Tamoxifen Levels Research Articles

Long-Term Oral Tamoxifen Administration Decreases Brain-Derived Neurotrophic Factor in the Hippocampus of Female Long-Evans Rats.

Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly used as an adjuvant drug therapy for estrogen-receptor-positive breast cancers. Though effective at reducing the rate of cancer recurrence, patients often report unwanted cognitive and affective side effects. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We, therefore, used long-term ad lib consumption of medicated food pellets to model chronic tamoxifen exposure in a clinically relevant way. Adult female Long-Evans Hooded rats consumed tamoxifen-medicated food pellets for approximately 12 weeks, while control animals received standard chow. At the conclusion of the experiment, blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography-tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain-derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. These findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.

Abstract P4-07-03: The impact of HIV on non-adherence for tamoxifen among women with breast cancer in South Africa

Abstract Introduction HIV-positive women with breast cancer (BC) have worse overall survival than HIV-negative women with BC, and poor adherence to prescribed tamoxifen is known to contribute to poor survival. We, therefore, investigated the association of HIV infection with adherence to adjuvant tamoxifen among women with localized hormone receptor (HR)-positive breast cancer in South Africa. Methods Among 4,097 women diagnosed with breast cancer at six hospitals in the prospective South African Breast Cancer and HIV Outcomes (SABCHO) cohort study between July 2015 and December 2020, we focused on women with stages I-III HR-positive breast cancer who were prescribed 20mg of adjuvant tamoxifen daily for ≥3 months during the study period. We collected venous blood once from each participant during a routine clinic visit and analyzed concentrations of tamoxifen and its metabolites using a triple quadruple mass spectrometer. We defined non-adherence as a tamoxifen level < 60ng/mL after 3 months of prescribed daily tamoxifen use. We compared socio-demographic, lifestyle factors, tamoxifen-related side effects, and concurrent medication use among women with and without HIV and developed multivariable logistic regression models of tamoxifen non-adherence. Results Among 369 participants, 78 (21.1%) were HIV-positive and 291 (78.9%) HIV-negative. After a median (interquartile range) time of 13.0 (6.2-25.2) months since tamoxifen initiation, the tamoxifen serum concentration ranged between 1.54 and 943.0ng/mL, with a median of 52.3ng/mL. In the full cohort, 208 women (56.4%) were non-adherent to tamoxifen; only 161 (43.6%) were adherent. Women < 40 years of age were less likely to adhere to tamoxifen than women >60 years (73.4% vs 52.6%, odds ratio (OR)=2.49, 95% confidence interval (CI)=1.26-4.94); likewise, HIV-positive women (70.5% vs 52.6%, OR=2.16, 95% CI=1.26-3.70) were less likely to adhere than HIV-negative women. In an adjusted model, only HIV was associated with non-adherence; HIV-positive women had twice the odds of non-adherence to tamoxifen, compared to HIV-negative women (OR=2.40, 95% CI=1.11-5.20). Conclusion Non-adherence to tamoxifen may limit the overall survival of women with HR-positive breast cancer; in our study, especially in HIV-positive women. Citation Format: Oluwatosin A Ayeni, Shingirai Chiwambutsa, Wenlong Carl Chen, Nyasha N. Kapungu, Comfort Kanji, Roslyn Thelingwani, Nivashni Murugan, Rophiwa Mathiba, Boitumelo Phakathi, Sarah Nietz, Duvern Ramiah, Daniel S. O’Neil, Judith S. Jacobson, Paul Ruff, Herbert Cubasch, Tobias Chirwa, Maureen Joffe, Collen Masimirembwa, Alfred I. Neugut. The impact of HIV on non-adherence for tamoxifen among women with breast cancer in South Africa [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-03.

Behavioral and transcriptomic effects of the cancer treatment tamoxifen in mice.

Tamoxifen is a common treatment for estrogen receptor-positive breast cancer. While tamoxifen treatment is generally accepted as safe, there are concerns about adverse effects on cognition. We used a mouse model of chronic tamoxifen exposure to examine the effects of tamoxifen on the brain. Female C57/BL6 mice were exposed to tamoxifen or vehicle control for six weeks; brains of 15 mice were analyzed for tamoxifen levels and transcriptomic changes, and an additional 32 mice were analyzed through a battery of behavioral tests. Tamoxifen and its metabolite 4-OH-tamoxifen were found at higher levels in the brain than in the plasma, demonstrating the facile entry of tamoxifen into the CNS. Behaviorally, tamoxifen-exposed mice showed no impairment in assays related to general health, exploration, motor function, sensorimotor gating, and spatial learning. Tamoxifen-treated mice showed a significantly increased freezing response in a fear conditioning paradigm, but no effects on anxiety measures in the absence of stressors. RNA sequencing analysis of whole hippocampi showed tamoxifen-induced reductions in gene pathways related to microtubule function, synapse regulation, and neurogenesis. These findings of the effects of tamoxifen exposure on fear conditioning and on gene expression related to neuronal connectivity suggest that there may be CNS side effects of this common breast cancer treatment.

The impact of HIV on non-adherence for tamoxifen among women with breast cancer in South Africa.

Women living with HIV (WLWH) and breast cancer (BC) have worse overall survival than HIV-negative women with BC, and poor adherence to prescribed tamoxifen is known to contribute to poor survival. We therefore investigated the association of HIV infection with adherence to adjuvant tamoxifen among women with localized hormone receptor (HR)-positive breast cancer in South Africa. Among 4,097 women diagnosed with breast cancer at six hospitals in the prospective South African Breast Cancer and HIV Outcomes (SABCHO) cohort study between July 2015 and December 2020, we focused on black women with stages I-III HR-positive breast cancer who were prescribed 20mg of adjuvant tamoxifen daily. We collected venous blood once from each participant during a routine clinic visit, and analyzed concentrations of tamoxifen and its metabolites using a triple quadruple mass spectrometer. We defined non-adherence as a tamoxifen level < 60ng/mL after 3months of daily tamoxifen use. We compared tamoxifen-related side effects, and concurrent medication use among women with and without HIV and developed multivariable logistic regression models of tamoxifen non-adherence. Among 369 subjects, 78 (21.1%) were WLWH and 291 (78.9%) were HIV-negative. After a median (interquartile range) time of 13.0 (6.2-25.2) months since tamoxifen initiation, the tamoxifen serum concentration ranged between 1.54 and 943.0ng/mL and 208 (56.4%) women were non-adherent to tamoxifen. Women < 40years of age were more likely to be non-adherent than women > 60years (73.4% vs 52.6%, odds ratio (OR) = 2.49, 95% confidence interval (CI) = 1.26-4.94); likewise, WLWH (70.5% vs 52.6%, OR = 2.16, 95% CI = 1.26-3.70) than HIV-negative women. In an adjusted model WLWH had twice the odds of non-adherence to tamoxifen, compared to HIV-negative women (OR = 2.40, 95% CI = 1.11-5.20). High rates of non-adherence to adjuvant tamoxifen may limit the overall survival of black South African women with HR-positive breast cancer, especially among WLWH.

Factors Associated with Plasma Levels of Tamoxifen and its Main Metabolites in Mexican Patients with Breast Cancer

Background: Tamoxifen (TAM) is commonly prescribed as adjuvant therapy in women with estrogen receptor-positive breast cancer. Unfortunately, not all patients respond adequately to this drug. This variation in pharmacological response has been associated with different factors, including genetic polymorphisms of enzymes responsible for the metabolism of TAM. Objective: To determine the concentrations of tamoxifen (TAM) and its main metabolites in Mexican women with breast cancer and to evaluate its relationship with genetic, demographic and anthropometric characteristics. Methods: Eighty-four patients with a mean age of 49.3 (± 8.8) years were included in the study. Plasma concentrations of TAM and its metabolites N-desmethyl-tamoxifen (NDT), 4- hydroxy-tamoxifen (4HT) and endoxifen (END) were determined in predose for each patient. CYP2D6 * 4, * 10 and CYP3A5 * 3 genetic polymorphisms were characterized. Demographic, anthropometric, biochemical and clinical data were recorded for each patient. Results: Plasma concentrations of 4HT and END were higher in the extensive metabolizer (EM) phenotype than in the intermediate metabolizer (IM) phenotype (p&lt;0.05). The metabolic ratio (MR) [END+4HT]/[TAM+NDT] was lower in patients with the CYP2D6 IM phenotype than those with the EM phenotype (p= 0.014). Regarding anthropometric factors, a positive correlation was found for 4HT and the END concerning age (R = 0.256 and 0.232, respectively). The body mass index (BMI) presented a statistically significant correlation with the concentrations of NDT (R=-0.351) and 4HT (R=-0.298). Conclusion: CYP2D6 phenotype, age and BMI could help to explain part of the interindividual variability of TAM plasma levels and its metabolites in the Mexican population.

Abstract P4-11-24: Patient's point of view on how to promote adherence to adjuvant endocrine therapy (ET): A large french survey

Abstract Purpose: Non-adherence to adjuvant ET remains a major issue in patients with localized breast cancer (BC) and negatively impacts the long-term recurrence and survival outcomes. Recently, we reported that 16.0% of premenopausal pts had a serum tamoxifen level below the set adherence threshold and had an increased their risk of breast cancer distant recurrences (NCT01993498). Thus, implementation of personalized effective strategies to improve patients adherence remains a topic of active research. As effective approaches must rely upon a comprehensive understanding of the multiple interplaying factors that affect adherence, we performed a survey among French breast cancer survivors that were receiving or had previously received adjuvant ET to explore patients’ expectations and preferences for mitigating ET side effects. Methods: From July 1st to July 31 2020, we addressed a large social media and web-based survey to premenopausal patients who currently or had been treated for a localised BC in collaboration with 2 major French patient advocacy groups “Les Seintinelles” and “ODYSSEA Foundation”. The survey aimed to determine: a. patient’s preferences on ET formulation and administration; b. patient’s opinion on the contents of a mobile application for managing ET. It comprised 3 items: information about the participants and the ET received or currently ongoing; preferences on ET formulation (type of pill, taste, color, shape), dosing and combination with active drugs controlling side effects; opinion on the usefulness of a mobile application and relevance of its possible contents for complementing ET administration. Results: Of the 1,616 survey responses collected, 1,474 were completely filled and could be used in the analysis. 65% of them were aged between 40 and 59 years, 68% were still receiving ET during data collection. Most of the patients considered the presentation of the drug (taste, shapes and colors) to have little impact on adherence to treatment. The preferred pharmaceutical forms were capsules or swallowable tablets (56%). 75% of participants favoured a single pill containing ET plus an active substance controlling side effects. 85% were favourable to the use of a mobile application, in particular to better understand the interest and the expected benefit of ET (15%), to be reminded when to take the treatment (11%), and to obtain advice concerning the management of side effects (29%).Conclusion: This large French survey identified two main leads that could potentially promote or improve adherence to ET: combined treatment formulation including substances. targeting side effects, and a mobile application allowing support throughout treatment duration. Patient’s opinions on ET dosing and management are essential to inform the development of personalized approaches for improving adherence. Keywords: Endocrine therapy, non-adherence, breast-cancer, survey. Citation Format: Sarra Akla, Elie Rassy, Antonio Di-Meglio, Elise Martin, Julie Havas, Andre Rieutord, Angelo Paci, David Combarel, Leonor Fasse, Florian Scotte, Guillemette Jacob, Anne Bergognoux, Suzette Delaloge, Ines Vas Luis, Barbara Pistilli. Patient's point of view on how to promote adherence to adjuvant endocrine therapy (ET): A large french survey [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-24.

A preliminary study on the association of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids in patients with breast cancer

The long-term treatment with tamoxifen can alter the lipid profile of patients with breast cancer. Only a few studies associated the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids, which is relevant as the distribution of these compounds for the tissues can be changed, negatively affecting the treatment. The variations in lipids also can account for the high interindividual variation in plasma concentrations of these compounds. The aim of this preliminary study was to associate the plasma levels of tamoxifen and the active metabolites with the lipid levels. An observational study of cases was conducted in patients with breast cancer using tamoxifen in a daily dose of 20 mg. The lipids were measured by spectrophotometric methods and the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen by high-performance liquid chromatography. A total of 20 patients were included in the study. The median plasma concentrations of tamoxifen, 4-hydroxytamoxifen and endoxifen were 62 ng/mL, 1.04 ng/mL and 8.79 ng/mL. Triglycerides levels ranged from 59 to 352 mg/dL, total cholesterol from 157 to 321 mg/dL, LDL-c from 72 mg/dL to 176 mg/dL and HDL-C from 25.1 mg/dL to 62.8 mg/dL. There were no significant associations between the plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen with the levels of triglycerides and total cholesterol. The multivariate analysis revealed a weak association between plasma concentrations of tamoxifen and the active metabolites with HDL-c, LDL-c and VLDL-c. This finding provides preliminary evidence of the low impact of lipoproteins levels in the exposure to tamoxifen, 4-hydroxytamoxifen and endoxifen.

Optimization of tamoxifen-induced Cre activity and its effect on immune cell populations

Tamoxifen (TAM) inducible Cre recombinase system is an essential tool to study gene function when early ablation or overexpression can cause developmental defects or embryonic lethality. However, there remains a lack of consensus on the optimal route and dosage of TAM administration in vivo. Here, we assessed dosage and delivery of TAM for activation of Cre in immune cell subsets assessed longitudinally and spatially using transgenic mice with ubiquitously expressed Cre/ER and the Cre-inducible fluorescent reporter YFP. After comparing two TAM delivery methods (intraperitoneal versus oral gavage) and different doses, we found that 3 mg of TAM administered orally for five consecutive days provides maximal reporter induction with minimal adverse effects in vivo. Serum levels of TAM peaked 1 week after initiating treatment then slowly decreased, regardless of dosing and delivery methods. TAM concentration in specific tissues (liver, spleen, lymph nodes, and thymus) was also dependent on delivery method and dose. Cre induction was highest in myeloid cells and B cells and substantially lower in T cells, and double-positive thymocytes had a notably higher response to TAM. In addition to establishing optimal dose and administration of TAM, our study reveals a disparate activity of Cre in different cell immune populations when using Cre/ER models.

Effect of the Single Oral Combination Treatment of Tamoxifen with Gamisoyo-san on the Pharmacokinetics Profiles of Tamoxifen

The effects of Gamisoyo-san (GMSYS) co-administration within 5 min on the pharmacokinetics (PK) of tamoxifen were observed. After 50 mg/kg of tamoxifen oral treatment, GMSYS 100 mg/kg was orally administered within 5 min to 7-wk old male SPF.VAF Outbred Crl:CD [Sprague-Dawley (SD)] rats. The plasma were collected at 30 min before administration, 30 min, 1, 2, 3, 4, 6, 8 and 24 hrs after end of GMSYS treatment, and plasma concentrations of tamoxifen were analyzed using LC-MS/MS methods. Tmax, Cmax, AUC, t1/2 and MRTinf of tamoxifen were analysis as compared with tamoxifen single administered rats. Although co-administration with GMSYS did not critically influenced on the pharmacokinetic parameters of oral tamoxifen, they induced increased trends of plasma tamoxifen concentrations, especially significant (p0.05) increases of plasma tamoxifen concentrations were demonstrated at 0.5 hr after end of co-administration with GMSYS as compared with tamoxifen single formula treated rats, at dosage levels of tamoxifen 10 mg/kg and GMSYS 100 mg/kg within 5 min. It is considered that pharmacokinetic studies should be tested like the effects of GMSYS on the pharmacokinetics of tamoxifen, when they were co-administered with prolonger intervals than Tmax of tamoxifen oral administration (about 2.5 hr-intervals), to achieve the optimal dosing regimen of GMSYS and tamoxifen co-administration.

Impairment of endoxifen formation in tamoxifen-treated premenopausal breast cancer patients carrying reduced-function CYP2D6 alleles.

AimsTamoxifen is bioactivated to endoxifen by polymorphic CYP2D6‐dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects.MethodsIn total, 118 Swedish premenopausal breast cancer patients diagnosed 2006–2014, with on‐going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real‐time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography–tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records.ResultsIn the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6–5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced‐function alleles, 2 null‐alleles, or a null/reduced‐function combination. CYP2D6*41 was the most common reduced‐function allele (82%) and 17 of 21 CYP2D6*41‐carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null‐alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderate‐to‐severe side effects were reported in a concentration‐dependent manner.ConclusionSignificantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null‐alleles, but also in carriers of 2 reduced‐function alleles. This finding may be highly relevant for future, genotype‐based dose considerations.

Impact of Oral Supplementation of Different Levels of Tamoxifen on Productive and Reproductive Efficiencies and Carcass Traits of Avian48 and Arbor Acres Broilers.

Simple SummaryThe effect of oral supplementation of Tamoxifen on productive and reproductive efficiencies and carcass characteristics of two broiler breeds was investigated in the current study. Tamoxifen supplementation can improve growth performance and carcass efficiency of broilers without changing the sex hormonal profile, however, treatment of broiler chicken with Tamoxifen in different doses caused a gradual decrease in follicle production rate and eventually led to an increase of the atretic follicles in different stages of atresia. Further research is required to estimate the best concentration required for each breed.This research was aimed at estimating the effect of oral supplementation of Tamoxifen on productive efficiency, carcass characteristics, hormonal profile and gonadal structure of two broiler breeds. One hundred and eighty chicks of each breed of Avian48 and Arbor Acres were divided into three groups: control group; TAM10 group, supplied with 10 mg Tamoxifen/kg of body weight at 3, 5, 7 and 9 days of life; and TAM20 group, supplied at the same intervals with 20 mg Tamoxifen/kg of body weight. Both levels of Tamoxifen improved productive performance at early ages, but Arbor Acres produced better results with TAM20 levels than TAM10, while Avian48 breeds reacted adversely. On the contrary, Tamoxifen supplementation significantly decreased feed intake and feed conversion (after the first two weeks of life) compared to control with a higher level of decrease reported for TAM20 treatments than TAM10 and for Arbor Acres compared to Avian48 breed. Carcass traits were not affected significantly with Tamoxifen supplementation compared to control although Arbor Acres responded better to TAM20 and Avian48 for TAM10. With regard to the effect of Tamoxifen (TAM) on sex hormones, it could be concluded that TAM10 treatments showed a stimulating effect on the level of such hormones as compared with the TAM20 group with the most favourable results being clearly detectable in 42-day-old birds although both concentrations of Tamoxifen did not differ significantly from control. However, treatment of broiler chickens with Tamoxifen in different doses caused a gradual decrease in follicle production rate and eventually led to an increase of the atretic follicles in different stages of atresia. Finally, we can conclude that Tamoxifen supplementation can improve performance and carcass efficiency of broilers without changing the hormonal profile, however much research is required to estimate the best concentration required for each breed.

Relationship between CYP2D6 genotype, tamoxifen metabolites, and adverse events, tumor biomarkers and breast cancer recurrence in a low-dose phase III trial in noninvasive disease.

1553 Background: Low dose tamoxifen (T, 5 mg/d) given for 3 years halved recurrence in 500 women with non-invasive disease (DeCensi et al. JCO 2019). Retrospective studies with 20 mg/d have shown an association between low levels of endoxifen (9-16 nM) or Z-4OHtam (3.26 nM) and recurrence, but recent prospective studies have not confirmed these findings. We measured CYP2D6 genotype and 8 metabolite levels to determine their associations with adverse events, tumor biomarkers (IGF-I, SHBG, C-reactive protein, CRP) and breast cancer recurrence. Methods: CYP2D6 genotyping was performed in the T arm (n = 183) as previously described (Johansson H et al. BCRT 2016). T and metabolites were measured at 1 (n = 169) and 3 y (n = 152) as previously described (Helland T et al. BCR 2017). We tested linear relationships between metabolite levels and biomarkers, adjusting for age, BMI, treatment compliance and baseline biomarker levels. Cumulative incidence of recurrence according to endoxifen levels was calculated by the Cox model. Results: Endoxifen concentrations were associated to CYP2D6 metabolizer status (p &lt; 0.001). Median (IQR) endoxifen levels were 8.4 (5.2-11.3) and 8.8 (5.8-11.5) at 1 and 3 y, with only 42% and 47% of subjects reaching 9 nM. Median endoxifen levels were related to pill count (5.5, 7.1 and 9.0 nM/L for medication possession rate &lt; 83.3%, 83.4-99.9%, 100%, respectively). There was no difference in metabolite levels and menopausal symptoms. There was an inverse relationship between endoxifen and endometrial thickness at 3 y (p = 0.04), and between endoxifen or tamoxifen levels and IGF-I levels at 3 y (p = 0.001). T levels were positively associated with SHBG levels in postmenopausal women (p-interaction = 0.04). Endoxifen, T and 4OHtam decreased CRP, with a greater effect in premenopausal women (p-interaction = 0.02). An increase in CRP after 3 years was associated with a HR of 4.37 (95% CI, 1.14-16.73, P = 0.03) of recurrence compared to women with no increase of CRP. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3-11.4) in patients who recurred vs 7.5 (5.1-10.2) in those who did not recur (p = 0.6), although this comparison was underpowered. Conclusions: T levels themselves may contribute to clinical activity by decreasing IGF-I and increasing SHBG. Elevated CRP is a predictive factor for recurrence which is down-regulated by T and metabolites. Endoxifen is below 9 nM in the majority of subjects treated with 5 mg/day, although this threshold was obtained in studies up to 20 years. Clinical trial information: NCT01357772.

Abstract P5-12-05: Clinical outcomes in early breast cancer patients on adjuvant tamoxifen: Impact of CYP2D6 genotype and observed endoxifen concentrations

Abstract Background: Tamoxifen is widely used in patients with hormone sensitive breast cancer in the adjuvant setting to decrease risk of recurrence and metastasis. 5-10 years of tamoxifen has demonstrated a near 50% reduction in recurrence risk. Despite marked interpatient variation in the metabolism of tamoxifen to its active metabolite endoxifen, all patients are prescribed 20 mg daily dose of tamoxifen. Current evidence suggests that patients are at risk for suboptimal benefit if measured endoxifen concentration is below 5.9 ng/ml (~15nM). However, there have been conflicting data on the clinical utility of CYP2D6 genotype testing, and measuring endoxifen plasma concentration as a predictor of breast cancer recurrence. The goal of this prospective study was to determine the impact of endoxifen levels and CYP2D6 genetic variations to clinical outcome among patients with early breast cancer. Methods: Since 2010, as part of Personalized Medicine Program in Oncology, our team has been prospectively enrolling patients on tamoxifen therapy. To date 950 patients have been enrolled and preliminary analysis has been completed in 429. After initial CYP2D6 genotype testing, plasma concentration of tamoxifen and its metabolites were quantified using liquid chromatography-tandem mass spectrometry during each clinic visit. Baseline characteristic are outlined in table 1. Primary outcome assessed was invasive disease-free survival (IDFS) defined as time since start of tamoxifen therapy till an event of interest such as loco-regional recurrence, distant metastasis, new contralateral primary breast cancer, death due to breast cancer and other causes. Patients were censored at their last encounter at our institution (London Health Sciences Centre). Results: IDFS data for 426 patients were obtained. Outcome was stratified by CYP2D6 phenotypes (ultra-rapid, extensive, intermediate and poor metabolizers) and endoxifen levels (&amp;gt;5.9ng/ml or &amp;lt;5.9ng/ml). CYP2D6 phenotype did not demonstrate a significant association for IDFS. However, Kaplan Meier analysis stratified for endoxifen concentration &amp;gt;vs&amp;lt; 5.9 ng/ml showed a clear trend towards lower IDFS (hazard ratio = 2.4, (95%CI,1.26-4.77) P=0.0002) among those with endoxifen &amp;lt; 5.9 ng/ml. We note this preliminary data analysis was unadjusted and will undergo further in-depth statistical analysis. Conclusion: Preliminary finding suggests endoxifen concentration, but not CYP2D6 phenotype, may be a predictor of risk for suboptimal benefit during tamoxifen therapy. Detailed statistical analysis is planned for the full cohort, including adjustment for covariates including tumor stage, menopausal status, drug interactions, and use of aromatase inhibitors. To our knowledge, this is the first study of its type to prospectively collect multiple plasma samples for tamoxifen and endoxifen level in real-world patients during tamoxifen therapy, with sufficient sample size and follow-up period for primary clinical outcome. Table 1: Baseline Characteristics of PatientsCharacteristicsCYP2D6-Phenotypes, n=429 (%)Endoxifen concentration, n=429 (%)UM/EMIMPM&amp;gt;5.9ng/ml(~15nm)&amp;lt;5.9ng/ml(~15nm)n= 256n= 153n= 20n=376n= 53Age at DiagnosisMean5049485048Range24-8928-7928-8324-8427-88SexMale3 (1)7(5)08(2)2(4)Female253 (99)146(95)20(100)368(98)51(96)Tumor statusT1121(47)70(46)9(45)177(47)23(43)T297(38)58(38)10(50)142(38)23(43)T318(7)16(10)1(5)30(8)5(9)T412(5)4(3)016(4)0unknown8(3)5(3)011(3)2(4)Nodal statusN0124(97)71(46)10(50)179(48)26(49)N195 (37)53(35)9(45)144(38)13(24)N217(7)18(12)1(5)28(7)8(15)N313(5)5(3)015(4)3(6)Unknown7(3)6(4)010(3)3(6)HistologyIDC205(80)128(84)16(80)303(81)48(91)ILC28(11)14(9)3(15)41(11)3(6)other5(2)2(1)06(2)0unknown18(7)9(6)1(5)26(7)2(4)Grade154(21)24(16)3(15)78(21)3(6)2139(54)84(55)13(65)202(54)34(64)354(21)39(25)4(20)84(3)13(24)unknown9(4)6(4)012(3)3(6)ER+251(98)151(99)20(100)369(98)53(100)-5(2)2(1)07(2)0unknown00000PR+232(90)142(93)20(100)343(91)51(96)-24(9)11(7)033(9)2(4)unknown00000Her2+55(21)25(16)5(25)75(20)10(19)-200(78)127(84)15(75)299(80)43(81)unknown1102(1)0Breast SurgeryMastectomy149(58)84(55)11(55)214(57)30(57)Lumpectomy105(41)68(44)9(45)159(42)23(43)Unknown2(1)103(1)0Axillary SurgerySLNB137(54)80(52)12(60)204(54)25(47)ALND113(44)70(46)8(40)165(44)26(49)Unknown6(2)3(2)07(2)2(4)Chemotherapy190(74)108(71)16(80)277(74)37(70)Radiation Therapy213(83)126(82)17(85)310(82)46(87)Herceptin57(22)23(15)6(30)77(16)9(17) Citation Format: Veera Durga Sravanthi Panuganty, Denise Keller, Wendy A Teft, John Gordon Lenehan, Kylea Raijann Potvin, Jawaid Younus, Theodorus Anthony Vandenberg, Diane Mary Logan, Karin Hahn, Muriel Brackstone, Phillip Stanley Blanchette, Francisco Perera, Yun-Hee Choi, Richard Brian Kim. Clinical outcomes in early breast cancer patients on adjuvant tamoxifen: Impact of CYP2D6 genotype and observed endoxifen concentrations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-05.

Abstract P2-11-12: The influences of adherence to tamoxifen and CYP2D6 pharmacogenetics on plasma concentrations of the active metabolite (Z)-endoxifen in breast cancer

Abstract One-third of early breast cancer patients with estrogen receptor (ER) positive tumors treated with the selective estrogen receptor modulator tamoxifen either relapse or die from the disease in the following decade. Improvement of tamoxifen efficacy requires a better knowledge of factors determining outcome of which the medication-taking behavior, i.e. adherence, is a strong suspect. Discontinuation and non-adherence to tamoxifen are frequent and result in increased mortality. Commonly used methods to assess drug adherence such as prescription-refill patterns infer that the medication is taken exactly as prescribed yet, partial adherence or actual use of the medication cannot be controlled. An objective surrogate of tamoxifen adherence is the monitoring of drug concentrations in the patients’ plasma including the parent drug and its active metabolite (Z)-endoxifen (endoxifen), however individual concentrations depend on pharmacogene polymorphisms particularly those of the liver enzyme cytochrome P450 2D6 (CYP2D6). Patients without CYP2D6 variants have normal enzyme function (extensive metabolizer, EM) and achieve high endoxifen concentrations compared to patients with variants conferring absent activity (poor metabolizer, PM) or reduced activity (intermediate metabolizer, IM) who have significantly lower plasma concentrations of the active metabolite. A putative threshold of 5.9 ng/mL endoxifen has been proposed suggesting that patients with endoxifen concentration above or below threshold have lower or higher risk for recurrence, assuming that low endoxifen exposure in the tumor likely results in incomplete inhibition of ER-dependent growth signaling. During tamoxifen treatment it is therefore important that patients achieve clinically relevant endoxifen levels while at the same time avoid confounders of which adherence is a prime candidate. To this end, we investigated patients’ ability to achieve relevant plasma concentrations during tamoxifen treatment in relation to their CYP2D6 metabolizer status and their tamoxifen adherence behavior. Our prospective study included 192 Brazilian breast cancer patients treated with 20 mg tamoxifen daily. Two-thirds of the patients were premenopausal. Plasma levels of tamoxifen and its metabolites were measured by LC-MS/MS at 3, 6 and 12 months of treatment. Adherence to tamoxifen was evaluated by the questionnaire-based Morisky medication adherence scale. CYP2D6 polymorphisms were determined by MALDI-TOF mass spectrometry and real-time PCR. Adherence to tamoxifen decreased from 74% at month 3 to 64% at month 12, and explained 47% of the variability of tamoxifen plasma concentrations (P&amp;lt;.001). Accordingly, plasma monitoring of tamoxifen is useful to inform on tamoxifen adherence. Endoxifen concentrations were associated with CYP2D6 status and adherence. While CYP2D6 explained 26.4% of endoxifen variability at 12 months, the combination with adherence explained 40% (P&amp;lt;.001). The influence of low adherence to not achieving therapeutic endoxifen levels was highest in patients with non-compromised CYP2D6 function (EM phenotype, RR 3.65; 95% CI: 1.48-8.99). we conclude that for patients with intact CYP2D6 function adherence to tamoxifen is critical to achieve therapeutic endoxifen plasma levels. CYP2D6 phenotyping and endoxifen plasma monitoring may help to guide EM (and IM) patients to adhere to tamoxifen which is particularly relevant for premenopausal women who are at higher risk to not adhere to tamoxifen. Citation Format: Jose Claudio Casali da Rocha, Jeanine M Nardin, Werner Schroth, Thais A Almeida, Thomas Mürdter, Solange Picolotto, Evelyn CL Vendramini, Reiner Hoppe, Jenifer P Kogin, Diandra Miqueleto, Silvia DR Moraes, Matthias Schwab, Roberto F Pecoits-Filho, Hiltrud Brauch. The influences of adherence to tamoxifen and CYP2D6 pharmacogenetics on plasma concentrations of the active metabolite (Z)-endoxifen in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-12.

Capecitabine-Based Chemoendocrine Combination as First-Line Treatment for Metastatic Hormone-Positive Metastatic Breast Cancer: Phase 2 Study

BackgroundPreclinical studies have suggested a synergistic effect of tamoxifen and capecitabine in estrogen receptor–positive cell lines. We evaluated the safety and efficacy of first-line chemoendocrine treatment in patients with metastatic breast cancer. Biochemical assessment was performed of serum levels of thymidine phosphorylase enzyme (TP), serum tamoxifen, hydroxytamoxifen, and 5-fluorouracil in relationship to efficacy. Patients and MethodsThis prospective phase 2 interventional study studied patients with estrogen receptor-positive, HER2− metastatic breast cancer who received either tamoxifen/capecitabine or letrozole/capecitabine as first-line treatment. The dose of capecitabine provided at 2000 mg per day continuously as a fixed dose. ResultsForty women with a median age of 49.3 years were enrolled. For the whole study group, median progression-free survival (PFS) was 10 months and median overall survival (OS) was 23.3 months. The overall response rate was 60% and the clinical benefit rate 82.5%. Progesterone receptor positivity was associated with significantly longer PFS (12 vs. 7 months, P = .021). The most frequent adverse events were palmar–plantar erythrodysesthesia (62.5%), fatigue (62.5%), diarrhea (30%), abdominal pain (12.5%), and constipation (10%). Changes in serum level of TP were not correlated to response to treatment, PFS, or OS. Higher serum levels of tamoxifen and hydroxytamoxifen were correlated with higher response rates and longer PFS but not OS. ConclusionChemoendocrine treatment is well tolerated, with no evidence of contradictory effects between the combination components. However, the efficacy data need more validation.

Medication Adherence of Tamoxifen to Breast Cancer Patients and the Affecting’s Factors in Dharmais Cancer Hospital Jakarta

Several previous studies show that adherence to hormonal therapy increases the survival rate in Breast Cancer (BC) with ER+ or PR+. Tamoxifen is one of oral chemotherapy which is the most used hormonal therapy in breast cancer treatment regimens. The focus of the study was to determine the level of adherence and factors influencing the adherence of the treatment of BC patients undergoing hormonal therapy with Tamoxifen in patients at Dharmais Cancer Hospital in the year 2018. The study is an observational study with a cross-sectional design. The study was followed by 109 respondents. Medication adherence levels assessed via questionnaire modified MARS-5. Sociodemographic and clinical characteristics obtained from interviews using structured questionnaires. Medication adherence’s level of Tamoxifen was 90.9% with the proportion of adhering patients was 75.2% (82 of 109 patients). Multivariate analysis showed that the age of respondents, level of education, level of knowledge is the most influential factor and determine the level of treatment adherence. Education level is the variable that has the greatest effect on medication adherence. Through this study, it is recommended to pay more attention to patients with specific characteristics such as patients with low education and or low income.

Oral versus topical tamoxifen in cyclical mastalgia-A randomized controlled trial.

Mastalgia affects premenopausal in which cyclical mastalgia affects up to 40% of women. In approximately 8% of these women, pain will be severe and interfere with their normal activities. oral tamoxifen widely used in the treatment of mastalgia is associated with a wide range of side effects. Topical tamoxifen has the potential to be a more efficacious and safer alternative with lower blood drug levels hence having lower systemic side effects. To compare reduction in the pain, nodularity and blood drug levels of tamoxifen using topical verus oral tamoxifen in cyclical mastalgia. Patients who presented to the surgery outpatient department with complaints of breast pain were provided with a breast pain evaluation questionnaire. Patients were randomized using a computer generated sequence into two groups with 75 participants in each group. In Group 1, the participants received topical tamoxifen gel and a placebo tablet for 3months, and in Group 2, the participants received Oral Tab Tamoxifen 10mg OD and a placebo gel for 3months. They were provided with a Cardiff Breast Pain assessment chart and asked to mark the severity of their pain and response to treatment in the following month and asked to report to the investigator. Patients were called for review every month, and the pain chart was monitored and documented. The response to therapy (relief of pain) was assessed after 3months of treatment and once more at the end of 6months for recurrence. After completion of 1month of treatment, blood sample was drawn to check for the blood drug levels. There is a significant difference of mean pain score between oral and topical tamoxifen groups (P<.001) at the end of 1month, 3months (P<.001), and 6months (P<.001). There is a significant difference in the Nodularity found between oral and topical groups at presentation (P=.004), at 1month (P=.003) and at 6months (P<.001). There is a significant difference of mean blood tamoxifen level (ng/mL) in oral and topical tamoxifen groups (P<.001). From this study, we conclude that topical tamoxifen is more effective than oral tamoxifen treatment in reducing cyclical breast pain and decreasing breast nodularity with lesser side effects and lower recurrence rates.

The Influences of Adherence to Tamoxifen and CYP2D6 Pharmacogenetics on Plasma Concentrations of the Active Metabolite (Z)-Endoxifen in Breast Cancer.

Tamoxifen efficacy in breast cancer is suspected to depend on adherence and intact drug metabolism. We evaluated the role of adherence behavior and pharmacogenetics on the formation rate of (Z)‐endoxifen. In 192 Brazilian patients, we assessed plasma levels of tamoxifen and its metabolites at 3, 6, and 12 months of treatment (liquid‐chromatography tandem mass spectrometry), adherence behavior (Morisky, Green, and Levine medication adherence scale), and cytochrome P450 2D6 (CYP2D6) and other pharmacogene polymorphisms (matrix‐assisted laser‐desorption‐ionization time of flight) mass spectrometry, real‐time polymerase chain reaction). Adherence explained 47% of the variability of tamoxifen plasma concentrations (P < 0.001). Although CYP2D6 alone explained 26.4%, the combination with adherence explained 40% of (Z)‐endoxifen variability at 12 months (P < 0.001). The influence of low adherence to not achieving relevant (Z)‐endoxifen levels was highest in patients with noncompromised CYP2D6 function (relative risk 3.65; 95% confidence interval 1.48–8.99). As a proof‐of‐concept, we demonstrated that (Z)‐endoxifen levels are influenced both by patient adherence to tamoxifen and CYP2D6, which is particularly relevant for patients with full CYP2D6 function.

Clinical Trial: CYP2D6 Related Dose Escalation of Tamoxifen in Breast Cancer Patients With Iranian Ethnic Background Resulted in Increased Concentrations of Tamoxifen and Its Metabolites.

Introduction: The polymorphic enzyme cytochrome P450 2D6 (CYP2D6) catalyzes a major step in the bioactivation of tamoxifen. Genotyping of clinically relevant CYP2D6 alleles and subsequent dose adjustment is a promising approach to individualize breast cancer therapy. The aim of this study was to investigate the relationship between the plasma levels of tamoxifen and its metabolites and different CYP2D6 genotypes under standard (20 mg/day) and dose-adjusted therapy (Registration ID in Iranian Registry of Clinical Trials: IRCT2015082323734N1).Materials and Methods: Using TaqMan® assays common alleles of CYP2D6 (∗1, ∗2, ∗4, ∗5, ∗6, ∗10, ∗17, and ∗41) and gene duplication were identified in 134 breast cancer patients. Based on CYP2D6 genotypes patients with an activity score 1 (n = 15) and 0–0.5 (n = 2) were treated with tamoxifen adjusted dosage of 30 and 40 mg/day, respectively. The concentration of tamoxifen and its metabolites before and after 4 and 8 months of dose adjustment were measured using LC-MS/MS technology.Results: At baseline, (Z)-endoxifen plasma concentrations (33 ± 15.5, 28.1 ± 14, 26.6 ± 23.4, 14.3 ± 8.6, and 10.7 ± 5.5 nmol/l for EM/EM, EM/IM, EM/PM, IM/IM and PM/PM, respectively) and the metabolic ratio (Z)-Endoxifen/N-desmethyltamoxifen (0.0558 ± 0.02, 0.0396 ± 0.0111, 0.0332 ± 0.0222, 0.0149 ± 0.0026, and 0.0169 ± 0.0177 for EM/EM, EM/IM, EM/PM, IM/IM, and PM/PM, respectively) correlated with CYP2D6 genotype (Kruskal–Wallis p = 0.013 and p < 0.0001, respectively). Dose escalation to 30 and 40 mg/day in patients with a CYP2D6 activity score of 1 (n = 15) and 0–0.5 (n = 2) resulted in a significant increase in (Z)-endoxifen plasma levels (22.17 ± 24.42, 34.43 ± 26.54, and 35.77 ± 28.89 nmol/l at baseline, after 4 and 8 months, respectively, Friedman p = 0.0388) along with the plasma concentrations of tamoxifen and its other metabolites. No severe side effects were recorded during dose escalation.Conclusion: For the first time, we show the feasibility of dose escalation of tamoxifen in breast cancer patients with compromised CYP2D6 activity and Iranian ethnic background to increase the plasma concentrations of (Z)-endoxifen.

Weekly vaginal administration of tamoxifen for three months in postmenopausal women with vulvar and vaginal atrophy: a possible new treatment approach?

An exploratory study was conducted recruiting four healthy postmenopausal women suffering from vulvar and vaginal atrophy (VVA). Subjects self-administered vaginal suppositories containing tamoxifen (20 mg). Subjects were instructed to insert one suppository vaginally once daily for one week and twice weekly over a period of three months. Vaginal pH and dryness scores using a visual analog scale (VAS) were recorded at enrollment and subsequent assessments were recorded using self-assessment questionnaires over a three-month period. Serum tamoxifen levels were measured after two months of suppository use. After three months, both vaginal pH and vaginal dryness symptoms showed significant improvement. Vaginal pH scores improved approximately 30% compared to baseline by completion of the study. Vaginal dryness scores improved approximately 63% compared to baseline. As expected, serum tamoxifen levels were negligible ranging from 1.0 ng/ml to 10.0 ng/ml determined after eight weeks on the treatment. The present results suggest that delivery of tamoxifen directly to the vaginal epithelium for the treatment of VVA may be a viable new treatment approach. Therefore, this route of administration may offer an important treatment modality for patients with a history of breast cancer, at risk for breast cancer, and who have hormone-receptor-positive breast cancer, including estrogen receptor-positive (ER-positive), and progesterone receptor-positive (PR-positive) in addition to node negative breast cancer.