The HOXB13:IL17BR index has been identified to predict clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer. Further studies have shown that HOXB13 in particular can ...indicate benefit of prolonged tamoxifen treatment. Patients with high-expressing tumors did not benefit from prolonged treatment, suggesting that HOXB13 might be involved in tamoxifen resistance. No studies have been made regarding the HOXB13 protein levels in breast cancer. The aim of our study was to investigate whether tamoxifen benefit can be correlated to different levels of HOXB13 protein expression.
We used immunohistochemistry to analyze protein levels of HOXB13 in tumor samples from 912 postmenopausal node-negative breast cancer patients randomized to adjuvant tamoxifen therapy or no endocrine treatment.
Tamoxifen-treated patients with estrogen receptor-positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (DRFS) (hazard ratio = 0.38, 95% confidence interval = 0.23 to 0.60, P = 0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the DRFS compared with the untreated patients (hazard ratio = 0.88, 95% confidence interval = 0.47 to 1.65, P = 0.69). Interaction between HOXB13 expression and benefit from tamoxifen was statistically significant for DRFS (P = 0.035). No prognostic value could be ascribed to HOXB13 among systemically untreated patients.
A high HOXB13 expression was associated with decreased benefit from tamoxifen, which indicates that HOXB13 protein level may be used as a predictive marker for tamoxifen treatment.
The dic(9;20)(p13.2;q11.2) is reported to be present in ∼2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, it easily escapes detection by G-banding analysis and its ...true prevalence is hence unknown. We performed interphase fluorescence in situ hybridization analyses-in a three-step manner-using probes for: (i) CDKN2A at 9p21, (ii) 20p and 20q subtelomeres and (iii) cen9 and cen20. Out of 1033 BCP ALLs diagnosed from 2001 to 2006, 533 were analyzed; 16% (84/533) displayed 9p21 deletions, of which 30% (25/84) had dic(9;20). Thus, dic(9;20)-positivity was found in 4.7% (25/533), making it the third most common genetic subgroup after high hyperdiploidy and t(12;21)(p13;q22). The dic(9;20) was associated with a female predominance and an age peak at 3 years; 18/25 (72%) were allocated to non-standard risk treatment at diagnosis. Including cases detected by G-banding alone, 29 dic(9;20)-positive cases were treated according to the NOPHO ALL 2000 protocol. Relapses occurred in 24% (7/29) resulting in a 5-year event-free survival of 0.69, which was significantly worse than for t(12;21) (0.87; P=0.002) and high hyperdiploidy (0.82; P=0.04). We conclude that dic(9;20) is twice as common as previously surmised, with many cases going undetected by G-banding analysis, and that dic(9;20) should be considered a non-standard risk abnormality.
In situ synthesis of estrogens is believed to be of great importance for the progression of breast cancer. In postmenopausal women most estrogens are synthesized in peripheral hormone-target tissues ...from circulating precursor steroids, by the enzymes involved in formation of active estrogens. One of the enzymes involved in this process is 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1. This enzyme catalyzes the interconversion of estrone (E1) to the biologically more potent estradiol (E2). The gene coding for 17β-HSD type 1 (
HSD17B1
) is located at 17q12-21. The aim of this study was to investigate altered gene copy number of
HSD17B1
in breast cancer. We used real-time PCR and examined 387 postmenopausal breast tumors for amplification of
HSD17B1
, and if an increased mRNA level of this enzyme is associated with amplification of the gene. We also investigated whether amplification of
HSD17B1
has a prognostic value. There was a significant correlation between gene copy number of
HSD17B1
and mRNA expression level (
P
= 0.00002). ER-positive patients with amplification of
HSD17B1
showed lower breast cancer survival than patients without amplification (
P
= 0.025). Among ER-negative patients there was no significant correlation between increased gene copy number of
HSD17B1
and prognosis. Furthermore, we found that amplification of the gene had prognostic significance in multivariate analysis adjusting for other clinicopathological variables.
Background:Although the androgen receptor (AR) is frequently expressed in breast cancer, its relevance in the disease is not fully understood. In addition, the relevance of AR in determining ...tamoxifen treatment efficiency requires evaluation.Purpose:To investigate the tamoxifen predictive relevance of the AR protein expression in breast cancer.MethodsPatients were randomised to tamoxifen 40 mg daily for 2 or 5 years or to no endocrine treatment. Mean follow-up was 15 years. Hazard ratios were calculated with recurrence-free survival as end point.Results:In patients with oestrogen receptor (ER)-negative tumours, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR)=0.34; 95% confidence interval (CI)=0.14-0.81; P=0.015), whereas the opposite was seen in the AR- group (HR=2.92; 95% CI=1.16-7.31; P=0.022). Interaction test was significant P<0.001. Patients with triple-negative and AR+ tumours benefitted from tamoxifen treatment (HR=0.12; 95% CI=0.014-0.95 P=0.044), whereas patients with AR- tumours had worse outcome when treated with tamoxifen (HR=3.98; 95% CI=1.32-12.03; P=0.014). Interaction test was significant P=0.003. Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression.Conclusions:AR can predict tamoxifen treatment benefit in patients with ER- tumours and triple-negative breast cancer.
Objective: To compare the effect of a GnRH-agonist, triptorelin, versus placebo on the symptoms of endometriosis.
Design: A prospective, randomized, double-blind study of 6 months of treatment ...followed by 12 months of follow-up.
Setting: Departments of Obstetrics and Gynecology at two universities and one general hospital.
Patient(s): Forty-nine women with symptoms of laparoscopically verified endometriosis.
Intervention(s): Triptorelin depot or placebo was given every 4 weeks. Clinical evaluation, including the Duration Intensity Behavior Scale and Visual Analogue Scale for pain, was performed before the injections and up to 12 months after treatment. A control laparoscopy was performed 4–6 weeks after the last injection.
Main Outcome Measure(s): Quantitation of pain.
Result(s): Twenty-four patients had active treatment and 25 received placebo. Pain symptoms according to both scales were significantly more reduced after 2 months of triptorelin treatment compared to placebo. The extent of endometriotic lesions was reduced 50% during triptorelin treatment and increased 17% during placebo. The average area of endometriotic lesions was reduced 45% during triptorelin treatment but was unchanged during placebo. Side effects, mainly hot flushes, were experienced by 80% of the actively treated group but also by 33% of patients in the placebo group. Because of recurrent symptoms, only five patients could be observed for 12 months after completion of treatment.
Conclusion(s): Triptorelin reduces endometriotic lesions and pain to a significantly higher degree than placebo.
Abstract
The androgen receptor (AR) is frequently expressed in normal breast epithelium and in a substantial fraction of malignant breast tumors, even though the importance of AR in breast cancer is ...not established. In estrogen receptor (ER) positive breast cancer, AR binds to estrogen responsive element and inhibits proliferation, on the contrary in ER negative and HER2 positive cells AR activates the Wnt and HER2 pathways and induces proliferation. There are several therapies against the ER pathway and resistance to treatment is a big problem, targeting AR may be one alternative for some of these patients. In this study, we investigate the role of AR protein expression with immunohistochemistry in a defined cohort of 912 lymph node negative post menopausal breast cancer patients with a long follow up period randomized to no endocrine treatment or tamoxifen independent of ER expression, to examine if AR is a prognostic factor and/or predictor of tamoxifen treatment. In our cohort 82.4% showed AR expression in the tumour cells. In the case of ER positive patients without tamoxifen treatment, no significant difference was found when grouped by AR status (p>0.05). Tamoxifen treated patients with ER positive tumours showed benefit from the treatment regardless of AR expression (negative cases (p=0.038); positive cases (p=0.00001)). Further, if ER negative tumours from patients treated with tamoxifen were investigated AR expression was a tamoxifen predictive factor (p=0.014) (HR = 0.40 95% C.I. 0.18-0.89; p=0.024) but among cases with ER negative and AR negative tumours treatment with tamoxifen tended to have a worse outcome (p=0.06) HR = 2.26 95% C.I. 0.99-5.15; p=0.053. The multivariate interaction tests was significant (HR = 0.18 95% C.I. 0.056-0.56 p=0.003). There was a significant correlation between expression of the androgen receptor and small tumour size (p=0.002), PgR expression (p<0.001) ER expression (p<0.001), Cyclin D1 (p<0.001) and HOXB13 (p<0.001). The expression of AR was inversely correlated to HER2 (p=0.002). Tamoxifen is known to bind strongly to ER, however there are studies showing that tamoxifen also binds to AR. In prostate cancer, cell growth and AR activity were inhibited by tamoxifen and the ER antagonist fulvastrant effectively down regulates AR in several human prostate cancer cells and induce growth inhibition. These results suggest an anti-androgenic aspect of anti-estrogen. Our results indicate that AR is a tamoxifen predictive factor in ER negative breast cancer and suggest that this group of patients could benefit from tamoxifen treatment.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B251.
Citation Format: Erik Hilborn, Jelena Gacic, Tommy Fornander, Lambert Skog, Bo Nordenskjöld, Olle Stål, Agneta Jansson. Androgen receptor expression can predict benefit of tamoxifen treatment in patients with ER negative breast cancer. abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B251.
17beta-hydroxysteroid dehydrogenases (17betaHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of ...17betaHSD14 in breast cancer, measuring 17betaHSD14 protein expression in breast tumours. An antibody targeting the 17betaHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17betaHSD14 protein expression with immunohistochemistry. Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17betaHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
COX-2 is upregulated in many breast tumors, and one of the products of COX-2 is PGE2 that is suggested to upregulate aromatase through cAMP signaling in breast cancer. Although aromatase can increase ...the estrogen levels in tumors, 17beta-hydroxysteroid dehydrogenase (17HSD) activity is finally needed for the estrone/estradiol regulation. The aim of this study was to investigate if the protein expression of enzymes involved in estrogen synthesis shows covariation with the expression of COX-2. We also wanted to correlate these results with prognosis. We analyzed the expression of COX-2, aromatase, 17HSD1 and 17HSD2 with immunohistochemistry using tissue microarrays composed of 356 primary breast tumors. In the present study COX-2 was correlated to aromatase (P<0.00001), 17HSD1 (P=0.0073), and 17HSD2 (P<0.00001). Patients with ER positive tumors expressing low amounts of 17HSD2 had decreased breast cancer survival (P=0.013). Elevated expression of COX-2 and aromatase was more frequent among larger tumors (P=0.017 and P=0.013). COX-2 expression correlates with the levels of the examined steroid converting enzymes and may contribute to increased estrogen levels in the tumor. In breast cancer cells, the regulatory function of 17HSD2 could be lost, and in the present study patients with low or non-detectable levels of 17HSD2 had worse prognosis than had breast cancer patients with higher levels of the enzyme.
Background: Rectal cancer is a common malignancy, with significant local recurrence and death rates. Preoperative radiotherapy and refined surgical technique can improve local control rates and ...disease-free survival.
Purpose: To investigate the relationship between the tumor growth fraction in rectal cancer measured with Ki-67 and the outcome, with and without short-term preoperative radiotherapy.
Method: Ki-67 (MIB-1) immunohistochemistry was used to measure tumor cell proliferation in the preoperative biopsy and the surgical specimen.
Materials: Specimens from 152 patients from the Southeast Swedish Health Care region were included in the Swedish rectal cancer trial 1987–1990.
Results: Tumors with low proliferation treated with preoperative radiotherapy had a significantly reduced recurrence rate. The influence on death from rectal cancer was shown only in the univariate analysis. Preoperative radiotherapy of tumors with high proliferation did not significantly improve local control and disease-free survival. The interaction between Ki-67 status and the benefit of radiotherapy was significant for the reduced recurrence rate (
p = 0.03), with a trend toward improved disease-free survival (
p = 0.08). In the surgery-alone group, Ki-67 staining did not significantly correlate with local recurrence or survival rates.
Conclusion: Many Ki-67 stained tumor cells in the preoperative biopsy predicts an increased treatment failure rate after preoperative radiotherapy of rectal cancer.
PDF
![17[beta]-Hydroxysteroid Deh...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1932-6203/small "17[beta]-Hydroxysteroid Dehydrogenase Type 14 Is a Predictive Marker for Tamoxifen Response in Oestrogen Receptor Positive Breast Cancer")
