufer (1), Aleksander Sadikov (2), Petra Nussdorfer (1), Pernille Autzen Usher (3), Nils Brunner (3), Manfred Schmitt (4), Ralf Lesche (5), Sabine Maier (5), Mieke ...Timmermans (6), John A. Foekens (6), John W. M. Martens (6) Keywords: ER; Immunohistochemistry; Primary breast carcinoma; S100A2; Stathmin-1; SYK; Tamoxifen Introduction We recently found that DNA methylation of S100A2, spleen tyrosine kinase (SYK), and Stathmin-1 (STMN1) correlates with response to tamoxifen therapy in metastatic breast cancer. In this retrospective study, we investigated immunohistochemically whether these three markers are predictors of relapse in early breast cancer (EBC) patients treated with adjuvant tamoxifen alone. Methods Immunohistochemical staining was performed for S100A2, SYK and STMN1 on a tissue microarray containing ER-positive invasive breast carcinomas from a study cohort of 215 operable breast cancer patients, who underwent radical local therapy and who were treated with adjuvant tamoxifen monotherapy. Cox regression was used to correlate staining intensity of the three markers with main endpoints in our study disease-free survival (DFS), and disease-specific survival (DSS). Results In univariate analysis, only STMN1 staining intensity strongly correlated with DFS (P = 0.014) and DSS (P = 0.002). In the groups of low and high STMN1 intensity, DFS was 84% and 63%, and DSS was 89% and 70%. STMN1 retained its prognostic value for DFS (P = 0.002) and DSS (<0.001) in the multivariate model together with lymph node status. We found also a trend to better DFS in patients with low STMN1 intensity in both lymph node-positive (P = 0.001) and -negative patients (P = 0.065). As the tumour cells did not express S100A2 (except in one case) the potential prognostic value of this marker was not evaluated. Conclusions Staining intensity of STMN1, but not SYK, predicted outcome in our collective of ER- positive tamoxifen treated EBC patients. Author Affiliation: (1) Institute of Oncology, Zaloska 2, Ljubljana, 1000, Slovenia (2) Artificial Intelligence Laboratory, University of Ljubljana, Ljubljana, Slovenia (3) Royal Veterinary and Agriculture University, Frederiksberg, Denmark (4) Department of Obstetrics and Gynaecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany (5) Epigenomics AG, Berlin, Germany (6) Department of Medical Oncology, Erasmus MC, Rotterdam, The Netherlands Article History: Registration Date: 31/07/2007 Received Date: 17/05/2007 Accepted Date: 31/07/2007 Online Date: 13/09/2007
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