Shorter disease-specific survival of ER-positive breast cancer patients with high cytoplasmic Src kinase expression after tamoxifen treatment

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.

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

Journal of Molecular Endocrinology ◽

10.1677/jme-08-0076 ◽

2008 ◽

Vol 42 (2) ◽

pp. 87-103 ◽

Cited By ~ 37

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.

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Distribution of Podoplanin-Positive Tumor Vessels Predicts Disease-Specific Survival of Node-Positive Breast Cancer Patients Treated with Anthracyclines and/or Taxanes

Cancer Investigation ◽

10.3109/07357907.2014.889704 ◽

2014 ◽

Vol 32 (5) ◽

pp. 168-177 ◽

Cited By ~ 1

Author(s):

Joanna A. Niemiec ◽

Agnieszka Adamczyk ◽

Aleksandra Ambicka ◽

Anna Mucha-Małecka ◽

Wojciech M. Wysocki ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Disease Specific Survival ◽

Breast Cancer Patients ◽

Tumor Vessels ◽

Node Positive ◽

Disease Specific ◽

Positive Breast Cancer

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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.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.8.1310 ◽

1990 ◽

Vol 8 (8) ◽

pp. 1310-1320 ◽

Cited By ~ 68

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.

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

International Journal of Surgical Oncology ◽

10.1155/2021/9947540 ◽

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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Abstract P6-08-10: Disease Specific Survival of Breast Cancer Patients Is Not Associated with Expression of Inactive or Even Partially Activated Src Kinase

10.1158/0008-5472.sabcs10-p6-08-10 ◽

2010 ◽

Author(s):

B Elsberger ◽

BA Tan ◽

SF Brown ◽

EA Mallon ◽

J. Edwards

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Src Kinase ◽

Disease Specific Survival ◽

Breast Cancer Patients ◽

Disease Specific

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113P Impact of local recurrence on disease-specific survival in breast cancer patients who underwent breast-conserving surgery

Annals of Oncology ◽

10.1016/j.annonc.2020.03.216 ◽

2020 ◽

Vol 31 ◽

pp. S54

Author(s):

D.G. Tiezzi ◽

L. de Mattos ◽

L.F. Orlandini ◽

F.J. Candido Dos Reis ◽

H.H. Carrara ◽

...

Keyword(s):

Breast Cancer ◽

Local Recurrence ◽

Cancer Patients ◽

Breast Conserving Surgery ◽

Disease Specific Survival ◽

Breast Cancer Patients ◽

Disease Specific

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Survival in Early Breast Cancer Patients Is Favorably Influenced by a Natural Humoral Immune Response to Polymorphic Epithelial Mucin

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.3.574 ◽

2000 ◽

Vol 18 (3) ◽

pp. 574-574 ◽

Cited By ~ 153

Author(s):

S. von Mensdorff-Pouilly ◽

A.A. Verstraeten ◽

P. Kenemans ◽

F.G. M. Snijdewint ◽

A. Kok ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Early Breast Cancer ◽

Humoral Response ◽

Disease Specific Survival ◽

Breast Cancer Patients ◽

Antibody Levels ◽

Pretreatment Serum ◽

Test Result ◽

Disease Specific

PURPOSE: Polymorphic epithelial mucin (PEM or MUC1) is being studied as a vaccine substrate for the immunotherapy of patients with adenocarcinoma. The present study analyzes the incidence of naturally occurring MUC1 antibodies in early breast cancer patients and relates the presence of these antibodies in pretreatment serum to outcome of disease.MATERIALS AND METHODS: We measured immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to MUC1 with an enzyme-linked immunoassay (PEM.CIg), which uses a MUC1 triple-tandem repeat peptide conjugated to bovine serum albumin, in pretreatment serum samples obtained from 154 breast cancer patients (52 with stage I disease and 102 with stage II) and 302 controls. The median disease-specific survival time of breast cancer patients was 74 months (range, 15 to 118 months). A positive test result was defined as MUC1 IgG or IgM antibody levels equal to or greater than the corresponding rounded-up median results obtained in the total breast cancer population.RESULTS: A positive test result for both MUC1 IgG and IgM antibodies in pretreatment serum was associated with a significant benefit in disease-specific survival in stage I and II (P = .0116) breast cancer patients. Positive IgG and IgM MUC1 antibody levels had significant additional prognostic value to stage (P = .0437) in multivariate analysis. Disease-free survival probability did not differ significantly. However, stage II patients who tested positive for MUC1 IgG and IgM antibody and who relapsed had predominantly local recurrences or contralateral disease, as opposed to recurrences at distant sites in the patients with a negative humoral response (P = .026).CONCLUSION: Early breast cancer patients with a natural humoral response to MUC1 have a higher probability of freedom from distant failure and a better disease-specific survival. MUC1 antibodies may control hematogenic tumor dissemination and outgrowth by aiding the destruction of circulating or seeded MUC1-expressing tumor cells. Vaccination of breast cancer patients with MUC1-derived (glyco)peptides in an adjuvant setting may favorably influence the outcome of disease.

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