Purpose
Intratumoral estradiol levels in postmenopausal women with breast cancer are thought to be mainly regulated by the aromatase-mediated conversion from androgens and estrogen sulfotransferase ...(EST)-mediated reduction of bioavailability. While in invasive breast cancer (IBC) the role of both enzymes has been extensively studied and has led to the use of aromatase inhibitors as a key therapeutic strategy, comparably little is still known about their role in the local regulation of estradiol in ductal carcinoma in situ (DCIS).
Methods
We have performed immunohistochemistry to investigate the expression of aromatase and sulfotransferase in custom-made breast cancer tissue arrays containing 96 samples of pure DCIS and in 104 tumor biopsies which contain both, DCIS and invasive components.
Results
We found that aromatase was equally detectable in epithelial components of both, DCIS and IBC (
P
= 0.884, Chi square test). However, stromal aromatase expression was significantly higher in IBC compared to adjacent DCIS components (
P
= 0.034, Chi square test). Whereas no significant difference was observed for epithelial aromatase expression in high versus non-high grade DCIS (
P
= 0.735 Chi square test), epithelial EST levels were found to be significantly down-regulated in high-grade DCIS compared to non-high grade cases (
P
= 0.042).
Conclusion
We have demonstrated the presence of both aromatase and EST in malignant epithelium and adjacent stromal fibroblasts in DCIS. Lower stromal aromatase expression in preinvasive breast cancer and lower EST levels in high-grade DCIS suggest that the net effect of intratumoral estradiol (E2)-modulating enzymes results in lower local E2 levels in earlier stages of breast tumorigenesis.
Proteomics in mammary cancer research Fink-Retter, A; Czerwenka, K; Gschwantler-Kaulich, D ...
European journal of gynaecological oncology,
2009, Letnik:
30, Številka:
6
Journal Article
Recenzirano
During the past few years, the intensified detection of small (mammary) carcinomas causes an increase in the number of mammary cancers. Cancer of the mammary tissues has an almost individually ...unpredictable behavior and aggressiveness. Therefore, a better insight in the molecular biological defects, which are responsible for initiation and progressive aggressiveness of mammary cancer, is necessary. Proteomics are an alternative to identify proteins which initiate carcinogenesis and can be useful to predict cancer prognosis. Today, the most commonly used technique for large-scale protein identification in clinical samples is two-dimensional electrophoresis (2-DE) in combination with image analysis and MS. Using these techniques, qualitative and quantitative information can be achieved regarding protein forms and post-translational modifications. In the following article we review proteomic techniques that are now commonly used in order to elucidate the role of proteins in breast cancer.
Abstract
Background: Sequential regimen of anthracyclines and taxanes are commonly used in patients with early stage breast cancer (BC) and curative treatment intent. Due to the associated ...myelotoxicity, internationally accepted guidelines recommend granulocyte-colony stimulating factors (G-CSF) as primary or secondary prophylaxis, dependent on chemotherapy (CT) and patient-associated risk of febrile neutropenia. As part of a quality control initiative at our center, we have analyzed rates of grade 1 or 2 (<2.0 to >1.0 × 109/L) and 3 or 4 (<1.0 to <0.5 × 109/L) neutropenia, febrile neutropenia (<0.5 × 109/L and single oral temperature ≥38.3°C/100.4°F), CT dose reductions, anti-infective use, and hospitalizations in cycles with pegfilgrastim prophylaxis.
Methods: Patients (pts) with BC stages I to III received four three-weekly (q21) cycles of adjuvant or neoadjuvant EC (Epirubicin 90 mg/m2 + Cyclophosphamide 600 mg/m2 q21) followed by four cycles of D (Docetaxel 100 mg/m2 q21) plus primary or secondary pegfilgrastim prophylaxis. Chart records were collected and analyzed retrospectively for patients treated between 2009 and 2012 at our institution for incidence of neutropenia and for the presence of neutropenia-associated risk factors. Only cycles with pegfilgrastim prophylaxis were considered for this analysis.
Results: 100 consecutive patients were identified who had overall received 200 EC cycles followed by 251 D cycles under G-CSF prophylaxis with pegfilgrastim. Pts age mean: 51,57 (SD:11,23), BMI mean: 25,8 (SD:5,03) were well controlled in both sequences. Overall, neutropenia was significantly higher for EC (p = 0.001), however higher grade neutropenia (Grade3 and 4) were comparable (p = 0.200). No statistically significant correlations were found between neutropenia and age or body mass index.
Conclusions: Sequential use of EC followed by D in combination with prophylactic pegfilgrastim results in lower den expected FN rate 1. In contrast to most published trials EC leads to significantly more neutropenias than D. However, the use of pegfilgrastim reduces both EC and D associated neutropenias grade 3 and 4 to a similar extent.
References:
1. Aapro, M.S., et al., 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 47(1): p. 8–32.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-10.
Neoadjuvant chemotherapy is the treatment of choice for locally-advanced breast cancer and leads to down staging and improved breast-conserving therapy (BCT) rates. While its efficacy is well ...established, considerably less is known about the most effective regimen.
We have performed a retrospective analysis of 132 breast cancer patients who had undergone neoadjuvant chemotherapy at our institution. Patients had either received a) anthracyclines ("A", n=35), b) anthracyclines and taxanes ("AT", n=55), or c) neither of the two compounds ("NoA/T", n=42). Clinical response, pathological response and survival were evaluated in each arm.
While all three regimens resulted in significant tumor regression, AT was most effective with a mean tumor shrinkage of 39% (ultrasound) and 41% (mammography) (Kruskal-Wallis, p=0.004, and p=0.027). Breast conservation was achieved in 75% by AT, in 49% by A, and in 19% by NoA/T (Kruskal-Wallis, p<0.001). The treatment groups did not differ in respect to pathological complete response (pCR) (χ
2
-test, p=0.068), although higher cumulative anthracycline doses were predictive of pCR in multivariate analyses (p=0.022). While the mammographic but not the ultrasound-determined tumor diameter determined whether a woman underwent BCT, only an ultrasound-determined size reduction was predictive for disease-free survival (DFS) and overall survival (OS) (log rank, p=0.0093, and p=0.044, respectively). Other parameters that affected BCT rates were age (p=0.003), year of diagnosis (p=<0.001), presence of multifocal disease (p= 0.032) and the cumulative anthracycline dose (p= <0.001).
While the combination of anthracyclines and taxanes is most effective in achieving clinical remission and BCT, the cumulative anthracycline dose appears most important for achieving pCR.
Proteomics in mammary cancer research Fink-Retter, A; Gschwantler-Kaulich, D; Hudelist, G ...
European journal of cancer supplements,
2008, Letnik:
6, Številka:
7
Journal Article
Abstract only
223
Background: Recently, we identified a six gene panel (CCNE2, DKFZp762E1312, EMP2, MAL2, PPIC, and SLC6A8) for the RT-qPCR based detection of circulating tumor cells (CTC) in breast ...cancer patients. The aim of the present study was to evaluate the gene panel in further blood samples.
Methods: Blood samples were taken from breast cancer patients with metastatic disease (MBC, N=10) or with no evidence of disease (NED, N=30). Putative CTC were enriched by Oncoquick density gradient centrifugation. Total RNA was isolated with RNeasy Micro Kit (QIAgen). Template cDNA was generated with M-MLV Reverse Transcriptase, RNase H Minus (Promega) and random nonamers as primers. RT-qPCR was performed in duplicate reactions using TaqMan Assays (Applied Biosystems) with default thermal cycling parameters. Raw data were analyzed with the AB7900 Sequence Detection Software version 2.2.2 using automatic baseline correction and manual cycle threshold setting. Gene expression was normalized to GAPDH expression. A threshold value T
X
for each gene X was set at two standard deviations above the mean dCt
X
value in the healthy control group. A patient was defined as CTC-positive, if at least one gene marker was over-expressed compared to the defined threshold.
Results: The gene panel consisting of CCNE2, DKFZp762E1312, EMP2, MAL2, PPIC, and SLC6A8 identified 4/11 MBC but only 5/27 NED patients as CTC positive (p=0.163). By adding known CTC markers (SCGB2A2, TFF1, FXYD3, AGR2, S100A18, and EPCAM) to the panel, 7/11 MBC but only 6/27 NED patients were CTC positive (p=0.018). The presence of CTC in NED patients correlated with pN staging (p=0.026). Only one out of the six CTC positive NED patients relapsed within the observation period (median 35 months, range 25-39 months from blood sampling). We observed no correlation of CTC positivity and recurrence in NED patients.
Conclusions: The sensitivity of the RT-qPCR based CTC detection in breast cancer patients may be enhanced by adding known CTC markers (SCGB2A2, TFF1, FXYD3, AGR2, S100A18, and EPCAM) to the six gene panel (CCNE2, DKFZp762E1312, EMP2, MAL2, PPIC, and SLC6A8). Longer follow-up times are needed to evaluate the predictive value of the gene markers on survival.
Abstract
Purpose: Although the use of (neo-)adjuvant chemotherapy in breast cancer patients has resulted in improved disease-free and overall survival, not all patients benefit equally. Nevertheless, ...chemotherapy is still applied empirically, since clinical tests for response prediction are not routinely available. We have evaluated the utility of an in vitro chemosensitivity assay (ATP-TCA) in predicting response to neoadjuvant chemotherapy. Methods: Pre-therapeutic tumor core biopsies were obtained from 65 breast cancer patients and subjected to a standardized ATP-based Epi/Doc tumor chemosensitivity assay (ATP-TCA). Of these, 30 breast cancer patients were also assigned to three cycles of neoadjuvant epirubicin 75 mg/m2 and docetaxel 75 mg/m2 (Epi/Doc) in a prospectively randomized clinical trial. Tumor response was evaluated by pre-and post-interventional ultrasound measurements of tumor diameter, and by differential Ki67 expression. Results: 3 Cycles of neoadjuvant Epi/Doc resulted in a clinical response according to RECIST criteria in 11/23 evaluable patients (48%), and in a profound reduction in tumor proliferation in 10/23 patients (43%). Similarly, in vitro treatment of tumor cell suspensions with Epi/Doc performed in 65 pre-treatment core-biopsies yielded chemosensitivity in comparable fraction of patients (30/65, 46%). When the differentail changes in tumor cell proliferation in response to 3 cycles Epi/Doc in 23 patients were compared with ATP-TCA results obtained from the pre-interventional tumor core-biopsies of the same individual patients, we found that the efficacy of Epi/Doc in vitro was significantly correlated with differential changes in tumor cell proliferation in response to 3 cycles Epi/Doc in vivo (p= 0.0011; r=0.73670, Spearman's rho), but did not predict for changes in tumor size when measured by ultrasound. Conclusion: This is the first prospective clinical trial to demonstrate the utility of a standardized in vitro chemosensitivity assay in predicting the individual response to chemotherapy in breast cancer patients.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-20.
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