{'fraction_non_alphanumeric': 0.03348044437680718, 'fraction_numerical': 0.025795160553949172, 'mean_word_length': 4.947058823529412, 'pattern_counts': {'":': 0, '<': 13, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Correlation between bone mineral density and endometrial thickness over time in women with breast cancer history

As the efficacy of chemotherapy and adjuvant endocrine therapy for breast cancer increase, the quality-of-life to cancer survivors could be more important issue in strategies of breast cancer treatment. Bone health has become more compelling in care of breast cancer survivor than ever before. This retrospective study was aimed to evaluate factors relating to the change in BMD and to ascertain the correlation between changes in BMD and EMT of women with breast cancer in follow-up. Records of 164 women who underwent surgery for breast cancer were reviewed in this study. The basal characteristics included parity, menopausal state, medication with vitamin D, bisphosphonate, selective estrogen modulator (SERM), aromatase inhibitor (AI), gonadotrophin releasing hormone agonist (GnRHa), chemotherapy, radiotherapy, cancer type including positivity of estrogen receptor, progesterone receptor and HER2, combined the other gynecologic disease or the other origin cancer. At initial and follow-up visit, all subjective were checked with BMD, endometrial thickness (EMT). The mean age was 52.1 ± 8.5 years old and overall interval between initial and follow-up visits were 17.6 ± 7.5 month in this study. The BMDs of L1–4 (1.040 ± 0.166 g/cm2 vs 1.070 ± 0.181 g/cm2, p < 0.001), femur neck (0.850 ± 0.121 g/cm2 vs 0.870 ± 0.136 g/cm2, p < 0.001), and femur total (0.902 ± 0.132 g/cm2 vs 0.915 ± 0.138 g/cm2, p < 0.001) at follow-up visit were significantly lower than those at initial visit. The change in BMDs of L1–4 (ΔBMDL1–4, r = 0.353, p < 0.001, and r = 0.228, p = 0.003), femur neck (ΔBMDNeck, r = 0.198, p = 0.011, and r = 0.282, p < 0.001), femur total (ΔBMDTotal, r = 0.294, p < 0.001, and r = 0.327, p < 0.001) had positive correlation with age and the change in EMT (ΔEMT). After age correction, ΔEMT had positive correlation with ΔBMDNeck (r = 0.245, p = 0.002) and ΔBMDTotal (r = 0.273, p < 0.001). ΔBMDL1–4 and ΔBMDNeck differed according to menopausal state (p < 0.001 and p = 0.035), bisphosphonate (p < 0.001 and p < 0.001), and GnRHa (p < 0.001 and p < 0.001). In follow-up of women with history of breast cancer, ΔEMT could be an alternative screening marker for BMD decrease.


Introduction
According to the Korean national cancer registration database, breast cancer is the leading cancer incidence in Korean women with 347.6 per 100,000 persons, and shows a relatively good prognosis with 92.7% of overall 5-year survival rate. 1 As the efficacy of chemotherapy and adjuvant endocrine therapy for breast cancer increase, the quality-of-life to cancer survivors could be more important issue in strategies of breast cancer treatment. So, follow-up of breast cancer survivors could be involved by multidisciplinary clinical care. [2][3][4] Breast cancer survivors, women on selective estrogen receptor modulator (SERM) therapies in particular, should be recommended for an annual gynecologic assessment to surveilling the uterine endometrium and screening the other cancer, because long-term SERM therapy of postmenopausal women with breast cancer is associated with uterine pathology. 4 For screening procedure, ultrasonography is useful in asymptomatic patients selecting cases with increased endometrial thickness for further investigation. 5 The previous studies reported that increased endometrial thickness (EMT) as assessed by ultrasonography was associated with increased risk of endometrial pathologies including carcinomas, and identification of cancer at an early stage could be possible by the regular endometrial surveillance. 6,7 However, a previous study suggested that frequent surveillance for EMT would not be necessary in the follow-up for this patients because most endometrial changes were not a serious problem even though adjuvant hormonal therapy after breast cancer surgery exhibited changes in the endometrium and ovary. 8 Bone health has become more compelling in care of breast cancer survivor than ever before. 9 The estrogen deprivation status after breast cancer treatment including chemotherapy and adjuvant hormone therapy disrupts the skeletal homeostasis, promoting loss of bone mineral density (BMD), and increasing the risk of osteoporosis. [10][11][12] Osteoporosis is a ''silent disease'' with rare symptoms in its early stages, and often goes undiagnosed until severe fractures occur. 13,14 Therefore, the multidisciplinary clinical care for breast cancer survivor should include surveillance of BMD change. 15,16 Some previous studies found SERM could increase BMD without significant EMT change in breast cancer survivors. 17,18 However, the correlation between changes in BMD and EMT has been rarely known up-to-date, even though both could be the alternative marker for estrogen status of breast cancer patients. This study was aimed to evaluate factors relating to the change in BMD and to ascertain the correlation between changes in BMD and EMT of women with breast cancer in follow-up.

Subjective
The patients who had been undergone operative treatment due to breast cancer and visited gynecology clinic were recruited in this retrospective study. Records of a 164 women were reviewed from January 1, 2015 to December 31, 2018. The purpose of visit to gynecology clinic was routine gynecologic examination. All patients visited gynecology clinic twice a year. The first and the following visits were terms as ''the initial visit'' and ''the follow-up visit.''

Clinical variables
The basal characteristics of all subject were checked at the initial visit. The basal clinical variables included age, parity, and menopausal state at breast cancer diagnosis. Cancer type including positivity of estrogen receptor, progesterone receptor and HER2 by pathologic report was checked. The information about receiving chemotherapy and/or radiotherapy after surgery, combined the other origin cancer and/or gynecologic disease was obtained. The current medication with vitamin D, bisphosphonate, selective estrogen modulator (SERM), aromatase inhibitor (AI), and gonadotrophin releasing hormone agonist (GnRHa) at visit were checked. All subjects were undertaken gynecologic ultrasonography for surveillance of EMT, and BMD at initial and follow-up visit.

Statistical analysis
Data were analyzed by Student t test, paired t test, and Pearson correlation test as appropriate. In all tests, significance was accepted for a p value of \0.05. All data were analyzed using Statistical Package for the Social Sciences for Windows (version 25; SPSS, Chicago, IL).

Ethics statement
The present study protocol was reviewed and approved by the Institutional Review

Change in BMD and EMT according to the categorical variables
Comparison of change in BMD and EMT according to the categorical variables were summarized in Table 6. DBMD L1-L4 showed significant differences according to menopausal status, Her2/neu and use of GnRH agonist and bisphosphonate. DBMD Neck showed significant differences according to use of GnRH agonist and bisphosphonate. DBMD Total showed significant differences according to menopausal status, use of GnRH agonist and bisphosphonate. DEMT showed significant differences according to menopausal status and use of GnRH agonist. There were no significant difference in BMD and EMT according to the other categorical variables.

Discussion
This study was aimed to evaluate factors relating to the change in BMD of women with history of breast cancer. We found change in EMT could be a screening marker of change in BMD in follow-up for breast cancer patients. Additionally, our results suggest some clinical factors including age, menopausal status, and use of GnRH agonist and bisphosphonate could have effects on the change in BMD.
Our results showed mean BMDs in all checked point decreased at the follow-up visit compared to the initial visit. These results suggest that breast cancer survivors could be at the risk of decrease in BMD during follow-up. Furthermore, DBMD had a positive correlation with age and DEMT, even though it had no significant correlation with BMI. In the analysis of partial coefficients of DBMD with DEMT by adjusting for age, DEMT still showed positive correlation with DBMD. Furthermore, the correlation scatter plots of DEMT correlated with DBMD by the linear and the quadratic model showed significant correlation. Ultrasonography is a popular screening tool for gynecologic surveillance of breast cancer follow-up, and measurement of EMT by ultrasonography could be an easily accessible screening marker. A few previous study reported that ultrasonographic EMT shows a positive correlation with BMD in postmenopausal women consistent with our results. 20,21 Considering mean age and proportion of postmenopausal status of this present study (52.1 6 8.5 and 63.4%), this result was consistent with the previous studies with subjects of similar age. 22,23 Unlike these studies which showed this correlation with healthy postmenopausal women, this present study was conducted with breast cancer survivors.    In the comparison of DBMD according to the categorical variables, use of GnRH agonist and bisphosphonate showed a significance. Use of GnRH agonist showed more decreased BMD in all points. This finding suggests that the patients with longterm use of GnRH agonist may need more careful check for bone change. The previous studies reported that adjuvant treatment including GnRH agonist could enhance the rate of bone loss in breast cancer patients, consistent with our data. 15,24 Use of bisphosphonate showed a protective effect against bone loss in this cohort study, and it was consistent with the previous studies. [25][26][27] Menopausal status had a significance in only DBMD L1-L4 in this present study. Premenopausal women showed larger difference in DBMD L1-L4 than postmenopausal women. It implicates cessation of ovarian hormone production could affect homeosis of lumbar bone first rather than femoral bone. Interestingly, consistent with our results, a previous study reported that surgically induced menopause is associated with loss of the lumbar BMD and no significant change of BMD in the femoral neck in 2 years. 28 In the comparison of DEMT according to the categorical variables, use of GnRH agonist and menopausal status showed a significance. Use of GnRH agonist enhanced change of EMT. A previous randomized controlled clinical trial also showed GnRH agonist had an effect of thinner EMT in breast cancer patients. 29 It could be due to GnRH agonist-induced estradiol suppression. There was no significant effect on change of EMT according to use of calcium, vitamin D, and bisphosphonate. Postmenopausal women showed a smaller change of EMT than premenopausal women. We presumed that EMT of postmenopausal status already could have a low capacity to change.
Some questions to be answered remain from our results. First of all, no correlation between BMD and BMI were shown in our study. Many previous data suggested higher BMI could act as a protective factor for decreased BMD. [30][31][32] However, in contrast with what has been reported above, some recent data suggested that lean body mass could have an impact on BMD rather than BMI in postmenopausal women, 33 and BMI could not be a predictor of fracture risk in obese postmenopausal women. 34 Our subjects included 23.7% (40/169) of obese women with BMI over 25.0 kg/m 2 . We inferred that this characteristic could affect these results, due to small sample size of this study. Further study with large sample size should be necessary. The second one could be the low R 2 of DEMT correlated with DBMD. Concerning to this in our data, linear model R 2 showed 0.052 to 0.107, and quadratic model R 2 showed 0.108 to 0.155. It suggests that our functional correlation model could interpret exactly only 5% to 15% of all cases. However, our results suggested that DEMT could be a useful screening marker for warning to a steep BMD decrease, rather than factor for calculating BMD decrease. Considering breast cancer survivors could be at the risk of BMD decrease, easy-accessible and cost-effective ultrasonographic screening could have an advantage.

Conclusions
In conclusion, DEMT by ultrasonography between patient's visits could be an alternative screening marker for BMD decrease in follow-up of women with history of breast cancer. Easy accessibility and cost-effectiveness could be beneficial by using this ultrasonographic screening of gynecology clinics adding values to previously reported efficacy of gynecologic follow-up. 35,36 Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by grant from the Ministry of Science and ICT (2020R1A2C1010293) and by the Medical Research Program at Seoul National University College of Medicine.