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Spaan M, van den Belt-Dusebout AW, Lambalk CB, van Boven H, van Loendersloot LL, Broekmans FJM, Laven JSE, van Santbrink EJP, Nap AW, van der Westerlaken LAJ, Cohlen BJ, Cantineau AEP, Smeenk JMJ, van Rumste MM, Goddijn M, van Golde RJT, Meeuwissen PAM, de Bruin JP, Ouwens GM, Gerritsma MA, Schaapveld M, Burger CW, van Leeuwen FE. Long-term risk of endometrial cancer after assisted reproductive technology. Hum Reprod 2025; 40:739-749. [PMID: 39919245 DOI: 10.1093/humrep/deaf018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 11/21/2024] [Indexed: 02/09/2025] Open
Abstract
STUDY QUESTION What is the risk of endometrial cancer after long-term follow-up in women treated with ART between 1983 and 2001 compared with women in the general population and subfertile women who did not undergo ART? SUMMARY ANSWER The risk of endometrial cancer is not increased in women who underwent ART in the Netherlands between 1983 and 2001, neither compared with women from the general population nor compared with subfertile women not treated with ART. WHAT IS KNOWN ALREADY Concerns have been raised that subfertility treatment may be associated with increased risk of endometrial cancer. However, published studies show inconsistent results regarding the effects of ovarian stimulation and specific subfertility diagnoses on endometrial cancer risk. STUDY DESIGN, SIZE, DURATION A nationwide historic cohort study (the OMEGA-cohort) was conducted to examine the risk of cancer in women after ovarian stimulation for ART. The OMEGA-cohort comprises 30 625 women who received ovarian stimulation for ART (ART group) in 1983-2000 and 9988 subfertile women not treated with ART (non-ART group). After a median follow-up of 24 years, endometrial cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Endometrial cancer risk in the cohort was compared with that in the general population using person-years analyses, and between the ART group and non-ART group using multivariable Cox regression analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS Detailed ART-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Personal Records Database. Information on hysterectomy and endometriosis was collected through linkage with the Dutch Nationwide Pathology Databank (Palga). Data about lifestyle factors, including BMI, were obtained through a self-administered questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE After a median follow-up duration of 24 years, 137 endometrial cancers were diagnosed. Endometrial cancer risk after ART was not significantly increased compared with that in the general population (standardized incidence ratio = 1.19; 95% CI = 0.97-1.44) nor compared with that in the non-ART group (multivariably adjusted hazard ratio = 1.11; 95% CI = 0.74-1.67). Risk of endometrial cancer did not increase with longer follow-up or with more ART cycles, and the risk within the cohort, did not vary by cause of subfertility (male, tubal, unexplained, and other). Irrespective of ART treatment, endometrial cancer risk was increased in obese women and women with endometriosis, but decreased among parous women and women who used oral contraceptives. LIMITATIONS, REASONS FOR CAUTION Although the findings of the study are reassuring, the median age of the women at the end of follow-up (median age 56 years) was still rather young. Therefore, there is a need for at least 10-15 additional follow-up years to draw definitive conclusions. In addition, other large studies are needed to investigate the risk of endometrial cancer in women who underwent ART. WIDER IMPLICATIONS OF THE FINDINGS The results of this study contribute to knowledge about long-term health after ART treatment, which is valuable to subfertile couples, considering or undergoing fertility treatments, and their healthcare providers. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by a grant from the Dutch Cancer Society (NKI 2006-3631) and a departmental grant from the Department of Obstetrics and Gynecology of Erasmus Medical Center, Rotterdam, the Netherlands (2011-019). Ma.S. is Associate Editor of Human Reproduction Open; A.W.vd.B.-D received support for attending meetings and/or travel from the Dutch Cancer Society; C.B.L. is Editor-in-Chief of Human Reproduction; A.E.P.C. is Associate Editor of Human Reproduction Update, received royalties from Uptodate Hyperthecosis, and participated at the Data Safety Monitoring Board of the DSMB POEM Study; F.B. has received research support from Merck, honoraria or consultation fees from Merck Healthcare KGaA, Bensis Healthcare, CooperSurgical, and participated in an advisory board for Merck and Ferring; J.L. has received research support from Ferring, Merck, and Roche Diagnostics, consulting fees and honoraria from Ferring, participated on a Data Safety Monitoring Board or Advisory Board of the LOCI trial, is President of the AE-PCOS society, and Member of the ASRM Integrity Committee; J.M.J.S. has received honoraria from Ferring and Merck, support for attending meetings and/or travel from Ferring, Merck, and Good Life, and participated in the advisory board of Merck; L.L.v.L. received support for attending meetings and/or travel from Olympus Medical Expert training; M.M.v.R. received support for attending meetings and/or travel from Ferring; M.G. declares departmental research and educational grants from Ferring (location VUmc), unrelated to the presented work. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- Mandy Spaan
- Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Epidemiology and Data Science, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Alexandra W van den Belt-Dusebout
- Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Cornelis B Lambalk
- Department of Obstetrics and Gynecology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Hester van Boven
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Laura L van Loendersloot
- Department of Obstetrics and Gynecology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Frank J M Broekmans
- Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Joop S E Laven
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Annemiek W Nap
- Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | | | - Ben J Cohlen
- Department of Obstetrics and Gynecology, Isala Clinics, Zwolle, The Netherlands
| | - Astrid E P Cantineau
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jesper M J Smeenk
- Department of Obstetrics and Gynecology, Elisabeth Twee Steden Ziekenhuis, Tilburg, The Netherlands
| | - Minouche M van Rumste
- Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven, The Netherlands
| | - Mariëtte Goddijn
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
- Department Obstetrics and Gynecology, Centre for Reproductive Medicine, Amsterdam UMC, Amsterdam, The Netherlands
| | - Ron J T van Golde
- Department of Obstetrics and Gynecology, Maastricht University Medical Center, Maastricht, The Netherlands
- GROW Institute for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
| | - Paul A M Meeuwissen
- Department of Obstetrics and Gynecology, Admiraal de Ruyter Hospital, Vlissingen, The Netherlands
| | - Jan P de Bruin
- Department of Obstetrics and Gynecology, Jeroen Bosch Ziekenhuis, 's-Hertogenbosch, The Netherlands
| | - Gabriële M Ouwens
- Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Miranda A Gerritsma
- Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Michael Schaapveld
- Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Curt W Burger
- Department of Gynecologic Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Flora E van Leeuwen
- Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Deng Z, Visvanathan K. Patterns of Subsequent Cancer Incidence Over Time in Patients with Breast Cancer. Cancer Epidemiol Biomarkers Prev 2025; 34:246-259. [PMID: 39570089 PMCID: PMC11802296 DOI: 10.1158/1055-9965.epi-24-1009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/24/2024] [Accepted: 11/19/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Breast cancer survivors face a higher risk of subsequent primary cancers. This study investigated the patterns of subsequent cancer risk according to time since breast cancer diagnosis. METHODS Using data from the Surveillance, Epidemiology, and End Results Program (2000-2018), we identified a cohort of 771,681 breast cancer survivors. Standard incidence ratios (SIR) were calculated by comparing the observed with the expected number of subsequent cancers over different follow-up periods since breast cancer diagnosis. Analyses were conducted for multiple cancer types, stratified by hormone receptor status, treatment of the first breast cancer, age, and race/ethnicity. RESULTS Survivors experienced a 16% increased risk of subsequent cancer with the SIR continuing to increase with longer follow-up (SIR = 1.04, 1.22, and 1.31 for 12-59, 60-119, and ≥120 months). This trend was driven primarily by a subsequent breast cancer, particularly among women <50 years of age, those with initial hormone receptor-negative cancer, and racial/ethnic minorities. The patterns of subsequent non-breast cancer risk varied by type. An early-onset and sustained increased risk was observed for subsequent leukemia, thyroid cancer, soft-tissue sarcoma, melanoma, pancreatic cancer, and uterine cancer. A delayed increased risk was observed for subsequent esophageal, ovarian, oral cavity/pharyngeal, and lung cancers, whereas for small intestine, stomach, kidney, and colorectal cancers, there was a decrease after an initial increased risk. CONCLUSIONS Patterns in subsequent cancer risk since breast cancer diagnosis differ by cancer type and characteristics of the first breast cancer. IMPACT These findings can inform etiology and tailored approaches to screening and prevention of subsequent cancers.
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Affiliation(s)
- Zhengyi Deng
- Stanford School of Medicine, Stanford, California, US
| | - Kala Visvanathan
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, US
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, US
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Shaoshan C, Niannian C, Ying M. Machine learning Nomogram for Predicting endometrial lesions after tamoxifen therapy in breast Cancer patients. Sci Rep 2025; 15:981. [PMID: 39762305 PMCID: PMC11704003 DOI: 10.1038/s41598-024-82373-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
Objective Endometrial lesions are a frequent complication following breast cancer, and current diagnostic tools have limitations. This study aims to develop a machine learning-based nomogram model for predicting the early detection of endometrial lesions in patients. The model is designed to assess risk and facilitate individualized treatment strategies for premenopausal breast cancer patients. Method A retrospective study was conducted on 224 patients who underwent diagnostic curettage post-tamoxifen (TAM) therapy between November 2012 and November 2023. These patients exhibited signs of endometrial abnormalities or symptoms such as colporrhagia. Clinical data were collected and analyzed using R software (version 4.3.2) to identify factors influencing the occurrence of endometrial lesions and evaluate their predictive values. Three machine learning methods were employed to develop a risk prediction model, and their performances were compared. The best-performing model was selected to construct a nomogram of endometrial lesions. Internal validation was conducted using the bootstrap method, and the model's accuracy and fit were assessed using the concordance index (C-index) and calibration curves. Results Independent risk factors for endometrial lesions included ultrasound characteristics, duration of TAM therapy, presence of colporrhagia, and endometrial thickness (P < 0.05). Among the machine learning methods compared, the LASSO regression integrated with a multifactorial logistic regression model demonstrated strong performance, with a concordance index (C-index) of 0.874 and effective calibration (mean absolute error of conformity: 0.014). This model achieved an accuracy of 0.853 and a precision of 0.917, with a training set AUC of 0.874 (95% CI: 0.794-0.831) and a test set AUC of 0.891 (95% CI: 0.777-1.000), closely aligning the predicted risk with the actual observed risk. Conclusion The developed prediction model is effective in evaluating endometrial lesions in premenopausal breast cancer patients. This model offers a theoretical foundation for improving clinical predictions and devising tailored treatment strategies for this patient group.
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Affiliation(s)
- Cao Shaoshan
- Department of Obstetrics and Gynecology, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, Sichuan, China
| | - Chen Niannian
- School of Information Engineering, Southwest University of Science and Technology, Mianyang, 621000, China
| | - Ma Ying
- Department of Obstetrics and Gynecology, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, Sichuan, China.
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Wang M, Li L, Li J, Li Y, Wang Z, Guo Y, Mao G. Causal effect of breast cancer on endometrial cancer risk: A two-sample Mendelian randomization study. Eur J Obstet Gynecol Reprod Biol 2025; 304:16-22. [PMID: 39549381 DOI: 10.1016/j.ejogrb.2024.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/05/2024] [Accepted: 11/09/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND Observational studies have indicated a higher incidence of endometrial cancer in individuals with breast cancer. However, to date, there is a dearth of Mendelian randomization (MR) studies that explore the causal relationship between breast cancer and the risk of endometrial cancer. MATERIAL AND METHODS We conducted MR to investigate the causal relationship between breast cancer and endometrial cancer risk in European populations. RESULTS A total of 112 valid instrumental variables (IVs) were included in the analysis. Our research has revealed a compelling causal association between genetic predisposition for breast cancer and an augmented likelihood of developing endometrial cancer (Inverse variance weighted (IVW) method, odds ratio (OR) = 1.105, 95 % confidence interval (CI): 1.025 to 1.181, p = 0.003; Weighted median method, OR = 1.109, 95 % CI: 1.020 to 1.205, p = 0.015; Weighted mode method, OR = 1.101, 95 % CI: 1.013 to 1.195, p = 0.025). CONCLUSION To our knowledge, this study is the first to report a causal association between breast cancer and endometrial cancer risk. Robust results were obtained through rigorous testing for heterogeneity and pleiotropy. Our findings indicate a causal effect of breast cancer on the risk of endometrial cancer.
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Affiliation(s)
- Meng Wang
- Breast Disease Diagnosis and Treatment Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lan Li
- Department of Breast Surgery, Shaanxi Provincial Cancer Hospital, Xi'an, China
| | - Jing Li
- Department of Breast Surgery, Shaanxi Provincial Cancer Hospital, Xi'an, China
| | - Yongwei Li
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhuoli Wang
- Department of Hematology, The Second Affiliated Hospital of Jiaotong University, Xi'an, China
| | - Yuan Guo
- Department of Breast Surgery, Shaanxi Provincial Cancer Hospital, Xi'an, China
| | - Guochao Mao
- Breast Disease Diagnosis and Treatment Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Benlghazi A, Messaoudi H, Benali S, Tazi I, Elhassani MM, Kouach J. Lobular carcinoma metastasis to endometrial polyps: Insights from a case report and literature analysis. Int J Surg Case Rep 2024; 124:110463. [PMID: 39437506 PMCID: PMC11532895 DOI: 10.1016/j.ijscr.2024.110463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 10/11/2024] [Accepted: 10/14/2024] [Indexed: 10/25/2024] Open
Abstract
INTRODUCTION AND IMPORTANCE Endometrial polyps are rare sites of metastatic breast carcinoma. Such cases have mainly been reported in tamoxifen-related polyps. CASE PRESENTATION We describe the case of a 56-year-old woman with invasive lobular carcinoma who was experiencing vaginal bleeding. She underwent hysteroscopy with biopsy. Microscopic examination revealed an endometrial polyp with foci of adenocarcinoma. The morphological features of the tumor matched those of the original breast carcinoma. CLINICAL DISCUSSION Neoplasms originating from extra-genital sites frequently spread to the female genital organs. However, these metastases are mainly concentrated in the ovaries and vagina, while those affecting the uterus are rare. Among non-genital malignant tumors, mammary carcinoma - particularly the lobular type - is the most common to affect the uterus, followed by digestive and pulmonary tumors. Metastases within an endometrial polyp are particularly unusual. CONCLUSIONS It is crucial to consider metastatic tumors when assessing vaginal bleeding in patients with breast carcinoma. Because of the possibility of endometrial polyps being affected by metastasis, pathologists must examine them rigorously and thoroughly.
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Affiliation(s)
- Abdelhamid Benlghazi
- Department of Gynecology-Obstetrics, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy of Rabat, University Mohammed V Rabat, Morocco.
| | - Hamza Messaoudi
- Department of Gynecology-Obstetrics, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy of Rabat, University Mohammed V Rabat, Morocco
| | - Saad Benali
- Department of Gynecology-Obstetrics, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy of Rabat, University Mohammed V Rabat, Morocco
| | - Imane Tazi
- Department of Pathology Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy of Rabat, University Mohammed V Rabat, Morocco
| | - Moulay Mehdi Elhassani
- Department of Gynecology-Obstetrics, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy of Rabat, University Mohammed V Rabat, Morocco
| | - Jaouad Kouach
- Department of Gynecology-Obstetrics, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy of Rabat, University Mohammed V Rabat, Morocco
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Jang S, Hwang SO. Risk factors for atypical hyperplasia or endometrial cancer in premenopausal women aged ≤ 45 years with abnormal uterine bleeding. Eur J Obstet Gynecol Reprod Biol 2024; 302:288-293. [PMID: 39348761 DOI: 10.1016/j.ejogrb.2024.09.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 09/15/2024] [Accepted: 09/17/2024] [Indexed: 10/02/2024]
Abstract
OBJECTIVES To assess the prevalence and risk factors for atypical hyperplasia (AH) or endometrial cancer (EC) in premenopausal women aged ≤ 45 years with abnormal uterine bleeding (AUB). METHODS This was a retrospective study of premenopausal patients aged 18 to 45 years who underwent hysteroscopy, dilation and curettage, or pipelle sampling at Inha University Hospital, South Korea, from 2014 to 2023. We used multivariable logistic regression analysis to identify risk factors and calculate the predicted probabilities of AH or EC with various combinations of these factors. RESULTS Of 821 patients included in the study, 6.0 % were diagnosed with AH or EC. The significant risk factors identified were nulliparity (odds ratio (OR): 4.75, 95 % confidence interval (CI): 2.11-10.70), PCOS (OR: 2.72, 95 % CI: 1.34-5.52), and multiple polyps (OR: 2.33, 95 % CI: 1.23-4.41). The predicted probabilities of developing AH or EC increased with the number of risk factors present, ranging from 1 % to 33.6 %. CONCLUSIONS The predicted probabilities within combinations of risk factors may be considered helpful in making better clinical decisions regarding endometrial sampling for patients ≤ 45 years with AUB.
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Affiliation(s)
- Shina Jang
- Department of Obstetrics and Gynecology, Inha University Hospital, Inha University College of Medicine, Incheon, South Korea.
| | - Sung-Ook Hwang
- Department of Obstetrics and Gynecology, Inha University Hospital, Inha University College of Medicine, Incheon, South Korea
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Chandra R, Kumari S. Environment and gynaecologic cancers. Oncol Rev 2024; 18:1430532. [PMID: 39440071 PMCID: PMC11493732 DOI: 10.3389/or.2024.1430532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024] Open
Abstract
In the current era, environmental factors are well established as major causative agents for all cancers especially lung and breast cancer. We sought to review the current available literature on the topic pertaining to gynaecologic cancers. Although a few factors are well established in literature, others need more research to conclude.
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Affiliation(s)
- Rudrika Chandra
- Obstetrics and Gynaecology, Command Hospital, Panchkula, Haryana, India
| | - Sarita Kumari
- Department of Gynaecologic Oncology, National Cancer Institute, All India Institute of Medical Sciences, New Delhi, India
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Zaluzec EK, Sempere LF. Systemic and Local Strategies for Primary Prevention of Breast Cancer. Cancers (Basel) 2024; 16:248. [PMID: 38254741 PMCID: PMC10814018 DOI: 10.3390/cancers16020248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/29/2023] [Accepted: 12/31/2023] [Indexed: 01/24/2024] Open
Abstract
One in eight women will develop breast cancer in the US. For women with moderate (15-20%) to average (12.5%) risk of breast cancer, there are few options available for risk reduction. For high-risk (>20%) women, such as BRCA mutation carriers, primary prevention strategies are limited to evidence-based surgical removal of breasts and/or ovaries and anti-estrogen treatment. Despite their effectiveness in risk reduction, not many high-risk individuals opt for surgical or hormonal interventions due to severe side effects and potentially life-changing outcomes as key deterrents. Thus, better communication about the benefits of existing strategies and the development of new strategies with minimal side effects are needed to offer women adequate risk-reducing interventions. We extensively review and discuss innovative investigational strategies for primary prevention. Most of these investigational strategies are at the pre-clinical stage, but some are already being evaluated in clinical trials and others are expected to lead to first-in-human clinical trials within 5 years. Likely, these strategies would be initially tested in high-risk individuals but may be applicable to lower-risk women, if shown to decrease risk at a similar rate to existing strategies, but with minimal side effects.
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Affiliation(s)
- Erin K. Zaluzec
- Precision Health Program, Michigan State University, East Lansing, MI 48824, USA;
- Department of Pharmacology & Toxicology, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Lorenzo F. Sempere
- Precision Health Program, Michigan State University, East Lansing, MI 48824, USA;
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
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Mukherjee A, Gu Z, Chen LH, Potosky AL, Haque R. Association of metabolic syndrome conditions with risk of second primary uterine cancer in breast cancer survivors. J Cancer Res Clin Oncol 2023; 149:17749-17755. [PMID: 37925391 DOI: 10.1007/s00432-023-05489-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 10/21/2023] [Indexed: 11/06/2023]
Abstract
PURPOSE Uterine cancer risk is high in breast cancer survivors. Although breast cancer and uterine cancer share some common epidemiological risk factors, association of metabolic syndrome with incident uterine cancer in breast cancer survivors is under-studied. We evaluated the association of metabolic syndrome conditions with second primary uterine cancer in breast cancer survivors. METHODS In this retrospective cohort study, 37,303 breast cancer patients diagnosed between 2008 and 2020 at Kaiser Permanente Southern California, an integrated healthcare system, were included. Data on cancer-related variables, sociodemographic, and clinical variables were extracted from KPSC's Surveillance, Epidemiology, and End Results (SEER)-affiliated cancer registry and electronic health records, as appropriate. Patients were followed from breast cancer diagnosis until 12/31/2021 for incident uterine cancer. Proportional hazards regression was used to report association [HR (95% CI)] between metabolic conditions and uterine cancer. RESULTS More than half (53.1%) of the breast cancer survivors had 1-2 metabolic conditions; 19.4% had 3 + , while 27. 5% had no metabolic conditions. Median time to follow-up was 5.33 years and 185 (0.5%) patients developed second primary uterine cancer. Obesity was associated with an elevated uterine cancer risk in the adjusted model [HR (95% CI) 1.64 (1.20-2.25)]. Having 1-2 metabolic conditions (versus none) was not associated with increased uterine cancer risk [adjusted HR (95% CI) 1.24 (0.85-1.82)]; however, there was an increased uterine cancer risk with 3 + metabolic conditions [adjusted HR (95% CI) 1.82 (1.16-2.87)]. CONCLUSION Although not statistically significant, we found a trend demonstrating greater uterine cancer risk by increasing numbers of metabolic syndrome conditions in breast cancer survivors.
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Affiliation(s)
- Amrita Mukherjee
- Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles, Pasadena, CA, 91101, USA.
| | - Zheng Gu
- Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles, Pasadena, CA, 91101, USA
| | - Lie Hong Chen
- Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles, Pasadena, CA, 91101, USA
| | - Arnold L Potosky
- Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Reina Haque
- Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles, Pasadena, CA, 91101, USA
- Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
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Kumar G, Mullick P, Nandakumar K, Mutalik S, Chamallamudi MR. Box-Behnken Design-Aided Validation and Optimization of a Stability-Indicating Reverse Phase-HPLC Method for the Estimation of Tamoxifen Citrate in Lipidic Nano-Vesicles. J Chromatogr Sci 2023; 61:827-837. [PMID: 37554069 DOI: 10.1093/chromsci/bmad059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 04/23/2023] [Indexed: 08/10/2023]
Abstract
Stability indicating a reverse-phase HPLC analytical method for the quantification of tamoxifen citrate (TMX) in the bulk and lipidic nano-vesicles (LNVs) was developed. The optimized method was validated according to the ICH Q2 (R1) guidelines by following a three-factor interaction Box-Behnken design using Design-Expert® software. The responses measured at 236 nm were retention time (Rt), peak area, tailing factor (TF) and the number of theoretical plates. TMX was eluted best using the Luna® C18 LC Column along with a mobile phase of methanol (MeOH) and ammonium acetate buffer (AAB pH 4.5) 80:20 v/v mixture at 25 ± 2°C temperature. The currently developed method was linear in 100-5,000 ng/mL range with a detection limit of 4.55 ng/mL and a quantification limit of 13.78 ng/mL. The optimized method was utilized to evaluate the stability of TMX in different stress conditions by performing forced degradation studies. The results from the degradation study stipulated that on exposure to various stressors namely acid, alkali, oxidative, thermal and UV light, the TMX did not show considerable degradation except for UV light exposure. Further, the method was successfully used for the quantification of TMX in LNVs.
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Affiliation(s)
- Gautam Kumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
- School of Pharmacy, Sharda University, Greater Noida, Uttar Pradesh 201310, India
| | - Prashansha Mullick
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Krishnadas Nandakumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Srinivas Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Mallikarjuna Rao Chamallamudi
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
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Sorouri K, Lynce F, Feltmate CM, Davis MR, Muto MG, Konstantinopoulos PA, Stover EH, Kurian AW, Hill SJ, Partridge AH, Tolaney SM, Garber JE, Bychkovsky BL. Endometrial Cancer Risk Among Germline BRCA1/ 2 Pathogenic Variant Carriers: Review of Our Current Understanding and Next Steps. JCO Precis Oncol 2023; 7:e2300290. [PMID: 38061009 PMCID: PMC10715772 DOI: 10.1200/po.23.00290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/02/2023] [Accepted: 09/14/2023] [Indexed: 12/18/2023] Open
Abstract
PURPOSE To review the literature exploring endometrial cancer (EC) risk among surgical candidates with germline BRCA1/2 pathogenic variants (PVs) to guide decisions around risk-reducing (rr) hysterectomy in this population. DESIGN A comprehensive review was conducted of the current literature that influences clinical practice and informs expert consensus. We present our understanding of EC risk among BRCA1/2 PV carriers, the risk-modifying factors specific to this patient population, and the available research technology that may guide clinical practice in the future. Limitations of the existing literature are outlined. RESULTS Patients with BRCA1/2 PVs, those with a personal history of tamoxifen use, those who desire long-term hormone replacement therapy, and/or have an elevated BMI are at higher risk of EC, primarily endometrioid EC and/or uterine papillary serous carcinoma, and may benefit from rr-hysterectomy. Although prescriptive clinical guidelines specific to BRCA1/2 PV carriers could inform decisions around rr-hysterectomy, limitations of the current literature prevent more definitive guidance at this time. A large population-based study of a contemporary cohort of BRCA1/2 PV carriers with lifetime follow-up compared with cancer-gene negative controls would advance this topic and facilitate care decisions. CONCLUSION This review validates a potential role for rr-hysterectomy to address EC risk among surgical candidates with BRCA1/2 PVs. Evidence-based clinical guidelines for rr-hysterectomy in BRCA1/2 PV carriers are essential to ensure equitable access to this preventive measure, supporting insurance coverage for patients with either BRCA1 or BRCA2 PVs to pursue rr-hysterectomy. Overall, this review highlights the complexity of EC risk in BRCA1/2 PV carriers and offers a comprehensive framework to shared decision making to inform rr-hysterectomy for BRCA1/2 PV carriers.
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Affiliation(s)
- Kimia Sorouri
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Filipa Lynce
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA
| | - Colleen M. Feltmate
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA
| | - Michelle R. Davis
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA
| | - Michael G. Muto
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA
| | - Panagiotis A. Konstantinopoulos
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Elizabeth H. Stover
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA
| | | | - Sarah J. Hill
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Ann H. Partridge
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA
| | - Sara M. Tolaney
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA
| | - Judy E. Garber
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA
| | - Brittany L. Bychkovsky
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA
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12
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Rej RK, Thomas JE, Acharyya RK, Rae JM, Wang S. Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and Challenges. J Med Chem 2023. [PMID: 37377342 DOI: 10.1021/acs.jmedchem.3c00136] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
Estrogen receptor alpha (ERα) is a well-established therapeutic target for the treatment of ER-positive (ER+) breast cancers. Despite the tremendous successes achieved with tamoxifen, a selective ER modulator, and aromatase inhibitors (AIs), resistance to these therapies is a major clinical problem. Therefore, induced protein degradation and covalent inhibition have been pursued as new therapeutic approaches to target ERα. This Perspective summarizes recent progress in the discovery and development of oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), and proteolysis targeting chimera (PROTAC) ER degraders. We focus on those compounds which have been advanced into clinical development.
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Affiliation(s)
- Rohan Kalyan Rej
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Junius Eugene Thomas
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States
- Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Ranjan Kumar Acharyya
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - James Michael Rae
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Shaomeng Wang
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
- Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States
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13
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Vizzotto AO, Nicolau SM, Lopes GM, Castelo Filho A. Risk factors for the development of endometrial lesions in breast cancer patients using tamoxyphen: a retrospective cohort study. Rev Col Bras Cir 2023; 50:e20233442. [PMID: 36995835 PMCID: PMC10595044 DOI: 10.1590/0100-6991e-20233442-en] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/13/2022] [Indexed: 03/29/2023] Open
Abstract
INTRODUCTION breast cancer is the cancer with the highest incidence in women in Brazil, representing 29.7% of all cancers. More than two thirds of women with breast cancer show expression for hormone receptors, and in these cases, hormone therapy with tamoxifen is indicated, which may represent a risk factor for the development of endometrial cancer (four-fold greater relative risk). OBJECTIVE this study aimed to evaluate the association of tamoxifen and the development of endometrial disturbances and to assess possible other associated risk factors. PATIENTS AND METHOD a total of 364 breast cancer patients were evaluated, 286 who used tamoxifen and 78 who did not use this hormone therapy. Results: patients who used tamoxifen had a mean follow-up time of 51.42 months similar to those without hormone therapy (p=0.081). A total of 21 (7.3%) women who used tamofixen and no cases among women without hormone therapy presented endometrial changes during follow-up (p=0.01). Despite information regarding obesity was available for only 270 women, obesity was also significantly associated with the development of endometrial changes (p=0.008). CONCLUSION furthermore, the association between tamofixen and endometrial changes remained significant (p=0.039) after adjusting for obesity.
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Affiliation(s)
| | - Sergio Mancini Nicolau
- - Universidade Federal de São Paulo - Escola Paulista de Medicina, Departamento de Ginecologia - São Paulo - SP - Brasil
- - Hospital Sírio Libanês, Instituto de Ensino e Pesquisa - IEP - São Paulo - SP - Brasil
| | | | - Adauto Castelo Filho
- - Universidade Federal de São Paulo - Escola Paulista de Medicina, Departamento de Medicina - São Paulo - SP - Brasil
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14
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Ghanavati M, Khorshidi Y, Shadnoush M, Akbari ME, Ardehali SH, Chavarri-Guerra Y, Akbari A, Barragan-Carrillo R, Amin Amlashi M, Javid Z, Rahmani J. Tamoxifen use and risk of endometrial cancer in breast cancer patients: A systematic review and dose-response meta-analysis. Cancer Rep (Hoboken) 2023; 6:e1806. [PMID: 36916539 PMCID: PMC10075294 DOI: 10.1002/cnr2.1806] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/26/2023] [Accepted: 03/01/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND Worse prognosis of endometrial cancers (EC) in tamoxifen-treated women compared to non-tamoxifen-treated women been proposed. The relationship between tamoxifen treatment of breast cancer (BC) and the risk of EC is controversial and there is no agreement between publication results on this issue (the answer to all comments provided in the page 2 of manuscript). The aim of this study is investigation the association between tamoxifen treatment and the risk of EC in patients with BC. METHODS AND RESULTS We conducted a comprehensive search with related keywords in MEDLINE/PubMed, SCOPUS, and Web of Science databases until April 16, 2022. Random-effects model (DerSimonian and Laird) was used to pool risk ratios (RRs) with 95% confidence intervals (CIs) of EC. Dose, cumulative dose, and duration-response analysis were performed in linear and non-linear states. Twenty-six studies reported a relation between tamoxifen treatment and risk of EC in patients with BC. Results showed a direct relationship between tamoxifen use and EC (RR: 2.03, 95% CI: 1.68-2.45; I2:76%). By increase the age of participants, the risk of EC was decrease (coef = -.0206), although this was not statistically significant (p = .37). Linear dose-response model indicated a direct significant association between dose and duration use of tamoxifen and EC (dose: exe(b) = 1.019, p = .001; duration: exe(b) = 1.014, p = .001). Non-linear dose-response analysis confirmed linear analysis. CONCLUSION This study highlights that tamoxifen use is a significant risk factor related to the incidence of EC in patients with BC.
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Affiliation(s)
- Matin Ghanavati
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Science and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Khorshidi
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Science and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Shadnoush
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Science and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Seyed Hossein Ardehali
- Department of Anesthesiology and Critical Care, Shohadaye Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yanin Chavarri-Guerra
- Department of Hemato-Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Atieh Akbari
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Regina Barragan-Carrillo
- Department of Hemato-Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Manoochehr Amin Amlashi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Javid
- Department of Nutrition, Farhikhtegan hospital, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Jamal Rahmani
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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15
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Kim D, Oh J, Seok JH, Lee HS, Jeon S, Yoon CI. Risk of Secondary Cancer after Adjuvant Tamoxifen Treatment for Ductal Carcinoma In Situ: A Nationwide Cohort Study in South Korea. Diagnostics (Basel) 2023; 13:diagnostics13040792. [PMID: 36832280 PMCID: PMC9954831 DOI: 10.3390/diagnostics13040792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/05/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Endocrine therapy is the mainstay treatment for hormone receptor-positive ductal carcinoma in situ. The aim of this study was to examine the long-term secondary malignancy risk of tamoxifen therapy. The data of patients diagnosed with breast cancer between January 2007 and December 2015 were retrieved from the database of the Health Insurance Review and Assessment Service of South Korea. The International Classification of Diseases, 10th revision, was used to track all-site cancers. Age at the time of surgery, chronic disease status, and type of surgery were considered covariates in the propensity score matching analysis. The median follow-up duration was 89 months. Forty-one patients in the tamoxifen group and nine in the control group developed endometrial cancer. The Cox regression hazard ratio model showed that tamoxifen therapy was the only significant predictor of the development of endometrial cancer (hazard ratio, 2.791; 95% confidence interval, 1.355-5.747; p = 0.0054). No other type of cancer was associated with long-term tamoxifen use. In consonance with the established knowledge, the real-world data in this study demonstrated that tamoxifen therapy is related to an increased incidence of endometrial cancer.
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Affiliation(s)
- Dooreh Kim
- Division of Breast Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jooyoung Oh
- Department of Psychiatry, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jeong-Ho Seok
- Department of Psychiatry, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Soyoung Jeon
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Chang Ik Yoon
- Division of Breast Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Correspondence: ; Tel.: +82-2-2258-6109
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VIZZOTTO JR ALVOORLANDO, NICOLAU SERGIOMANCINI, LOPES GUILHERMEMUNHOZ, CASTELO FILHO ADAUTO. Estudo de coorte retrospectivo para avaliação de fatores de risco para desenvolvimento de lesão endometrial em pacientes com câncer da mama em uso de tamoxifeno. Rev Col Bras Cir 2023. [DOI: 10.1590/0100-6991e-20233442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023] Open
Abstract
RESUMO Introdução: o câncer da mama é o câncer de maior incidência no sexo feminino no Brasil, representando 29,7% de todos os cânceres. Mais de dois terços das mulheres com câncer da mama apresentam expressão para receptores hormonais, estando, nestes casos, indicada a terapia hormonal com tamoxifeno, que pode representar fator de risco para o desenvolvimento do câncer do endométrio (risco relativo quatro vezes maior). Objetivo: este trabalho teve como objetivo avaliar a associação entre o uso de tamoxifeno e o desenvolvimento de distúrbios endometriais bem como eventuais outros fatores associados. Pacientes e método: Estudo de coorte retrospectivo de 364 pacientes com câncer da mama, das quais 286 utilizaram tamoxifeno e 78 não utilizaram esta hormonioterapia. Resultados: pacientes que usaram tamoxifeno tiveram um seguimento médio de 51,42 meses, semelhante àquelas sem terapia hormonal (p=0,081). Um total de 21 (7,3%) mulheres que usaram tamofixeno e nenhuma mulher sem terapia hormonal apresentaram alterações endometriais durante o seguimento (p=0,01). Nas 270 mulheres que tinham informação sobre obesidade, esta se associou significantemente com o desenvolvimento de alterações endometriais (p=0,008). A associação entre tamofixeno e alterações endometriais permaneceu significante (p=0,039) após ajustar para interação com obesidade. Conclusão: o uso de tamoxifeno no tratamento do câncer da mama esteve associado ao maior risco para desenvolvimento de alterações endometriais especialmente quando associado à obesidade.
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Tariq MR, Ali SW, Khan SA, Yamen R, Iqbal S, Safdar W, Sheas MN. Hormonal Therapies in Cancers. Cancer Treat Res 2023; 185:91-104. [PMID: 37306906 DOI: 10.1007/978-3-031-27156-4_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
The hormonal therapy for cancer has become a household name and the series of experiments performed leading to the discovery of hormones use in the treatments of breast cancer. The hormones like antiestrogen, aromatase restrictors, antiandrogens, and use of extremely strong luteinizing hormone-releasing hormone agonists to perform a "medical hypophysectomy" because of their ability of causing desensitization in the pituitary gland have proven their value in the treatment of cancers over the last two decades. Millions of women still use hormonal therapy for menopause symptoms. Estrogen plus progestin or estrogen separately utilized as a menopause hormonal therapy throughout the world. Women receiving different premenopausal and postmenopausal hormonal therapies are on higher risk of having ovarian cancer. The risk of ovarian cancer did not increase with the increase of duration of hormonal therapy. Postmenopausal hormone use was found to be inversely related to major colorectal adenomas.
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Affiliation(s)
- Muhammad Rizwan Tariq
- Department of Food Sciences, University of the Punjab, Quid-i-Azam Campus, Lahore, Pakistan.
| | - Shinawar Waseem Ali
- Department of Food Sciences, University of the Punjab, Quid-i-Azam Campus, Lahore, Pakistan
| | - Sehar Anam Khan
- Department of Food Sciences, University of the Punjab, Quid-i-Azam Campus, Lahore, Pakistan
| | - Roshan Yamen
- Department of Food Sciences, University of the Punjab, Quid-i-Azam Campus, Lahore, Pakistan
| | - Sara Iqbal
- Department of Food Sciences, University of the Punjab, Quid-i-Azam Campus, Lahore, Pakistan
| | - Waseem Safdar
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Muhammad Naveed Sheas
- Department of Diet and Nutritional Sciences, Ibadat International University, Islamabad, Pakistan
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18
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Wang L, Sharma A. SERDs: a case study in targeted protein degradation. Chem Soc Rev 2022; 51:8149-8159. [PMID: 36073297 DOI: 10.1039/d2cs00117a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Endocrine therapies for breast cancer target ERα which is found in more than 70% of breast cancers. Unfortunately, endocrine resistance typically occurs, in which case Selective Estrogen Receptor Degraders (SERDs) represent the last line of treatment for metastatic breast cancer patients. Fulvestrant, the only currently approved SERD and one of the first targeted protein degradation therapies, presents poor drug-like properties which has led to the development of a new generation of oral SERDs. This review summarizes recent progress in the evolution of SERDs, focusing on clinical candidates and their degradation motifs within the broader context of targeted protein degradation therapies.
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Affiliation(s)
- Lucia Wang
- Department of Chemistry and Chemical Biology Stevens Institute of Technology Hoboken, New Jersey 07030, USA.
| | - Abhishek Sharma
- Department of Chemistry and Chemical Biology Stevens Institute of Technology Hoboken, New Jersey 07030, USA.
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19
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Xiao P, Yao C, Wang G. The top 100 most cited papers on endometrial carcinoma: A bibliometric analysis. Front Oncol 2022; 12:987980. [PMID: 36059668 PMCID: PMC9433873 DOI: 10.3389/fonc.2022.987980] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/02/2022] [Indexed: 11/26/2022] Open
Abstract
Objective This study aimed to analyze the top 100 most cited papers and research trends on endometrial carcinoma via bibliometric methods. Methods On the 1st of March 2022, the top 100 most cited papers regarding endometrial carcinoma published from 1971 to 2021 were identified through searching Web of Science Core Collection database and the following data: title, author, journal, publication year, country and institution were extracted. Microsoft Office Excel (2019) was used for descriptive statistical analysis. VOSviewer (1.6.18) was used to perform and visualize co-authorship analysis and co-occurrence analysis. Results These 100 papers were cited a total of 45, 685 times, and the mean number of citations was 456.85 (range, 228 to 2487). Most papers were published between 1996 and 2000, and between 2006 and 2010. The Lancet published the largest number of papers (n=12), followed by Gynecologic Oncology (n=11). Most of the papers were from the United States (n=58), followed by Italy (n=8) and Netherlands (n=7). Duke University, Johns Hopkins University, University of California San Francisco and University of Southern California (all in United States) contributed the most papers (n=4, respectively). Nicoletta Colombo contributed the most papers (n=3) as the corresponding author. The co-occurrence keywords were classified into three clusters: cluster 1 (epidemiology study), cluster 2 (molecular biology study) and cluster 3 (clinical treatment study). Early research that was published prior to 2005 in this field was mainly focused on epidemiology and molecular biology; the mean publication year for keywords in cluster 3 was later than other clusters. The keywords “external-beam radiotherapy,” “uterine serous carcinoma,” and “intermediate-risk” showed relatively later mean publication year and lower mean frequency of occurrence. Conclusions This study provides medical researchers with bibliometric information relating to endometrial carcinoma. Our results show that the United States is a clear leader in this field. The clinical treatment of endometrial carcinoma has received increasing levels of attention over recent years and is likely to remain a major area of research in the future. Meanwhile, it is recommended to pay attention to potential research hotspots, such as external-beam radiotherapy, uterine serous carcinoma and intermediate-risk.
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Affiliation(s)
- Peichen Xiao
- Department of gynecology, Jinan Central Hospital, Shandong University, Jinan, Shandong, China
- Shandong Innovation Center of Intelligent Diagnosis, Jinan Central Hospital, Shandong University, Jinan, Shandong, China
| | - Chenchen Yao
- Department of gynecology, Jinan Central Hospital, Shandong University, Jinan, Shandong, China
| | - Guangxin Wang
- Shandong Innovation Center of Intelligent Diagnosis, Jinan Central Hospital, Shandong University, Jinan, Shandong, China
- *Correspondence: Guangxin Wang,
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20
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Liu J, Cui G, Ye J, Wang Y, Wang C, Bai J. Comprehensive Analysis of the Prognostic Signature of Mutation-Derived Genome Instability-Related lncRNAs for Patients With Endometrial Cancer. Front Cell Dev Biol 2022; 10:753957. [PMID: 35433686 PMCID: PMC9012522 DOI: 10.3389/fcell.2022.753957] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 02/21/2022] [Indexed: 01/18/2023] Open
Abstract
Background: Emerging evidence shows that genome instability-related long non-coding RNAs (lncRNAs) contribute to tumor–cell proliferation, differentiation, and metastasis. However, the biological functions and molecular mechanisms of genome instability-related lncRNAs in endometrial cancer (EC) are underexplored.Methods: EC RNA sequencing and corresponding clinical data obtained from The Cancer Genome Atlas (TCGA) database were used to screen prognostic lncRNAs associated with genomic instability via univariate and multivariate Cox regression analysis. The genomic instability-related lncRNA signature (GILncSig) was developed to assess the prognostic risk of high- and low-risk groups. The prediction performance was analyzed using receiver operating characteristic (ROC) curves. The immune status and mutational loading of different risk groups were compared. The Genomics of Drug Sensitivity in Cancer (GDSC) and the CellMiner database were used to elucidate the relationship between the correlation of prognostic lncRNAs and drug sensitivity. Finally, we used quantitative real-time PCR (qRT-PCR) to detect the expression levels of genomic instability-related lncRNAs in clinical samples.Results: GILncSig was built using five lncRNAs (AC007389.3, PIK3CD-AS2, LINC01224, AC129507.4, and GLIS3-AS1) associated with genomic instability, and their expression levels were verified using qRT-PCR. Further analysis revealed that risk score was negatively correlated with prognosis, and the ROC curve demonstrated the higher accuracy of GILncSig. Patients with a lower risk score had higher immune cell infiltration, a higher immune score, lower tumor purity, higher immunophenoscores (IPSs), lower mismatch repair protein expression, higher microsatellite instability (MSI), and a higher tumor mutation burden (TMB). Furthermore, the level of expression of prognostic lncRNAs was significantly related to the sensitivity of cancer cells to anti-tumor drugs.Conclusion: A novel signature composed of five prognostic lncRNAs associated with genome instability can be used to predict prognosis, influence immune status, and chemotherapeutic drug sensitivity in EC.
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Affiliation(s)
- Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guoliang Cui
- Department of Gastroenterology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jun Ye
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Yutong Wang
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Can Wang
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jianling Bai
- Department of Biostatistics, School of Public Heath, Nanjing Medical University, Nanjing, China
- *Correspondence: Jianling Bai,
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Nees LK, Heublein S, Steinmacher S, Juhasz-Böss I, Brucker S, Tempfer CB, Wallwiener M. Endometrial hyperplasia as a risk factor of endometrial cancer. Arch Gynecol Obstet 2022; 306:407-421. [PMID: 35001185 PMCID: PMC9349105 DOI: 10.1007/s00404-021-06380-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 12/23/2021] [Indexed: 12/30/2022]
Abstract
Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female reproductive tract in industrialized countries. The most important risk factor for the development of EH is chronic exposure to unopposed estrogen. Histopathologically, EH can be classified into EH without atypia (benign EH) and atypical EH/endometrial intraepithelial neoplasia (EIN). Clinical management ranges from surveillance or progestin therapy through to hysterectomy, depending on the risk of progression to or concomitant EC and the patient´s desire to preserve fertility. Multiple studies support the efficacy of progestins in treating both benign and atypical EH. This review summarizes the evidence base regarding risk factors and management of EH. Additionally, we performed a systematic literature search of the databases PubMed and Cochrane Controlled Trials register for studies analyzing the efficacy of progestin treatment in women with EH.
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Affiliation(s)
- Lisa K Nees
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Sabine Heublein
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Sahra Steinmacher
- Department of Obstetrics and Gynecology, Universität Tübingen, Tübingen, Germany
| | - Ingolf Juhasz-Böss
- Department of Obstetrics and Gynecology, Universität Freiburg, Freiburg, Germany
| | - Sara Brucker
- Department of Obstetrics and Gynecology, Universität Tübingen, Tübingen, Germany
| | - Clemens B Tempfer
- Comprehensive Cancer Center, Ruhr University Bochum (RUCCC), Bochum, Germany
| | - Markus Wallwiener
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.
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22
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Zhou L, Wong KY, Poon CCW, Yu W, Xiao H, Chan CO, Mok DKW, Wong MS. Water Extract of Rhizoma Drynaria Selectively Exerts Estrogenic Activities in Ovariectomized Rats and Estrogen Receptor-Positive Cells. Front Endocrinol (Lausanne) 2022; 13:817146. [PMID: 35282447 PMCID: PMC8908013 DOI: 10.3389/fendo.2022.817146] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/27/2022] [Indexed: 12/18/2022] Open
Abstract
Our previous study demonstrated that the bone protective actions of herbal medicine Rhizoma Drynariae (Gusuibu, RD) were mainly mediated by flavonoid phytoestrogens via estrogen receptors, raising concerns about the safety of using RD as it may induce estrogen-like risk-benefit profile and interact with other ER ligands, such as selective estrogen receptor modulators (SERMs), when coadministered. The present study evaluated the estrogenic activities of RD and its potential interaction with tamoxifen, a SERM, in estrogen-sensitive tissues by using mature ovariectomized (OVX) rats and ER-positive cells. Similar to but weaker than tamoxifen, RD at its clinical dose dramatically ameliorated OVX-induced changes in bone and dopamine metabolism-related markers in OVX rats. However, tamoxifen, but not RD, induced uterotrophic effects. No significant alteration in mammary gland was observed in OVX rats treated with RD, which was different from the inhibitory actions of tamoxifen. The two-way ANOVA results indicated the interactions between RD and tamoxifen in the bone, brain, and uterus of OVX rats while RD did not alter their responses to tamoxifen. Our results demonstrate that RD selectively exerts estrogenic actions in a different manner from tamoxifen. Moreover, RD interacts with tamoxifen without altering its effects in OVX rats.
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Affiliation(s)
- Liping Zhou
- Cell Therapy Center, Xuanwu Hospital Capital Medical University, Beijing, China
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Ka-Ying Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Christina Chui-Wa Poon
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Research Center for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Wenxuan Yu
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Huihui Xiao
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Research Center for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Chi-On Chan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
| | - Daniel Kam-Wah Mok
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
| | - Man-Sau Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Research Center for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
- *Correspondence: Man-Sau Wong,
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23
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Yang EJ, Lee JH, Lee AJ, Kim NR, Ouh YT, Kim MK, Shim SH, Lee SJ, Kim TJ, So KA. Multiple Primary Malignancies in Patients with Gynecologic Cancer. J Clin Med 2021; 11:jcm11010115. [PMID: 35011855 PMCID: PMC8745177 DOI: 10.3390/jcm11010115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/18/2021] [Accepted: 12/23/2021] [Indexed: 11/16/2022] Open
Abstract
Objective: To investigate the prevalence and oncologic outcomes of patients with multiple primary malignant tumors (MPMT) with gynecologic cancer. Methods: This retrospective study included 1929 patients diagnosed with gynecologic cancer at a tertiary medical center between August 2005 and April 2021. The clinical data included cancer location, age at primary malignancy diagnosis, interval between primary and secondary cancer, stage of cancer, family history of cancer, genetic testing, dates of last follow-up, recurrence, and death. Results: The prevalence of MPMT with gynecologic cancer in patients was 8.6% and the mean diagnostic period between primary and secondary cancer was 60 months. Furthermore, 20 of the 165 patients with MPMT had multiple primary gynecologic cancers (MPGC), whereas 145 had gynecologic cancer coexisting with non-gynecologic cancer (GNC). Endometrial-ovarian cancer (60%) was the most common coexisting cancer in the MPGC group, whereas the most common non-gynecologic cancer in the GNC group was breast cancer (34.5%). There were 48 patients with synchronous cancer and 117 patients with metachronous cancer. The incidence of synchronous cancer was higher in the MPGC group than in the GNC group (p = 0.037). Significantly more patients had early-stage ovarian cancer in the MPGC group than in the GNC group (p = 0.031). The overall recurrence and mortality rates were 15.8% and 8.5%, respectively, in patients with MPMT. Conclusion: Synchronous cancer incidence was significantly higher in the MPGC than in the GNC group. Early-stage ovarian cancer was more highly diagnosed in patients with MPGC than in those with GNC. A systematic examination after primary cancer diagnosis could facilitate the early diagnosis of secondary primary malignancy, thereby improving patient prognosis.
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Affiliation(s)
- Eun-Jung Yang
- Department of Obstetrics and Gynecology, KonKuk University Hospital, Seoul 05030, Korea; (E.-J.Y.); (J.-H.L.); (A.-J.L.); (N.-R.K.); (S.-H.S.); (S.-J.L.); (T.-J.K.)
| | - Ji-Hyeon Lee
- Department of Obstetrics and Gynecology, KonKuk University Hospital, Seoul 05030, Korea; (E.-J.Y.); (J.-H.L.); (A.-J.L.); (N.-R.K.); (S.-H.S.); (S.-J.L.); (T.-J.K.)
| | - A-Jin Lee
- Department of Obstetrics and Gynecology, KonKuk University Hospital, Seoul 05030, Korea; (E.-J.Y.); (J.-H.L.); (A.-J.L.); (N.-R.K.); (S.-H.S.); (S.-J.L.); (T.-J.K.)
| | - Nae-Ry Kim
- Department of Obstetrics and Gynecology, KonKuk University Hospital, Seoul 05030, Korea; (E.-J.Y.); (J.-H.L.); (A.-J.L.); (N.-R.K.); (S.-H.S.); (S.-J.L.); (T.-J.K.)
| | - Yong-Taek Ouh
- Department of Obstetrics and Gynecology, Grauate School of Medicine, Kangwon National University, Chuncheon 24289, Korea;
| | - Mi-Kyung Kim
- Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, Seoul 07804, Korea;
| | - Seung-Hyuk Shim
- Department of Obstetrics and Gynecology, KonKuk University Hospital, Seoul 05030, Korea; (E.-J.Y.); (J.-H.L.); (A.-J.L.); (N.-R.K.); (S.-H.S.); (S.-J.L.); (T.-J.K.)
| | - Sun-Joo Lee
- Department of Obstetrics and Gynecology, KonKuk University Hospital, Seoul 05030, Korea; (E.-J.Y.); (J.-H.L.); (A.-J.L.); (N.-R.K.); (S.-H.S.); (S.-J.L.); (T.-J.K.)
| | - Tae-Jin Kim
- Department of Obstetrics and Gynecology, KonKuk University Hospital, Seoul 05030, Korea; (E.-J.Y.); (J.-H.L.); (A.-J.L.); (N.-R.K.); (S.-H.S.); (S.-J.L.); (T.-J.K.)
| | - Kyeong-A So
- Department of Obstetrics and Gynecology, KonKuk University Hospital, Seoul 05030, Korea; (E.-J.Y.); (J.-H.L.); (A.-J.L.); (N.-R.K.); (S.-H.S.); (S.-J.L.); (T.-J.K.)
- Correspondence: ; Tel.: +82-2-2030-7524
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24
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Holcakova J, Bartosik M, Anton M, Minar L, Hausnerova J, Bednarikova M, Weinberger V, Hrstka R. New Trends in the Detection of Gynecological Precancerous Lesions and Early-Stage Cancers. Cancers (Basel) 2021; 13:6339. [PMID: 34944963 PMCID: PMC8699592 DOI: 10.3390/cancers13246339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/07/2021] [Accepted: 12/14/2021] [Indexed: 12/24/2022] Open
Abstract
The prevention and early diagnostics of precancerous stages are key aspects of contemporary oncology. In cervical cancer, well-organized screening and vaccination programs, especially in developed countries, are responsible for the dramatic decline of invasive cancer incidence and mortality. Cytological screening has a long and successful history, and the ongoing implementation of HPV triage with increased sensitivity can further decrease mortality. On the other hand, endometrial and ovarian cancers are characterized by a poor accessibility to specimen collection, which represents a major complication for early diagnostics. Therefore, despite relatively promising data from evaluating the combined effects of genetic variants, population screening does not exist, and the implementation of new biomarkers is, thus, necessary. The introduction of various circulating biomarkers is of potential interest due to the considerable heterogeneity of cancer, as highlighted in this review, which focuses exclusively on the most common tumors of the genital tract, namely, cervical, endometrial, and ovarian cancers. However, it is clearly shown that these malignancies represent different entities that evolve in different ways, and it is therefore necessary to use different methods for their diagnosis and treatment.
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Affiliation(s)
- Jitka Holcakova
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; (J.H.); (M.B.)
| | - Martin Bartosik
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; (J.H.); (M.B.)
| | - Milan Anton
- Department of Obstetrics and Gynecology, Masaryk University and University Hospital, 625 00 Brno, Czech Republic; (M.A.); (L.M.)
| | - Lubos Minar
- Department of Obstetrics and Gynecology, Masaryk University and University Hospital, 625 00 Brno, Czech Republic; (M.A.); (L.M.)
| | - Jitka Hausnerova
- Department of Pathology, Masaryk University and University Hospital, 625 00 Brno, Czech Republic;
| | - Marketa Bednarikova
- Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital, 625 00 Brno, Czech Republic;
| | - Vit Weinberger
- Department of Obstetrics and Gynecology, Masaryk University and University Hospital, 625 00 Brno, Czech Republic; (M.A.); (L.M.)
| | - Roman Hrstka
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; (J.H.); (M.B.)
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25
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Jayaraman S, Reid JM, Hawse JR, Goetz MP. Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside. Endocrinology 2021; 162:6364076. [PMID: 34480554 PMCID: PMC8787422 DOI: 10.1210/endocr/bqab191] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Indexed: 11/19/2022]
Abstract
The selective estrogen receptor (ER) modulator, tamoxifen, is the only endocrine agent with approvals for both the prevention and treatment of premenopausal and postmenopausal estrogen-receptor positive breast cancer as well as for the treatment of male breast cancer. Endoxifen, a secondary metabolite resulting from CYP2D6-dependent biotransformation of the primary tamoxifen metabolite, N-desmethyltamoxifen (NDT), is a more potent antiestrogen than either NDT or the parent drug, tamoxifen. However, endoxifen's antitumor effects may be related to additional molecular mechanisms of action, apart from its effects on ER. In phase 1/2 clinical studies, the efficacy of Z-endoxifen, the active isomer of endoxifen, was evaluated in patients with endocrine-refractory metastatic breast cancer as well as in patients with gynecologic, desmoid, and hormone-receptor positive solid tumors, and demonstrated substantial oral bioavailability and promising antitumor activity. Apart from its potent anticancer effects, Z-endoxifen appears to result in similar or even greater bone agonistic effects while resulting in little or no endometrial proliferative effects compared with tamoxifen. In this review, we summarize the preclinical and clinical studies evaluating endoxifen in the context of breast and other solid tumors, the potential benefits of endoxifen in bone, as well as its emerging role as an antimanic agent in bipolar disorder. In total, the summarized body of literature provides compelling arguments for the ongoing development of Z-endoxifen as a novel drug for multiple indications.
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Affiliation(s)
| | - Joel M Reid
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - John R Hawse
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Matthew P Goetz
- Correspondence: Matthew P. Goetz, MD, Department of Medical Oncology and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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26
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AlZaabi A, AlAmri H, ALAjmi G, Allawati M, Muhanna F, Alabri R, AlBusaidi F, AlGhafri S, Al-Mirza AA, Al Baimani K. Endometrial Surveillance in Tamoxifen and Letrozole Treated Breast Cancer Patients. Cureus 2021; 13:e20030. [PMID: 34987915 PMCID: PMC8716161 DOI: 10.7759/cureus.20030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2021] [Indexed: 11/19/2022] Open
Abstract
Background: Our study aimed to assess the risk of endometrial pathologies after tamoxifen and aromatase inhibitors (AIs) adjuvant treatment for female breast cancer patients treated at Sultan Qaboos University Hospital in Oman. Materials and Methods: A total of 457 patients diagnosed with estrogen positive breast cancer between January 2011 and December 2018 were screened. Two hundred and four patients met the inclusion criteria, and their detailed clinicopathological and endometrial surveillance data were collected from their electronic health records. Results: All patients underwent endometrial assessment during tamoxifen or letrozole therapy. The mean diagnostic age of breast cancer patients is 43.6 years, ranging from 27-84 years. Eighty-three percent of those patients are premenopausal, and 17% are postmenopausal. The mean tamoxifen use duration was 33 months. The majority of patients, 123 (60.3%), have had tamoxifen for three years or less, 47 (23.1%) for 3-5 years, and only 22 (10.8%) were on tamoxifen for more than five years. Increased endometrial thickness was reported in 8% of the premenopausal and 14% of the postmenopausal group. Other endometrial pathologies that were detected are inactive endometrium three (1.47%), atrophic endometrium three (1.47%), serous carcinoma one (0.50%), endometrial cancer two (0.98%), and chronic endometritis one (0.50%), which were not significantly associated with tamoxifen or letrozole therapy duration. Two patients have developed endometrial cancer, and both are postmenopausal and > 60 years old. Conclusions: Tamoxifen and letrozole did not increase the risk of endometrial cancer in premenopausal patients. Breast Cancer (BC) patients on tamoxifen or letrozole might need a pre-treatment endometrial evaluation and explanation of alarming symptoms to guide further endometrial surveillance.
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27
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Stern T, Peleg Hasson S, Saad A, Levanon K, Michaan N, Laskov I, Wolf I, Safra T. Concomitant diagnosis of endometrial and breast cancer - does the sequence matters? Gynecol Oncol Rep 2021; 38:100863. [PMID: 34621946 PMCID: PMC8479413 DOI: 10.1016/j.gore.2021.100863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/07/2021] [Accepted: 09/14/2021] [Indexed: 11/21/2022] Open
Abstract
OBJECTIVE To examine whether patients with both breast cancer (BC) and endometrial cancer (EC) have different features of disease, and whether the sequence of appearance of these tumors is correlated with a more aggressive course. METHODS A retrospective, multi-center observational cohort study of patients treated in two tertiary medical centers between 2014 and 2020. Files of patients who had a co-diagnosis of BC and EC were reviewed and clinical, epidemiological, pathological and genetic characteristics were collected. RESULTS 67 patients with a co-diagnosis of both malignances were divided into two groups according to primary tumor diagnosis: BC first group (43/67, 64%) and EC first group (24/67, 36%). The time interval between diagnosis of malignancies was significantly longer in the BC first group (mean 144.5 months vs. 67 months, p < 0.05). BRCA mutations were found in higher numbers in the BC first group (27.5% vs. 9.5%, p = 0.18). A significantly higher number of patients in the BC first group had uterine serous carcinoma (USC) histology (44% vs. 12.5%, p < 0.05). This was independent of tamoxifen usage among patients (OR 0.65, 95% CI 0.17-2.49). CONCLUSIONS In patients suffering from both BC and EC, the sequence of occurrence of malignancies has relevance: When EC presents as a second primary tumor, it tends to present in a more aggressive form, independent of previous tamoxifen use. The time interval between the diagnosis of malignancies was significantly longer in this group, offering an opportunity to improve preventive measures to decrease the likelihood of a subsequent lethal second cancer.
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Affiliation(s)
- Tomer Stern
- Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Shira Peleg Hasson
- Sackler Faculty of Medicine, Tel Aviv University, Israel
- Oncology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Akram Saad
- Sackler Faculty of Medicine, Tel Aviv University, Israel
- Breast Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel
| | - Keren Levanon
- Sackler Faculty of Medicine, Tel Aviv University, Israel
- Breast Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel
| | - Nadav Michaan
- Sackler Faculty of Medicine, Tel Aviv University, Israel
- Gynecological Oncology Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ido Laskov
- Sackler Faculty of Medicine, Tel Aviv University, Israel
- Gynecological Oncology Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ido Wolf
- Sackler Faculty of Medicine, Tel Aviv University, Israel
- Oncology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Tamar Safra
- Sackler Faculty of Medicine, Tel Aviv University, Israel
- Oncology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
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28
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Wallander K, Thonberg H, Nilsson D, Tham E. Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis. Hered Cancer Clin Pract 2021; 19:46. [PMID: 34711244 PMCID: PMC8555269 DOI: 10.1186/s13053-021-00203-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 10/12/2021] [Indexed: 11/17/2022] Open
Abstract
Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in the MEN1 gene. The variant (c.654C > A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we found a likely pathogenic variant in the MLH1 gene (c.27G > A), and two risk factor variants in the genes CHEK2 and HOXB13. The MLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of the MLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without any findings. We conclude that, in individuals with an unequivocal clinical diagnosis of a specific hereditary cancer syndrome, where standard clinical testing failed to detect a causative variant, re-analysis may lead to a diagnosis.
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Affiliation(s)
- Karin Wallander
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
| | - Håkan Thonberg
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Daniel Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Emma Tham
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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29
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Jiang R, Sun Y, Chen X, Shi P. Estrogen-regulated AGR3 activates the estrogen receptor signaling pathway to promote tamoxifen resistance in breast cancer. Breast Cancer Res Treat 2021; 190:203-211. [PMID: 34519905 DOI: 10.1007/s10549-021-06385-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/06/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE Anterior gradient 3 (AGR3) is associated with breast cancer progression, but its relationship with estrogen and tamoxifen resistance in breast cancer is still unclear. This study was designed to investigate the correlation of ARG3 and estrogen as well as the roles of ARG3 in tamoxifen resistance in breast cancer. METHODS Online database including GEPIA, UALCAN, and TCGA and rVista predictive tool were applied to analyze the expression patterns of AGR3 and its relationship with estrogen receptor 1. AGR3 knockdown and overexpression cell models were constructed. Luciferase reporter assay and ChIP were performed to investigate intermolecular interactions. Western blotting and qPCR were applied to assess targets at mRNA and protein levels, respectively. Cell counting and MTT assay were applied to determine the cell proliferation. RESULTS An elevation of AGR3 was observed in patients with breast cancer, especially in the patients with estrogen receptor (ER)-positive breast cancer. The TCGA dataset and in vitro data supported that AGR3 was positively correlated to ER. Further results demonstrated that ER protein bound to AGR3 promoter sites. AGR3 expression exhibited a positive correlation to cell viability. Besides, AGR3 promoted tamoxifen resistance in breast cancer. CONCLUSION AGR3 is associated with estrogen and promotes tamoxifen resistance in breast cancer.
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Affiliation(s)
- Rui Jiang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, Huaiyin District, Jinan, 250000, China
| | - Yongjie Sun
- Department of Breast and Thyroid Diseases, Shandong Second Provincial General Hospital, Shandong Provincial ENT Hospital, No. 4 Duanxing West Road, Huaiyin District, Jinan, 250000, China
| | - Xiao Chen
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, Huaiyin District, Jinan, 250000, China
| | - Peng Shi
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, Huaiyin District, Jinan, 250000, China.
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30
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de Jonge MM, de Kroon CD, Jenner DJ, Oosting J, de Hullu JA, Mourits MJE, Gómez Garcia EB, Ausems MGEM, Margriet Collée J, van Engelen K, van de Beek I, Smit VTHBM, Rookus MA, de Bock GH, van Leeuwen FE, Bosse T, Dekkers OM, van Asperen CJ. Endometrial Cancer Risk in Women With Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study. J Natl Cancer Inst 2021; 113:1203-1211. [PMID: 33710348 PMCID: PMC8418438 DOI: 10.1093/jnci/djab036] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/17/2021] [Accepted: 02/03/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain; therefore, we assessed this in a large Dutch nationwide cohort study. METHODS We selected 5980 BRCA1/2 (3788 BRCA1, 2151 gBRCA2, 41 both BRCA1/BRCA2) and 8451 non-BRCA1/2 mutation carriers from the Hereditary Breast and Ovarian cancer study, the Netherlands cohort. Follow-up started at the date of the nationwide Dutch Pathology Registry coverage (January 1, 1989) or at the age of 25 years (whichever came last) and ended at date of EC diagnosis, last follow-up, or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared with 1) the general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were 2-sided. RESULTS Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119 296 and 160 841 person-years, respectively (SIR = 2.83, 95% confidence interval [CI] = 2.18 to 3.65; and HR = 2.37, 95% CI = 1.53 to 3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61 to 4.72; HR = 2.91, 95% CI = 1.83 to 4.66), serous-like EC (SIR = 12.64, 95% CI = 7.62 to 20.96; HR = 10.48, 95% CI = 2.95 to 37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80 to 3.83; HR = 2.01, 95% CI = 1.18 to 3.45), and TP53-mutated EC (HR = 15.71, 95% CI = 4.62 to 53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01 to 2.87) and serous-like EC risks (SIR = 5.11, 95% CI = 1.92 to 13.63) were increased compared with the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%). CONCLUSIONS BRCA1/2 mutation carriers have a two- to threefold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.
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Affiliation(s)
- Marthe M de Jonge
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Cornelis D de Kroon
- Department of Gynaecology, Leiden University Medical Center, Leiden, the Netherlands
| | - Denise J Jenner
- Department of Epidemiology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Jan Oosting
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Marian J E Mourits
- Department of Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Encarna B Gómez Garcia
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Margreet G E M Ausems
- Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - J Margriet Collée
- Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Klaartje van Engelen
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Irma van de Beek
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - The Hebon Group
- Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Coordinating Center: Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Vincent T H B M Smit
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Matti A Rookus
- Department of Epidemiology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Geertruida H de Bock
- Department of Epidemiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Flora E van Leeuwen
- Department of Epidemiology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Tjalling Bosse
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Olaf M Dekkers
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Christi J van Asperen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
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31
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Johnatty SE, Pesaran T, Dolinsky J, Yussuf A, LaDuca H, James PA, O'Mara TA, Spurdle AB. Case-case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer. Hum Mutat 2021; 42:1265-1278. [PMID: 34245638 DOI: 10.1002/humu.24256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 06/17/2021] [Accepted: 07/06/2021] [Indexed: 12/24/2022]
Abstract
Hereditary endometrial cancer (EC) is most commonly attributed to pathogenic variants in mismatch repair genes. Evidence supports the existence of additional genetic risk factors in the context of multiple cancer diagnoses and/or family history of EC. EC patients (n = 5292) referred for diagnostic multigene cancer panel testing were annotated for presence of a pathogenic gene variant; personal history of prior, concurrent, or subsequent cancer of another type; reported family history of Lynch syndrome or EC. The Pearson χ2 test was used to assess differences in gene variant prevalence between case sub-groups defined by personal and/or family history of cancer/s, using cases with no family history of Lynch/EC as reference. Another cancer diagnosis was reported for 55% of EC cases. EC cases with a prior and reported family history of Lynch cancer were enriched for variants in MLH1 (p = 3.5 × 10-7 ), MSH2 (p = 3.1 × 10-7 ), and PMS2 (p = .02). Consistent with expectations for a breast cancer gene also predisposing to EC, the variant frequency was increased in EC patients with prior BC and family history of EC for BRCA1 (p = 1.7 × 10-5 ) and PALB2 (p = .0002). Strategic case-case analyses to address cohort ascertainment bias have provided a rationale to direct future studies of candidate hereditary EC genes.
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Affiliation(s)
- Sharon E Johnatty
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | | | | | - Amal Yussuf
- Ambry Genetics, Aliso Viejo, California, USA
| | | | - Paul A James
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Tracy A O'Mara
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Amanda B Spurdle
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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32
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Vail KJ, Madrigal R, Washburn K, Romano J, Edwards JF, Rech R, Delgado J. Pathology in Practice. J Am Vet Med Assoc 2021; 259:45-48. [PMID: 34125611 DOI: 10.2460/javma.259.1.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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33
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O'Flynn H, Jones E, Njoku K, Rana D, Shelton D, Narine N, Ramchander NC, Patel V, Walter FM, Walsh T, Crosbie EJ. Cytology for the diagnosis of endometrial cancer in symptomatic women. Hippokratia 2021. [DOI: 10.1002/14651858.cd014560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Helena O'Flynn
- Division of Cancer Sciences; Faculty of Biology, Medicine and Health, The University of Manchester; Manchester UK
| | - Eleanor Jones
- Division of Cancer Sciences; Faculty of Biology, Medicine and Health, The University of Manchester ; Manchester UK
| | - Kelechi Njoku
- Division of Cancer Sciences; Faculty of Biology, Medicine and Health, The University of Manchester; Manchester UK
| | - Durgesh Rana
- Cytopathology; Manchester University Foundation Trust ; Manchester UK
| | - David Shelton
- Cytopathology; Manchester University Foundation Trust ; Manchester UK
| | - Nadira Narine
- Cytopathology; Manchester University Foundation Trust ; Manchester UK
| | - Neal C Ramchander
- Division of Cancer Sciences; Faculty of Biology, Medicine and Health, The University of Manchester; Manchester UK
| | - Vaishali Patel
- Division of Cancer Sciences; Faculty of Biology, Medicine and Health, The University of Manchester; Manchester UK
| | - Fiona M Walter
- Public Health & Primary Care; University of Cambridge; Cambridge UK
| | - Tanya Walsh
- Division of Dentistry, School of Medical Sciences, Faculty of Biology, Medicine and Health; The University of Manchester; Manchester UK
| | - Emma J Crosbie
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health; The University of Manchester; Manchester UK
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34
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Oka E, Sakai K, Yamagami W, Hirano T, Makabe T, Yoshihama T, Chiyoda T, Kataoka F, Banno K, Aoki D. Atypical vessels in hysteroscopy: Usefulness in prediction of malignant diseases in patients treated with tamoxifen. J Obstet Gynaecol Res 2021; 47:1510-1515. [PMID: 33522085 DOI: 10.1111/jog.14690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 12/11/2020] [Accepted: 01/11/2021] [Indexed: 11/26/2022]
Abstract
AIM Tamoxifen (TAM) is widely used in adjuvant endocrine therapy for invasive breast cancer as a selective estrogen modulator, but this treatment has a risk of developing endometrial malignancy. However, hysteroscopic findings during or after TAM treatment are unclear. The aim of this study is to examine the association between hysteroscopic patterns and malignant histological findings during or after treatment with TAM. METHODS The subjects were patients who received TAM after surgery for breast cancer and underwent hysteroscopy at our institution from January 2016 to December 2019. Clinicopathological factors and hysteroscopic findings were collected from medical records and investigated retrospectively. Histologically, atypical endometrial hyperplasia, endometrial cancer, and carcinosarcoma were classified as malignant diseases. RESULTS A total of 26 patients were eligible for the study. Hysteroscopic findings included an irregular surface of the endometrium (n = 3, 11.5%), atypical vessels (n = 10, 38.5%), papillary structure (n = 3, 11.5%), and polypoid structure (n = 18, 69.2%). Histological examination revealed malignancy in six patients (23.0%). The percentage of atypical vessels in patients with malignancies was significantly higher than that in patients with a normal endometrium or benign lesion (100% vs. 20%, p = 0.0009). The sensitivity and specificity of atypical vessels in hysteroscopy for diagnosis of malignant diseases were 100% and 80%, respectively. CONCLUSIONS Hysteroscopic findings of atypical vessels may be useful for prediction of malignant diseases in patients treated with TAM.
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Affiliation(s)
- Emiko Oka
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Kensuke Sakai
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.,Department of Obstetrics and Gynecology, National Hospital Organization Saitama Hospital, Saitama, Japan
| | - Wataru Yamagami
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Takuro Hirano
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Takeshi Makabe
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Tomoko Yoshihama
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Tatsuyuki Chiyoda
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Fumio Kataoka
- Department of Obstetrics and Gynecology, International University of Health and Welfare School of Medicine, Chiba, Japan
| | - Kouji Banno
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
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35
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Portela S, Cunningham A, Laios A, Hutson R, Theophilou G. Breast Cancer Patients at Increased Risk of Developing Type II Endometrial Cancer: Relative and Absolute Risk Estimation and Implications for Counseling. Cureus 2021; 13:e12981. [PMID: 33659121 PMCID: PMC7920226 DOI: 10.7759/cureus.12981] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Introduction Breast cancer (BC) is a recognized risk factor for endometrial cancer (EC). Emerging literature indicates that it confers a higher risk of type II EC (T2EC) than type I EC (T1EC). Although some surgeons offer a prophylactic hysterectomy to BC patients referred for risk-reducing bilateral salpingo-oophorectomy, insufficient evidence prevents this from being the standard practice. We aimed to quantify their absolute risk and relative risk (RR) of developing both EC subtypes and identify a higher-risk group that could be considered for prophylactic hysterectomy. Methodology This retrospective service evaluation compared patients diagnosed with BC between 2008 and 2014, who subsequently developed EC within 10 years to those who did not. Absolute risk and RR were calculated using the numbers of regional BC and EC cases within this group, alongside 2009 UK female population and EC incidence statistics. Binary logistic regression generated adjusted odds ratios (ORs) for patient- and disease-specific variables. Results A total of 45 BC patients developed EC, 24 had T1EC and 21 had T2EC. Their RR of developing EC was greater than that of the general population (RR: 12.44, p < 0.0001). Notably, this was higher for T2EC (RR: 33.96, p < 0.001) than T1EC (RR: 8.63, p < 0.0001). Nonetheless, the absolute risk remained low. Tamoxifen exposure was significantly more prevalent among T2EC patients (adjusted OR: 79.61, p = 0.003). Increased age at BC diagnosis was associated with T1EC (adjusted OR: 1.10, p = 0.043) and T2EC (adjusted OR: 1.13, p = 0.03). Neither smoking status nor family history of BC was significantly associated with any outcome. Conclusion Women with BC were more likely to develop T2EC than T1EC, and although the absolute risk was low, the cumulative risk was substantial enough to warrant vigilance. Tamoxifen exposure was significantly predictive of EC, particularly T2EC, and might facilitate risk estimation. Older women at BC diagnosis who receive tamoxifen treatment should be screened and closely monitored for EC. However, given the limitations of normal screening methods for the detection of T2EC, counseling for a prophylactic hysterectomy should also be considered. Clarification of the menopausal status will help make more meaningful recommendations.
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Affiliation(s)
- Sara Portela
- Gynaecological Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, GBR
| | - Aimee Cunningham
- Gynaecological Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, GBR
| | - Alexandros Laios
- Gynaecological Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, GBR
| | - Richard Hutson
- Gynaecological Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, GBR
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36
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Liu J, Jiang P, Chen X, Shen Y, Cui G, Ma Z, Zhao S, Zhang Y. Construction of a nine DNA repair-related gene prognostic classifier to predict prognosis in patients with endometrial carcinoma. BMC Cancer 2021; 21:29. [PMID: 33407221 PMCID: PMC7789410 DOI: 10.1186/s12885-020-07712-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/04/2020] [Indexed: 02/01/2023] Open
Abstract
Background Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. However, the molecular mechanisms and the prognostic prediction for EC patients remain unclear. Methods In the current study, we performed an in-depth analysis of over 500 patients which were obtained from the Cancer Genome Atlas (TCGA) database. The bioinformatics analysis included gene set enrichment analysis (GSEA) and Cox and lasso regression analyses to ensure overall survival (OS)-related genes, moreover, to construct a prognostic model and a nomogram for EC patients. Results GSEA identified 4 gene sets significantly associated with EC, which are DNA repair, unfolded protein response, reactive oxygen species pathway and UV response up. Twenty-five OS-related DNA repair genes were screened out, after that, a 9-mRNA signature was constructed to measure the risk scores of patients with different outcomes. In addition, a nomogram contained the 9-mRNA model and clinical parameters was also presented to assess the prognosis. Patients with low risk were more likely to have sensitivity to paclitaxel, vinblastine, rapamycin, metformin, imatinib, Akt inhibitor and lapatinib. Conclusions The identified highly enriched gene sets may offer a novel insight into the tumorigenesis and treatment of EC. Additionally, the constructed 9-mRNA model and the nomogram have prominent clinical implications for prognosis evaluation and specific therapy guidance for EC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07712-5.
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Affiliation(s)
- Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pinping Jiang
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xucheng Chen
- College of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Yujie Shen
- Department of Otorhinolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guoliang Cui
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ziyan Ma
- University of New South Wales, Sydney, Australia
| | - Shaojie Zhao
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, No. 48, Huaishu Road, Wuxi, 214000, Jiangsu, China.
| | - Yan Zhang
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, No. 48, Huaishu Road, Wuxi, 214000, Jiangsu, China.
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37
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Lu Y, Liu W. Selective Estrogen Receptor Degraders (SERDs): A Promising Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer. J Med Chem 2020; 63:15094-15114. [PMID: 33138369 DOI: 10.1021/acs.jmedchem.0c00913] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Estrogen receptor (ER) plays important roles in gene transcription and the proliferation of ER positive breast cancers. Selective modulation of ER has been a therapeutic target for this specific type of breast cancer for more than 30 years. Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have been demonstrated to be effective therapeutic approaches for ER positive breast cancers. Unfortunately, 30-50% of ER positive tumors become resistant to SERM/AI treatment after 3-5 years. Fulvestrant, the only approved selective estrogen receptor degrader (SERD), is currently an important therapeutic approach for the treatment of endocrine-resistant breast cancers. The poor pharmacokinetic properties of fulvestrant have inspired the development of a new generation of oral SERDs to overcome drug resistance. In this review, we describe recent advances in ERα structure, functions, and mechanisms of endocrine resistance and summarize the development of oral SERDs in both academic and industrial areas.
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Affiliation(s)
- Yunlong Lu
- School of Medicine & Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States
| | - Wukun Liu
- School of Medicine & Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China.,State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.,State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210023, P. R. China
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38
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Şahin Uysal N, Boyraz G, Usubütün A, Tuncer ZS. The evaluation of laparotomy results in breast cancer patients with gynecological pathologies. J Obstet Gynaecol Res 2020; 46:2126-2133. [PMID: 32779347 DOI: 10.1111/jog.14408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/08/2020] [Indexed: 12/24/2022]
Abstract
AIM The aim of the study was to evaluate the results of the laparotomies due to gynecological pathologies in breast cancer patients and to assess the distribution of gynecological pathologies and the clinical and laboratory findings contributing to the diagnosis. METHODS This study was conducted between years 2002 and 2011 at Hacettepe University Hospital. We obtained information about 86 consecutive breast cancer patients, including age, time of diagnosis and pathology of breast cancer, hormone receptor status, history of endocrine therapy, presenting symptoms, ultrasonography findings, CA 125 levels, endometrial biopsy results, type of gynecological surgery and pathology results. Data were analyzed with the use of SPSS software. RESULTS Twenty-one (24.4%) out of 86 patients had endometrial pathology, and 24 (27.9%) had adnexal pathology. Fourteen patients (16.2%) had malignant pathology, and of them, 11 had ovarian cancer 3 had endometrial cancer. There were five abnormal cytological findings: 2 ASCUS, 1 LSIL, 1 ASC-H and 1 adenocarcinoma. The patient with the cytology report of adenocarcinoma had the final diagnosis of endometrial cancer. Of the patients, 67 (77.9%) used tamoxifen, whereas 19 (22.1%) did not. Thirty-three patients (38.4%) with gynecological pathologies were detected incidentally during routine follow-up of breast cancer. CONCLUSION This study supports the increase of the gynecological pathology incidence in breast cancer patients and the recommendation of close gynecological follow-up in these patients. Asymptomatic patients might also develop genital cancer. The ultrasonographic appearance of the adnexal masses or endometrial thickness and any abnormal vaginal bleeding or high CA 125 levels are important parameters for evaluating breast cancer patients.
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Affiliation(s)
- Nihal Şahin Uysal
- Department of Obstetrics and Gynecology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Gökhan Boyraz
- Department of Obstetrics and Gynecology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Alp Usubütün
- Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Zafer S Tuncer
- Department of Obstetrics and Gynecology, Hacettepe University Faculty of Medicine, Ankara, Turkey
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39
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Liang J, Blake R, Chang J, Friedman LS, Goodacre S, Hartman S, Ingalla ER, Kiefer JR, Kleinheinz T, Labadie S, Li J, Lai KW, Liao J, Mody V, McLean N, Metcalfe C, Nannini M, Otwine D, Ran Y, Ray N, Roussel F, Sambrone A, Sampath D, Vinogradova M, Wai J, Wang T, Yeap K, Young A, Zbieg J, Zhang B, Zheng X, Zhong Y, Wang X. Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer. ACS Med Chem Lett 2020; 11:1342-1347. [PMID: 32551022 PMCID: PMC7294714 DOI: 10.1021/acsmedchemlett.0c00224] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 05/26/2020] [Indexed: 12/19/2022] Open
Abstract
Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule 12 (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of 6 that showed ionic interaction of azetidine with Asp351 residue. Importantly, 12 showed favorable metabolic stability and good oral exposure. 12 exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
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Affiliation(s)
- Jun Liang
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Robert Blake
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Jae Chang
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Lori S. Friedman
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Simon Goodacre
- Charles
River Discovery Research Services UK Limited, 7-9 Spire Green Center, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom
| | - Steven Hartman
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Ellen Rei Ingalla
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - James R. Kiefer
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Tracy Kleinheinz
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Sharada Labadie
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Jun Li
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Kwong Wah Lai
- WuXi
AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R.
China
| | - Jiangpeng Liao
- WuXi
AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R.
China
| | - Vidhi Mody
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Neville McLean
- Charles
River Discovery Research Services UK Limited, 7-9 Spire Green Center, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom
| | - Ciara Metcalfe
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Michelle Nannini
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Daniel Otwine
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Yingqing Ran
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Nick Ray
- Charles
River Discovery Research Services UK Limited, 7-9 Spire Green Center, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom
| | - Fabien Roussel
- Charles
River Discovery Research Services UK Limited, 7-9 Spire Green Center, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom
| | - Amy Sambrone
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Deepak Sampath
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Maia Vinogradova
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - John Wai
- WuXi
AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R.
China
| | - Tao Wang
- WuXi
AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R.
China
| | - Kuen Yeap
- Charles
River Discovery Research Services UK Limited, 7-9 Spire Green Center, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom
| | - Amy Young
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Jason Zbieg
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Birong Zhang
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Xiaoping Zheng
- WuXi
AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R.
China
| | - Yu Zhong
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
| | - Xiaojing Wang
- Genentech,
Inc., 1 DNA Way, South San Francisco, California 94080, United States
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40
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Yong YF, Tan SC, Liew MWO, Yaacob NS. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development for screening of potential tamoxifen-drug/herb interaction via in vitro cytochrome P450 inhibition assay. J Chromatogr B Analyt Technol Biomed Life Sci 2020; 1148:122148. [PMID: 32416571 DOI: 10.1016/j.jchromb.2020.122148] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/19/2020] [Accepted: 05/04/2020] [Indexed: 11/30/2022]
Abstract
Screening for potential drug-drug interaction (DDI) or herb-drug interaction (HDI) using in vitro cytochrome P450 inhibition (IVCI) assays requires robust analytical methods with high sensitivity and reproducibility. Utilization of liquid chromatography-mass spectrometry (LC-MS) for analyte quantification is often hampered by the presence of non-volatile IVCI sample buffer constituents that often results in ion suppression. In this study, to enable screening of drug interactions involving tamoxifen (TAM) metabolism using IVCI-LC-MS/MS, a liquid-liquid extraction (LLE) method was developed and optimized for sample clean-up. Utilization of chloroform as extraction solvent and adjustment of sample pH to 11 was found to result in satisfactory recovery (>70%) and low ion suppression (<19%). A LC-MS/MS method was subsequently developed and validated for simultaneous quantification of major TAM metabolites, such as N-desmethyltamoxifen (NDT), endoxifen (EDF) and 4-hydroxytamoxifen (HTF) to enable IVCI sample analysis. Satisfactory separation of E-/Z-isomers of endoxifen with peak resolution (Rs) of 1.9 was achieved. Accuracy and precision of the method was verified within the linear range of 0-50 ng/mL for NDT, 0-25 ng/mL for HTF and 0-25 ng/mL for EDF (E/Z isomers). Inhibitory potency (IC50, Ki and mode of inhibition) of known CYP inhibitors and Strobilanthes crispus extract was then evaluated using the validated method. In summary, the results demonstrated applicability of the developed LLE and validated LC-MS/MS method for in vitro screening of DDI and HDI involving TAM metabolism.
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Affiliation(s)
- Y F Yong
- Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
| | - S C Tan
- Usains Biomics Laboratory Testing Services Sdn. Bhd., Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
| | - Mervyn W O Liew
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
| | - N S Yaacob
- Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.
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Chu SC, Hsieh CJ, Wang TF, Hong MK, Chu TY. Younger tamoxifen-treated breast cancer patients also had higher risk of endometrial cancer and the risk could be reduced by sequenced aromatase inhibitor use: A population-based study in Taiwan. Tzu Chi Med J 2020; 32:175-180. [PMID: 32269951 PMCID: PMC7137368 DOI: 10.4103/tcmj.tcmj_17_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/21/2019] [Accepted: 04/06/2019] [Indexed: 01/13/2023] Open
Abstract
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 (<50 years) tamoxifen-treated breast cancer patients also had higher risk of endometrial cancer and to examine whether sequenced aromatase inhibitor (AI) use could reduce the risk. Materials and Methods A population-based cohort of 39,216 newly diagnosed breast cancer patients was identified from Taiwan National Health Insurance Database from 1999 to 2012. The risk of endometrial cancer in nonusers (n = 14,588), tamoxifen-only (n = 19,302), and sequenced AI (n = 5326) users was compared with Cox regression analysis and was adjusted with age, diabetes, hypertension, and chemotherapy. Results During the 14-year study period, 133 patients were diagnosed with subsequent endometrial cancers. Compared with nonusers, tamoxifen-only users had higher risk of endometrial cancer (14-year incidence 1.7% vs. 0.3%; adjusted hazard ratio [HR] 3.90; 95% confidence interval [CI], 2.37-6.42). This was observed in both older (≥50 years) and younger (40-50 years) age groups. Adjusted HR (95% CI) for the latter was 3.74 (1.65-8.48). This risk persisted after cessation of tamoxifen use. The risk of endometrial cancer was lower in sequenced AI when compared with tamoxifen-only users (adjusted HR 0.43; 95% CI, 0.25-0.72). Conclusions Not only patients ≥50 years but also younger (40-49 years) patients with tamoxifen treatment had higher risk of subsequent endometrial cancer in this nation-wide cohort. We suggest regular gynecologic monitoring not only during active use but also during follow-up phase. Sequenced AI use may reduce the risk of endometrial cancer in tamoxifen-treated breast cancer patients.
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Affiliation(s)
- Sung-Chao Chu
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
- School of Medicine, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chia-Jung Hsieh
- Department of Public Health, Tzu Chi University, Hualien, Taiwan
| | - Tso-Fu Wang
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- School of Medicine, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Mun-Kun Hong
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Tang-Yuan Chu
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Center for Prevention of Gynecological Cancer, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
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Lee M, Piao J, Jeon MJ. Risk Factors Associated with Endometrial Pathology in Premenopausal Breast Cancer Patients Treated with Tamoxifen. Yonsei Med J 2020; 61:317-322. [PMID: 32233174 PMCID: PMC7105402 DOI: 10.3349/ymj.2020.61.4.317] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/11/2020] [Accepted: 02/27/2020] [Indexed: 11/27/2022] Open
Abstract
PURPOSE To evaluate factors associated with endometrial pathology during tamoxifen use in premenopausal breast cancer (BC) patients. MATERIALS AND METHODS We reviewed the medical records of premenopausal BC patients treated with tamoxifen who underwent endometrial biopsy with or without hysteroscopy. Clinical characteristics were compared between women with endometrial pathology (endometrial hyperplasia or cancer) and those with normal histology or endometrial polyps. RESULTS Among 284 endometrial biopsies, endometrial hyperplasia was diagnosed in 7 patients (2.5%), endometrial cancer was diagnosed in 5 patients (1.8%), normal histology was noted in 146 patients (51.4%), and endometrial polyp was present in 114 patients (40.1%). When comparing women with endometrial cancer (n=5) to women with normal histology, abnormal uterine bleeding was more common (p=0.007), and endometrial thickness was greater (p=0.007) in women with endometrial cancer. Chemotherapy for BC was also more common in patients with endometrial cancer (p=0.037). When comparing women with endometrial polyps and those with endometrial hyperplasia or cancer, the presence of abnormal uterine bleeding was more common in patients with endometrial hyperplasia or cancer (p<0.001); however, tamoxifen duration and endometrial thickness did not differ significantly between the two groups. CONCLUSION In premenopausal BC patients treated with tamoxifen, abnormal uterine bleeding, increased endometrial thickness, and chemotherapy for BC were associated with the occurrence of endometrial cancer. These findings may provide useful information for gynecologic surveillance and counseling during tamoxifen treatment in premenopausal BC patients.
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Affiliation(s)
- Maria Lee
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Korea
| | - Jinlan Piao
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Myung Jae Jeon
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Korea.
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Wijayabahu AT, Egan KM, Yaghjyan L. Uterine cancer in breast cancer survivors: a systematic review. Breast Cancer Res Treat 2020; 180:1-19. [PMID: 31897901 DOI: 10.1007/s10549-019-05516-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 12/21/2019] [Indexed: 01/17/2023]
Abstract
PURPOSE Epidemiological evidence on the risk factors for uterine/endometrial cancer in breast cancer (BCa) survivors is limited and inconsistent. Therefore, we critically reviewed and summarized available evidence related to the risk factors for uterine/endometrial cancer in BCa survivors. METHODS We conducted a literature search through PubMed, Web of Science Core Collection/Cited Reference Search, as well as through manual searches of the bibliographies of the articles identified in electronic searches. We included in this review studies that were published up to November 30, 2018 that were accessible in full-text format and were published in English. RESULTS Of the 27 eligible studies, 96% had > 700 participants, 74% were prospective cohorts, 70% originated outside of the US, 44% reported as having pre-/postmenopausal women, and 26% reported having racially heterogeneous populations. Risk factors positively associated with uterine/endometrial cancer risk among BCa survivors included age at BCa diagnosis > 50 years, African American race, greater BMI/weight gain, and Tamoxifen treatment. For other lifestyle, reproductive and clinical factors, associations were either not significant (parity) or inconsistent (HRT use, menopausal status, smoking status) or had limited evidence (alcohol intake, family history of cancer, age at first birth, oral contraceptive use, age at menopause, comorbidities). CONCLUSION We identified several methodological concerns and limitations across epidemiological studies on potential risk factors for uterine/endometrial cancer in BCa survivors, including lack of details on uterine/endometrial cancer case ascertainment, varying and imprecise definitions of important covariates, insufficient adjustment for potential confounders, and small numbers of uterine/endometrial cancer cases in the overall as well as stratified analyses. Based on the available evidence, older age and higher body weight measures appear to be a shared risk factor for uterine/endometrial cancer in the general population as well as in BCa survivors. In addition, there is suggestive evidence that African American BCa survivors have a higher risk of uterine/endometrial cancer as compared to their White counterparts. There is also evidence that Tamoxifen contributes to uterine/endometrial cancer in BCa survivors. Given limitations of existing studies, more thorough investigation of these associations is warranted to identify additional preventive strategies needed for BCa survivors to reduce uterine/endometrial cancer risk and improve overall survival.
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Affiliation(s)
- Akemi T Wijayabahu
- Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, 2004 Mowry Rd, Gainesville, FL, 32610, USA
| | - Kathleen M Egan
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
| | - Lusine Yaghjyan
- Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, 2004 Mowry Rd, Gainesville, FL, 32610, USA.
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Pepermans RA, Prossnitz ER. ERα-targeted endocrine therapy, resistance and the role of GPER. Steroids 2019; 152:108493. [PMID: 31518595 PMCID: PMC6859199 DOI: 10.1016/j.steroids.2019.108493] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 08/30/2019] [Accepted: 09/06/2019] [Indexed: 01/01/2023]
Abstract
Endocrine therapy is an effective option for the treatment of estrogen receptor alpha (ERα)-positive breast cancers. Unfortunately, a large fraction of women relapse with endocrine-resistant tumors. The presence of constitutively active ERα mutants, found in a subset of relapse tumors, is thought to be an important endocrine resistance mechanism and has prompted the search for more effective anti-hormone drugs that can effectively inhibit these mutant versions of the receptor. The G protein-coupled estrogen receptor (GPER) is also thought to contribute to the development of endocrine resistance, in part, due to its activation by clinically used selective estrogen receptor modulators and downregulators (SERMs/SERDs). Therefore, next-generation drugs should be screened for potential activity towards GPER. Here, we highlight the need for truly ERα-selective SERMs and SERDs that do not cross-react with GPER for the treatment of ERα-positive breast cancers.
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Affiliation(s)
- Richard A Pepermans
- Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States
| | - Eric R Prossnitz
- Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States; University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States.
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Shetty A, Venkatesh T, Tsutsumi R, Suresh PS. Gene expression changes and promoter methylation with the combined effects of estradiol and leptin in uterine tissue of the ovariectomized mice model of menopause. Mol Biol Rep 2019; 47:151-168. [PMID: 31602590 DOI: 10.1007/s11033-019-05116-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 09/27/2019] [Indexed: 12/19/2022]
Abstract
Substantial epidemiological studies have shown an association of obesity with the common gynecological malignancy, endometrial cancer. The relevant interactions and contribution of estradiol and the adipose cytokine, leptin, in endometrial lesions are not completely understood. Suitable animal models to understand the physiological response of uterine tissue to the combined effects of estradiol-leptin are lacking. To investigate the effect of estradiol-leptin crosstalk on gene expression and associated altered pathways, we established an ovariectomized mouse model, treated with 17-β estradiol (0.1 µg/mouse subcutaenously., for every 12 h) and/or recombinant mouse leptin (1 μg/g Bwt intraperitoneally., for every 12 h) for 4 h, 20 h, and 40 h. Gene expressions by semi-quantitative RT-PCR, uterine tissue protein phosphorylation status by western blotting and promoter methylation were analyzed in estradiol, progesterone insufficient animals. Semi-quantitative RT-PCR demonstrated significantly increased expression of Esr, Igf1, Igfbp3, Vegfr1, and Vegf, and significantly decreased expression of Mmp9 after co-treatment with estradiol and leptin, indicating a common transcriptional network regulated by the treatments. Ovariectomy-induced histomorphological changes were only reversed by estradiol. Methylation-specific PCR, analyzing methylation of CpG sites of Vegfa, Pgr, and Igf1, revealed that transcriptional regulation after hormonal treatments is independent of methylation at the examined CpG sites. Western blot confirmed the increased expression of PSTAT-3 (Ser-727) and PERK1/2 proteins after estradiol + leptin treatment, confirming the estradiol + leptin cross-talk hypothesis. In conclusion, our in vivo studies determined specific gene expression and signaling protein changes, and further unraveled the molecular targets of estradiol + leptin that may perturb endometrial homeostasis and lead to endometrial hyperplasia development in the chronic stimulated state.
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Affiliation(s)
- Abhishek Shetty
- Department of Biosciences, Mangalore University, Mangalagangothri, Mangalore, Karnataka, 574 199, India
| | - Thejaswini Venkatesh
- Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasaragod, Kerala, 671316, India
| | - Rie Tsutsumi
- Department of Nutrition and Metabolism. Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan
| | - Padmanaban S Suresh
- School of Biotechnology, National Institute of Technology, Calicut, Kerala, 673601, India.
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Jeon J, Kim SE, Lee DY, Choi D. Factors associated with endometrial pathology during tamoxifen therapy in women with breast cancer: a retrospective analysis of 821 biopsies. Breast Cancer Res Treat 2019; 179:125-130. [DOI: 10.1007/s10549-019-05448-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 09/13/2019] [Indexed: 10/26/2022]
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de Jonge MM, Ritterhouse LL, de Kroon CD, Vreeswijk MPG, Segal JP, Puranik R, Hollema H, Rookus MA, van Asperen CJ, van Leeuwen FE, Smit VTHBM, Howitt BE, Bosse T. Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity. Clin Cancer Res 2019; 25:7517-7526. [PMID: 31492746 DOI: 10.1158/1078-0432.ccr-19-0848] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 06/05/2019] [Accepted: 08/20/2019] [Indexed: 11/16/2022]
Abstract
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.
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Affiliation(s)
- Marthe M de Jonge
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Lauren L Ritterhouse
- Division of Genomic and Molecular Pathology, Department of Pathology, The University of Chicago, Chicago, Illinois
| | - Cornelis D de Kroon
- Department of Gynaecology, Leiden University Medical Center, Leiden, the Netherlands
| | - Maaike P G Vreeswijk
- Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Jeremy P Segal
- Division of Genomic and Molecular Pathology, Department of Pathology, The University of Chicago, Chicago, Illinois
| | | | - Harry Hollema
- Department of Pathology, University Medical Center Groningen, Groningen, the Netherlands
| | - Matti A Rookus
- Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Christi J van Asperen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Flora E van Leeuwen
- Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Vincent T H B M Smit
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Brooke E Howitt
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Tjalling Bosse
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
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Polo JF, Puentes LO, Falla NF, Mendoza J, Parra Medina R. Prevalencia de carcinoma en pólipos endometriales resecados por histeroscopia. REPERTORIO DE MEDICINA Y CIRUGÍA 2019. [DOI: 10.31260/repertmedcir.v28.n2.2019.919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
La prevalencia de pólipos endometriales (PE) es alrededor de 24% en la población femenina general y entre 10 y 30% en aquellas con hemorragia uterina anormal. Son lesiones de crecimiento rápido que pueden transformarse en una neoplasia maligna. Objetivo: determinar la frecuencia de cáncer endometrial en pacientes con PE diagnosticados por histeroscopia. Metodología: serie de casos retrospectivos atendidos en el Hospital de San José, Bogotá, Colombia, de 2005 a 2014. Resultados: se analizaron en total 408 historias clínicas de pacientes con diagnóstico histopatológico de PE, 10 (2.4%) presentaron patología premaligna y 9 (2,2%) lesión maligna confirmada por microscopía (endometrioides 6, seroso papilar 2 y carcinosarcoma 1). Todas las pacientes con patología maligna tenían más de 60 años y estaban en posmenopausia. Cuatro eran nulíparas, ninguna consumía tamoxifeno ni medicamentos hormonales Conclusión: la prevalencia de carcinomas endometriales en PE diagnosticados a través de histeroscopia en mujeres posmenopáusicas fue de 7.7%. Estos datos son similares a los reportados en la literatura, por lo que recomendamos la implementación de histeroscopia para el tratamiento de todos los PE y su riguroso estudio histopatológico.
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Decreasing secondary primary uterine cancer after breast cancer: A population-based analysis. Gynecol Oncol 2019; 154:169-176. [PMID: 31130286 DOI: 10.1016/j.ygyno.2019.05.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 05/14/2019] [Accepted: 05/17/2019] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To report population-based statistics of women with uterine cancer and a history of prior breast cancer. METHODS This is a retrospective study examining the Surveillance, Epidemiology, and End Results Program between 1973 and 2013. Temporal trends, clinico-pathological characteristics, and survival of women with uterine cancer who had prior breast cancer were assessed. RESULTS Among 237,686 women with uterine cancer, 8235 (3.5%) women had antecedent breast cancer. The number of women with uterine cancer who had a history of breast cancer increased between 1975 and 1989 (21.1-fold relative risk-increase, P < 0.001) and then decreased between 1989 and 2013 (relative risk-reduction [RRR] 11.1%, P = 0.008). The number of uterine cancer among breast cancer survivors decreased between 1990 and 2008 (RRR, 86.0%, P < 0.001). Women with uterine cancer and antecedent breast cancer were more likely to be older and white compared to those without a history of breast cancer (P < 0.05). Uterine tumors after breast cancer were more likely to have serous (10.5% versus 5.7%), carcinosarcoma (8.9% versus 4.4%), or clear cell (2.1% versus 1.2%) histology and present with grade 3 (30.8% versus 21.5%) and stage I disease (64.6% versus 62.5%) compared to tumors in women without breast cancer (all, P < 0.05). After propensity score matching, women with uterine cancer after breast cancer were less likely to die from uterine cancer (adjusted-hazard ratio [HR] 0.675) but more likely to die from other malignancies (adjusted-HR 4.090), particularly breast cancer, and had poorer overall survival (adjusted-HR 1.154) compared to those without breast cancer. CONCLUSION The diagnosis of uterine cancer after breast cancer is decreasing. While uterine tumors following breast cancer are associated with high-risk tumor characteristics, women with uterine cancer after breast cancer are more likely to die from other malignancies.
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Fortini F, Vieceli Dalla Sega F, Caliceti C, Lambertini E, Pannuti A, Peiffer DS, Balla C, Rizzo P. Estrogen-mediated protection against coronary heart disease: The role of the Notch pathway. J Steroid Biochem Mol Biol 2019; 189:87-100. [PMID: 30817989 DOI: 10.1016/j.jsbmb.2019.02.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 02/05/2019] [Accepted: 02/20/2019] [Indexed: 12/28/2022]
Abstract
Estrogen regulates a plethora of biological processes, under physiological and pathological conditions, by affecting key pathways involved in the regulation of cell proliferation, fate, survival and metabolism. The Notch receptors are mediators of communication between adjacent cells and are key determinants of cell fate during development and in postnatal life. Crosstalk between estrogen and the Notch pathway intervenes in many processes underlying the development and maintenance of the cardiovascular system. The identification of molecular mechanisms underlying the interaction between these types of endocrine and juxtacrine signaling are leading to a deeper understanding of physiological conditions regulated by these steroid hormones and, potentially, to novel therapeutic approaches to prevent pathologies linked to reduced levels of estrogen, such as coronary heart disease, and cardiotoxicity caused by hormone therapy for estrogen-receptor-positive breast cancer.
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Affiliation(s)
| | | | - Cristiana Caliceti
- Department of Chemistry "Giacomo Ciamician", Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Elisabetta Lambertini
- Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy
| | - Antonio Pannuti
- University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA
| | - Daniel S Peiffer
- Oncology Research Institute, Loyola University Chicago: Health Sciences Division, Maywood, Illinois, USA; Department of Microbiology and Immunology, Loyola University Chicago: Health Sciences Division, Maywood, Illinois, USA
| | - Cristina Balla
- Cardiovascular Center, University of Ferrara, Ferrara, Italy
| | - Paola Rizzo
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, RA, Italy; Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
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