Tamoxifen Effectiveness Research Articles

Serotoninergic receptor ligands improve Tamoxifen effectiveness on breast cancer cells

BackgroundSerotonin (or 5-Hydroxytryptamine, 5-HT) signals in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis, and angiogenesis. Thus, the discovery of novel compounds targeting serotonin signaling may contribute to tailor new therapeutic strategies usable in combination with endocrine therapies. We have previously synthesized serotoninergic receptor ligands (SER) with high affinity and selectivity towards 5-HT2A and 5-HT2C receptors, the main mediators of mitogenic effect of serotonin in breast cancer (BC). Here, we investigated the effect of 10 SER on viability of MCF7, SKBR3 and MDA-MB231 BC cells and focused on their potential ability to affect Tamoxifen responsiveness in ER+ cells.MethodsCell viability has been assessed by sulforhodamine B assay. Cell cycle has been analyzed by flow cytometry. Gene expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) has been checked by RT-PCR; mRNA levels of CTGF and ABC transporters have been further measured by qPCR. Protein levels of 5-HT2C receptors have been analyzed by Western blot. All data were statistically analyzed using GraphPad Prism 7.ResultsWe found that treatment with SER for 72 h reduced viability of BC cells. SER were more effective on MCF7 ER+ cells (IC50 range 10.2 μM - 99.2 μM) compared to SKBR3 (IC50 range 43.3 μM - 260 μM) and MDA-MB231 BC cells (IC50 range 91.3 μM - 306 μM). This was paralleled by accumulation of cells in G0/G1 phase of cell cycle. Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 cells and modulated the expression of CTGF, without affecting viability of MCF10A non-cancer breast epithelial cells. In a cell model of Tamoxifen resistance, SER68 also restored drug effect independently of CTGF.ConclusionsThese results identified serotoninergic receptor ligands potentially usable in combination with Tamoxifen to improve its effectiveness on ER+ BC patients.

Abstract 757: 17β-hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark

Abstract Background: Breast cancer is the most commonly diagnosed malignancy among women worldwide. Despite high survival rates, 20%-40% of women will experience a recurrence, with risks extending beyond 20 years after diagnosis. Premenopausal women diagnosed with estrogen receptor (ER) positive disease are prescribed 5-10 years of tamoxifen therapy to prevent a recurrence. 17β-hydroxysteroid dehydrogenase 1 and 2 expression (HSD17B1 and HSD17B2, respectively) regulate the relative concentrations of estrogen metabolites and may modify tamoxifen effectiveness. We evaluated the prognostic and predictive value of these biomarkers. Methods: Premenopausal women diagnosed during 2002-2011 with a first primary stage I-III breast cancer were identified in the Danish Breast Cancer Group database, and categorized based on ER status and receipt of tamoxifen (4600 ER+/TAM+ and 1359 ER−/TAM−). HSD17B1 and HSD17B2 were assayed by immunohistochemistry and scored using automated image analysis [Visiopharm (Hoersholm, Denmark)]. The biomarkers were assessed within ER/TAM strata, to differentiate the enzymes predictive of treatment response from enzymes prognostic for breast cancer recurrence. We used Cox proportional hazards regression and probabilistic bias analysis to account for mismeasurement of biomarker expression and baseline selection bias from tumor sample availability to calculate the hazard ratios (HRs) and 95% simulation intervals (SIs) associating each biomarker with recurrence. Results: 24% of ER+/TAM+ and 13% of ER−/TAM− breast cancers had any HSD17B1 expression. In the bias-adjusted analyses, women diagnosed with tumors positive for HSD17B1 expression had an increased rate of recurrence: HR=1.40 (95% SI: 1.02, 2.92) in the ER+/TAM+ stratum, and HR=1.32 (95% SI: 0.82, 2.74) in the ER−/TAM− stratum. A 10-unit increase in HSD17B2 expression corresponded with a decreased recurrence rate among women in the ER+/TAM+ (HR=0.85, 95% SI: 0.69, 1.05) stratum, but not among women in the ER−/TAM− stratum (HR=1.07, 95% SI: 0.82, 1.42). Conclusions: We observed that HSD17B1 expression was associated with a higher rate of recurrence among premenopausal women, and that HSD17B2 expression was associated with a lower rate of recurrence among premenopausal tamoxifen-treated women diagnosed with ER+ disease. HSD17B1 may be an important prognostic marker of breast cancer recurrence among premenopausal breast cancer patients and HSD17B2 may be predictive of response among tamoxifen-treated premenopausal women diagnosed with ER+ breast cancer. Citation Format: Lindsay Jane Collin, Anders Kjærsgaard, Thomas P. Ahern, Michael Goodman, Lauren E. McCullough, Lance A. Waller, Kristina B. Christensen, Per Damkier, Stephen J. Hamilton-Dutoit, Kristina Lauridsen, Peer M. Chistiansen, Bent Ejlertsen, Henrik Toft Sørensen, Deirdre Cronin-Fenton, Timothy L. Lash. 17β-hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 757.

FEN1 is a prognostic biomarker for ER+ breast cancer and associated with tamoxifen resistance through the ERα/cyclin D1/Rb axis.

BackgroundTamoxifen is an important choice in endocrine therapy for patients with oestrogen receptor-positive (ER+) breast cancer, and disease progression-associated resistance to tamoxifen therapy is still challenging. Flap endonuclease-1 (FEN1) is used as a prognostic biomarker and is considered to participate in proliferation, migration, and drug resistance in multiple cancers, especially breast cancer, but the prognostic function of FEN1 in ER+ breast cancer, and whether FEN1 is related to tamoxifen resistance or not, remain to be explored.MethodsOn-line database Kaplan-Meier (KM) plotter, GEO datasets, and immunohistochemistry were used to analyse the prognostic value of FEN1 in ER+ breast cancer from mRNA and protein levels. Cell viability assay and colony formation assays showed the response of tamoxifen in MCF-7 and T47D cells. Microarray data with FEN1 siRNA versus control group in MCF-7 cells were analysed by Gene Set Enrichment Analysis (GSEA). The protein levels downstream of FEN1 were detected by western blot assay.ResultsER+ breast cancer patients who received tamoxifen for adjuvant endocrine therapy with poor prognosis showed a high expression of FEN1. MCF-7 and T47D appeared resistant to tamoxifen after FEN1 over-expression and increased sensitivity to tamoxifen after FEN1 knockdown. Importantly, FEN1 over-expression could activate tamoxifen resistance through the ERα/cyclin D1/Rb axis.ConclusionsAs a biomarker of tamoxifen effectiveness, FEN1 participates in tamoxifen resistance through ERα/cyclin D1/Rb axis. In the future, reversing tamoxifen resistance by knocking-down FEN1 or by way of action as a small molecular inhibitor of FEN1 warrants further investigation.

Low Z-4OHtam concentrations are associated with adverse clinical outcome among early stage premenopausal breast cancer patients treated with adjuvant tamoxifen.

Low steady-state levels of active tamoxifen metabolites have been associated with inferior treatment outcomes. In this retrospective analysis of 406 estrogen receptor-positive breast cancer (BC) patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z-endoxifen and Z-4-hydroxy-tamoxifen (Z-4OHtam), with treatment outcomes in an independent cohort of BC patients. Among all patients, metabolite levels did not affect survival. However, in the premenopausal subgroup receiving tamoxifen alone (n=191) we confirmed an inferior BC -specific survival in patients with the previously described serum concentration threshold of Z-4OHtam≤3.26nm (HR=2.37, 95% CI=1.02-5.48, P=0.039). The 'dose-response' survival trend in patients categorized to ordinal concentration cut-points of Z-4OHtamoxifen (≤3.26, 3.27-8.13, >8.13nm) was also replicated (P-trend log-rank=0.048). Z-endoxifen was not associated with outcome. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and BC outcome in an independent patient cohort. Premenopausal patients receiving 5-year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness.

Multi-drug resistance protein 2 (MRP2) expression, adjuvant tamoxifen therapy, and risk of breast cancer recurrence: a Danish population-based nested case-control study

Background: Adjuvant tamoxifen therapy approximately halves the risk of recurrence in estrogen receptor-positive (ER+) breast cancer patients, but many women respond insufficiently to therapy. Expression of multi-drug resistance protein 2 (MRP2) in breast cancer may potentiate tamoxifen resistance. Thus, we investigated the expression of MRP2 in breast cancer as a predictor of tamoxifen therapy effectiveness.Material and methods: We conducted a case-control study nested in the Danish Breast Cancer Group clinical database. The study included women aged 35–69 years diagnosed with stage l–lll breast cancer during 1985–2001, in Jutland, Denmark. We identified 541 recurrent breast cancers (cases) among women with estrogen receptor positive (ER+) disease treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 cases among women with estrogen receptor-negative (ER−) disease, never treated with tamoxifen (ER−/TAM−). We matched one recurrence-free control to each recurrent case. We retrieved paraffin-embedded primary tumor tissue for all patients, and all available recurrent tumor tissue from pathology archives. MRP2 expression was evaluated using immunohistochemistry. We computed odds ratios (ORs) and 95% confidence intervals (95% CIs) associating MRP2 expression (positive vs. none) with breast cancer recurrence in conditional logistic regression models. We compared MRP2 expression in paired primary- and recurrent tumors.Results: MRP2 expression was more prevalent in the ER+/TAM + group, than in the ER−/TAM − group. No predictive utility of MRP2 for breast cancer recurrence was found in the ER+/TAM + group (ORadj = 0.96, 95% CI 0.70, 1.33). Further, no prognostic utility was found in the ER−/TAM − group (ORadj = 0.81, 95% CI 0.53, 1.23). MRP2 expression was not increased in recurrent versus primary tumors.Conclusions: MRP2 expression is neither a predictive marker of tamoxifen effectiveness nor a prognostic marker in breast cancer.

Cohort Profile: the Predictors of Breast Cancer Recurrence (ProBe CaRE) Premenopausal Breast Cancer Cohort Study in Denmark

PurposeThe Predictors of Breast Cancer Recurrence (ProBe CaRe) study was established to evaluate modification of tamoxifen (TAM) effectiveness in premenopausal women through reduced activity of TAM-metabolising enzymes. It comprehensively evaluates...

Precautions for Patients Taking Tamoxifen

Tamoxifen is a lifesaving treatment for millions of breast cancer patients worldwide. Yet taking tamoxifen may be challenging for some patients due to issues of compliance, drug interactions, and surgical considerations. Educating patients with a one-page teaching sheet, "Precautions for Patients Taking Tamoxifen," may improve tamoxifen's effectiveness and prevent complications. Advanced practitioners are in a position to prescribe tamoxifen, review medication interactions, educate patients, impact patients' quality of life, improve patients' sense of control, and increase patients' partnerships with their oncology providers.

Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics.

Tamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2D6 activity or concurrent use of CYP2D6-inhibiting drugs may reduce the clinical efficacy of tamoxifen. The issue of the clinical utility of CYP2D6 genotype testing is subject to considerable and ongoing academic and clinical controversy. In this chapter, we outline tamoxifen's clinical pharmacology and give an overview of the research to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Based on the evidence to date, the impact of drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline approved endocrine therapy.

ESR1 and PGR polymorphisms are associated with estrogen and progesterone receptor expression in breast tumors.

Hormone receptor-positive (HR+) breast cancers express the estrogen (ERα) and/or progesterone (PgR) receptors. Inherited single nucleotide polymorphisms (SNPs) in ESR1, the gene encoding ERα, have been reported to predict tamoxifen effectiveness. We hypothesized that these associations could be attributed to altered tumor gene/protein expression of ESR1/ERα and that SNPs in the PGR gene predict tumor PGR/PgR expression. Formalin-fixed paraffin-embedded breast cancer tumor specimens were analyzed for ESR1 and PGR gene transcript expression by the reverse transcription polymerase chain reaction based Oncotype DX assay and for ERα and PgR protein expression by immunohistochemistry (IHC) and an automated quantitative immunofluorescence assay (AQUA). Germline genotypes for SNPs in ESR1 (n = 41) and PGR (n = 8) were determined by allele-specific TaqMan assays. One SNP in ESR1 (rs9322336) was significantly associated with ESR1 gene transcript expression (P = 0.006) but not ERα protein expression (P > 0.05). A PGR SNP (rs518162) was associated with decreased PGR gene transcript expression (P = 0.003) and PgR protein expression measured by IHC (P = 0.016), but not AQUA (P = 0.054). There were modest, but statistically significant correlations between gene and protein expression for ESR1/ERα and PGR/PgR and for protein expression measured by IHC and AQUA (Pearson correlation = 0.32-0.64, all P < 0.001). Inherited ESR1 and PGR genotypes may affect tumor ESR1/ERα and PGR/PgR expression, respectively, which are moderately correlated. This work supports further research into germline predictors of tumor characteristics and treatment effectiveness, which may someday inform selection of hormonal treatments for patients with HR+ breast cancer.

Mammographic Density as a Biosensor of Tamoxifen Effectiveness in Adjuvant Endocrine Treatment of Breast Cancer: Opportunities and Implications.

Tamoxifen is highly effective in treating estrogen receptor (ER) –positive breast cancer. Meta-analyses of adjuvant tamoxifen treatment for 5 years have shown reduced breast cancer recurrence at 10 years, with reduced breast cancer mortality observed at 15 years(event rate ratio, 0.70; 95% CI, 0.64 to 0.75). 1 Given thattamoxifenmetabolitesbindtothe ER more avidly than the parent drug, tamoxifen recipients are hypothesized to be divisible into a group of excellent metabolizers, who receive benefit with standard dosing, and poor metabolizers, who do not benefit. 2 Accordingly, the development of validated measures for monitoring tamoxifen effectiveness would have great value, particularly among premenopausal women, a group in which tamoxifen is first-line therapy. We highlight the potential relevance of assessing mammographic breast density as a marker of tamoxifen efficacy, particularly among premenopausal women in a clinical setting. Mammographic density is a radiologic measure of the fibroglandular content within the breast and is usually expressed as the percentage of total breast area composed of dense tissue. 3,4 Women with the highest levels of percent density (ie, . 75%) experience a four- to six-fold increased relative risk of developing breast cancer compared with women who have the lowest percentage mammographic density when adjusted for confounders. 3,4 Amassing data suggest that a decline in mammographic density could serve as a much-needed predictor of a favorable response to the selective ER modulator tamoxifen. The results of four retrospective analyses, which include one that evaluated breast cancer–specific mortality among patients with ER-positive disease treated with tamoxifen, indicated that women whose mammographic density declined in the unaffected breast after initiation of tamoxifen therapy had better outcomes (reduced risk of recurrence 5,6 or death from breast cancer 7,8 ). The magnitude of the observed benefit associated with a decline (approximately 10%) in breast density was remarkably similar across studies, despite differences in the methods of mammographic density assessment and analytic approaches, which suggests that these findings are robust. The results from studies that included premenopausalwomen are shown in Table 1 .Ofthe two prior studies that examined tamoxifen-related changes and breast cancer death, 7,8 one excluded premenopausal women, 7 for whom tamoxifen remains as the primary endocrine therapy. Assessment of mammographic density change after tamoxifen treatment, specifically among younger women, merits further study to maximize the potential translational benefit of monitoring mammographic breast density change as a prognostic indicator in the clinic. In our prior retrospective analysis of patients with ER-positive breast cancer (age range, 32 to 87 years) who were diagnosed at Kaiser Permanente Northwest, 8 we compared the change in mammographic density after 1 year of tamoxifen treatment among 97 patients who died of breast cancer with 252 matched patients who did not. Women who were in the highest tertile of mammographic density decline were less likely to die of breast cancer (odds ratio [OR], 0.44; 95% CI, 0.22 to 0.88). 8 To explore the potential utility of assessing mammographic density decline as a measure of effectiveness among premenopausal women who received adjuvant tamoxifen, we performed a subset analysis that examined recurrences and deaths among 136 women with ER-positive breast cancer diagnosed at age 55 years or younger (a surrogate for premenopausal status) who were included in the initial report. Among these women, there were 34 recurrences or deaths at 5 years of follow-up and 50 such events during the whole study period (1990 to 2010). Although this analysis is limited by statistical power, multivariate Cox proportional hazards regression models demonstrated that patients with $ 10% decline in mammographic density after 1 year of tamoxifen therapy had an onsignificant improvement in disease-free survival (DFS) at 5-year follow-up (hazard ratio [HR], 0.78; 95% CI, 0.38 to 1.61);

Abstract P3-07-23: CYP2D6 genotype and breast cancer recurrence in tamoxifen treated patients: An evaluation of the importance of loss-of-heterozygosity

Abstract Background: Tamoxifen therapy for estrogen receptor positive (ER+) breast cancer reduces recurrence risk by about half. Steady-state concentrations of endoxifen, a potent anti-estrogenic tamoxifen metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Many studies have measured associations between genetically impaired CYP2D6 function and tamoxifen resistance. It has been suggested that the subset of studies using DNA extracted from tumor-infiltrated tissue may have been susceptible to genotyping error induced by loss of heterozygosity (LOH); the putative non-differential genotype misclassification may have biased these studies' estimates toward the null. We reviewed the clinical epidemiology studies conducted to date to assess the importance of loss-of-heterozygosity (LOH) at the CYP2D6 locus and its implications for assessing tamoxifen effectiveness. Methods: We searched for the terms "tamoxifen" and "CYP2D6" in PubMed, including all papers and abstracts through 31 May 2015 on the association of CYP2D6 gene variants and the risk of breast cancer recurrence or mortality. We used a quantitative bias analysis (QBA) to evaluate the importance of genotype misclassification in studies that extracted DNA from tumor-infiltrated tissue. We conducted a random effects meta-analysis to evaluate all studies simultaneously, and within groups according to whether DNA was derived from tumor-infiltrated tissue or non-neoplastic tissue. Results: Thirty-one studies investigated CYP2D6 genotype and breast cancer recurrence, yielding relative effect estimates ranging from 0.08 to 14. DNA was extracted from blood or non-neoplastic tissue in 21 of these 31 studies (68%), and from tumor-infiltrated tissue in the remaining 10 (32%). Our analysis of the association between variant/variant genotype compared with wildtype/wildtype genotype included 21 of the 31 studies. Sixteen (76%) of these 21 studies extracted DNA from blood or non-neoplastic tissue and five (24%) extracted DNA from tumor-infiltrated tissue. Genotype misclassification parameters for the QBA were estimated from six concordance studies. There was little difference between the effect estimates (EE) and 95% confidence/simulation intervals (95% CI/SI) before and after QBA (EE=1.71, 95%CI=1.24, 2.36, and 1.80 95%SI=1.28, 2.54, respectively). Studies using non-neoplastic DNA had higher variance than those based on tumor-infiltrated tissue DNA, half reported implausibly high EE, and many were susceptible to design and analysis errors that would bias estimates of association away from the null. Conclusions: We found little relative bias in the summary estimates of association, either overall or when limited to the tumor-infiltrated tissue DNA studies. Three guideline panels, based on robust evidence, recommend against CYP2D6 genotype-guided tamoxifen therapy. Alternatives for optimizing the effectiveness of tamoxifen therapy, such as assuring adherence and persistence, are more likely to achieve clinically important benefits. Citation Format: Ahern TP, Hertz DL, Damkier P, Ejlertsen B, Hamilton-Dutoit SJ, Rae JM, Regan MM, Thompson AM, Lash TL, Cronin-Fenton DP. CYP2D6 genotype and breast cancer recurrence in tamoxifen treated patients: An evaluation of the importance of loss-of-heterozygosity. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-23.

Tamoxifen effectiveness not impaired by SSRIs

Tamoxifen effectiveness not impaired by SSRIs

Tamoxifen and Antidepressant Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors.

Controversy persists about whether certain antidepressants reduce tamoxifen's effectiveness on lowering breast cancer recurrence. We investigated whether taking tamoxifen and antidepressants (in particular, paroxetine) concomitantly is associated with an increased risk of recurrence or contralateral breast cancer. We examined 16 887 breast cancer survivors (TNM stages 0-II) diagnosed between 1996 and 2007 and treated with tamoxifen in two California health plans. Women were followed-up through December 31, 2009, for subsequent breast cancer. The main exposure was the percent of days of overlap when both tamoxifen and an antidepressant (paroxetine, fluoxetine, other selective serotonin reuptake inhibitors, tricyclics, and other classes) were used. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models with time-varying medication variables. Of the 16 887 women, half (n = 8099) used antidepressants and 2946 women developed subsequent breast cancer during the 14-year study period. We did not find a statistically significant increased risk of subsequent breast cancer in women who concurrently used paroxetine and tamoxifen. For 25%, 50%, and 75% increases in percent overlap days between paroxetine and tamoxifen, hazard ratios were 1.06 (95% CI = 0.98 to 1.14, P = .09), 1.13 (95% CI = 0.98 to 1.30, P = .09), and 1.20 (95% CI = 0.97 to 1.49, P = .09), respectively, in the first year of tamoxifen treatment but were not statistically significant. Hazard ratios decreased to 0.94 (95% CI = 0.81 to 1.10, P = .46), 0.89 (95% CI = 0.66 to 1.20, P = .46), and 0.85 (95% CI = 0.54 to 1.32, P = .46) by the fifth year (all non-statistically significantly). Absolute subsequent breast cancer rates were similar among women who used paroxetine concomitantly with tamoxifen vs tamoxifen-only users. For the other antidepressants, we again found no such associations. Using the comprehensive electronic health records of insured patients, we did not observe an increased risk of subsequent breast cancer in women who concurrently used tamoxifen and antidepressants, including paroxetine.

Abstract OT3-2-07: Predicting hormonal therapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Ongoing clinical study

Abstract Background: The goal of this multi-site prospective study is to validate a safe, painless imaging method to measure the change in breast density caused by hormonal chemotherapy treatments such as tamoxifen. Recent studies have demonstrated that hormonal therapies are more effective at reducing risk in women who exhibit &amp;gt;10% reduction in breast density compared to women who had little or no density change, suggesting that breast density is a predictor of tamoxifen effectiveness. Current methods to measure breast density include MRI and mammography, however frequent applications of these modalities are limited due to cost and x-ray exposure, respectively. Alternatively, we are testing an imaging method that uses safe near-infrared light to measure breast tissue physiology called diffuse optical spectroscopic imaging (DOSI). Trial Design and Eligibility: The primary aim of the study is to determine whether the percentage change in the DOSI measurement of water correlates with the change in the MRI measurement of breast density after 18 months of treatment in the contralateral normal breast of breast cancer patients receiving tamoxifen. Other DOSI-derived parameters such as lipid content and hemoglobin concentration will be examined in secondary aims. Two groups of women are being recruited for the study: Pre-menopausal subjects receiving tamoxifen (treatment group) and pre-menopausal subjects not receiving chemoprevention agents (control group). Participants are measured with DOSI and non-contrast MRI before, and 6, 12 and 18 months after beginning tamoxifen. Eligible subjects are pre- and peri-menopausal females older than 21 years of age who have not and do not intend to receive chemotherapy, radiation, or surgical cancer treatment to the imaged breast, and are not pregnant or nursing. Study sites include the University of California, Irvine and San Francisco campuses. Statistical Methods: At a 5% significance level, the pre-determined power of the study is sufficient to detect the difference between the treatment and control groups by measuring the percentage change of breast tissue water concentration with DOSI. The research hypothesis is that the mean difference from baseline for tissue water concentration from DOSI will be greater for the tamoxifen-treated group than the control group. For water concentration and for MRI breast density, a two-sided independent sample t-test will be used to test the null hypothesis that the mean difference from baseline is the same for the tamoxifen-treated and control groups. As a secondary analysis, a multivariate mixed effects model will be built using the observed DOSI parameter or MRI breast density measured from each patient as the outcome variable, and predictor variables to include treatment group and measurement time, in addition to relevant clinical and demographic variables. Accrual Update: Out of the target accrual of 36, 11 subjects (6 treatment and 5 control group) have been enrolled to date. Enrollment is open until 11/30/2015. Citation Format: Thomas D OSullivan, Anais Leproux, Alice M Police, Dorota Wisner, Christine McLaren, Wen-Pin Chen, Albert E Cerussi, Min-Ying Su, Bruce J Tromberg. Predicting hormonal therapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Ongoing clinical study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-07.

Flaxseed and its lignan and oil components: can they play a role in reducing the risk of and improving the treatment of breast cancer?

Flaxseed (FS), rich in the phytoestrogen lignans and α-linolenic acid-rich oil, has been suggested to have an anticancer effect. Questions remain whether FS and its lignan and oil components are effective in reducing breast cancer risk and tumour growth, and can interact beneficially with breast cancer drugs. To find answers, in vitro, animal, observational, and clinical studies on FS and its lignan and oil components were reviewed. The majority of studies in various rodent models show that 2.5%-10% FS diet or the equivalent amount of lignan or oil reduces tumour growth. Ten percent FS and equivalent lignans do not interfere with but rather increase the effectiveness of tamoxifen (80 mg/day) while the 4% FS oil increases trastuzumab/Herceptin (2.5 mg/kg) effectiveness. Observational studies show that FS and lignan intake, urinary excretion, or serum levels are associated with reduced risk, particularly in postmenopausal women. Lignans reduce breast cancer and all-cause mortality by 33%-70% and 40%-53%, respectively, without reducing tamoxifen effectiveness. Clinical trials show that FS (25 g/day with 50 mg lignans; 32 days) reduces tumour growth in breast cancer patients and lignans (50 mg/day; 1 year) reduces risk in premenopausal women. Mechanisms include decreased cell proliferation and angiogenesis and increased apoptosis through modulation of estrogen metabolism and estrogen receptor and growth factor receptor signalling pathways. More clinical trials are needed but current overall evidence indicates that FS and its components are effective in the risk reduction and treatment of breast cancer and safe for consumption by breast cancer patients.

Metabolism and Transport of Tamoxifen in Relation to its Effectiveness: New Perspectives on an Ongoing Controversy

Tamoxifen reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6). Tamoxifen is a substrate for ATP-binding cassette transporter proteins. We review tamoxifen's clinical pharmacology and use meta-analyses to evaluate the clinical epidemiology studies conducted to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Our findings indicate that the effect of both drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline endocrine therapy.

Tamoxifen Benefits and &lt;i&gt;CYP2D6&lt;/i&gt; Testing in Women With Hormone Receptor-Positive Breast Cancer

Cancer intervention strategies have been increasingly focused on developing therapies that are personalized and tailored to each individual's unique genetic profile. Evolving understanding of the metabolism and pharmacogenomics of tamoxifen, an early example of targeted therapy for women with hormone receptor-positive breast cancer, has created decision-making challenges for healthcare providers and their patients. This article reviews the pharmacology of tamoxifen, the genetics and physiology of the CYP2D6 enzyme system that has important effects on tamoxifen metabolism, and subset data analyses from large controlled, clinical trials that cast new light on previously held beliefs about the utility of CYP2D6 genotyping for predicting tamoxifen effectiveness and improved breast cancer outcomes in women with early-stage, hormone receptor-positive breast cancer.

Prioritizing Pharmacogenetic Research: A Value of Information Analysis of CYP2D6 Testing to Guide Breast Cancer Treatment

Objectives To demonstrate how value of information (VOI) analysis can be used to establish research priorities regarding the use of pharmacogenetic tests using CYP2D6 testing to select adjuvant hormonal therapy in early stage breast cancer as a case study. Methods The following four treatment pathways are compared in a Markov model: tamoxifen treatment; CYP2D6 test and treat homozygous and heterozygous wild type patients (wt/wt; wt/*4) with tamoxifen and *4/*4 patients with anastrozole (HetTam); CYP2D6 test and treat homozygous wild type patients with tamoxifen and others with anastrozole (HomTam); and anastrozole treatment. Pharmacogenetic testing efficacy is estimated by synthesizing randomized controlled trial data comparing tamoxifen to anastrozole with observational data linking CYP2D6 genotype to tamoxifen outcomes. Results In order of increasing effectiveness the comparators are tamoxifen, HetTam, HomTam, anastrozole. Health outcomes for test and treatment strategies are highly uncertain. Differences in comparator costs depend on assumptions made regarding anastrozole patent expiry. The expected value of a decision taken with perfect information is £69 to £106 million (pound sterling) for the United Kingdom depending on patent expiry assumptions and the acceptable cost-effectiveness threshold. The most valuable research (VOI £53–£82 million) elucidates the relationship between CYP2D6 genotype and tamoxifen effectiveness. It is uncertain whether values of other research designs would exceed their costs. Conclusions Retrospective analysis of one of the large adjuvant aromatase inhibitor trials is warranted to better understand any association between CYP2D6 genotype and tamoxifen outcomes. VOI approaches may be helpful for prioritising evidence needs and structuring coverage with evidence development agreements for pharmacogenetics.

Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in Women Treated for Breast Cancer Chemoprevention: Results from the NSABP P1 and P2 Clinical Trials

Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however, this association in the primary prevention of breast cancer is unknown. We conducted a nested case-control study in the context of the NSABP P1 and P2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, and metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both noninvasive and invasive) while on 5 years of selective estrogen receptor modulators therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was conducted for alleles associated with absent (*3, *4, *5, and *6), reduced (*10, *17, and *41), and increased (*1XN and *2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded. A total of 591 cases were matched to 1,126 controls and DNA was genotyped in more than 97%. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR (extensive/poor metabolizer): 0.90; 95% CI: 0.46-1.74, P = 0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI: 0.575-1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI: 0.669-1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene-treated patients. In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy.

Clinical epidemiology and pharmacology of CYP2D6 inhibition related to breast cancer outcomes

Adjuvant tamoxifen therapy of breast cancer patients with estrogen receptor-positive tumors reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized by several polymorphic enzymes, including cytochrome P450 2D6 (CYP2D6), to more active metabolites. We have reviewed the clinical pharmacology of tamoxifen and evaluated the evidence from clinical epidemiology studies regarding the association between CYP2D6 inhibition and tamoxifen effectiveness. We conclude that the impact of CYP2D6 inhibition on tamoxifen effectiveness is likely to be null or small, at least in the populations studied so far. Understanding the effect of variations in tamoxifen metabolism on breast cancer outcomes, if any, will likely require a broader perspective, including examination of the complete metabolic pathway and subgroups of patients with other markers of potentially poor tamoxifen response.