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Evaluation of the ability of adjuvant tamoxifen-benefit gene signatures to predict outcome of hormone-naive estrogen receptor-positive breast cancer patients treated with tamoxifen in the advanced setting.

ABSTRACT: To identify molecular markers indicative of response to tamoxifen and easily implemented in the routine setting, we recently reported three gene signatures that could stratify post-menopausal tamoxifen-treated, estrogen receptor-positive (ER+) patients according to outcome in the adjuvant setting. Here, we evaluated the predictive potential of the total of 14 genes included in the 3 gene signatures using 2 hormone-naïve Dutch ER+ cohorts of a total of 285 recurrent breast cancer patients treated with first-line tamoxifen. mRNA levels were measured by reverse transcriptase quantitative PCR (RT-qPCR) and the length of progression-free survival (PFS) was used as the primary endpoint. A Mann-Whitney U test was used to select for differentially expressed genes between tumors of patients who showed or did not show progressive disease within 6 months after start of tamoxifen treatment. Cox univariate and multivariate regression analysis for PFS were used to further assess their (independent) predictive potential. Five (BCAR3, BCL2, ESR1, IGF1R, and NCOA1) of the 14 genes analyzed showed significantly higher mRNA levels in tumors of patients who showed no disease progression within 6 months. Only BCAR3, BCL2 and NAT1 were significantly associated with a favorable PFS in multivariate analysis that included the traditional predictive factors: age, dominant relapse site, disease-free interval, ER and progesterone receptor (PGR), and adjuvant chemotherapy. This study shows that BCAR3, BCL2 and NAT1 in particular exhibit predictive promise regarding the efficacy of tamoxifen treatment in recurrent disease, in addition to the previously shown favorable outcome in the adjuvant setting.

SUBMITTER: Sieuwerts AM

PROVIDER: S-EPMC5528606 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Evaluation of the ability of adjuvant tamoxifen-benefit gene signatures to predict outcome of hormone-naive estrogen receptor-positive breast cancer patients treated with tamoxifen in the advanced setting.

Sieuwerts Anieta M AM Lyng Maria B MB Meijer-van Gelder Marion E ME de Weerd Vanja V Sweep Fred C G J FC Foekens John A JA Span Paul N PN Martens John W M JW Ditzel Henrik J HJ

Molecular oncology 20140710 8

To identify molecular markers indicative of response to tamoxifen and easily implemented in the routine setting, we recently reported three gene signatures that could stratify post-menopausal tamoxifen-treated, estrogen receptor-positive (ER+) patients according to outcome in the adjuvant setting. Here, we evaluated the predictive potential of the total of 14 genes included in the 3 gene signatures using 2 hormone-naïve Dutch ER+ cohorts of a total of 285 recurrent breast cancer patients treated ...[more]

PMID: 25081647

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Project description:IntroductionLittle is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability.MethodsTo test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes (12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast (and liver) tissues, and in estrogen receptor alpha (ERalpha)-negative and ERalpha-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERalpha-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone.ResultsSeven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes (CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERalpha-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERalpha-positive breast tumors than in ERalpha-negative breast tumors. In the 97 ERalpha-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERalpha-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis (P = 0.0013).ConclusionsTaken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an attractive candidate molecular predictor of antiestrogen responsiveness.

Project description:BackgroundControversy exists for the use of Ki67 protein expression as a predictive marker to select patients who do or do not derive benefit from adjuvant endocrine therapy. Whether other proliferation markers, like Cyclin D1, and mitotic count can also be used to identify those estrogen receptor α (ERα) positive breast cancer patients that derive benefit from tamoxifen is not well established. We tested the predictive value of these markers for tamoxifen benefit in ERα positive postmenopausal breast cancer patients.MethodsWe collected primary tumor blocks from 563 ERα positive patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial) with a median follow-up of 7.8 years. Mitotic count, Ki67 and Cyclin D1 protein expression were centrally assessed by immunohistochemistry on tissue microarrays. In addition, we tested the predictive value of CCND1 gene copy number variation using MLPA technology. Multivariate Cox proportional hazard models including interaction between marker and treatment were used to test the predictive value of these markers.ResultsPatients with high Ki67 (≥5%) as well as low (< 5%) expressing tumors equally benefitted from adjuvant tamoxifen (adjusted hazard ratio (HR) 0.5 for both groups)(p for interaction 0.97). We did not observe a significant interaction between either Cyclin D1 or Ki67 and tamoxifen, indicating that the relative benefit from tamoxifen was not dependent on the level of these markers. Patients with tumors with low mitotic count derived substantial benefit from tamoxifen (adjusted HR 0.24, p < 0.0001), while patients with tumors with high mitotic count derived no significant benefit (adjusted HR 0.64, p = 0.14) (p for interaction 0.03).ConclusionPostmenopausal breast cancer patients with high Ki67 counts do significantly benefit from adjuvant tamoxifen, while those with high mitotic count do not. Mitotic count is a better selection marker for reduced tamoxifen benefit than Ki67.

Dataset Information

Evaluation of the ability of adjuvant tamoxifen-benefit gene signatures to predict outcome of hormone-naive estrogen receptor-positive breast cancer patients treated with tamoxifen in the advanced setting.

Publications

Evaluation of the ability of adjuvant tamoxifen-benefit gene signatures to predict outcome of hormone-naive estrogen receptor-positive breast cancer patients treated with tamoxifen in the advanced setting.

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