Ki-67 Expression In Breast Cancer Research Articles

Abstract PO5-08-07: Ki-67 Expression in Breast Cancer associated with ATM, BRCA1, BRCA2, CHEK2 and PALB2 Pathogenic Variants

Abstract Background: Germline Pathogenic Variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are known to increase breast cancer (BCa) risk, but the effect of these PVs on tumor biology is not well-understood. Ki-67 is an established prognostic marker in hormone receptor (HR) positive breast cancer but the distribution of Ki-67 in breast cancer associated with germline PVs is not known. Methods: The study included patients with loco-regional (Stage I-III) HR-positive (ER+ or PR+), HER2-negative invasive ductal or lobular breast cancer evaluated at Mayo Clinic for curative intent treatment between 2012 and 2021. PV carrier status was ascertained in more than two-thirds of cases from germline whole exome sequencing (Regeneron) of patients who participated in a prospective registry at Mayo Clinic. Additional PV carriers were identified through a review of the results of clinical germline genetic testing in electronic medical records aided by natural language processing. Clinically performed Ki-67 values were abstracted from electronic medical records and analyzed as continuous and categorical variables (low: < 20% vs. high: ≥20%). Throughout the timeline of the study, a consistent method for assessment of Ki-67 was utilized at Mayo Clinic, Rochester: Immunohistochemical staining of the Ki-67 antigen in formalin-fixed paraffin-embedded tissue was performed using MIB-1 clone, the scanned slides were reviewed by a technologist and traced areas further analyzed for Ki-67 using Aperio Software. Patients who received neoadjuvant therapy prior to the assessment of Ki-67, with metastatic disease at diagnosis, with PVs in two or more genes of interest, or unknown germline PV or Ki-67 status were excluded from the analysis. Multiple primary tumors in the same patient diagnosed within one year of each other were analyzed independently. The control (non-carrier) group included randomly selected patients from the prospective registry who tested negative for PVs in the five genes over the same time period. Ki-67 values were compared between germline PV carriers and non-carriers in a multivariable logistic regression analysis adjusting for sex, race, age at diagnosis, stage at presentation, and histology of the tumor. Results: A total of 113 HR+/HER2- tumors from 111 PV carriers (ATM: 27, BRCA1: 24, BRCA2: 28, CHEK2: 22, and PALB2:12) along with 431 HR+/HER2- tumors from 422 randomly selected non-carriers were evaluated. The majority (>95%) of patients were non-Hispanic White. Germline PV carriers in each gene were diagnosed at a significantly younger age (P< 0.05) compared to non-carriers. The median Ki-67 value was 12 (Range: 1 to 93) for non-carriers, 16 (Range: 0 to 79) for ATM, 31 (Range: 4 to 86) for BRCA1, 30 (Range: 6 to 80) for BRCA2, 13 (Range: 1 to 38) for CHEK2, and 20 (Range: 3 to 46) for PALB2 PV carriers. In multivariable analysis, compared to non-carriers, we observed significantly higher odds of a high Ki67 value (≥20%) for tumors arising from germline PV carriers in BRCA1 (Odds Ratio (OR): 7.3, 95%CI: 2.3 – 23.3, p< 0.001), BRCA2 (OR: 3.0, 95%CI: 1.2 – 7.4, p=0.02) and PALB2 (OR: 3.9, 95%CI: 1.1 – 14.5, p=0.04). No such relationship was observed with either ATM (OR: 1.1, 95%CI: 0.4 – 2.9, p=0.81) or CHEK2 (OR: 0.8, 95%CI: 0.3 – 2.2, p=0.63). Conclusion: This study reveals that HR+/HER2- tumors in BRCA1, BRCA2, and PALB2 PV carriers have a significantly higher Ki-67 expression compared to non-carriers. These findings have implications for understanding prognosis and endocrine response PV with HR+ breast cancer. Further exploration of the relationships between Ki67 and germline PV status is necessary to personalize systemic therapy options in germline PV carriers. Acknowledgments: Thank you to Regeneron Genetics Center. The study was funded in part by the NIH Specialized Program of Research Excellence in Breast Cancer [P50CA116201] to Mayo Clinic, Mayo Clinic Department of Oncology Small Grants Program, and the Paul Calabresi Program at Mayo Clinic Citation Format: Robert Scheel, Grace Choong, Tara Rao, Nicholas Boddicker, Chunling Hu, Jie Na, Vinod Kaggal, Sean Murphy, Karthik Giridhar, Saba Yasir, Matthew Goetz, Fergus Couch, Siddhartha Yadav. Ki-67 Expression in Breast Cancer associated with ATM, BRCA1, BRCA2, CHEK2 and PALB2 Pathogenic Variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-07.

A Preliminary Analysis of Ki-67 Expression in Breast Cancer in the Caribbean.

There has been a void of data regarding Ki-67 expression in breast cancer in the Caribbean. Ki-67 is a widely used marker to determine the grade and prognosis of breast cancer. Ki-67 has been shown to be a valuable tool in predicting the response to chemotherapy and hormonal therapy in breast cancer patients.The objective of this preliminary study aims to describe the Ki-67 (Ki) status in this population and its correlations with other parameters in breast cancer histology. This study also aims to lay the groundwork for Ki-67 analysis in this population so that future studies may better describe it. The methodology involved gathering data from histology reports for all breast cancer-related biopsies from the 1st of January 2018 to the 12th of July 2021. This data was retrospectively analyzed. Twenty-three Ki-67 cases were obtained, 19 of which had Ki expression >10%. This >10% group was mostly staged from T1c up (one T1, three T1c cases, two T2 cases, four T3 cases while nine were not T staged). Two were N2/M1 while 9 were N0 and two were M0, the rest werenot staged. The mean age was 65.6 years with a range of 54 and a standard deviation of 12.5. Lymphovascular invasion was confirmed in four cases and suspected in three. Axillary lymph node dissection (ALND) yielded >10 nodes involved in two cases while <5 nodes in the remaining. The most common receptor status was hormone positive/ human epidermal growth factor receptor-2 (HER) negative (eight). Invasive Ductal Carcinoma (IDC) occurred in 10 cases while intermediate grade was in 14 cases. The Ki 6-10 % group consisted of two cases, one staged at T1aN0Mx while the other T2NxMx. Lymphovascular invasion was suspected in one. The average age was 67.5 years. ALND yielded less than five nodes in one case and 5-10 nodes in the other. Grades were high and intermediate. Histology was invasive ductal carcinoma/ductal carcinoma in situ (IDC/DCIS), and ductal carcinoma in situ ( DCIS) respectively. The Ki <6% group comprised two cases, staged at T1NxMx and T3N2M1. Lymphovascular invasion was absent in both. The mean age was 58.5 years. ALND yielded >10 nodes in one case and <5 in the other.Grades were high and intermediate. Histology was IDC/DCIS in both. There were no sentinel nodes involved in all but two cases belonging to the Ki >10% group. This preliminary study was the first to describe the Ki-67 marker in the Caribbean population. The vast majority of this population has a Ki-67 level of>10%. Higher Ki-67 expression is associated with larger tumors, lymphovascular invasion, metastases, and higher tumor grades. There is a need for consistent Ki-67 reporting in histology samples before follow-up studies are conducted.

Correlation between semiquantitative and volumetric 18F-FDG PET/computed tomography parameters and Ki-67 expression in breast cancer.

To evaluate the relationship between semiquantitative and volumetric parameters on 18F-FDG PET/computed tomography (CT), including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), tumor to liver ratio (TLR) and tumor to mediastinum ratio (TMR) with the level of Ki-67 expression in breast cancer. We retrospectively reviewed 105 female patients with newly diagnosed breast cancer who underwent baseline 18F-FDG PET/CT and had immunohistochemical staining to determine the level of Ki-67 expression. The following PET parameters were measured (SUVmax, SUVmean, MTV, TLG, TLR and TMR) and correlated with level of Ki-67 expression. Significant moderate positive correlations were found between the PET parameters (primary SUVmax, SUVmean, TLG, TLR and TMR) and level of Ki-67 expression. The primary SUVmax had the highest correlation coefficient (r = 0.461) followed by TMR (r = 0.455) and P value of <0.001 for both. In ROC analysis, primary SUVmax had the largest area under the curve (0.806, P = 0.0001), with sensitivity of 76.5 % and specificity of 75% for prediction of high Ki-67 level. In univariate analysis, all PET parameters, patient age, tumor grade, molecular subtype, estrogen receptor and progesterone receptor status were significantly associated with Ki-67 level. In multivariate regression analysis, only tumor grade [odds ratio (OR) = 20.460, 95% confidence interval (CI): 11.360-29.559, P = <0.0001], molecular subtype (OR = -21.894, 95% CI: -37.921 to -5.866, P = 0.008), SUVmax (OR = 2.299, 95% CI: 0.703-3.895, P = 0.005) and TLR (OR = -4.908, 95% CI: -9.476 to -0.340, P = 0.035) were found to be the strongest independent predictor factors for the level of Ki-67 expression and hence proliferative activity of malignant cells in breast cancer. The semiquantitative parameters and volumetric 18F-FDG PET/CT parameter, that is, TLG correlated well with proliferation marker Ki-67 in breast cancer. 18F-FDG PET/CT imaging can be used as a useful noninvasive diagnostic tool in imaging cellular proliferation and hence may substitute for in vitro testing of molecular markers in the diagnoses and staging of breast cancer.

Ki-67 Expression in Breast Cancer, Its Correlation with ER, PR and Other Prognostic Factors in Nineveh Province

Objectives: The aggressiveness of malignant tumors of breast can be correlated with the proliferation of neoplastic cells, and this detected by immunohistochemical study of proliferative index (Ki-67). American Society of Clinical Oncology (ASCO) does not recommend the use of Ki-67 routinely to predict the outcome of breast cancers, therefore the aim of current study is to detect the expression of Ki-67 in patients with primary breast cancer in Nineveh Province/North of Iraq and to correlate it with estrogen and progesterone receptors in addition to other prognostic factors. Methods: In this retrospective-case series study eighty cases of histologically proven primary breast carcinomas were included. The cases were collected from hospitals and private laboratories in Nineveh Province / North of Iraq and studied Immunohistochemicaly for Ki-67, estrogen receptor (ER) and progesterone receptor (PR) were done on tissue sections embedded in paraffin wax. An area with the maximum proliferation was chosen to evaluate Ki-67 and the cases with ≥20% positive nuclei were considered as high Ki-67 expression while those with <20% positive nuclei were considered as low Ki-67 expression.(10-14). The findings of Ki-67 were correlated with the age of the patients, histological type, grade of the tumors and with the estrogen and progesterone receptors. Results: The Ki-67 immunoreactivity was highly expressed in (45%) of the cases. Estrogen and progesterone receptors observed in (77.5%) and (67.5%) of the cases respectively. The Ki-67 was significantly associated with grade of tumor, estrogen receptor and progesterone receptor (P= 0.0057, 0.037 and 0.006 respectively). While the association with patientsˈage and histological types were not statistically significant. Conclusion: Ki-67 expression shows a significant direct correlation with grade of tumors and a significant inverse correlation has been shown with a well-known predictive factors, (estrogen and progesterone receptors).

Breast cancer Ki-67 expression prediction by digital breast tomosynthesis radiomics features

BackgroundTo investigate whether quantitative radiomic features extracted from digital breast tomosynthesis (DBT) are associated with Ki-67 expression of breast cancer.Materials and methodsThis is a prospective ethically approved study of 70 women diagnosed with invasive breast cancer in 2018, including 40 low Ki-67 expression (Ki-67 proliferation index <14%) cases and 30 high Ki-67 expression (Ki-67 proliferation index ≥ 14%) cases. A set of 106 quantitative radiomic features, including morphological, grey/scale statistics, and texture features, were extracted from DBT images. After applying least absolute shrinkage and selection operator (LASSO) method to select the most predictive features set for the classifiers, low versus high Ki-67 expression was evaluated by the area under the curve (AUC) at receiver operating characteristic analysis. Correlation coefficient was calculated for the most significant features.ResultsA combination of five features yielded AUC of up to 0.698. The five most predictive features (sphericity, autocorrelation, interquartile range, robust mean absolute deviation, and short-run high grey-level emphasis) showed a statistical significance (p ≤ 0.001) in the classification. Thirty-four features were significantly (p ≤ 0.001) correlated with Ki-67, and five of these had a correlation coefficient of > 0.5.ConclusionThe present study showed that quantitative radiomic imaging features of breast tumour extracted from DBT images are associated with breast cancer Ki-67 expression. Larger studies are needed in order to further evaluate these findings.

Associations Between PET Parameters and Expression of Ki-67 in Breast Cancer

OBJECTIVES: Numerous studies investigated relationships between positron emission tomography and proliferation index Ki-67 in breast cancer (BC) with inconsistent results. The aim of the present analysis was to provide evident data about associations between standardized uptake value (SUV) and expression of Ki-67 in BC. METHODS: MEDLINE library, SCOPUS and EMBASE data bases were screened for relationships between SUV and Ki-67 in BC up to April 2018. Overall, 32 studies with 1802 patients were identified. The following data were extracted from the literature: authors, year of publication, number of patients, and correlation coefficients. Associations between SUV and Ki-67 were analyzed by Spearman's correlation coefficient. RESULTS: Associations between SUVmax derived from 18F-FDG PET and Ki-67 were reported in 25 studies (1624 patients). The pooled correlation coefficient was 0.40, (95% CI = [0.34; 0.46]). Furthermore, 7 studies analyzed associations between SUVmax derived from 18F-fluorthymidin (FLT) PET and Ki-67 (178 patients). The pooled correlation coefficient was 0.54, (95% CI = [0.37; 0.70]). CONCLUSION: SUVmax correlated moderately with expression of Ki-67 and, therefore, cannot be used as a surrogate marker for tumor proliferation. Further studies are needed to evaluate associations between PET parameters and histopathological findings like hormone receptor status in breast cancer.

Breast cancer Ki67 expression prediction by DCE-MRI radiomics features

To investigate whether quantitative radiomics features extracted from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are associated with Ki67 expression of breast cancer. This institutional review board-approved retrospective study comprised 377 Chinese women who were diagnosed with invasive breast cancer in 2015. This cohort included 53 low-Ki67 expression (Ki67 proliferation index less than 14%) and 324 cases with high-Ki67 expression (Ki67 proliferation index more than 14%). A binary-classification of low-versus high- Ki67 expression was performed. A set of 56 quantitative radiomics features, including morphological, greyscale statistic, and texture features, were extracted from the segmented lesion area. Three machine learning classification methods, including naive Bayes, k-nearest neighbour and support vector machine, were employed for the classification and the least absolute shrink age and selection operator (LASSO) method was used to select most predictive features set for the classifiers. Classification performance was evaluated by the area under receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. The model that used naive Bayes classification method achieved the best performance than the other two methods, yielding 0.773 AUC, 0.757 accuracy, 0.777 sensitivity and 0.769 specificity. Three most predictive features, i.e., contrast, entropy and line likeness, were selected by the LASSO method and showed a statistical significance (p<0.05) in the classification. The present study showed that quantitative radiomics imaging features of breast tumour extracted from DCE-MRI are associated with breast cancer Ki67 expression. Future larger studies are needed in order to further evaluate the findings.

Ki-67 expression as an indicator of invasiveness in patients with breast cancer

Background: Tumor markers have a key role in guiding breast cancer management protocols and predicting prognosis. Objective: The aim of the study is to explore the role of Ki-67 expression in breast cancer and correlate it to well-known indicators of invasiveness such as age, tumor size, grade, hormonal receptors, and lymph nodes involvement. Materials and Methods: This retrospective study was conducted on (214) patients who were newly diagnosed with breast cancer and referred to Azadi Teaching Hospital/Duhok-Iraq, from November 1st, 2016, to October 31st, 2017. Data regarding patient's demographics, tumor size, histological type and grade, nuclear grade, and lymph node involvement were obtained from medical records. Patients underwent either mastectomy with axillary lymph node dissection or breast conservation surgery. Collected specimens were sent for histopathological examination and immunohistochemistry assessments of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2), and Ki67 expressions. Results: Our study showed that histological grade, nuclear grade, mitotic index, and HER2 status were positively correlated to Ki67 index (P

Targeting breast cancer cells with a CuInS2/ZnS quantum dot-labeled Ki-67 bioprobe.

The aim of the present study was to develop a water-soluble biomarker for the detection of breast cancer using quantum dots (QDs) conjugated to Ki-67, a nuclear protein associated with the cell cycle. Ki-67 is also a marker of cell proliferation, with expression levels categorizing good and poor prognosis in invasive breast cancer. Ki-67 is a clinically used biomarker for breast cancer diagnosis, treatment and prognosis. Owing to the optical and chemical advantages of QDs, QD-based nanotechnology may aid the construction of a biomedical imaging platform for the study of cancer cell behavior. In the present study, a biomarker was prepared by employing the water-soluble CuInS2/ZnS QDs conjugated to an anti-Ki-67 monoclonal antibody to detect Ki-67 expression in breast cancer. The QDs, which were hydrophobic and coated with octadecylamine, were encapsulated with an amphiphilic biocompatible centipede-like polymer, and then conjugated to anti-Ki-67 monoclonal antibodies (QD-Ki-67 probes). The QD-Ki-67 probes retained the original optical properties of the unadorned QDs and did not exhibit distinct toxic side effects in in vitro cytotoxicity experiments. Therefore, this CuInS2/ZnS QD-labeled bioprobe, with a high quantum yield and low cytotoxicity, is a promising candidate for bioimaging and may be used as a cell label.

Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer.

In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P<0.001). The least variability between the different slides was observed with HS scoring. Although the associations between Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r=0.98, P<0.001). In conclusion, assessment of Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.

Ki67 expression in breast cancer. Correlation with prognostic markers and clinicopathological parameters in Saudi patients.

Objectives:To evaluate Ki67 immunoexpression pattern in Saudi breast cancer (BC) patients and investigate any possible predictive or prognostic value for Ki67.Methods:This is a retrospective study designed to quantitatively assess the Ki67 proliferative index (PI) in retrieved paraffin blocks of 115 Saudi BC patients diagnosed between January 2005 and March 2015 at the Department of Pathology, King Fahd Hospital, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. The Ki67 PI was correlated with individual and combined immunoprofile data of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) with their clinicopathological parameters.Results:Ki67 immunoreactivity was highly expressed (>25% of the tumor cells were positive) in 85 (73.9%) patients. The Ki67 PI was significantly associated with poor prognostic clinicopathological parameters including old age (p<0.02), high tumor grade (p<0.01), lymph node metastasis (p<0.001), and Her-2/neu positivity (p<0.009). However, the association with ER positivity, PR positivity, tumor size, and lymphovascular invasion were not statistically significant. The Ki67 PI was significantly associated with BC molecular subtypes that were Her2/neu positive (luminal B and HER-2) subtypes compared with the Her2/neu negative (luminal A) subtype (p<0.04).Conclusion:The Ki67 PI is significantly higher in Saudi BC patients comparing with the reported literature. Ki67 PI was highest in the HER-2 and luminal-B molecular subtypes. Along with other prognostic indicators, Ki67 PI may be useful in predicting prognosis and management of Saudi BC patients.

Menstrual cycle could affect Ki67 expression in estrogen receptor-positive breast cancer patients

BackgroundKi67 is a potent prognostic marker for determining systemic treatment of patients with hormone receptor-positive breast cancer. However, evaluation of Ki67 expression can be difficult, due mostly to its heterogeneity....

Abstract P6-01-04: Changes in Ki67 expression in breast cancer during the menstrual cycle and menopause

Abstract Background Previous studies have shown that the menstrual cycle phase can influence PgR status of breast cancer. But data on whether the menstrual cycle phase affects Ki67 expression is inconsistent. This study aims to compare the Ki67 expression on ultrasonography guided vacuum-assisted breast biopsy (US-guided VABB) with matched breast cancer surgical specimens. Materials and Methods In 120 breast cancer patients without neoadjuvant chemotherapy who underwent US-guided VABB and surgical resection from April 2008 and March 2012 at Aichi Cancer Center Hospital, we examined the concordance of Ki67 level between US-guided VABB and surgical specimen. All the US-guided VABB were performed using 11-gauge Mammotome. In this study, the Ki67 cut-off level for positivity was defined at 20%. Two phases of the menstrual cycle were pre-defined as indicated; phase 1 (low estrogen) days 27–35 or 1–6; phase 2 (high and intermediate estrogen) days 7–26 (Hayes BP, et al. Breast Cancer Res Treat 2013). We defined the three groups as follows: the non-matching menstrual phase group (different menstrual cycle phase at the time of biopsy and surgery: n=18), the matching menstrual phase group (same menstrual cycle phase at the time of biopsy and surgery: n=25), and the post-menstrual group (n=77). We evaluated the discordance of Ki67 expression between US-guided VABB and surgical specimens in the three groups. Results A differential expression of Ki67 was found in 13 patients and the concordance rate of Ki67 expression between US-guided VABB and surgical specimens was 89.2% with a Kappa statistic value of 0.78. (The concordance rate of ER, PgR, and HER2 status were 96.4%, 90.2%, and 97.0%, respectively.) There were no major differences in tumor and patient characteristics (age, pathological tumor size, and number of biopsy specimens) between the non-matching menstrual phase group and the matching menstrual phase group. The discordance rate of Ki67 expression for the non-matching menstrual phase group, the matching menstrual phase group, and the post-menstrual group were 22.2%, 4.0%, and 10.4%, respectively. In the patients with ER positive tumors, the discordance rate of Ki67 expression for the non-matching menstrual phase group, the matching menstrual phase group, and the post-menstrual group were 23.5%, 4.8%, and 10.9%, respectively. The discordance rate of Ki67 expression tended to be higher in the non-matching menstrual phase group than in the matching menstrual phase group. (p=0.11) Conclusions Though limited by the low number of patients, our study suggested that the menstrual cycle could affect Ki67 expression as patients with different menstrual cycle phase at the time of biopsy and surgery show discordant results. Prospective evaluation of Ki67 expression in premenopausal patients with ER positive tumor is needed. Citation Format: Takashi Fujita, Masataka Sawaki, Masaya Hattori, Naoto Kondo, Akiyo Yoshimura, Mari Ichikawa, Yayoi Adachi, Tomoka Hisada, Haruru Kotani, Junko Ishigro, Hiroji Iwata. Changes in Ki67 expression in breast cancer during the menstrual cycle and menopause [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-04.

Expression and clinicopathological significance of FSIP1 in breast cancer.

To investigate the clinicopathological significance of the expression of fibrous sheath interacting protein 1 (FSIP1) in breast cancer, serum samples, and wound fluid from patients with breast cancer. Wound fluid and serum samples from female patients with primary breast cancer, recurrent and metastatic breast cancer, and benign tumors were analyzed for FSIP1 expression using ELISA. 286 paraffin-embedded surgical specimens from breast cancer patients with at least 5 years of follow-up were included for FSIP1 expression assay using immunohistochemistry. Expression of FSIP1 protein was significantly higher in breast cancer tissues compared to tumor-adjacent tissues (p = 0.001). Strong correlation was observed between FSIP1 expression and human epidermal growth factor receptor 2 (Her-2) or Ki67 expression in breast cancer (p = 0.027 and 0.002, respectively). Similarly, serum level of FSIP1 was higher in patients with recurrent and metastatic breast cancer compared to that of primary breast cancer (7, 713 ± 3, 065 vs. 4, 713 ± 3, 065 pg/ml, p = 0.003). Finally, patients with high FSIP1 expression showed a worse post-operative disease-specific survival (p = 0.024). FSIP1 may play an important role in the tumorigenesis and invasion of breast cancer and is a potential biomarker for breast cancer diagnosis or prognosis.

Abnormal expression of the Notch and Wnt/β-catenin signaling pathways in stem-like ALDHhiCD44+ cells correlates highly with Ki-67 expression in breast cancer.

Previous studies have reported that breast cancer stem cells may be closely associated with tumor metastasis, recurrence, and even the failure of chemotherapy and radiotherapy. The aim of the present study was to investigate whether important cell signaling pathways associated with drug resistance are activated in stem-like acetaldehyde dehydrogenase (ALDH)hi cluster of differentiation (CD)44+ cells, and to analyze the association between ALDHhiCD44+ cells and specific pathological features. ALDHhiCD44+ cells and non-stem-like ALDHlowCD44+ cells were separated from MDA-MB-231 cells by fluorescence-activated cell sorting, and the mRNA expression levels of Notch1 and β-catenin were estimated by performing quantitative polymerase chain reaction in the stem-like and non-stem-like cells. Line correlation analysis was used to evaluate the correlation between an immunohistochemical panel of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67, and ALDHhiCD44+ cells from patients with invasive breast carcinoma. The mRNA levels of Notch1 and β-catenin were significantly higher in the ALDHhiCD44+ cells compared with those in the ALDHlowCD44+ cells (P<0.05); furthermore, the present study determined a high correlation (P<0.05) between the ALDHhiCD44+ cells and Ki-67 expression (P=0.007), but no correlation (P≥0.05) with ER (P=0.065), PR (P=0.107) and HER2 (P=0.050). Overall, these data clearly indicate that ALDHhiCD44+ cells may serve as novel diagnostic and prognostic factors in breast cancer.

Ki-67 expression in residual triple-negative breast tumors after neoadjuvant chemotherapy to predict for recurrence-free survival.

89 Background: Ki-67 expression in breast cancer has been described as predictive of pathological complete response and prognostic of recurrence free survival (RFS). Our aim was to evaluate in a retrospective cohort of triple negative breast cancer patients if tumor proliferation measured by ki-67 expression is correlated with the outcome. Methods: We evaluated a retrospective cohort of 109 cases of triple negative breast cancer (ER-, PR- and HER2- determined by immunohistochemistry). Ki-67 labeling index was determined in Formalin-Fixed, Paraffin-Embedded residual tumors after neoadjuvant chemotherapy. Patients were stratified in Ki67&lt;15% and Ki67≥15%. Clinicopathological data was retrieved from clinical records. RFS and overall survival (OS) were calculated using the Kaplan–Meier method and variables compared using the log-rank or Breslow test and Hazard Ratios (HR) estimated by the Cox regression. Results: The median age for patients was 47.5 years, 55 (50.5%) were premenopausal and 54 (49.5%) postmenopausal. Eight patients (7.3%) were clinical stages II and 101 (92.7%) stages III. Median of Ki-67 expression was 35.97% (0.96% - 77.7%). There was not association between Ki-67 expression (&lt;15% VS ≥15%) with tumor size, nodal involvement, clinical stage and menopausal status. After a median of follow of 21.6 months, 62 patients (56.9%) have relapsed and 53 (48.6%) have die. The median time for RFS and OS were 21.2 and 31.4 months, respectively. Median of RFS was 12.6 months for Ki67&lt;15% vs 21.2 months for Ki67≥15%, P=0.421 (HR=0.91). Median of OS was 34.9 months for Ki67&lt;15% vs 31.4 months for Ki67≥15%, P=0.755 (HR=1.18). Only nodal involvement was found predictor of shorter RFS (0 nodes, 25.2 months vs 1 -3 nodes, 26.1 months, vs &gt;3 nodes, 9.4 months, P=0.020). Conclusions: Ki-67 labeling index was not related with the outcome in terms of OS and RFS in patients with residual triple negative breast tumors that were treated with neoadjuvant chemotherapy.

Association of mammographic density with the proliferation marker Ki-67 in a cohort of patients with invasive breast cancer

There is growing evidence that certain breast cancer (BC) risk factors specifically increase the risk for specific molecular tumor subtypes. Different molecular subtypes of BC can partly be described by analyzing proliferation in tumors. Very few data are available regarding the association of mammographic density (MD), as a BC risk factor, with proliferation. The aim of this study was to analyze the association between Ki-67 expression in BCs and MD. In this case-only study, data on BC risk factors, hormone receptor expression, and MD were available for 1,975 patients with incident BC. MD was assessed as percentage mammographic density (PMD) using a semiautomated method by two readers for every patient. The association of the Ki-67 proliferation index and PMD was studied using multifactorial analyses of covariance (ANCOVA), with PMD as the target variable and including well-known factors that are also associated with MD such as age, parity, use of hormone replacement therapy (HRT), and body mass index (BMI). There were no significant differences in PMD between women with BC who had low and high Ki-67 values (P = 0.31). However, there were relevant differences in women with low BMI (P = 0.07), and in women using postmenopausal HRT (P = 0.06) as well as in women with low PR values (P = 0.07). In these subgroups, the Ki-67 expression index increased with decreasing PMD. Likewise PMD is correlated with BMI, parity status, and menopausal status stronger in patients with low proliferating tumors, and with progesterone receptor expression in patients with high proliferating tumors. MD correlates inversely with Ki-67 proliferation in BC tumors only in some subgroups of BC patients, defined by commonly known BC risk factors that are usually associated with MD as well.

Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer

BackgroundThe aim of the study was to develop a virtual microscopy enabled method for assessment of Ki-67 expression and to study the prognostic value of the automated analysis in a comprehensive series of patients with breast cancer.MethodsUsing a previously reported virtual microscopy platform and an open source image processing tool, ImageJ, a method for assessment of immunohistochemically (IHC) stained area and intensity was created. A tissue microarray (TMA) series of breast cancer specimens from 1931 patients was immunostained for Ki-67, digitized with a whole slide scanner and uploaded to an image web server. The extent of Ki-67 staining in the tumour specimens was assessed both visually and with the image analysis algorithm. The prognostic value of the computer vision assessment of Ki-67 was evaluated by comparison of distant disease-free survival in patients with low, moderate or high expression of the protein.Results1648 evaluable image files from 1334 patients were analysed in less than two hours. Visual and automated Ki-67 extent of staining assessments showed a percentage agreement of 87% and weighted kappa value of 0.57. The hazard ratio for distant recurrence for patients with a computer determined moderate Ki-67 extent of staining was 1.77 (95% CI 1.31-2.37) and for high extent 2.34 (95% CI 1.76-3.10), compared to patients with a low extent. In multivariate survival analyses, automated assessment of Ki-67 extent of staining was retained as a significant prognostic factor.ConclusionsRunning high-throughput automated IHC algorithms on a virtual microscopy platform is feasible. Comparison of visual and automated assessments of Ki-67 expression shows moderate agreement. In multivariate survival analysis, the automated assessment of Ki-67 extent of staining is a significant and independent predictor of outcome in breast cancer.

Value of Ki67 in breast cancer: the debate is still open

We read with interest the exhaustive review by Yerushalmi and colleagues1 on the potential prognostic and predictive role of Ki67 expression in breast cancer. The authors conclude that, at present, Ki67 cannot be used as a tool for selecting specific chemotherapy or endocrine treatment, nor for assigning patients to specific risk groups. They recommend the adoption of standard methods and cutoff points in interpreting immunohistochemical specimens. Similar conclusions were drawn in other reviews,2,3 with the reported cutoffs for Ki67 ranging from 3·5 to 34%.

The association between telomerase, histopathological parameters, and Ki-67 expression in breast cancer

Background: Telomerase is a ribonucleoprotein enzyme that appears to play an important role in carcinogenesis. Telomerase reactivation seems to be associated with immortalization and malignancy. Methods: Using a polymerase chain reaction (PCR)-based assay known as the TRAP (telomeric repeat and amplification protocol) assay, we examined telomerase activity in 60 breast specimens prospectively collected from 39 patients undergoing elective breast surgery in our center. The specimens included adjacent noncancerous breast (n = 21), benign breast disease (n = 5), and infiltrating carcinoma (n = 34). Ki-67 expression was determined in 32 invasive breast cancer specimens using immunohistochemistry techniques. The histopathological features were determined by light microscopy by an experienced breast pathologist. Results: Telomerase activity was detected in 24 (71%) of 34 infiltrating carcinomas. None of the adjacent noncancerous specimens nor the benign breast lesions expressed telomerase activity. Telomerase reactivation was significantly associated with nodal metastasis and Ki-67 expression. There was no significant association between telomerase activity and menopausal status, tumor grade, or tumor size. Conclusions: Telomerase reactivation is associated with the acquisition of malignancy in the human breast. Telomerase activity is significantly associated with nodal metastasis and cellular proliferation as measured by Ki-67 expression in human breast cancer.