Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: results of a multicentric Italian study. Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group.

1990 ◽  
Vol 8 (8) ◽  
pp. 1310-1320 ◽  
Author(s):  
F Boccardo ◽  
A Rubagotti ◽  
P Bruzzi ◽  
M Cappellini ◽  
G Isola ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Cancer Patients ◽  
Combined Treatment ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Node Positive ◽  
Er Positive ◽  
Positive Breast Cancer

Between November 1, 1983 and June 30, 1987, 510 node-positive, estrogen receptor (ER)-positive breast cancer patients have been randomly allocated to receive either chemotherapy (six intravenous [IV] cyclophosphamide, methotrexate, and fluorouracil [CMF] courses followed by four IV epirubicin courses) or 5 years of tamoxifen treatment or a combination of both therapies. After a median follow-up of 40 months, patients receiving the combined treatment achieved the best results, and those treated with chemotherapy alone achieved the worst, the difference being particularly evident in postmenopausal women. However, while the concurrent use of chemotherapy and tamoxifen did improve the results achieved by chemotherapy alone, particularly in postmenopausal women and in those with four or more involved nodes, it did not significantly improve the results achieved by tamoxifen alone, particularly in patients with higher ER tumor concentrations. Side effects were more numerous and more severe in patients receiving chemotherapy (with or without tamoxifen). Our findings, although still preliminary, confirm that tamoxifen should be the treatment of choice for postmenopausal breast cancer patients with node-positive, ER-positive tumors. In addition, the findings suggest that tamoxifen may represent a safe alternative to chemotherapy (at least to the cytotoxic regimen we used) for younger women, provided they have ER-positive tumors. In patients with ER-positive tumors, the addition of chemotherapy to tamoxifen does not seem to improve significantly the effectiveness of tamoxifen alone.

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.

scholarly journals ESR1-Stabilizing Long Noncoding RNA TMPO-AS1 Promotes Hormone-Refractory Breast Cancer Progression

2019 ◽  
Vol 39 (23) ◽  
Author(s):  
Yuichi Mitobe ◽  
Kazuhiro Ikeda ◽  
Takashi Suzuki ◽  
Kiyoshi Takagi ◽  
Hidetaka Kawabata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Cancer Progression ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

ABSTRACT Acquired endocrine therapy resistance is a significant clinical problem for breast cancer patients. In recent years, increasing attention has been paid to long noncoding RNA (lncRNA) as a critical modulator for cancer progression. Based on RNA-sequencing data of breast invasive carcinomas in The Cancer Genome Atlas database, we identified thymopoietin antisense transcript 1 (TMPO-AS1) as a functional lncRNA that significantly correlates with proliferative biomarkers. TMPO-AS1 positivity analyzed by in situ hybridization significantly correlates with poor prognosis of breast cancer patients. TMPO-AS1 expression was upregulated in endocrine therapy-resistant MCF-7 cells compared with levels in parental cells and was estrogen inducible. Gain and loss of TMPO-AS1 experiments showed that TMPO-AS1 promotes the proliferation and viability of estrogen receptor (ER)-positive breast cancer cells in vitro and in vivo. Global expression analysis using a microarray demonstrated that TMPO-AS1 is closely associated with the estrogen signaling pathway. TMPO-AS1 could positively regulate estrogen receptor 1 (ESR1) mRNA expression by stabilizing ESR1 mRNA through interaction with ESR1 mRNA. Enhanced expression of ESR1 mRNA by TMPO-AS1 could play a critical role in the proliferation of ER-positive breast cancer. Our findings provide a new insight into the understanding of molecular mechanisms underlying hormone-dependent breast cancer progression and endocrine resistance.

Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.

1994 ◽  
Vol 12 (10) ◽  
pp. 2078-2085 ◽  
Author(s):  
S E Rivkin ◽  
S Green ◽  
B Metch ◽  
A B Cruz ◽  
M D Abeloff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Eastern Cooperative Oncology Group ◽  
Operable Breast Cancer ◽  
Oncology Group ◽  
Southwest Oncology Group ◽  
Node Positive ◽  
Er Positive ◽  
Positive Breast Cancer

PURPOSE To compare chemohormonal therapy, chemotherapy alone, and hormonal therapy alone in postmenopausal patients with estrogen receptor (ER)-positive operable breast cancer and positive axillary nodes with respect to survival and disease-free survival (DFS). PATIENTS AND METHODS Eight hundred ninety-two postmenopausal women with ER-positive, node-positive breast cancer were enrolled by the Southwest Oncology Group (SWOG) from July 1979 to March 1989 and 74 by the Eastern Cooperative Oncology Group (ECOG) between June 1987 and March 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive the following: (1) tamoxifen 10 mg twice daily by mouth for 1 year; (2) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (IV) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 IV weekly for 1 year, vincristine .625 mg/m2 IV weekly for the first 10 weeks, and prednisone during weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (3) the combination of tamoxifen and CMFVP. RESULTS The median follow-up duration is 6.5 years, with a maximum of 12.8 years. Treatment arms are not significantly different with respect to either survival or DFS (log-rank, 2 df, P = .82 and .23, respectively). The 5-year survival rate is 77% for the tamoxifen arm, 78% for CMFVP, and 75% for the combination. No significant differences were observed in node or receptor level subsets. Severe or worse toxicity was experienced by 56% of patients on CMFVP and 61% on CMFVP plus tamoxifen, compared with 5% on tamoxifen alone. CONCLUSION CMFVP chemotherapy, either alone or in combination with tamoxifen, has not been shown to be superior to tamoxifen alone in the treatment of postmenopausal women with node-positive, ER-positive, operable breast cancer.

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.

The CYP2C19 rs4917623 single nucleotide polymorphism to predict tamoxifen efficacy in estrogen receptor-positive breast cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12001-e12001
Author(s):  
Nobuyasu Yoshimoto ◽  
Akihiro Naito ◽  
Nobuko Kawaguchi ◽  
Miwa Kato ◽  
Naoto Kondo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Hazard Ratio ◽  
Breast Cancer Patients ◽  
Single Nucleotide ◽  
Free Survival ◽  
Er Positive ◽  
Tamoxifen Efficacy ◽  
Positive Breast Cancer

e12001 Background: Tamoxifen is a selective estrogen receptor modulator that is widely used to treat estrogen receptor (ER)-positive breast cancer. However, not all patients benefit from the incorporation of tamoxifen into an adjuvant therapy. This is also the case when tamoxifen is used in chemoprevention, since only half of participants benefit from the drug. In order to improve treatment response, we attempted to identify single nucleotide polymorphisms (SNPs) that correlated with tamoxifen efficacy. Methods: ER-positive breast cancer patients at our hospital were enrolled on this study between January 2007 and September 2010. The primary endpoint was ER-positive breast cancer-free survival. We examined 17 SNPs in these patients. The survival benefit associated with each genotype was determined with a log-rank test, and the hazard ratio was analyzed using a Cox proportional-hazards model. Results: The median follow-up time of the 320 patients enrolled on the study was 3298 days. Of 240 patients who received any endocrine therapy, ER-positive breast cancer-free survival in patients with the 2q35 rs13387042 AA genotype was significantly shorter than in those who had the AG or GG genotype (p < 0.0001), and the hazard ratio was significantly higher (HR 8.83; 95% CI 2.09–25.53, p = 0.0064). Of the 145 patients who received tamoxifen therapy, there was a trend among ER-positive breast cancer patients with the CYP2C19 rs4917623 TT genotype to have a shorter disease-free period (p = 0.0635) when compared to patients with TC or CC genotypes. Similarly, there was a trend for the TT genotype patients to exhibit a higher hazard ratio (HR 2.62; 95% CI 0.86–7.55, p = 0.0861). Conclusions: The rs4917623 SNP in the CYP2C19 gene, which encodes a metabolic enzyme, predicts tamoxifen efficacy. This finding will facilitate selection of ER-positive breast cancer patients for tamoxifen treatment; it may also be useful for selection of patients most likely to benefit from tamoxifen-dependent chemoprevention.

scholarly journals The Utility of SOX2 and AGR2 Biomarkers as Early Predictors of Tamoxifen Resistance in ER-Positive Breast Cancer Patients

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yomna Zamzam ◽  
Yosra Abdelmonem Zamzam ◽  
Marwa Aboalsoud ◽  
Heba Harras
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tamoxifen Resistance ◽  
Tamoxifen Treatment ◽  
Time To Failure ◽  
Breast Cancer Patients ◽  
Early Predictors ◽  
Er Positive ◽  
Group 1 ◽  
Positive Breast Cancer

Background. Despite the undeniable benefit of tamoxifen therapy for ER-positive breast cancer patients, approximately one-third of those patients either do not respond to tamoxifen or develop resistance. Thus, it is a crucial step to identify novel, reliable, and easily detectable biomarkers indicating resistance to this drug. Objective. The aim of this work is to explore SOX2 and AGR2 biomarker expression in the tumor tissue of ER-positive breast cancer patients in combination with the evaluation of serum AGR2 level of these patients in order to validate these biomarkers as early predictors of tamoxifen resistance. Methods. This study was conducted on 224 ER-positive breast cancer patients. All patients were primarily subjected to serum AGR2 levelling by ELISA and their breast cancer tissue immunostained for SOX2 and AGR2. After 5 years of follow-up, the patients were divided into 3 groups: group 1 was tamoxifen sensitive and groups 2 and 3 were tamoxifen resistant. Time to failure of tamoxifen treatment was considered the time from the beginning of tamoxifen therapy to the time of discovery of breast cancer recurrence or metastases (in months). Results. SOX2 and AGR2 biomarkers expression and serum AGR2 level were significantly higher in groups 2 and 3 in comparison to group 1, while the relationship between Her2 neu expression and Ki67 index in the 3 different groups was statistically nonsignificant. Lower SOX2 and AGR2 expression and low AGR2 serum levels in the studied patients of groups 2 and 3 were significantly associated with longer time-to-failure of tamoxifen treatment. According to the ROC curve, the combined use of studied markers validity was with a sensitivity of 100%, specificity of 96%, PPV 96%, and NPV 100% ( p < 0.001 ; AUC: 0.984). Conclusions. Integrated use of SOX2 and AGR2 biomarkers with serum AGR2 assay holds a promising hope for their future use as predictive markers for early detection of tamoxifen resistance in ER-positive breast cancer patients.

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