Uterine Malignancy following Tamoxifen Use in Breast Cancer Patients in Iran: Case Series and Literature Review

Background: This study evaluated tumor characteristics and survival in women with breast cancer whosubsequently developed uterine cancer. Methods: Information about endometrial cancer in tamoxifen usersfollowing breast cancer refered to the gynecologic oncology clinic of Vali-Asr hospital between 1997-2007 wasevaluated. Results: Among 330 patients with endometrial cancer, 5 were in women previously diagnosed withbreast cancer. Two cancers were malignant mixed Mullerian tumors of the uterus (MMMT), 2 were endometrioidadenocarcinomas, and one was a papillary clear cell carcinoma. Patients received tamoxifen for 4-8 years. Theendometrial cancers occurred 2-11 years after initial treatment for the breast cancers. Four of the endometrialcancers featured abnormal uterine bleeding and one of them had increased vaginal discharge and all werediagnosed on endometrial curetting. All patients received standard surgical staging for endometrial cancer andall except one were stage I. At laparotomy of one patient, an advanced stage MMMT was found with diffusedperitoneal spread and ascites. In spite of the surgery, she died of disease, 3 months later. The other patientsremain recurrence-free for breast cancer and uterine cancer after 6-120 months. Conclusion: Breast cancerpatients who use tamoxifen and have early stage endometrial cancers demonstrate a good prognosis. Abnormaluterine bleeding or vaginal discharge is the most important symptom.     

Cigarette smoking in women with cancers of the breast and reproductive organs

This case-control study addressed the relationship between cigarette smoking and cancers of the breast (1,741 cases), endometrium (476 cases), uterine cervix (1,174 cases), and ovary (296 cases). The lifetime smoking history of cases was compared with that of 2,128 controls, and relative risks (odds ratios) for smoking were estimated using multiple logistic regression to adjust for potential confounding by age, marital status, number of pregnancies, and Quetelet's index. With increasing amount smoked there was a statistically significant decrease in endometrial cancer risk and a statistically significant increase in cervical cancer risk. In the highest smoking category (greater than or equal to 15 pack-yr), the endometrial cancer relative risk was 0.57 [95% confidence interval (CI) of 0.37, 0.86] and the cervical cancer relative risk was 1.81 (95% CI of 1.47, 2.22). There was no apparent relationship between smoking and cancers of the breast or ovary.     

Tamoxifen and the endometrium: findings of pelvic ultrasound examination

The need for endometrial surveillance in breast cancer patients undergoing adjuvant treatment with tamoxifen is still controversial. In this study, 164 asymptomatic breast cancer patients (110 on treatment with tamoxifen, 20 mg/day, and 54 controls) were examined with pelvic ultrasound and endometrial biopsy. No differences in ultrasound and biopsy findings were observed in the pre- and perimenopausal group between patients treated with tamoxifen and controls. Postmenopausal patients on tamoxifen had a significantly thicker endometrium (mean ± SD, 7.2 ± 8.5 vs. 1.5 ± 4.3 mm, p=0.00002) and significantly larger uterine volume (mean ± SD, 63.2 ± 39.9 vs. 43.7 ± 38.8 cm³, p=0.0001) than controls. Fifty-four percent of patients on tamoxifen had an endometrial thickness 5 mm, often with multiple irregular sonolucencies suggesting the presence of cysts. Ultrasound findings, however, did not correlate with the presence of endometrial abnormalities on biopsy, and no endometrial cancer or atypical hyperplasia were found. This lack of correlation makes questionable the use of routine sonography in asymptomatic breast cancer patients on tamoxifen. Obtaining routine endometrial samples, on the other hand, may be difficult in some patients because of cervical stenosis or refusal. Until the benefits of endometrial surveillance will be proved, asymptomatic patients should not be submitted routinely to ultrasound examination or biopsy, but encouraged to report promptly any abnormal vaginal bleeding.     

Association between endometrial cancer and tamoxifen treatment of breast cancer

A retrospective cohortstudy in 4109 breast cancer patients was undertaken to determine how tamoxifen affected the risk of endometrial cancer. Data on 1701 tamoxifentreated women were analysed. Two thousand four hundred and eight nontamoxifen users served as control group. The occurrence of new primary uterine cancers was assessed by computerized linkage to the Austrian Cancer Registry. Twentyfive women who subsequently developed endometrial cancer were identified. Eight uterine cancers occurred in the tamoxifen group, whereas 17 uterine cancers were found in the control group. The estimate of the relative risk (RR) showed an increased risk to develop endometrial cancer for the tamoxifen group RR 1.136 (95% CI 0.71; 1.80). Analysis of relevant confounding variables did not show any differences in the two groups.In conclusion, this retrospective study demonstrated a nonsignificant increased risk of endometrial cancer in women receiving tamoxifen as treatment for breast cancer. However, the magnitude of RR and the absolute number of endometrial cancer cases in this long term observation demonstrate clearly that the clinical benefit of tamoxifen therapy greatly outweighs the risk.     

Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients.

BACKGROUND: Tamoxifen may induce uterine abnormalities of clinical concern. Our aim was to compare early uterine changes occurring in postmenopausal breast cancer patients treated in first-line with tamoxifen or third generation aromatase inhibitors. We also assessed the effect of aromatase inhibitors on tamoxifen-induced uterine changes. PATIENTS AND METHODS: Seventy-seven consecutive postmenopausal breast cancer patients scheduled to start endocrine treatment were included in this prospective study. Transvaginal ultrasonography (TVUS) was carried out before and after 3 months of therapy. No interventions were done on pre-existing asymptomatic uterine abnormalities seen on baseline sonography. RESULTS: After 3 months of therapy, tamoxifen significantly increased endometrial thickness and uterine volume. Additionally, tamoxifen induced endometrial cysts and polyps, and increased the size of pre-existing fibroids. In contrast, aromatase inhibitors did not stimulate endometrial growth and were not associated with endometrial pathologies seen under tamoxifen. Furthermore, aromatase inhibitors decreased endometrial thickness and uterine volume in patients previously treated with tamoxifen. CONCLUSIONS: Our study demonstrates that tamoxifen induces uterine abnormalities from as early as 3 months of therapy. In contrast, these abnormalities are not seen in patients on aromatase inhibitors. Furthermore, our data indicate that tamoxifen therapy followed by an aromatase inhibitor may lead to a reduction in endometrial pathologies associated with tamoxifen.     

Endometrial mullerian adenosarcoma after toremifene treatment in breast cancer patients: a case report

Toremifene is an anti-estrogen which has been shown to be effective in the treatment of breast cancer, and is thought to be a less uterotrophic agent than tamoxifen. The risk assessment concerning endometrial cancer has been inconclusive because of its rare use up to the mid-1990s. We report a case of an adenosarcoma, which is a very rare type of uterine malignancy, after toremifene treatment for 5 years in a breast cancer patient. After 1 year of toremifene use, the patient had a benign Mullerian adenofibroma. After an additional 4 years of toremifene treatment, the endometrial polypoid lesion was transformed into a Mullerian adenosarcoma. Although toremifene is a promising anti-estrogenic agent in the treatment of breast cancer patients, clinicians should not neglect the possibility of a uterine malignancy.     

Outcomes in patients with primary breast cancer and a subsequent diagnosis of endometrial cancer : comparison of cohorts treated with and without tamoxifen

BACKGROUND: The study compared tumor characteristics and survival in women with breast cancer who subsequently developed endometrial cancer with or without a history of tamoxifen use. METHODS: The British Columbia Cancer Agency registry identified 163 women diagnosed with breast cancer between 1989-1999 who received a subsequent diagnosis of endometrial cancer. Of these, 55% (n = 90) had a history of tamoxifen use. Outcomes analyzed were breast cancer-specific survival (BCSS), endometrial cancer-specific survival (ECSS), and overall survival (OS). RESULTS: Median follow-up was 9.4 years. Distributions of age, menopausal status, body mass index, and comorbidities were similar in the tamoxifen-treated and nontamoxifen cohorts. Proportions of aggressive endometrial cancer subtypes including papillary serous, clear cell, and mixed mullerian tumors were higher in the tamoxifen cohort (28% vs14%, P = .03). Distributions of endometrial cancer grade and stage were similar in the 2 groups (P > .05). Hysterectomy and/or oophorectomy were the primary treatments for endometrial cancer in 99% of patients, with comparable pelvic control rates in the tamoxifen and nontamoxifen groups. At 10 years, patients in the tamoxifen group experienced lower BCSS compared with the nontamoxifen group (89% vs 97%, P = .02). No significant differences in ECSS and OS were observed between the 2 groups (ECSS 82% and 82%, P = .85; and OS 69% v. 66%, P = .85). CONCLUSIONS: In patients with breast cancer who developed a subsequent endometrial cancer, tamoxifen-treated patients had higher proportions of aggressive endometrial cancer subtypes, but almost all cases were amenable to surgery, thus resulting in similar endometrial cancer control and survival when compared with nontamoxifen treated patients.     

An epidemiological study to identify the risk factors with two different types of controls in high-grade cervical lesions including invasive cancer

A multidisciplinary study on pre-cancerous and early cancerous lesions of uterine cervix was carried out at our Institute from which the subjects (cases and one group of control) for the present study were selected with the objective to identify the possible risk factors related to high-grade cervical lesions including invasive cancer through an epidemiological study by selecting two different types of controls and to assess the feasibility whether the cancers of other organs could be taken as controls at the same time studying the risk factors associated with cervical cancer. One group of control was women with negative Pap smear and second group of control was the women with breast cancer but negative Pap smear. A total of 100 biopsy-proven cases of high-grade cervical intraepithelial lesions and Invasive cancer were recruited. The results of the study show that some of the risk factors associated with the cervical cancer get exaggerated when breast cancer cases were used as controls because risk factors of both cancers are opposite to each other. So it is concluded that in order to remove any bias, normal hospital controls or controls selected from multiple cancers should be taken to study the risk factors involved in cervical carcinogenesis.     

Breast cancer metastasizing to the uterine cervix

Three cases of breast cancer that metastasized to the uterine cervix are presented. A review of the literature disclosed 21 additional cases. Seventy-five percent of the patients presented with abnormal vaginal bleeding, 62% had no gross evidence of malignancy on examination, and in 89% the cervical metastases were a manifestation of widespread disease.     

乳腺癌患者术后服用三苯氧胺后子宫内膜病变的临床病理分析

目的分析乳腺癌患者术后服用三苯氧胺(tamoxifen,TAM)后子宫内膜的病理变化。方法研究组为服用TAM出现阴道不规则出血或B型超声提示子宫内膜异常患者69例;对照组为同时期非乳腺癌因绝经后出血就诊的患者60例。TAM组又分为绝经前、后两组(20例、49例)及根据服用TAM时间(T)长短,分为T≤1年组、1年＜T＜2年组、T≥2年组,进行宫腔镜检查及子宫内膜活检。结果TAM组子宫内膜息肉及子宫内膜增生明显高于对照组(P<0.001,P<0.05)。绝经后TAM组较绝经前TAM组更易发生子宫内膜病变(P<0.01),且子宫内膜重度不典型增生和子宫内膜癌均发生在绝经后组。随着用药时间的延长,子宫内膜病变的发生增加(P<0.01),且子宫内膜癌均发生在服药2年后。结论乳腺癌患者使用TAM治疗发生子宫内膜病变的风险增加,尤其对于绝经后使用且用药2年以上的妇女。     

Prevalence of Cancers of Female Organs among Patients with Diabetes Type 2 in Kelantan,Malaysia: Observations over an 11 Year Period and Strategies to Reduce the Incidence

Introduction: Kelantan is one of the states in Malaysia which has a high prevalence of type 2 diabetes (DM2).Other than with endometrial carcinoma, the association of DM2 with particular female cancers is not known.Objective: To determine the proportion of breast, cervical, ovarian and endometrial cancers among femaleswith DM2 diagnosed in Hospital Universiti Sains Malaysia (HUSM) over an 11 year period. Materials andMethods: All histologically confirmed cases of breast, endometrial, cervical and ovarian carcinomas admittedto the Hospital were included in the study. The patient diabetic status was traced from the hospital medicalrecords. Results: There was a total of 860 cases of breast, cervical, ovarian and endometrial carcinomas overthis period. Breast carcinoma was the commonest, accounting for 437/860 (50.8%) followed by cervix, 159/860(18.5%), ovarian, 143/860 (16.6%) and endometrial carcinomas, 121/860 (14.1%). Out of these, 228/860 (26.5%)were confirmed diabetics. Endometrial carcinoma patients showed the highest proportion being diabetics, 42.1%(51/121), followed by ovarian cancer, 25.9% (37/143), breast carcinoma, 23.6% (103/437) and cervical cancer23.3% (37/159). Conclusions: There is a significant proportion of DM2 among women with these four cancers,endometrial carcinoma being the highest followed by ovarian, breast and cervical carcinoma. The rising trend ofthese four cancers is in tandem with an increasing trend of DM2 in the community. In populations where diabetesis prevalent, screening for epithelial cancers should be rigourous. Diabetic clinics should include screening forthese cancers among their female patients and gynecology clinics should screen the women they treat for theirdiabetes status.     

Educational Interventions for Cervical Cancer Screening Behavior of Women: A Systematic Review

Background: Cervical cancer is the second most common cancer in women worldwide; early detection can playa key role in reducing the associated morbidity. The objective of this study was to systematically assess the effects ofeducational interventions on cervical cancer screening (CCS) behavior of women. Methods: In this review the Cochranelibrary, Web of Science, Science Direct, PubMed, Scopus and search engine of Google scholar were searched for allinterventional studies (trails, pre- and post-test or quasi-experimental) published in 2000-2017 for a systematic review,The search was based on the following keywords: cervix cancer, uterine cervical neoplasms, screening, prevention andcontrol, Papanicolaou Test, pap test, pap smear, education, intervention, systematic review. Due to the heterogeneityof the data, a qualitative analysis was performed. Results: Thirty seven articles with 15,658 female participants indifferent parts of world were included in the review. About three quarters of the articles covered behavior changeinterventions. About one fourth of the articles were based on health education methods. The heath belief model isthe most popular used framework for cervical cancer screening interventions. The results of our study showed thatdifferent health education methods (such as calls, mailed postcards, mother/daughter education. consultation sessions,picture books, videos, PowerPoint slides, small group discussions, educational brochures, radio broadcast education,lecture presentations, tailored counseling and a fact sheet, Self-learning package, face-to- face interviews and etc) areeffective in modifying cervical cancer screening behavior of women. Conclusions: Our results showed that the differentinterventions and health behavior change frameworks provide an effective base for cervical cancer prevention. Heathproviders can chose educational methods based on the particular client situations.     

Tamoxifen Use in Indian Women - Adverse Effects Revisited

Background: Tamoxifen is generally considered a safe drug for Indian womenwith breast cancer. Indian women seem to tolerate tamoxifen therapy better than western women, but thereare no data regarding safety and local adverse effect profiles in typical Indian populations. Methods and Results:A total of 3,000 case records of patients who had received tamoxifen daily for any period of time, betweenJanuary 1988 and December 2007, were identified for study. Hot flashes were reported by 800 (26%), mildvaginal dryness by 450 (15%) and vaginal discharge by 300 (10%), with vaginal bleeding experienced by 40(1.3%) patients. A total of 1,100 (36.6%) asymptomatic patients had a thickened endometrium(defined as >8mmin thickness) on ultrasonography. Endometrial curettage was performed in all of these. None of the patientsdeveloped endometrial carcinoma. Fatty infiltration of liver was found in 1,440 (48%) patients with a meantime interval for development of 7 months (range 6-30 months). Conclusions: Fatty infiltration of liver is foundin almost half of the Eastern Indian women who receive tamoxifen. Increased endometrial thickness, whichremains asymptomatic, was documented in more than one third of patients on ultrasound examination. Tamoxifenseems to have a negligible potential for causation of uterine malignancies in eastern Indian women. Rates ofhysterectomies in Indian patients on tamoxifen are substantially lower than those of western patients on tamoxifen.     

Endometrial cancer survival after breast cancer in relation to tamoxifen treatment: Pooled results from three countries

Introduction

Tamoxifen is an effective treatment for breast cancer but an undesirable side-effect is an increased risk of endometrial cancer, particularly rare tumor types associated with poor prognosis. We investigated whether tamoxifen therapy increases mortality among breast cancer patients subsequently diagnosed with endometrial cancer.

Methods

We pooled case-patient data from the three largest case-control studies of tamoxifen in relation to endometrial cancer after breast cancer (1,875 patients: Netherlands, 765; United Kingdom, 786; United States, 324) and collected follow-up information on vital status. Breast cancers were diagnosed in 1972 to 2005 with endometrial cancers diagnosed in 1978 to 2006. We used Cox proportional hazards survival analysis to estimate hazard ratios (HRs) and 95% confidence intervals (CI).

Results

A total of 1,104 deaths occurred during, on average, 5.8 years following endometrial cancer (32% attributed to breast cancer, 25% to endometrial cancer). Mortality from endometrial cancer increased significantly with unfavorable non-endometrioid morphologies (P < 0.0001), International Federation of Gynaecology and Obstetrics staging system for gynecological malignancy (FIGO) stage (P < 0.0001) and age (P < 0.0001). No overall association was observed between tamoxifen treatment and endometrial cancer mortality (HR = 1.17 (95% CI: (0.89 to 1.55)). Tamoxifen use for at least five years was associated with increased endometrial cancer mortality (HR = 1.59 (1.13 to 2.25)). This association appeared to be due primarily to the excess of unfavorable histologies and advanced stage in women using tamoxifen for five or more years since the association with mortality was no longer significant after adjustment for morphological type and FIGO stage (HR = 1.37 (0.97 to 1.93)). Those patients with endometrioid tumors, who stopped tamoxifen use at least five years before their endometrial cancer diagnosis, had a greater mortality risk from endometrial cancer than endometrioid patients with no tamoxifen exposure (HR = 2.11 (1.13 to 3.94)). The explanation for this latter observation is not apparent.

Conclusions

Patients with endometrial cancer after breast cancer who received tamoxifen treatment for five years for breast cancer have greater endometrial cancer mortality risk than those who did not receive tamoxifen. This can be attributed to non-endometrioid histological subtypes with poorer prognosis among long term tamoxifen users.     

Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice

BACKGROUND: In patients with early-stage breast cancer, 5 years of treatment with the selective estrogen receptor modulator (SERM) tamoxifen reduces breast cancer recurrence and mortality, whereas more than 5 years of tamoxifen does not further reduce breast cancer recurrence and doubles the risk of endometrial cancer. We evaluated the effects on tumor growth of raloxifene, another SERM, after tamoxifen treatment in mouse models of breast and endometrial cancers. METHODS: Athymic, ovariectomized mice were bitransplanted with tumors derived from human breast cancer and endometrial cancer cells that either were tamoxifen-naive or had been exposed to tamoxifen for short (6 months) or long (>5 years) terms. The effects of raloxifene (two dose levels) and tamoxifen on tumor growth in the presence and absence of low-dose estrogen were evaluated. All statistical tests were two-sided. RESULTS: Raloxifene was less effective than tamoxifen in blocking the stimulatory effects of low-dose estrogen on the growth of tamoxifen-naive breast (P<.001) and endometrial (P =.001) tumors. Raloxifene and tamoxifen had similar inhibitory effects on the growth of short-term tamoxifen-exposed breast tumors. Raloxifene and tamoxifen had similar stimulatory effects on the growth of breast and endometrial tumors that had been exposed to at least 5 years of tamoxifen. However, neither drug blocked the stimulatory effects of estrogen on the growth of these tumors. Raloxifene was less effective than tamoxifen (P<.001) in blocking the stimulatory effects of estrogen on endometrial tumors that had been exposed to tamoxifen in the past. CONCLUSIONS: Raloxifene and tamoxifen had similar effects on these mouse models of tamoxifen-naive and tamoxifen-resistant breast and endometrial cancer. Treatment with raloxifene following 5 years of adjuvant tamoxifen may not further decrease breast cancer recurrence and may increase endometrial cancer incidence.     

Tamoxifen and toremifene treatment of breast cancer and risk of subsequent endometrial cancer: a population-based case-control study

A population-based case-control study was performed to evaluate the risk of endometrial cancer related to tamoxifen or toremifene treatment. All patients with breast cancer diagnosis since 1980 in Finland who subsequently developed an endometrial cancer by the end of 1995 and 3 matched controls were identified among the 38,000 breast cancer patients of the Finnish Cancer Registry database. Detailed information on treatment of breast cancer and potential confounders was collected from hospital records. The OR for tamoxifen treatment (59 cases), adjusted for significant cofactors (increased risk associated with obesity, low parity and PR positivity) was 2.9 (95% CI 1.8-4.7). The OR for toremifene (3 cases) was 0.9 (95% CI 0.3-3.9). The OR related to adjuvant tamoxifen treatment reached its maximum 2-5 years after the beginning of treatment (OR 5.1, 95% CI 2.1-13), while the OR for tamoxifen used for palliative treatment of advanced breast cancer was especially high after a lag of over 5 years (OR 9.5, 95% CI 2.5-36). The risk increase due to tamoxifen was slightly higher if the age at initiation was below 55, and risk was more pronounced among patients with well-differentiated endometrial cancer than patients with cancers of clinical grades 2 or 3. According to our results, treatment with tamoxifen increases the risk of endometrial cancer. Due to the rare use of toremifene up to the mid-1990s, the risk assessment concerning it was inconclusive.     

Preventing breast cancer in high-risk women, 2008

Several large, prospective trials have evaluated tamoxifen compared with placebo for breast cancer risk reduction in women at increased risk for breast cancer. Analysis of the large, prospective breast cancer risk-reduction trials that used tamoxifen estimated that tamoxifen decreased breast cancer incidence by 38% on average and estrogen receptor-positive tumors by 48%. Tamoxifen is known to have several serious side effects, including uterine malignancy, thromboembolic events, cataracts, and menopausal symptoms, that have limited its usefulness in the risk-reduction setting. Raloxifene (Evista) is a benzothiophene selective estrogen-receptor modulator that has antiestrogenic effects on breast and endometrial tissue as well as estrogenic effects that are similar to but distinct from tamoxifen. Among postmenopausal women who are at increased risk for breast cancer, raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer but appears to be less effective than tamoxifen in reducing the risk of in situ breast cancer. Raloxifene causes less benign and malignant uterine changes and fewer thromboembolic events than tamoxifen. Symptomatic side effects are comparable for the two drugs. Raloxifene is more appropriate than tamoxifen for reduction of breast cancer risk among postmenopausal women at increased risk for breast cancer.     

Endometrial Metastasis from Breast Cancer during Adjuvant Endocrine Therapy

It is well-known that tamoxifen increases the risk of endometrial cancer. Although metastasis to the uterus from breast cancer is uncommon, there have been some case reports on uterine metastasis. If an endometrial abnormality is detected, the differential diagnosis of whether the uterine tumor is metastatic or primary is very important to determine the course of treatment. We herein report a case in which we detected a uterine tumor during follow-up after treatment with tamoxifen, and demonstrate that GCDFP-15 is useful in diagnosing metastatic uterine tumors arising from breast cancer.Key Words: Breast cancer, Uterine metastases, Tamoxifen therapy