Abnormal mismatch repair and other clinicopathologic predictors of poor response to progestin treatment in young women with endometrial complex atypical hyperplasia and well-differentiated endometrial adenocarcinoma: a consecutive case series.

OBJECTIVE: To report the response to progestin therapy in young women with endometrial complex atypical hyperplasia (CAH) or FIGO grade 1 endometrial adenocarcinoma (FIGO 1 EAC) based on clinicopathologic features, including abnormal DNA mismatch repair (MMR) by immunohistochemistry (IHC). DESIGN: Consecutive case series. SETTING: Olive View-UCLA Medical Center in Sylmar, CA, USA, and Cedars-Sinai Medical Center in Los Angeles, CA, USA. POPULATION: Women ≤55 years old with CAH or FIGO 1 EAC. METHODS: Response to progestin therapy in 84 consecutive patients was assessed based on clinicopathologic factors, including age, body mass index (BMI), initial histology, and IHC staining for MMR proteins. MAIN OUTCOME MEASURES: Rates of abnormal MMR protein expression and response to progestin therapy were determined. RESULTS: Six (7%) patients had abnormal IHC staining, of whom five (83%) had FIGO 1 EAC at initial diagnosis. Following progestin treatment, none of the endometrial lesions in patients with abnormal IHC for MMR proteins had resolution of hyperplasia or malignancy, in contrast to 41 (53%) with normal staining (P = 0.028). Age ≤40 years and initial lesion (CAH versus FIGO 1 EAC) were predictors of response to progestin; BMI was not. CONCLUSIONS: In this cohort, 7% of women ≤55 years of age with CAH or FIGO 1 EAC had loss of MMR proteins by IHC. These patients had a higher incidence of invasive cancer and a lower incidence of resolution with progestin therapy. TWEETABLE ABSTRACT: Abnormal MMR protein expression predicts poor response to progestins in young women with CAH or FIGO 1 EAC.

LEA.135 expression: its comparison with other prognostic biomarkers for patients with primary breast carcinoma.

The purpose of this retrospective study was to examine the prognostic value of expression of luminal epithelial antigen (LEA.135) for recurrence and overall survival of patients with primary invasive breast carcinoma by both univariate and multivariate analyses. The possible prognostic value of LEA.135 was also compared with some widely utilized prognostic biomarkers such as c-erbB 2, topoisomerase II.alpha (TPII.alpha), MIB 1, estrogen receptor (ER) and progesterone receptor (PR), as well as age of the patients and clinicopathologic parameters. The study was carried out by immunohistochemical methods on formalin-fixed/paraffin-embedded tissue sections in a series of 225 patients with median follow-up of 8.5 years. Prognostic significance of the biomarkers was determined by two-sided p value. In this series of patients, among the age and clinicopathologic parameters, only age, was significantly associated with a decreased overall survival (logrank p = 0.027). Among the prognostic biomarkers, TPII a expression at high (> 50% positive cells) or moderate (6-50% positive cells) level was associated with an increased rate of recurrence (logrank p < 0.001). However, the association of TPII.alpha expression with a decreased overall survival failed to reach a statistically significance. Expression of c-erbB 2 showed a trend of being associated with an increased probability of recurrence, but the association did not reach statistical significance. The remaining biomarkers were not associated with either the probability of recurrence or overall survival. LEA.135 expression was observed in 163 (72.4%) of the 225 patients. The patients with high (> 50% positive cells) or moderate (6-50% positive cells) level of LEA.135-positive cancer cells showed a significantly decreased probability of recurrence (logrank p < 0.001) and an increased overall survival (logrank p < 0.001) compared with those with LEA.135-negative cancer cells. The association remained significant by multivariate analysis for recurrence (likelihood ratio test p < 0.001) and overall survival (likelihood ratio test p < 0.001) when assessed with other prognostic parameters. Furthermore, the combination of LEA.135 with other prognostic biomarkers stratified four subgroups of patients with distinct clinical outcome. The subgroup of patients who were LEA.135+/TPII.alpha- showed the lowest probability of recurrence and the longest overall survival compared with those who were LEA.135-/TPII.alpha+ (logrank p < 0.001). Interestingly, the patients whose cancer cells were LEA.135+/TPII.alpha+, LEA.135+ MIB.1+ or LEA.135+/c-erbB 2+ experienced a decreased probability of recurrence and an increased overall survival compared with those with LEA.135-/TPII.alpha+, LEA.135- MIB.1+ or LEA.135-/c-erbB 2+ (logrank p < 0.001). The results demonstrated that LEA.135 is an independent and favorable prognostic biomarker for patients with primary invasive breast carcinoma, that the loss of LEA.135 expression is associated with aggressive phenotype of cancer cells during the breast cancer progression, and that its continued expression seems to override the adverse effects of expression of an oncogene or cell proliferation-associated molecules.

Reduction of BRCA1 expression in sporadic ovarian cancer.

OBJECTIVE: The purpose of this study was to examine BRCA1 expression and its relationship to cell proliferation in sporadic ovarian epithelial tumors (OETs). METHODS: We investigated BRCA1 expression and cell proliferative activity in 72 unselected OETs. They comprised 16 benign cystadenomas, 18 borderline (low malignant potential) tumors, and 38 carcinomas (OECs). These patients had no known family history of breast and/or ovarian cancer. BRCA1 and the cell proliferation marker, MIB-1, expressions in fixed tissue were investigated in all 72 cases by immunohistochemistry (IHC). BRCA1 mRNA in fresh frozen tissue samples from 20 of these cases was measured by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS: The average percentage of BRCA1-positive cells was 5.6% in cystadenomas, 29.7% in borderline tumors, and 6.6% in OECs. The average decreased steadily with increasing grade of OECs: grade 1 (21.4%), grade 2 (1.1%), and grade 3 (0%). The average percentage of MIB-1-positive cells increased steadily from cystadenomas (7.5%) to borderline tumors (22.6%) to carcinomas (41.2%). BRCA1 expression was highly correlated with MIB-1 expression in cystadenomas and borderline tumors. Six of seven OECs negative for BRCA1 by IHC showed low levels of BRCA1 mRNA by RT-PCR. CONCLUSIONS: BRCA1 expression paralleled cell proliferation in benign and borderline OETs, but not in OECs. Sporadic OECs showed significantly reduced levels, rather than complete loss, of BRCA1 expression. The reduction was closely related to tumor grade. Reduction of BRCA1 expression may be of etiologic significance in the occurrence and progression of sporadic ovarian cancer.