Sonographic Changes in Endometrium after Use of Tamoxifen in Breast Cancer

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Tamoxifen is a selective ER modulator. It has an antagonistic effect on the ER-α receptors in breast tissues and an agonistic effect on the ER-β receptors in the endometrial tissues. This agonistic effect has been shown to increase the rate of several benign and malignant endometrial pathologies such as hyperplasia, atypia, carcinomas, and sarcomas [5,6]. These concerns have prompted the need for monitoring the endometrial changes induced by TMF to ensure early detection and appropriate management of any abnormalities [4][5][6]. Transvaginal ultrasound (TVUS) has emerged as a valuable Sonographic Changes in Endometrium

I N T R O D U C T I O N
Breast cancer poses a signi cant global health concern affecting a large number of women. Treatment strategies for breast cancer often involve the use of hormonal therapy, such as tamoxifen. However, the use of tamoxifen is associated with potential side effects, particularly in the endometrium. Objective: To evaluate the sonographic changes in the endometrium following the use of tamoxifen therapy in breast cancer patients. Methods: It was a quasiexperimental trial conducted at the Department of medical oncology, Jinnah Postgraduate Medical Center, Karachi, Pakistan from Jan 2023 to Jun 2023. Patients aged 18 years or older, histologically con rmed hormone receptor-positive breast cancer, and having tamoxifen treatment with a dose of 20mg/day for at least six months were included. Endometrial evaluation using transvaginal ultrasonography performed by experienced sonographer and sonographic parameters were assessed. Endometrial evaluation was conducted at baseline and 6 months after start of tamoxifen at regular interval as determined by the treating physician. Results: The median duration of tamoxifen therapy was 24 months with IQR as 10 to 36 months. There was statistically signi cant difference in pre-treatment and post-treatment endometrial thickness with p-value=0.0001. About 80.5% of the females had endometrial thickness difference of less and equal to 5mm and polyps were observed in 5 cases. Conclusions: Tamoxifen increases the risk of endometrial abnormality; this study highlights the need for monitoring endometrial changes before and after starting tamoxifen therapy in breast cancer patients to detect early suspected neoplastic changes in endometrium.

M E T H O D S
non-invasive imaging modality to assess the endometrium and detect tamoxifen-induced changes. TVUS provides a high-resolution image of the endometrium, enabling the evaluation of parameters like endometrial thickness, echogenicity, and morphological characteristics [7,8] This imaging technique has become a routine practice in monitoring endometrial changes in breast cancer patients receiving tamoxifen therapy [7][8][9]. Early detection of TMFinduced changes in the endometrium can facilitate timely intervention and management, reducing the risk of developing endometrial pathologies. Sonographic assessment of the endometrium provides a non-invasive, easily accessible, and cost-effective method to monitor these changes throughout the course of TMF therapy. However, limited studies in Pakistan are available to assess the sonographic changes in the endometrium following the use of TMF in breast cancer patients. So, the aim of current study was to see sonographic changes in endometrium by tamoxifen in our population, by assessing endometrial thickness, morphology, and other relevant parameters using transvaginal ultrasound, we aim to provide further insights into the impact of TMF on the endometrium and contribute to the development of effective monitoring strategies in our population.
It was a Quasi-Experimental trial conducted at the Department of Medical Oncology, Jinnah Postgraduate Medical Center, Karachi, Pakistan from Jan 2023 to Jun 2023. Sample size of 154 was estimated using Open epi sample size calculator by taking statistics of endometrial hyperplasia as 16.3% among post-menopausal females with breast cancer after Tmf use [10], margin of error as 5% and 95% con dence level. Inclusion criteria was consisted of patients aged 18 years or older, histologically con rmed hormone receptor-positive breast cancer, and having tamoxifen treatment for at least six months. Females having pre-existing endometrial pathology (benign or malignant) or severe renal or liver impairment or pregnancy or Venous thrombo embolism or breast-feeding mothers was excluded from the study. Non-probability consecutive sampling technique was applied for sample selection. The study protocol was reviewed and approved by the institutional ethics committee, ensuring the protection of patients' rights, con dentiality, and informed consent. Verbal informed consent was obtained from all the patients. Demographic and clinical data were collected from all the patients, including age, body mass index (BMI), parity, gravida, family history of breast cancer, menopausal status, and duration of TMF therapy. All non-metastatic ER/PR +ve patients were treated with tamoxifen 20mg/day. Transvaginal ultrasound was performed by experienced sonographers using high-resolution ultrasound machines.
Sonographic measurements were conducted at baseline (prior to tamoxifen initiation) and 6 months after start of tamoxifen therapy, as determined by the treating physician. Here we consider an endometrial thickness of ≥ 12 mm as thickened endometrium in an asymptomatic premenopausal woman with regular menses. For postmenopausal and amenorrheic premenopausal women, an endometrial thickness ≥5 mm was de ned as endometrial thickening. Endometrial biopsy was indicated if the patient has thickened endometrium, abnormal TVS u/s, or abnormal uterine bleeding. Sonographic parameters including endometrial thickness, the presence of any focal lesions or abnormalities were assessed. Data were managed and analyzed using SPSS version-20. Mean and SD were reported for numeric data like age, BMI, and duration of TMF. Frequency and percentage were reported for categorical data like parity and gravida categories, family history of breast cancer, menopausal status, endometrial pattern, and the presence of any focal lesions or abnormalities. The distribution of pre and post TMF endometrial thickness was assessed using Shapiro-Wilk's test, which showed non-parametric distribution (p<0.05). The comparison between pre and post TMF endometrial thickness was done using Wilcoxon Sign Rank test. Level of signi cance was set at 5%.  Lee et al. 12% of the pre-menopausal and 10.6% of the postmenopausal women had endometrial thickness [6]. Another study by Jeon et al., also concluded that endometrial thickness is signi cantly associated with endometrial pathology in breast cancer females treated with TMF [18]. Cohen et al., also found endometrial thickness of more than 5mm in postmenopausal breast cancer females who were using TMF 20 mg/day for median duration of thirty-six months [19]. While, Lee et al., found pre-menopausal breast females on TMF had signi cant association between endometrial thickness and endometrial cancer [20]. In another study by Parveen et al., TMF showed positive correlation with uterine volume, endometrial thickness and abnormal ndings as compared to females without TMF [21]. Hence, these nding suggests that the TMF treatment may have an effect on the proliferative properties of the endometrium. The study addresses an important clinical concern regarding the D I S C U S S I O N

R E S U L T S
The therapeutic approach of TMF has been extensively utilized in female patients diagnosed with breast cancer [11][12][13]. However, despite of having positive effects, it has been observed that TMF treatment can have detrimental effects on the uterus, leading to various benign and malignant changes [14]. This study was designed to investigate the risk of sonographic abnormalities in endometrium associated with tamoxifen use in breast cancer patients. Transvaginal ultrasonography was used as a method to evaluate endometrial status. The cut-off value of 5 mm on TVS was used to designate abnormally thickened endometrium since there have been several reports indicating that endometrial thickness greater than 5mm in breast cancer patient is associated with increase chance for endometrial abnormalities. Additionally, there is a potential risk of malignant transformation, leading to Data presented as Mean ± SD or Median (IQR) or n (%) The endometrial thickness pre-treatment and posttreatment was compared using Wilcoxon signed rank test, w h i c h r e v e a l e d s i g n i c a n t d i f fe r e n c e i n b o t h measurements. Thus, the TMF caused a signi cant increase in endometrial thickness with p-value=0.0001. Almost 80.5% of the females had endometrial thickness difference of less than and equal to 5mm and 19.5% of the females had endometrial thickness difference of greater than 5 mm, respectively as shown in Figure 1. Among 154 females with breast cancer, polyps observed in 5 cases, those patients in which endometrial abnormality was seen undergone for biopsy to rule out malignancy. The ndings seen on pathology after tamoxifen therapy were simple hyperplasia in 10, hyperplastic polyps in 5 and endometrial carcinoma in 4 cases. potential impact of TMF therapy on the endometrium in breast cancer patients. But the study has few limitations like the study is based on a single-center, quasiexperimental trial, which may limit the generalizability of the ndings to a broader population. The study lacks a control group, making it di cult to establish a direct causal relationship between TMF use and the obser ved endometrial changes. The duration of TMF therapy varied among patients, which could introduce confounding factors and impact the interpretation of the results. The study relies on transvaginal ultrasound as the imaging modality for assessing endometrial changes, which may have limitations in detecting certain abnormalities compared to other imaging techniques or histopathological examination. However, the study utilizes transvaginal ultrasound, a widely accessible and costeffective imaging modality, to assess endometrial changes, allowing for non-invasive monitoring during TMF therapy.
This study highlights the need for monitoring endometrial changes in breast cancer patients receiving TMF therapy. The ndings suggest that TMF use may lead to an increased risk of endometrial pathologies, including polyps, hyperplasia, and carcinoma.