Pretreatment and prospective assessment of endometrium in menopausal women taking tamoxifen for breast cancer.

OBJECTIVES: To estimate the pretreatment incidence of endometrial pathology and to prospectively assess the endometrial morbidity emerging during tamoxifen intake for breast cancer. STUDY DESIGN: One-hundred and forty-six menopausal breast cancer patients, candidate to receive tamoxifen underwent endometrial assessment by Transvaginal Ultrasonography (TU) before the start of therapy. A double-layered endometrial stripe measuring more than 4mm indicated hysteroscopy and endometrial biopsy. Endometrial abnormalities detected before the start of tamoxifen were treated by operative hysteroscopy or by hysterectomy; no therapy and yearly hysteroscopic follow-up was scheduled for patients showing non-atypical hyperplasias. All women were asked to undergo TU on a yearly basis; during the follow-up period, indication for hysteroscopy and endometrial biopsy were the following: (i) an endometrial lining measured above 4mm at the first time, (ii) at least a 50% increase of endometrial thickness since the last finding in patients previously assessed by hysteroscopy, (iii) a recorded vaginal bleeding, and (iv) previous findings of endometrial hyperplasia. Histopathologic result from biopsy or hysterectomy was the reference test to establish the baseline prevalence of endometrial pathology and the emerging prevalences of morbidity after 12, 24, 36, 48 and 60 months of tamoxifen therapy. RESULTS: One-hundred and five patients were followed for 60 months, whereas 113, 126, 137 and 141 patients were evaluated up to 48, 36, 24 and 12 months, respectively. In 44 out of 146 patients, pretreatment TU showed an endometrium thicker than 4mm and in 31 (21.2%) of these patients abnormalities consisting of 16 endometrial polyps, seven polyps harboring simple hyperplasia, four simple hyperplasias, three atypical hyperplasias and one adenocarcinoma were found. During tamoxifen intake benign endometrial abnormalities were detected in 36 out of 114 assessable patients showing normal endometrium before the start of tamoxifen therapy (31.5%) and in seven out of 27 patients with baseline endometrial abnormalities (25.9%). Overall, an endometrial pathology emerged in 30.4% of patients during tamoxifen administration and in no patients we found an atypical lesion. CONCLUSIONS: In menopausal breast cancer patients the incidence of endometrial abnormalities before the start of tamoxifen therapy is high and includes 2.7% of atypical pathology. After the diagnosis and treatment of baseline atypical lesions were accomplished, no atypical endometrial lesion emerged after the start of tamoxifen administration. Based on these findings, we believe that pretreatment assessment of endometrium is recommended in all menopausal women candidate to receive tamoxifen therapy.

Prospective endometrial assessment of breast cancer patients treated with third generation aromatase inhibitors.

OBJECTIVE: A prospective evaluation of the effects on endometrium of third generation aromatase inhibitors (AIs), administered as adjuvant up-front therapy or switched therapy in menopausal patients suffering from breast cancer. METHODS: Forty-five patients suffering from estrogen-receptor positive breast cancer were treated with AIs as adjuvant endocrine therapy; 27 patients switched from tamoxifen to AIs (group 1) due to adverse medical events related to tamoxifen intake (22 patients) or to an extended endocrine treatment after 60 months of tamoxifen therapy (5 patients); whereas 18 patients received AIs as up-front adjuvant therapy (group 2). All patients underwent endometrial investigation before the start of AIs therapy and, thereafter, at 12 month intervals. Endometrial assessment was based on Transvaginal Ultrasonography (TU), followed by hysteroscopy and endometrial biopsy when a double layered endometrial stripe above 4 mm was measured on the longitudinal plane of uterine scanning. Six patients, showing endometrial hyperplasia before the start of AIs therapy, underwent hysteroscopy on a yearly basis, disregarding the endometrial thickness measured by TU. Histopathologic results on endometrial biopsies represented the reference test in order to estimate the prevalence of endometrial morbidity. RESULTS: Demographic and clinical variables evaluated (age, parity, age at menarche and menopause, Body Mass Index, previous chemotherapy and radiotherapy) did not differ in groups 1 and 2. The average period of endometrial surveillance after the start of AIs therapy was 24.8 +/-10.8 months for group 1 and 21.4 +/- 11.5 months for group 2. A progressive decrease of endometrial thickness, from 8.2 +/- 5.0 to 3.0 +/- 1.2 in group 1 and from 4.7 +/- 4.3 to 1.9 +/- 0.3 in group 2, was found before the start and after 36-48 months of AIs therapy. The second line endometrial investigations' rate dropped from 70.3% to 12.5% in group 1 and from 27.7% to 0.0% in group 2, at baseline and after 36-48 months of AIs therapy, respectively. We found baseline endometrial abnormalities in 25.9% and in 22.2% of patients in groups 1 and 2 (P = 0.4), respectively. During AIs administration, an endometrial pathology was found in 1 patient of group 1 and in 3 patients of group 2. In 3 patients, the abnormality consisted of simple hyperplasias and in all these patients an abnormal endometrium (1 complex atypical hyperplasia and 2 simple hyperplasias) was already detected at baseline assessment. Only in 1 patient (2.2%) of group 2 did we find an emerging pathology, consisting of adenosarcoma harbored within an endometrial polyp, detected after 12 months of therapy with letrozole. In 3 out of 5 patients showing simple hyperplasia and in 1 patient showing atypical hyperplasia before the start of AIs therapy, we observed a reversal to normal endometrium and to simple hyperplasia, respectively, after 12 months of therapy with anastrozole. CONCLUSIONS: AIs delivered as up-front therapy for breast cancer have no effects on unspecific endometrial thickening. When administered as switched therapy after tamoxifen withdrawal, AIs may reverse tamoxifen-associated endometrial thickening. As a consequence, we reduced unnecessary second-line endometrial investigations. A low rate of emerging endometrial pathology was found during AIs therapy.

Histopathologic behavior of endometrial hyperplasia during tamoxifen therapy for breast cancer.

OBJECTIVE: The purpose of the present study is to prospectively evaluate the effects of tamoxifen on the pathological behavior of endometrial hyperplasias without atypia, diagnosed before the start of adjuvant endocrine therapy, in menopausal patients suffering from breast cancer. METHODS: Twenty-six patients suffering from estrogen-receptor positive breast cancer and candidate to receive adjuvant tamoxifen, were found to be affected by endometrial hyperplasias before the start of endocrine therapy. All women showed a baseline endometrial stripe, measured by transvaginal ultrasonography, thicker than 4 mm and the diagnosis of endometrial hyperplasia was made by hysteroscopy and endometrial biopsy. Two patients showing complex atypical hyperplasia underwent vaginal hysterectomy, whereas the remaining 24 patients, suffering from endometrial hyperplasia without atypia, were followed on a yearly basis during the period of tamoxifen intake, by hysteroscopy and endometrial biopsy. RESULTS: Baseline histopathology showed simple and complex hyperplasia in 20 and in 4 patients, respectively. The median follow-up period was 38 months; in particular, all patients underwent endometrial assessment after 12 months, while 22, 16, 10 and 4 patients were followed-up after 24, 36, 48 and 60 months of tamoxifen therapy, respectively. Progression from complex hyperplasia to complex atypical hyperplasia (1 patient) and from complex and simple hyperplasia to adenocarcinomas (2 patients) was found within 24 months of tamoxifen intake in 3 patients (12.5%). In 2 patients (8.3%), a progression from simple to complex hyperplasia was detected within 36 months of tamoxifen treatment. In 13 patients (54.1%), stable histology of simple or complex hyperplasia was found, whereas 6 patients (25.0%), with focal hyperplasia harbored in an endometrial polyp, showed a normalization of endometrial histology after polyp resection. CONCLUSIONS: Endometrial hyperplasias without atypia diagnosed before endocrine therapy for breast cancer in menopausal patients show an early and high progression-rate to atypical lesions under tamoxifen influence.

Baseline endometrial assessment before tamoxifen for breast cancer in asymptomatic menopausal women.

OBJECTIVE: The aim of this study is to estimate the prevalence of endometrial pathology before the start of tamoxifen therapy in menopausal breast cancer patients. METHODS: Ninety-one gynecologically asymptomatic patients, suffering from estrogen receptor-positive breast cancer and scheduled for adjuvant tamoxifen, underwent pretreatment endometrial assessment. In all patients, a transvaginal ultrasonography was carried out; a double-layered endometrial stripe measuring above 4 mm was considered as abnormal. In these patients, outpatient hysteroscopy and endometrial biopsy were performed. Pathologic findings were considered the reference test in estimating the prevalence of endometrial morbidity. RESULTS: In 34 patients (37.3%) a thickened endometrium was an indication for hysteroscopic and pathologic assessment. Endometrial polyps, simple hyperplasias, and complex atypical hyperplasias were found in 10 (10.9%), 4 (4.3%), and 3 (3.2%) patients, respectively, leading to an overall prevalence of baseline endometrial morbidity of 18.6%. Established individual risk factors for development of endometrial pathology, such as body mass index, age at menarche and menopause, and parity, did not significantly differ in patients with and without endometrial abnormalities. Only patients' age (63.8 +/- 8.6 and 52.2 +/- 11.8; P = 0.03) and endometrial thickness (10.5 +/- 3.5 and 3.9 +/- 3.0; P > 0.001) were significant predictive factors of endometrial pathology. CONCLUSIONS: Menopausal women with estrogen receptor-positive breast cancer appear to have high risk of baseline subclinical endometrial abnormalities; therefore, an endometrial assessment, before the start of tamoxifen therapy, is always recommended in such patients.

High prevalence of a screening-detected, HFE-unrelated, mild idiopathic iron overload in Northern Italy.

BACKGROUND AND OBJECTIVES: In Italy, typical HFE mutations account for only 64% of the cases with overt hereditary hemochromatosis (HH), and a common HFE-unrelated disease was hypothesized. DESIGN AND METHODS: One thousand and fifty potential blood donors were screened by iron tests, C282Y and H63D HFE mutation analysis in a region in North Italy. Subjects with repeated fasting transferrin saturation of 45% or more and no secondary iron overload were defined as probands with idiopathic iron overload. To assess the inheritance of iron overload, relatives of probands were screened. RESULTS: The overall frequency of probands with idiopathic iron overload was 3.43% (95% confidence interval, 2.32 to 4.52). Of these, 8.4% had genotypes associated with HH (compound heterozygous for H63D/C282Y or homozygous for H63D HFE mutations), and 91.6% had atypical genotypes: 47.2% were heterozygous for C282Y or H63D HFE mutations, and 44.4% had wild type/wild type genotype. A family history of iron overload was proven in 33.3% of probands with atypical genotypes (1.04% of the overall population). Pedigree analysis excluded linkage of heterozygous HFE mutations with iron overload (cumulative lod score 2.41) and documented a recessive non-HLA-linked locus accounting for iron overload in wild type/wild type genotypes. None of the probands had clinical signs of iron accumulation; in males, serum ferritin positively correlated with age (r=0.63, p<0.01), and the regression model predicted a serum ferritin of 700 ng/mL at the age of 58. INTERPRETATION AND CONCLUSIONS: In Northern Italy an HFE-unrelated, mild idiopathic iron overload is highly prevalent. A recessive locus accounts for iron overload in at least 1.04% of the overall population.