scholarly journals AGR2 Predicts Tamoxifen Resistance in Postmenopausal Breast Cancer Patients

2013 ◽  
Vol 35 ◽  
pp. 207-212 ◽  
Author(s):  
Roman Hrstka ◽  
Veronika Brychtova ◽  
Pavel Fabian ◽  
Borivoj Vojtesek ◽  
Marek Svoboda
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Optimal Algorithm ◽  
Endocrine Resistance ◽  
Postmenopausal Breast Cancer ◽  
Progression Free Survival ◽  
Tamoxifen Treatment ◽  
Mrna Levels ◽  
Breast Cancer Patients ◽  
Er Positive

Endocrine resistance is a significant problem in breast cancer treatment. Thus identification and validation of novel resistance determinants is important to improve treatment efficacy and patient outcome. In our work, AGR2 expression was determined by qRT-PCR in Tru-Cut needle biopsies from tamoxifen-treated postmenopausal breast cancer patients. Our results showed inversed association of AGR2 mRNA levels with primary treatment response (P=0.0011) and progression-free survival (P=0.0366) in 61 ER-positive breast carcinomas. As shown by our experimental and clinical evaluations, elevated AGR2 expression predicts decreased efficacy of tamoxifen treatment. From this perspective, AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in postmenopausal ER-positive breast cancer patients.

scholarly journals Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 771
Author(s):  
Tessa A. M. Mulder ◽  
Mirjam de With ◽  
Marzia del Re ◽  
Romano Danesi ◽  
Ron H. J. Mathijssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Tamoxifen Treatment ◽  
Current Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients.

1997 ◽  
Vol 15 (4) ◽  
pp. 1385-1394 ◽  
Author(s):  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Disease Free Survival ◽  
Postmenopausal Breast Cancer ◽  
Breast Cancer Patients ◽  
Node Positive ◽  
Increased Risk ◽  
Node Positive Disease ◽  
Er Positive ◽  
Risk Of Relapse

PURPOSE Adjuvant tamoxifen has been shown to reduce relapse and mortality among node-positive post-menopausal breast cancer patients. The value of adding chemotherapy to tamoxifen is controversial. PATIENTS AND METHODS Between July 1986 and April 1993, 1,266 postmenopausal breast cancer patients with node-positive disease were randomly assigned to receive one of four adjuvant therapy regimens: (A) tamoxifen alone for 5 years; (B) tamoxifen plus three courses of early cyclophosphamide, methotrexate, and fluorouracil (CMF) on months 1, 2, and 3; (C) tamoxifen plus delayed single courses of CMF on months 9, 12, and 15; (D) tamoxifen plus early and delayed CMF on months 1, 2, 3, 9, 12, and 15. The two-by-two factorial design allowed two direct comparisons: early CMF (B and D) versus no early CMF (A and C), and delayed CMF (C and D) versus no delayed CMF (A and B). Estrogen receptor (ER) status was known for all patients and was used to stratify the randomization. A total of 1, 212 patients (96%) were eligible and assessable. The median follow-up duration was 60 months. RESULTS The results of the two-by-two factorial comparisons were as follows: (1) early CMF added to tamoxifen significantly improved 5-year disease-free survival (DFS; 64% v 57%; hazards ratio [HR], 0.79; 95% confidence interval [CI], 0.66 to 0.95; P = .01); and (2) delayed CMF added to tamoxifen did not improve DFS (5-year DFS, 61% v 60%; HR, 0.97; 95% CI, 0.81 to 1.17; P = .77). For patients with ER-positive tumors, the addition of CMF, either early or delayed or both, reduced the relative risk of relapse by 22% to 36%. In contrast, for patients with ER-negative tumors, tamoxifen with delayed CMF was associated with a nonsignificant increased risk of relapse (HR, 1.27; 95% CI, 0.92 to 1.76; P = .15). CONCLUSION Postmenopausal patients with node-positive breast cancer should be offered combination chemotherapy in addition to tamoxifen. Tamoxifen should not be initiated before CMF, as this might be detrimental, especially for patients with ER-negative tumors.

scholarly journals Identification of TACC1, NOV, and PTTG1 as new candidate genes associated with endocrine therapy resistance in breast cancer

2008 ◽  
Vol 42 (2) ◽  
pp. 87-103 ◽  
Author(s):  
Sandra E Ghayad ◽  
Julie A Vendrell ◽  
Ivan Bieche ◽  
Frédérique Spyratos ◽  
Charles Dumontet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Candidate Genes ◽  
Endocrine Therapy ◽  
Cell Lines ◽  
Tamoxifen Treatment ◽  
Cross Resistance ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Cross-resistance to molecules used in endocrine therapy is among the main challenges in the treatment of estrogen receptor-α (ERα) positive breast cancer. In this study, we used two different cell models of resistance to anti-estrogens: MVLN/CL6.7 cells and VP229/VP267 cells selected after exposure to tamoxifen respectively in vitro and in vivo to characterize a phenotype rarely observed, i.e. acquisition of cross-resistance to the pure ER antagonist fulvestrant. As MVLN/CL6.7 cells and VP229/VP267 cell lines are original and valuable models of cross-resistance to tamoxifen and fulvestrant, we examined candidate genes using a RTQ-PCR strategy to identify new biomarkers of endocrine resistance. Out of the 26 candidate genes tested, 19 displayed deregulation of expression at the basal level in at least one of the two resistant cell lines. Eight genes (TACC1, NOV, PTTG1, MAD2L1, BAK1, TGFB2, BIRC5, and CCNE2) were significantly overexpressed in samples from ER-positive breast cancer patients who relapsed after tamoxifen treatment (n=24) compared with samples from patients who did not (n=24). Five genes (TACC1, NOV, PTTG1, BAK1, and TGFB2) were correlated with significantly shorter relapse-free survival (univariate analysis). Finally, we identified TACC1 and a three-gene expression signature (TACC1, NOV, and PTTG1) as independent prognostic markers (multivariate analysis). Aberrant mRNA and protein levels of TACC1, NOV, and PTTG1 were also observed under tamoxifen and/or fulvestrant exposure in resistant CL6.7 cells compared with their respective control MVLN cells. In conclusion, our data identify TACC1, NOV, and PTTG1 as promising new markers that could be used in the clinical management of ER-positive breast cancer patients.

Association of the phosphorylation of the estrogen receptor at serine 118 and 167 with prognosis in postmenopausal breast cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 562-562
Author(s):  
Karin J. Beelen ◽  
Mark Opdam ◽  
Rutger H.T. Koornstra ◽  
Andrew D. Vincent ◽  
Jan Baptist Vermorken ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Estrogen Therapy ◽  
Postmenopausal Breast Cancer ◽  
Tamoxifen Treatment ◽  
Adjuvant Tamoxifen ◽  
Breast Cancer Patients ◽  
Premenopausal Breast Cancer ◽  
Cox Models

562 Background: The sensitivity of the estrogen receptor (ERα) to anti-estrogen therapy can be affected by phosphorylation events. In premenopausal breast cancer patients, phosphorylation of the ERα at serine 118 (ERαS118-p) is predictive for benefit from adjuvant tamoxifen. Since ERαS118-p represents the common hallmark of different signaling cascades that differ in E2 dependency, the resulting effect on estrogen sensitivity may differ between pre- and postmenopausal patients. Phosphorylation of serine 167 (ERαS167-p) has been associated with favorable disease outcome, but whether ERαS167-p can predict tamoxifen sensitivity is currently unknown. We tested the predictive value of both ERαS118-p and ERαS167-p for benefit from adjuvant tamoxifen in postmenopausal breast cancer patients. Methods: We collected primary tumor blocks from 563 ERα positive (stage I-III) postmenopausal patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial). The median follow-up of patients without a recurrence event was 9.4 years. Immunohistochemistry was performed on a TMA using monoclonal antibodies for ERαS118-p and ERαS167-p. The percentage of positive nuclei was scored and a score of ≥ 10 % was considered as positive. Multivariate Cox models were used to assess hazard ratios (HRs) for recurrence free interval and the interaction between these phosphorylations and tamoxifen treatment. Results: We did not find a significant interaction between either ERαS118-p (p=0.99) or ERαS167-p (p=0.44) and tamoxifen, suggesting that the relative benefit from adjuvant tamoxifen in postmenopausal patients is not dependent on the presence of one of these phosphorylations. Both tamoxifen treated patients as well as control patients had a better prognosis when their tumor was positive for ERαS118-p (adjusted HR 0.60 p=0.02) or ERαS167-p (adjusted HR 0.62, p=0.02) compared to patients whose tumor did not express these ERα phosphorylations. Conclusions: In postmenopausal patients ERαS118-p and ERαS167-p are both associated with better prognosis, but do not predict differential benefit from tamoxifen.

Risk of Endometrial Cancer in Breast Cancer Patients under Long-Term Adjuvant Treatment with Tamoxifen

1998 ◽  
Vol 84 (1) ◽  
pp. 21-23 ◽  
Author(s):  
Silvia Cecchini ◽  
Stefano Ciatto ◽  
Rita Bonardi ◽  
Antonia Mazzotta ◽  
Paolo Pacini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endometrial Cancer ◽  
Cancer Patients ◽  
Endometrial Thickness ◽  
Postmenopausal Breast Cancer ◽  
Cancer Surveillance ◽  
Tamoxifen Treatment ◽  
Adjuvant Tamoxifen ◽  
Breast Cancer Patients

Aims To evaluate the relative risk of endometrial cancer with respect to the expected underlying incidence in breast cancer patients undergoing long-term adjuvant tamoxifen therapy. Methods A total of 1010 postmenopausal breast cancer patients receiving adjuvant tamoxifen and with a first negative endometrial ultrasonography (cutoff for abnormal endometrial thickness >5 mm) were followed by annual transvaginal ultrasonography. Abnormal endometrial thickness prompted an outpatient endometrial biopsy or curettage under anesthesia in the case of cervical stenosis and increasing endometrial thickness. The standardized incidence ratio (SIR) with respect to underlying incidence was determined. Results A total of 1,010 eligible subjects who had been receiving tamoxifen for an average of 51 months were enrolled and followed for a total of 2,361 patient-years between January 1993 and December 1996. Five cases of endometrial cancer were observed in the study period: 1 was detected at screening, and 4 were diagnosed for vaginal bleeding in the interval between screening examinations. SIR was 4.0 (95% confidence interval, 1.39.4) and increased to 4.8 (CI, 1.6-10.5) when the single cancer detected at first screening was considered as incident. Conclusions This study adds evidence to the hypothesis that long-term tamoxifen treatment may be responsible for a relevant increase in the risk of developing endometrial cancer. Surveillance based on endometrial ultrasonography was poorly sensitive, but the favorable stage at diagnosis of screen-detected or interval endometrial cancers does not support a more aggressive screening approach.

Endometrial Cancers in Postmenopausal Breast Cancer Patients with Tamoxifen Treatment

1999 ◽  
Vol 18 (4) ◽  
pp. 304-309 ◽  
Author(s):  
Ilan Cohen ◽  
Ron Azaria ◽  
Ami Fishman ◽  
Ron Tepper ◽  
Jeremiah Shapira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Postmenopausal Breast Cancer ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Endometrial Cancers
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