GATA3 mRNA expression, but not mutation, associates with longer progression-free survival in ER-positive breast cancer patients treated with first-line tamoxifen for recurrent disease

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.

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Changes in ER pathway activity score during neoadjuvant letrozole to assess therapy response and predict disease free survival (DFS) in ER positive breast cancer patients

Annals of Oncology ◽

10.1093/annonc/mdz240.107 ◽

2019 ◽

Vol 30 ◽

pp. v95

Author(s):

A.K. Turnbull ◽

M.A. Inda ◽

A. van de Stolpe ◽

D. Keizer ◽

D. Clout ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Disease Free Survival ◽

Therapy Response ◽

Breast Cancer Patients ◽

Free Survival ◽

Pathway Activity ◽

Er Positive ◽

Disease Free ◽

Positive Breast Cancer

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Abstract P2-08-06: Usefulness of the pre-treatment neutrophil-to-lymphocyte ratio in predicting first-line progression free-survival in triple-negative breast cancer patients

10.1158/1538-7445.sabcs15-p2-08-06 ◽

2016 ◽

Author(s):

C Fontanella ◽

V Fanotto ◽

L Gerratana ◽

M Bonotto ◽

M Cinausero ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Progression Free Survival ◽

Breast Cancer Patients ◽

First Line ◽

Free Survival ◽

Lymphocyte Ratio ◽

Pre Treatment

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Effect of Wnt5a on aggressiveness of ER-positive breast cancer and cancer cell migration through JNK-ALCAM pathway.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11614 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11614-11614

Author(s):

Yoshie Kobayashi ◽

Takayuki Kadoya ◽

Ai Amioka ◽

Noriko Gohda ◽

Miho Kono ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Survival Rates ◽

Breast Cancer Patients ◽

Mcf7 Cells ◽

Relapse Free Survival ◽

Free Survival ◽

Wnt5a Expression ◽

Er Positive ◽

Positive Breast Cancer

11614 Background: Wnt5a is a representative ligand that activates β-catenin-independent pathways and involved in cell motility and cell polarity, and the like, being mediated by JNK. We elucidated the implication of Wnt5a expression in breast cancer. Methods: One hundred seventy eight breast cancer patients (mean age ± SD: 60.0 ± 13.2 years) with clinical Stage I-III between January 2011 and February 2014, were prospectively evaluated. We examined relationships between Wnt5a expression and clinicopathological factors by immunohistochemical analyses. 5-year relapse-free survival rates and sites of recurrence were analyzed. In addition, molecules induced by Wnt5a in cultured cells were identified by DNA microarray analysis. Results: Wnt5a expression was significantly more frequent when estrogen receptor (ER) was present, 68/153 (44%) than when ER was absent, 1/25 (4%) (P <0.001) (Table). In ER-positive breast cancer, a significant interaction between expression of Wnt5a with lymph node metastasis (P<0.001), high nuclear grade (P=0.004), and lymphatic invasion (P=0.001). 5-year relapse-free survival rates were 81.1% and 100% in Wnt5a-positive and Wnt5a-negative breast cancers, respectively (P = 0.024). All recurrent breast cancer patients in this study had bone metastasis. We established MCF7 stably expressing Wnt5a (Wnt5a/MCF7 cells) and microarray analyses identified several genes induced by Wnt5a (>3.0 fold), involving activated leukocyte cell adhesion molecule (ALCAM). ALCAM is known to be related with apoptosis, invasion and prognosis of breast cancer. We focused on ALCAM and investigated its protein expression by Western blotting, and found remarkable increase of ALCAM in Wnt5a/MCF7 cells. Conclusions: Wnt5a expresses in ER-positive breast cancer and is associated with high-grade malignancy and a poor prognosis through JNK-ALCAM pathway. Wnt5a could be a novel prognostic factor of ER-positive breast cancer. [Table: see text]

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

Cancers ◽

10.3390/cancers13040771 ◽

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.

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