Hormone receptors and proliferation in breast carcinomas of equivalent histologic grades in pre‐ and postmenopausal women

Abstract

Breast cancers in younger, premenopausal women are more likely to exhibit an adverse prognostic profile (including negative steroid hormone receptors and a high rate of cellular proliferation) and poor outcome than breast cancers in postmenopausal women. It has been hypothesized that this adverse prognostic profile is a result of the higher histologic grade of breast cancers in pre-compared with post-menopausal women. To assess the association of expression of steroid hormone receptors and indicators of proliferation while controlling for histologic grade, we identified 100 infiltrating ductal carcinomas from premenopausal women 45 years of age or younger and 100 from postmenopausal women 65 years of age or older. The carcinomas were selected so that the histologic grades (low versus high) were distributed equally between the 2 groups. Estrogen receptors (ER), progesterone receptors (PR), p27 Kip1 and Ki-67 (to measure rate of proliferation) were assessed by immunohistochemistry and compared between groups. Clinical information and survival data were also analyzed. ER content was lower and proliferation was higher in carcinomas in premenopausal women (p ‫؍‬ 0.048 and p ‫؍‬ 0.005, respectively). By univariate analysis, p27 Kip1 and PR were not different between the groups; however, in multivariate analysis, p27 Kip1 was higher in postmenopausal women, but only in a subgroup with highly proliferative carcinomas. Overall survival was similar in the pre-and postmenopausal women. Furthermore, low p27 Kip1 and African-American ethnicity predicted a poorer overall survival in the premenopausal, but not in the postmenopausal, women in our study. After controlling for histologic grade, a lower expression of ER and a higher proliferative index were detected in breast carcinomas in premenopausal women. Therefore, some prognostic indicators, such as ER and proliferative rate, may be more closely associated with menopausal status than histologic grade. Our data also suggest that some prognostic factors are not equally effective as predictors of survival in pre-and postmenopausal women. Prognosis in women with breast cancer has been reported to differ according to age and menopausal status. Studies examining this issue have varied in design, age categorization and outcome measures. A few large population-based studies and more limited analyses 1-5 have indicated that women under the ages of 30 -40 years have a worse prognosis. Some retrospective studies have attempted to explain the less favorable outcome in younger women and have reported that breast cancers in younger women exhibit more adverse characteristics, including a high clinical stage at diagnosis, high histologic grade, lack of steroid hormone receptors and increased proliferation. 6 -9 Multivariate analyses to assess associations of age and menopausal status with other clinical and pathologic characteristics have not consistently retained either variable as an independent adverse prognosticator, 8 although several multivariate analyses have indicated that young ag...

Hedgehog signaling and response to cyclopamine differs in epithelial and stromal cells in benign breast and breast cancer

“…The cytoplasmic staining was semi-quantified by an immunoscore that incorporated both the percentage of cells that stained as well as the intensity of staining. 39,40 Overall, mean immunoscores for GLI1, PTCH1 and SHH were increased 1.8-, 1.9-and 2.9-fold, respectively, in cancer epithelial cells in comparison to corresponding normal epithelium (Fig. 2B and Table 1).…”

Higher Ki67 Expression is Associates With Unfavorable Prognostic Factors and Shorter Survival in Breast Cancer

“…First, the optimal cut-off level for Ki67 expression in breast cancer has not yet been universally established. Some authors defined 20% or more Ki67 staining as a high expression level, while others justified the median value of percent positively stained cells as the distinguishing value to segregate high expression from low (Spyratos et al, 2002;Talley et al, 2002). Herein, 20% staining was defined as the cut-off value for Ki67 expression.…”

Immunohistochemical detection of Ki67 in breast cancer correlates with transcriptional regulation of genes related to apoptosis and cell death

“…2 This has traditionally taken the form of mitotic activity scoring, which is an integral component of histologic grading, an established prognostic marker in breast cancer. 20 While the role of Ki67 immunohistochemistry as a prognostic and predictive marker in breast cancer has been widely investigated, 5,6,8,[21][22][23][24][25] staining thresholds and cutoffs have been mostly arbitrary and are not universally standardized. Percent positively stained nuclei, 26,27 number of nuclei stained per 10 high power fields, 5 stratification of MIB-1 staining in tertiles 8 have been described.…”

“…Some authors use Ki67 staining of 20% or more to define a high level, 6 while others advocate segregating high from low staining via the median of positively stained cells as the distinguishing value. 25 Recently, Spyratos et al 7 have suggested that the optimal threshold level should be 25% based on multivariate analyses of MIB-1 immunostaining at different cutoffs. Additional variation issues include selection of the appropriate area for evaluation of immunostaining, be it the center or periphery of the tumor; area of highest cell density; or zone of highest tumor cell immunohistochemical reactivity.…”