Search

Bertha Alejandra Martinez-Cannon,1,2 Andrea Castro-Sanchez,2 Regina Barragan-Carrillo,2 Sylvia de la Rosa Pacheco,1 Alejandra Platas,2,3 Alan Fonseca,2,3 Yoatzin Vega,2 Karen Bojorquez-Velazquez,3 Juan Enrique Bargallo-Rocha,2,3 Alejandro Mohar,3,4 Cynthia Villarreal-Garza1,2 1Breast Cancer Center, Hospital Zambrano Hellion TecSalud, Tecnologico de Monterrey, San Pedro Garza Garcia, Mexico; 2Joven & Fuerte: Programa para la Atencion e Investigacion de Mujeres Jovenes con Cancer de Mama, Mexico City, Mexico; 3Departamento de Investigacion y de Tumores Mamarios, Instituto Nacional de Cancerologia, Mexico City, Mexico; 4Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México, Mexico City, MexicoCorrespondence: Cynthia Villarreal-GarzaBreast Cancer Center, Hospital Zambrano Hellion TecSalud, Tecnologico de Monterrey, Av. Batallon de San Patricio 112, Real San Agustin, 66278, San Pedro Garza Garcia, Nuevo Leon, MexicoEmail cynthiavg@gmail.comBackground: Breast cancer (BC) in young women is characterized by an unfavorable prognosis in hormone receptor-positive/HER2-negative tumors, which may be explained by low rates of tamoxifen adherence. In Mexico, up to 14% of all BC diagnoses occur in young women and no data on tamoxifen adherence has been reported.Objective: To estimate the rate of adherence to adjuvant tamoxifen in Mexican young women with BC (YWBC).Methods: A cross-sectional survey was conducted at the National Cancer Institute in Mexico City, among YWBC (≤ 40 years at diagnosis) receiving adjuvant tamoxifen. Adherence was measured subjectively, through self-reported surveys, and objectively, through medication possession ratio (MPR). Descriptive statistics were used to analyze sociodemographic characteristics. To compare associations between patients’ characteristics and adherence, Chi-square test was used for categorical variables and Student’s t-test or Mann–Whitney U-test for quantitative variables.Results: A total of 141 YWBC receiving adjuvant tamoxifen were included. Regarding subjective adherence, 95% expressed taking tamoxifen regularly, 70% reported missing 0 doses in the past 30 days, and 71.6% reported having adverse effects. Regarding objective adherence, 74.8% of patients had an MPR ≥ 80%. The association between subjective and objective adherence was statistically significant (p = 0.004). Subjective adherence was associated with not skipping tamoxifen doses when feeling worse. Objective adherence was associated with having a stable job, not skipping tamoxifen doses when feeling worse, taking additional medications, and time on tamoxifen treatment. Fifty-six percent considered the information on tamoxifen to be insufficient and 37% not understandable.Conclusion: In our study, high subjective and objective adherence rates to adjuvant tamoxifen were reported, although an important proportion of women reported high rates of adverse effects and not fully understanding the benefits of tamoxifen. Strategies to increase tamoxifen adherence may be even more important now that longer durations of treatment or further ovarian function suppression have become the standard of care in YWBC.Keywords: young women, breast cancer, tamoxifen, adherence, Mexico

Background: Metastatic breast cancer (MBC) represents a major health problem in Egypt and worldwide. Prognostic and predictive factors for patients with MBC are highly required for better management and improved survival. The aim of this study was to assess the prognostic and predictive value(s) of CYP2D6 polymorphisms in Tamoxifen responders and non-responders. Methods: A cohort of 157 hormone receptor positive, locally recurrent inoperable and/or metastatic (MBC) Egyptian female patients was assessed for CYP2D6 polymorphisms. Data were correlated to relevant clinic-pathological features of the patients, response to tamoxifen, and survival rates. Results: CYP2D6 polymorphisms were detected in 44/157 cases (28%), 30 of them (68.2%) were refractory and 14 (31.8%) were responders (P=0.027). The CYP2D6 *3,*4 variants were significantly prevalent in the refractory group 26/30 (86.6%), while the *10/*10 and *10/*3 variants were more common in the responders 12/14 (85.71%, P=0.027). CYP2D6 polymorphism associated significantly with Her-2 amplification (P=0.001) as well as reduced overall survival rates in both refractory and responder patients (P< 0.001). Conclusion: CYP2D6 polymorphisms can significantly predict response to Tamoxifen treatment, and also associates with poor overall survival rates in MBC patients.

Oral mucosal involvement of autoimmune progesterone dermatitis is exceedingly rare. This report presents a woman with very painful ulcerative stomatitis that recurred with every menstrual period, in the absence of other clinical manifestations. Ulcers were eventually controlled with oral tamoxifen treatment for three months. Subsequent follow-up visits showed complete resolution of her oral ulcerative lesions. The nonspecific nature of her oral ulcers resulted in multiple medical and dental consultations and a delay in reaching the final diagnosis. Clinicians should be aware of the possibility of progesterone hypersensitivity when painful oral ulcerative lesions appear concurrently with each progesterone surge.

Aim: We conducted a retrospective analysis in 71 Mexican Mestizo patients to evaluate the breast cancer-free survival (BCFS) among the inferred genetic phenotypes (GP) of CYP2D6. Patients & methods: CYP2D6 was genotyped through Taqman-probe analysis; GP were inferred according to international guidelines. The BCFS was estimated through Kaplan–Meier method and analyzed with a log-rank test; hazard ratios were calculated with 95% CI and p < 0.05. Results: The BCFS did not differ among CYP2D6 GP (p = 0.45) and recurrence risk was similar between gNM + gUM and gPM + gIM groups (hazard ratio: 1.54, 95% CI: 0.37–6.38; p = 0.55). Conclusion: The findings do not support any impact of CYP2D6 on BCFS. Evaluation of other genetic/nongenetic biomarkers is needed in Mexican Mestizo patients under tamoxifen treatment.

Pancreatic adenocarcinoma remains a chemotherapy-resistant and refractory malignancy with high mortality, unaffected by recent progress in anticancer treatment. Expression of estrogen receptors was detected almost 50 years ago, in both benign and malignant pancreatic cells. However, early preclinical studies in pancreatic cancer led to contradictory findings, and most clinical studies failed to demonstrate an effect with tamoxifen treatment. The identification of a second form of estrogen receptor seems to provide some explanation for these discrepancies. Predominantly expressed in malignant cells and structurally different from what was considered the only estrogen receptor, estrogen receptor β was recognized as a negative prognostic factor and a possible therapeutic target in pancreatic ductal adenocarcinoma. Therefore, findings of research before the identification of estrogen receptor β should be reconsidered, and further studies should be designed to reassess the expression and effect of this specific estrogen receptor type in pancreatic cancer.

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.

Aim: The aim of the present study was to investigate the efficacy of osthole (7-metoxy-8-isopenthenocoumarin) alone and combined with tamoxifen (TAM) in the elimination of human cervical cancer cells via programmed death. The involvement of heat shock proteins, i.e. well-known molecular chaperones, will be investigated. Material/Methods: Three human cervical cancer cell lines, infected with human papilloma virus (HPV), i.e. HeLa (HPV 18), SiHa (HPV 16), and CaSki (HPV 16 and 18), were used in the experiments. After osthole and TAM treatment, cells stained with fluorochromes were analyzed microscopically according to apoptotic, autophagic, and necrotic morphology. Hsp27, Hsp72, and Hsp90 levels were analyzed by immunoblotting. Transfection with specific siRNA was used for blocking of Hsp expression. Results: In the HeLa, CaSki, and SiHa cell lines, osthole and TAM applied alone had no significant effect on cell death induction. This was correlated with an overexpression of heat shock proteins 27, 72, and 90. In the case of a combination of both drugs, the level of apoptosis was elevated only in SiHa cells. Preincubation with osthole followed by TAM addition as well as simultaneous incubation with both drugs was the most effective. This was correlated with the inhibition of Hsp27, Hsp72, and Hsp90 expression. Blocking of Hsp expression with specific siRNA increased the sensitivity of the studied cell lines to the induction of apoptosis, but not to autophagy or necrosis. Conclusions: Our results indicated that the elimination of heat shock proteins from cervical cancer cells sensitized them to initiation of apoptosis after osthole and tamoxifen treatment.

Objective: The aim of the present work is to evaluate the molecular structure changes of the lens of rabbits and DNA damage of epithelial cells due to tamoxifen administration. Methods: Twenty four healthy New Zealand white rabbits were divided into 2 main groups. The first group is served as control (n=12) kept untreated, second one is Tamoxifen administrative group (n=12) received orally daily dose of 15 mg/kg. Rabbits were decapitated after 2, 4, 6 and 8 mo, respectively. Using fourior transform infrared (FTIR) to study the molecular structure changes due to tamoxifen and comet assay analysis for discovering DNA damage. Results: FTIR data indicated that tamoxifen affects structural components in NHOH and fingerprint region. Increases of β-turns of the protein secondary structure while, reducing the content of both α-helix after 8 mo and Turns appeared for all periods of administrative tamoxifen were observed. On the other hand tamoxifen induced a statistically significant increase in comet assay parameters as tail moment compared to control animals that indicated DNA damage due to single or double strand break. Conclusion: Tamoxifen uses for more than 6 mo may lead to changes in the molecular structure of the lens and damage of DNA cells. An ophthalmic baseline examination prior to anti-cancer treatment may help detect any pre-existing ocular condition and lead to reduction of ocular side effects when predisposed patients are screened and examined regularly during and after chemotherapeutic therapy.

Objective: Previous Western studies reported that older (≥50 years) breast cancer survivors with tamoxifen treatment had higher risk of endometrial cancer. This study aims to disclose whether younger (

BACKGROUND: Approximately 70–80% of breast cancer express ER-alpha and hormonal therapies, given significant improvements in patient survival. About 50% of ER-positive breast cancer patients with advanced disease insensitive to tamoxifen treatment when diagnosed. Recent studies have shown that ERα-36 is a crucial factor in the resistance of tamoxifen. OBJECTIVE: This study aims to determine the association between ERα-36 expression and de novo resistance of tamoxifen in patients with ER-positive breast cancer. METHODS: This study was an observational study using a cross-sectional method and was conducted at Wahidin Sudirohusodo Hospital and Unhas Hospital. ERα-36 protein expression was assessed using an immunohistochemistry assay. The association of ERα-36 expression and resistance of tamoxifen was tested with the Chi-square test. RESULTS: A total of 50 locally advanced breast cancer cases were included in this study, 22 cases (44%) had overexpression of ERα-36, and 28 cases (56%) had not, 24 cases (48%) had experience resistance to tamoxifen and 26 cases (52%) had not. There was a significant association between ERα-36 expressions and resistance of tamoxifen (p = 0.000). CONCLUSIONS: There was an association between the expression of ER-α36 with de novo resistance of tamoxifen in ER-positive breast cancer. ER-α36 could act as a worth considering biomarker for de novo resistance of tamoxifen in therapeutic strategies.

There have been few experiments on the treatment of elderly women with low-risk breast cancer. Although their clinical behaviour is similar to that of younger patients, there is a tendency to undertreat them, which may increase the risk of local relapses and reduce their survival. Even in low-risk patients, the rate of local recurrences after breast conserving surgery without adjuvant treatment (tamoxifen or radiotherapy) is high, approaching 20%, which is unacceptable. Despite the fact that tamoxifen and radiotherapy seem to have a similar impact in reducing local recurrence with similar overall survival, the combination of the two provides the best results with local relapses of less than 2%. Two studies that were designed specifically for elderly patients were published in recent years. Based on similar survival, these trials recommend omitting radiotherapy in patients with low-risk tumours treated with breast conserving surgery and tamoxifen, but with an increase in local relapses when radiotherapy is omitted, 10% at 10 years vs 2%. There is no evidence that tamoxifen treatment is less toxic in this group of patients who are typically poly-treated, and treatment compliance appears to be much lower than expected. This recommendation is highly contentious due to the reduction in the number of sessions in external radiotherapy with hypofractionation and the acceleration of partial breast irradiation, especially intraoperative radiotherapy with a single session. After breast conserving surgery, elderly patients may benefit from radiation therapy.

Simple Summary Tamoxifen is an important adjuvant endocrine therapy in estrogen receptor (ER)-positive breast cancer patients. It is mainly catalyzed by the enzyme CYP2D6 into the most active metabolite endoxifen. Genetic variation in the CYP2D6 gene influences endoxifen formation and thereby potentially therapy outcome. However, the association between CYP2D6 genotype and clinical outcome on tamoxifen is still under debate, as contradictory outcomes have been published. This review describes the latest insights in both CYP2D6 genotype and endoxifen concentrations, as well CYP2D6 genotype and clinical outcome, from 2018 to 2020. Abstract Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

Cancer cells acquire drug resistance through following non-resistant, pre-resitant and resistant stages. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here, we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing of tamoxifen-treated cells revealed that tamoxifen-resistant cells can be subgrouped into two, one showing cancer stem cell-like metabolic regulation and the other showing high expression of genes encoding adhesion molecules and histone modifying-enzymes. Pseudotime analyses showed a cell transition trajectory to the two resistant subgroups that stems from shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted that inhibition of transition to both subtype would be required to prevent the appearance of tamoxifen resistance.

Thyroid and breast cancer are the most common cancers among young women, which are either synchronous or metachronous, but the association is yet to be elucidated. With the improvement of diagnosis and treatment, there is an increase in breast and thyroid cancer survivors. Hence, attention is shifting towards survivorship. Here, we report the case of a young lady diagnosed with synchronous thyroid and breast cancer who unexpectedly became pregnant during tamoxifen treatment. After a multidisciplinary discussion, endocrine therapy was interrupted and she delivered a healthy baby at term. In conclusion, oncologists should be aware of breast and thyroid cancer co-occurrence and examinations should be conducted together in diagnosis and follow-up. Also, pregnancy is feasible and can be considered after synchronous breast and thyroid cancer diagnosis. Physicians need to emphasise the use of barrier contraceptives to patients undergoing endocrine therapy. However, the optimum timing for pregnancy after breast cancer and the safety of endocrine therapy interruption in hormonal-positive patients should be discussed and managed by a multidisciplinary team.

Aim: To evaluate plasma endoxifen levels and metabolic phenotype-associated factors in Mexican Mestizo patients under tamoxifen treatment. Patients & methods: A total of 138 breast cancer patients under tamoxifen treatment were cross-sectionally evaluated and side effects (SE) were recorded. CYP2D6 genetic phenotypes (GP) and metabolic phenotypes (MP) were assessed (metabolic poor [mPM], intermediate [mIM], normal [mNM], and ultrarapid [mUM] metabolizer). Associations were tested in uni-multivariate models for endoxifen >5.9 ng/ml and for mNM + mUM MP. Results: The main SE was hot flashes (62%). Distribution of the CYP2D6 MP was 4.3% mPM; 14.5% mIM; 75.4% mNM; and 5.8% mUM. Endoxifen >5.9 ng/ml was partially associated with SE (p = 0.06); the mNM + mUM MP was associated with treatment time (p = 0.03). Conclusion: The endoxifen-associated factors in Mexican Mestizo patients remain inconclusive, although treatment time was associated with MP.

Background Numerous cases with ocular toxicity secondary to tamoxifen have been reported, and became more apparent with keratopathy, cataract, optic neuritis, macular holes, crystalline retinopathy with or without cystoid macular edema (CME). Withdrawing tamoxifen with the approval of the oncologist is the major treatment for cases with tamoxifen-induced retinopathy. Case presentation We herein reported a patient with a two-year history of painless and reduced visual acuity in both eyes who received tamoxifen therapy for 6 years. Tamoxifen-induced rentinopathy with CME showed significant development even though the patient has already discontinued tamoxifen treatment for 6 months. Anatomic improvements after intravitreal ranibizumab injection in both eyes were significant but were temporary. Surprisingly, CME in both eyes has been resolved spontaneously after 10 months in the penultimate visit without any therapy. Conclusion Intravitreal ranibizumab injection temporarily improved the anatomy of the eyes in a case with tamoxifen-induced CME, and only tamoxifen withdrawal can bring a sustained effect.

Hormone therapy with Tamoxifen is an effective treatment that can decrease recurrence rate and mortality. Numerous molecular mechanisms can modify the response to Tamoxifen. The objective of this study was to determine Tamoxifen efficacy on patients’ recurrence and mortality rates, according to the human epidermal growth factor receptor 2 (HER2) status. In this meta-analysis of published studies, relapse and death rates were measured in both HER2 negative and positive patients treated with Tamoxifen. Besides, the relative risk of treatment with Tamoxifen compared to no Tamoxifen treatment was evaluated in both HER2 positive and negative patients. There was an increased risk of recurrence in HER2 positive patients who received Tamoxifen compared with HER2 negative ones (RR = 1.63, p value

BackgroundTo determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on ovarian reserve by serum anti-Mullerian hormone (AMH) levels in women with breast cancer.MethodsOne-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate+5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI.ResultsBoth chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (pConclusionsBoth AC-based and CMF regimens significantly compromise ovarian reserve, which does not recover during the 12-24-month post-chemotherapy follow up. In contrast, tamoxifen treatment does not seem to alter ovarian reserve. This novel information should be valuable for fertility preservation counselling and in assessing future reproductive potential of breast cancer survivors.

Monitoring drug uptake, its metabolism, and response on the single-cell level is invaluable for sustaining drug discovery efforts. In this study, we show the possibility of accessing the information about the aforementioned processes at the single-cell level by monitoring the anticancer drug tamoxifen using live single-cell mass spectrometry (LSC-MS) and Raman spectroscopy. First, we explored whether Raman spectroscopy could be used as a label-free and nondestructive screening technique to identify and predict the drug response at the single-cell level. Then, a subset of the screened cells was isolated and analyzed by LSC-MS to measure tamoxifen and its metabolite, 4-Hydroxytamoxifen (4-OHT) in a highly selective, sensitive, and semiquantitative manner. Our results show the Raman spectral signature changed in response to tamoxifen treatment which allowed us to identify and predict the drug response. Tamoxifen and 4-OHT abundances quantified by LSC-MS suggested some heterogeneity among single-cells. A similar phenomenon was observed in the ratio of metabolized to unmetabolized tamoxifen across single-cells. Moreover, a correlation was found between tamoxifen and its metabolite, suggesting that the drug was up taken and metabolized by the cell. Finally, we found some potential correlations between Raman spectral intensities and tamoxifen abundance, or its metabolism, suggesting a possible relationship between the two signals. This study demonstrates for the first time the potential of using Raman spectroscopy and LSC-MS to investigate pharmacokinetics at the single-cell level.

Justification and objectives: oral antineoplastic therapy has advantages compared to other therapies for the treatment of cancer, as it is administered at home, in a simple and fast way. However, this therapy increases patients’ responsibility for their treatment, and compliance is critical to its effectiveness. Few studies are evident regarding pharmacotherapeutic follow-up in oral antineoplastic therapy. In this context, this study seeks to assess adherence to tamoxifen treatment in women with breast cancer, before and after pharmacotherapeutic follow-up. Methods: this is a randomized, quantitative clinical study. Data collection was carried out for six months. Random randomization was divided into a control group and a follow-up group, with the follow-up subdivided into before and after follow-up. The follow-up group received individual pharmaceutical interventions monthly. Adherence was assessed by The Brief Medication Questionnaire, Brazilian version and drug-related problems as to necessity, effectiveness, and safety. Results: after pharmaceutical follow-p, a difference was observed between the follow-up group and the control group regarding physical activity (p=0.043), treatment adherence (p=0.006), reduction of side effects (p=0.003) and associated diseases (p=0.002). The most frequent drug-related problems were safety and adherence, for which 54 pharmaceutical interventions were performed. The side effects described by patients mainly affected the genital system and gastrointestinal tract. Conclusion: it was evident that pharmacotherapeutic follow-up effectively contributed to adherence to treatment with tamoxifen and the pharmaceutical interventions performed contributed to prevention and reduction of drug-related problems.

Purpose: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship. Experimental Design: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined “gBRCA-associated,” those without LOH (gBRCA/LOHneg) were defined “sporadic.” Results: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P < 0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P < 0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%). Conclusions: We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers.

Tamoxifen is frequently used as adjuvant treatment in premenopausal patients with hormone receptor-positive early breast cancer. According to guidelines, the use of nonhormonal barrier contraception is recommended during tamoxifen treatment and up to 3 months after its interruption prior to attempting conception. Nevertheless, when conception occurs inadvertently during tamoxifen treatment, the effects on the fetus and on the course of pregnancy are still not completely known. Here, we report 3 cases of young women who accidentally became pregnant while taking tamoxifen and perform a systematic review of the literature to provide more elements for better and clear multidisciplinary counselling of women facing this challenging situation.

Recent identification of the neonatal 2nd coronary vascular population (2nd CVP) suggests that a subset of these vessels form de novo and mature in the inner myocardial wall of the postnatal heart. However, the origin of smooth muscle cells (SMCs) in the postnatal 2nd CVP remains undetermined. Using a tamoxifen-inducible Wt1-CreER driver and a Rosa26-RFP reporter line, we traced the lineage of epicardial cells to determine if they contribute to SMCs of the 2nd CVP. Late embryonic and postnatal induction of Wt1-CreER activity demonstrated that at these stages Wt1-labeled epicardium does not significantly migrate into the myocardium to form SMCs. However, following tamoxifen treatment at an early embryonic stage (E10.5), we detected Wt1 descendants (epicardium-derived cells, or EPDCs) in the outer myocardial wall at E17.5. When the 2nd CVP forms and remodels at postnatal stage, these early labeled EDPCs re-migrate deep into the inner myocardial wall and contribute to 2nd CVP-SMCs in the adult heart. Our findings reveal that SMCs in the postnatal 2nd CVP are pre-specified as EPDCs from the earliest wave of epicardial cell migration. Rather than the re-activation and migration of epicardial cells at later stages, these resident EPDCs mobilize and contribute to smooth muscle of the 2nd CVP during postnatal development.

Background: Endocrine therapy for breast cancer is directed at reducing oestrogen synthesis or alternatively blocking oestrogen receptors (ER) in tumour-sensitive tumors. Despite side effects, the use of systemic adjuvant therapy after local management of breast cancer substantially improves survival and reduces the risk of relapse. The study objective was to assess the recurrence of breast cancer and the complications seen in breast cancer patients on tamoxifen therapy at a hospital-based cancer registry, Thrissur, Kerala.Methods: After obtaining institutional ethical clearance, included 75 patients of histologically diagnosed breast carcinoma currently on tamoxifen, diagnosed in the year of 2016. Data was obtained from the patient files and by personal intimation.Results: Of the 75 patients on tamoxifen, four (5.33%) patients had history of recurrence. 22.6% of patients on tamoxifen were noted to have increased endometrial thickness. Other side effects noted were weight gain, TIA, bone pain and vaginal discharge.Conclusions: It was found that the recurrence rate at three years for the study population was 5.33%. More studies from developing countries, with larger sample size and clinical trials will give us more accurate information regarding the efficacy of the drug.

Aim: We aimed to develop a long noncoding RNA (lncRNA) expression signature that can predict response to tamoxifen. Materials & methods: LncRNA expression profiling was mined in two cohorts from Gene Expression Omnibus (GSE6532, GSE9195, n = 412). Results: A set of lncRNAs (LINC01191, RP4-639F20.1 and CTC-429P9.3) associated with distant metastasis-free survival was established. Estrogen receptor-positive breast cancer patients in the training series could be classified into high- and low-risk groups with significantly different distant metastasis-free survival values based on this signature (hazard ratio [HR]: 5.11; p = 7.28 × 10-8). The prognostic ability of this signature was confirmed in validation sets 1 (HR: 2.58; p = 1.54 × 10-2) and 2 (HR: 10.06; p = 6.85 × 10-3). Conclusion: The lncRNA signature may have possible clinical implications in the selection of high-risk patients for tamoxifen therapy.

Short-term tamoxifen treatment has effects on lipid and glucose metabolism in mice fed chow. However, its effects on metabolism in mice fed high-fat diet (HFD) and the underlying mechanisms are unclear. Here, we show that tamoxifen treatment for 5 days decreases fat mass for as long as 18 weeks in mice fed HFD. Tamoxifen alters mRNA levels of some genes involved in lipid metabolism in white adipose tissue and improves glucose and insulin tolerance as well as hepatic insulin signaling for 12-20 weeks. Proopiomelanocortin (POMC) neuron-specific deletion of nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) attenuates the effects of tamoxifen on glucose and insulin tolerance. These data demonstrate that short-term injection of tamoxifen has long-term effects on lipid and glucose metabolism in HFD mice with involvement of Nmnat2 in POMC neurons.

Purpose The association between tamoxifen (TMX) treatment and the risk of developing hyperlipidemia remains unclear. Methods The records of 41,726 patients with breast cancer (28,266 received TMX and 13,460 did not) were obtained from the Taiwan National Health Insurance Research Database for the period from January 2000 to December 2008. Three-fold women without breast cancer were the control group (N = 125, 178). The main end point was developing hyperlipidemia during the follow-up. Results During a mean follow-up of 9 years, the patients with breast cancer demonstrated a rate of developing hyperlipidemia that was 6% less (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90-0.97) than that of the control participants without breast cancer. Stratification by age group indicated that only women aged ≥ 55 years who were diagnosed with breast cancer exhibited a significantly reduced risk of hyperlipidemia compared with the control group. With the use of 2 types of adjusted models, we observed that the TMX users (aged ≥ 55 years) consistently exhibited a significantly lower risk of hyperlipidemia than the non-TMX users and control participants (adjusted HRs, 0.79 and 0.82 from models 1 and 2, respectively). Within the 8-year follow-up period, patients with breast cancer and 366 to 1500 days of TMX therapy and > 1500 days of TMX therapy had significantly lower risks of hyperlipidemia compared with patients with ≤ 365 days of TMX therapy (adjusted HR, 0.54; 95% CI, 0.50-0.59; adjusted HR, 0.21; 95% CI, 0.18-0.24, respectively). Conclusions In Asian patients with breast cancer, TMX use was associated with reduced risks of hyperlipidemia.

ObjectiveTo evaluate the role of transvaginal ultrasound triage in women with a history of tamoxifen treatment who present with post-menopausal bleeding.Study designA retrospective review was undertaken of patients who presented with symptoms of post-menopausal bleeding and underwent ultrasound triage. Endometrial thickness and ultrasonographic features were then correlated with hysteroscopic and histopathological outcome data. The findings and outcomes for women with a history of tamoxifen use (tamoxifen group) were compared to those who had not taken tamoxifen (non-tamoxifen group).ResultsA total of 614 women with post-menopausal bleeding underwent transvaginal ultrasound triage, of whom 53 had a history of current or previous tamoxifen treatment. An endometrial thickness of ≥5 mm or the presence of other abnormal features was used to triage women to further investigation by hysteroscopy and biopsy. Endometrial thickness was significantly greater in the tamoxifen group (11 mm vs. 6 mm). Nearly all of the tamoxifen group were triaged to further investigation (98.1%), compared with significantly fewer in the non-tamoxifen group (68.3%) Overall, the incidence of endometrial pathology was also significantly higher in tamoxifen patients (43.4% vs. 31.7%).ConclusionFor women presenting with post-menopausal bleeding, the use of transvaginal ultrasound as a triage tool is rarely helpful in evaluating women who have a history as tamoxifen use, as most will require further investigation with hysteroscopy and biopsy. A post-menopausal bleeding protocol that omits transvaginal ultrasound for women with a history of tamoxifen use may be an appropriate and effective pathway for managing these patients.