Assessment Of Ki-67 Expression Research Articles

Assessment of Ki-67 expression in cases of prostatic carcinoma and its correlation with clinical outcomes.

Treatment decisions after diagnosis of clinically localized prostate cancer are difficult due to variability in tumor behavior. As there is a high prevalence of low-grade prostate cancer with an indolent course, we need improved markers of prostate cancer lethality in order to reduce the overtreatment. In the current study, we assessed Ki-67 expression in cases of prostate carcinoma and correlated its expression with clinical outcomes. It was a single-center retrospective descriptive type of study. A total of 50 cases were included. Diagnosed cases of adenocarcinoma on Transurethral Resection of the Prostate (TURP) chips and Trucut prostatic biopsies (Archival biopsy specimens) for whom five years follow-up was available from record files and/or telephonic interviews were included. The clinical outcomes (rate of distant metastases, disease specific survival, and overall survival) over a period of five years were recorded. In the current study, 78% of the cases of carcinoma prostate were positive for Ki-67 expression. The mean Ki-67 staining index was 15.22% among the cases. The cases with High Ki-67 Staining index had a significantly higher rate of distant metastasis, poor disease-specific survival, and overall survival compared to cases with low Ki-67 staining index. Ki-67 can be used along with the other established prognostic parameters to assess the lethality of prostate cancer.

Assessment of Ki-67 expression in Phyllodes tumor of breast: An Indian study

Phyllodes tumor (PT) accounts for 0.3-1% of all breast tumors and classified into benign (BP), borderline (BLP) and malignant (MP). However, grading system is somewhat subjective and diagnosis remains challenging. Ancillary techniques may help in classification and prognostication of the tumor.Evaluation of the proliferative activity by Ki-67 index in Indian scenario.50 PTs received from January 2014 to December 2018 were graded using WHO criteria 2019. Ki-67 labelling index (LI) was calculated and graded 1+ (1-35%), 2+ (35-70%), 3+ (70-100%). Relevant statistical analysis was applied. P value of <0.05 was considered significant.70% (35) were BP, 26% (13) BLP and 4% (2) MP. Infiltrative margin, increased stromal cellularity, overgrowth, nuclear atypia and mitotic index were significantly associated with higher grade (P<0.000). The proportion of Ki-67 positive stromal cells in MP (mean76%) was higher than in BLP (mean 56.2%) and BP (mean 23.1%). Increasing Ki-67 index was significantly associated with infiltrative margin, presence of stromal overgrowth, increasing stromal cellularity, nuclear atypia, mitotic index and histological grade (P<0.000). Ki-67 statistically distinguished BP from BLP and MP (P<0.000, P<0.001 respectively), but not between BLP and MP (P<0.329). As a prognostic feature, high Ki-67 index expression did not predict local recurrence and due to fewer recurrent cases, the statistical correlation with any parameter could not be done.Histopathologic characteristics correlated with Ki-67 index. However, it was uncertain whether Ki-67 could provide independent prognostic information beyond histopathological typing. Continued follow-up with greater number of significant episodes may yield more informative correlations.

Quantitative parameters in novel spectral computed tomography: Assessment of Ki-67 expression in patients with gastric adenocarcinoma.

The level of Ki-67 expression has served as a prognostic factor in gastric cancer. The quantitative parameters based on the novel dual-layer spectral detector computed tomography (DLSDCT) in discriminating the Ki-67 expression status are unclear. To investigate the diagnostic ability of DLSDCT-derived parameters for Ki-67 expression status in gastric carcinoma (GC). Dual-phase enhanced abdominal DLSDCT was performed preoperatively in 108 patients with gastric adenocarcinoma. Primary tumor monoenergetic CT attenuation value at 40-100 kilo electron volt (kev), the slope of the spectral curve (λHU), iodine concentration (IC), normalized IC (nIC), effective atomic number (Zeff) and normalized Zeff (nZeff) in the arterial phase (AP) and venous phase (VP) were retrospectively compared between patients with low and high Ki-67 expression in gastric adenocarcinoma. Spearman's correlation coefficient was used to analyze the association between the above parameters and Ki-67 expression status. Receiver operating characteristic (ROC) curve analysis was performed to compare the diagnostic efficacy of the statistically significant parameters between two groups. Thirty-seven and 71 patients were classified as having low and high Ki-67 expression, respectively. CT40 kev-VP, CT70 kev-VP, CT100 kev-VP, and Zeff-related parameters were significantly higher, but IC-related parameters were lower in the group with low Ki-67 expression status than the group with high Ki-67 expression status, and other analyzed parameters showed no statistical difference between the two groups. Spearman's correlation analysis showed that CT40 kev-VP, CT70 kev-VP, CT100 kev-VP, Zeff, and nZeff exhibited a negative correlation with Ki-67 status, whereas IC and nIC had positive correlation with Ki-67 status. The ROC analysis demonstrated that the multi-variable model of spectral parameters performed well in identifying the Ki-67 status [area under the curve (AUC) = 0.967; sensitivity 95.77%; specificity 91.89%)]. Nevertheless, the differentiating capabilities of single-variable model were moderate (AUC value 0.630 - 0.835). In addition, the nZeff VP and nICVP (AUC 0.835 and 0.805) showed better performance than CT40 kev-VP, CT70 kev-VP and CT100 kev-VP (AUC 0.630, 0.631 and 0.662) in discriminating the Ki-67 status. Quantitative spectral parameters are feasible to distinguish low and high Ki-67 expression in gastric adenocarcinoma. Zeff and IC may be useful parameters for evaluating the Ki-67 expression.

Quantitative parameters in novel spectral computed tomography: Assessment of Ki-67 expression in patients with gastric adenocarcinoma

Quantitative parameters in novel spectral computed tomography: Assessment of Ki-67 expression in patients with gastric adenocarcinoma

The impact of different adjuvant intravesical therapy methods on tumor biology in patients with high-risk non-muscle-invasive bladder cancer.

IntroductionExpression level of the cell proliferation marker Ki-67 correlates with the degree of differentiation of tumor cells and stage in primary patients with non-muscle-invasive bladder cancer (NMIBC), but the marker is currently not used in assessing the efficacy of adjuvant intravesical therapy and risk stratification in patients with recurrent bladder tumors.Material and methodsA retroprospective study included 107 patients with high-risk NMIBC; the patients were divided into 2 groups. The first group included patients who received adjuvant therapy after transurethral resection of the bladder using the Bacillus Calmette-Guérin (BCG) vaccine (BCG therapy group; n = 54), the second group consisted of patients who received hyperthermic intravesical chemotherapy (HIVEC® therapy group; n = 53) using the device for local hyperthermia Combat BRS HIVEC®.ResultsTumor recurrences were recorded in 21 (39%) patients receiving intravesical BCG therapy and in 9 (17%) patients after intravesical hyperthermic chemotherapy (p = 0.012). The expression level of Ki-67 in primary tumors did not differ; in recurrent tumors it was significantly different in both groups (32.05 ±13.80 vs 11.00 ± 6.86). The frequency of recurrence-free survival (RFS) in patients receiving chemohyperthermia was significantly higher than in patients after the BCG therapy (log-rank test result: p = 0.048).ConclusionsAssessment of Ki-67 expression in recurrent tumors can be a criterion for the effectiveness of intravesical bladder-preserving treatment. The use of hyperthermic chemotherapy can reduce the number of radical cystectomies in a separate group of patients with NMIBC.

Abstract P1-03-01: An international multicenter study to evaluate reproducibility of automated scoring methods for assessment of Ki67 in breast cancer

Abstract Background: The nuclear proliferation biomarker Ki67 has multiple potential roles in breast cancer, including prognosis-based decisions, but unacceptable between-laboratory variability has limited its clinical value. The International Ki67 Working Group (IKWG) has undertaken a systematic program to determine whether Ki67 immunohistochemistry can be analytically validated and standardized across laboratories. Technological advances and broader availability of devices for automated assessment of stained slides raise the possibility that these machines may improve on reproducibility of traditional pathologist-based visual Ki67 assessment. Aims: To characterize reproducibility of automated machine-measured Ki67 expression using slides previously analyzed in the IKWG phase 3 study that evaluated reproducibility of visual Ki67 assessment. Methods: Two sets of 30 previously stained slides containing core-cut biopsy sections of breast tumors were circulated to 14 laboratories for scanning and automated assessment of Ki67 expression. Sites were instructed to return average and maximum percentage of tumor cells positive for Ki67 for each slide, where maximum is designed to reflect “hot spot” analysis. Two laboratories returned scores from 2 operators; not all laboratories reported values for maximum Ki67 scores. Different operators were treated as distinct laboratories in analyses. Sixteen and 10 score sets were available for average and maximum Ki67 analyses, respectively, encompassing 7 unique scanner and 10 software platforms. Pre-specified analyses included evaluation of reproducibility across all laboratories as well as within a subgroup limited to those using Aperio scanners. The primary reproducibility metric was intraclass correlation coefficient between laboratories (ICC), regardless of device platform or software. Results: Geometric means across 30 cases for 16 operators ranged from 11.06% to 38.11% with overall mean 16.75% (95% CI:14.45-19.42) for average scores. Geometric means for 10 operators ranged from 16.44% to 68.73% with overall mean 25.16% (95% CI: 18.71-33.84) for maximum scores. ICC for automated average scores across 16 operators was 0.83 (95% CI: 0.73-0.91) and ICC for maximum scores across 10 operators was 0.63 (95% CI: 0.44-0.80) although one outlier lab dramatically affected results. For the laboratories using the Aperio platform (8 score sets), ICC for automated average scores was 0.89 (95% CI; 0.81-0.96). These results are similar to ICC of 0.87 (95%CI; 0.81-0.93) reported using these same slides in the Phase 3 visual assessment reproducibility study in which observers counted 500 cells per slide (Leung et al, NPJBrCancer, in press). Conclusions: Between-laboratory reproducibility for automated machine assessment of average Ki67 is similar to that for pathologist-based visual assessment of Ki67. However, the observed ICC was markedly numerically lower for the maximum score method compared to the average method, suggesting that the maximum score may not be useful as a reproducible measure of proliferation. Automated average scoring methods show promise for standardization of Ki67 scoring, supporting future studies to clinically validate Ki67. Citation Format: Rimm DL, McShane LM, Leung SCY, Bai Y, Bane AL, Bartlett JMS, Bayani J, Chang MC, Dean M, Denkert C, Enwere E, Galderisi C, Gholap A, Hugh JC, Jadhav A, Kornaga E, Laurinavicius A, Levenson R, Lima J, Miller K, Pantanowitz L, Piper T, Ruan J, Srinivasan M, Virk S, Wu Y, Yang H, Hayes DF, Nielsen TO, Dowsett M. An international multicenter study to evaluate reproducibility of automated scoring methods for assessment of Ki67 in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-01.

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.

Abstract 5285: Ki-67 expression and mitotic count in lymph node metastasis and their association with clinico-pathologic features and survival in aggressive breast carcinoma

Abstract Background: Proliferation markers in breast cancer are prognostic and might be predictive for therapy response. However, their prognostic and predictive power in lymph node metastasis is not well established. The aim of our study was to examine the prognostic role of these markers in lymph node metastasis in comparison with the matched primary tumor. Study design: A retrospective series of node-positive breast cancers (n = 111) was used, as a part of the Norwegian Breast Cancer Screening Program (1996-2003). Sections from the largest node with metastasis (&amp;gt; 2mm) were used. The percentage of Ki-67 staining per 500 tumor cells was counted in hot-spot areas. The mitotic count was determined in the most active areas, using 10 consecutive high power fields (x400), and the number of mitotic figures per mm2 was calculated. Assessment of Ki-67 expression and mitotic count was performed on corresponding primary tumors. Results: The two proliferation markers were highly correlated between metastasis and their matched primary tumors (r = 0.58, 0.46 for Ki-67 and mitotic count, respectively). Ki-67% in metastasis was slightly but significantly lower than in their primary tumors (median = 15.8 vs 17.2, P = 0.013). In contrast, mitotic count in metastasis was slightly but significantly higher than in their primary lesions (median = 1.4 vs 1.2, P = 0.02). The proliferation markers in metastasis showed a significant association with known unfavorable prognostic features in the primary tumor, including tumor diameter, histologic grade, hormone receptor status, HER2 status and molecular subtype. A subgroup of concordant cases with high proliferation (in matched metastasis and primary tumors) was significantly associated with large tumor diameter (&amp;gt;2 cm), negative hormone receptors, positivity for Her2 status, as well as the triple negative molecular subtype. Survival analysis (Kaplan-Meier method, log-rank test) for Ki-67 and mitosis alone in lymph node metastasis showed no statistical significant association with breast cancer specific survival. However, this association was significant when comparing the subgroup with concordant high proliferation to all other subgroups with different proliferation patterns (P = 0.01, 0.01 for Ki-67 and mitosis, respectively). In multivariate analysis, the subgroup with concordant high proliferation for Ki67, and tumor diameter, were the only prognostic factors of independent importance. Conclusion: Proliferation markers in lymph node metastasis are strongly associated with the most unfavorable features of the primary tumors. Combined high proliferation in metastases and primary lesions is associated with reduced breast cancer specific survival. In multivariate analysis, combined high Ki67 was prognostic together with tumor diameter. Citation Format: Sura M. Aziz, Elisabeth Wik, Gøril Knutsvik, Karin Collett, Lars Andreas Akslen. Ki-67 expression and mitotic count in lymph node metastasis and their association with clinico-pathologic features and survival in aggressive breast carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5285. doi:10.1158/1538-7445.AM2015-5285

Assessment of proliferative potential of tumor cells using KI-67 expression and morphometrical analysis for prognostication of oral squamous cell carcinomas

Background: Cancer cells exhibit a characteristic intrinsic ability of uncontrolled cell proliferation which plays a vital role in tumor development and progression. The Ki-67 antigen expression is strictly associated with cell proliferation which detects the cells entering the cell cycle. In addition, computer aided image analysis provides an objective and highly reproducible histological evaluation of OSCC. Assessment of Ki-67 expression along with morphometry may help in early and precise diagnosis and prognostication of OSCC. Aims: To correlate the ki-67 expression and the morphometrical parameters of oral squamous cell carcinomas and to assess the efficacy of the correlation in OSCC prognostication. Methods and material: OSCC cases (n=105) were examined immuno histochemically using Ki-67 antigen The nuclear area (NA), cell area (CA), nuclear perimeter (NP) and cell perimeter (CP) assessed using “image J 1.34 software”. The data was statistically analyzed. Results: Highly significant correlation was found between Ki-67 expression and the advancing grades of OSCC (p<.0001). NA (p=0.025), CA (p<.0001), NP (p=.027) and CP (p<.0001) of poorly differentiated OSCC were significantly lower than well differentiated and moderately differentiated OSCC. Follow up analysis revealed nuclear area and cell area to be higher in the recurrent cases than the non recurrent ones. Conclusion: Assessment of Ki- 67 expression and morphometry help in early and precise diagnosis and prognostication of OSCC. A correlation between Ki-67 expression and morphometrical analysis could not be ascertained in this study. Further studies with a larger sample number may provide more definitive results.

Prognostic histopathological and molecular markers in feline mammary neoplasia

Feline mammary tumours comprise approximately 11% of feline non-integumentary neoplasms, are more commonly malignant than benign, and carry a poor prognosis attributable to a high probability of local recurrence and metastasis. This review discusses histopathological and molecular markers that could aid in prognostic discrimination, and draws comparisons with studies examining prognostic markers in breast cancer. Tumour grade and mitotic index correlate with survival data and could be useful for prognostication. Although assessment of Ki67 expression might have prognostic potential, further studies are required to corroborate the correlation between expression and clinical outcome. Additional molecular markers that have been investigated for prognostic potential can be grouped according to the 'hallmarks of cancer'. Many studies utilise 'surrogate markers' of clinical outcome, such as correlation with histological grade, to assess the prognostic value of molecular markers, and further investigation is therefore necessary before reaching firm conclusions regarding the prognostic value of some markers. Feline mammary tumours have been proposed as spontaneous models of breast cancer but might only be suitable models for certain molecular sub-types. Compared to humans, cats tend to have a high percentage of mammary tumours which are oestrogen receptor-negative and they might therefore be suitable models for late stage oestrogen receptor-negative breast cancer. The basal-like properties of feline mammary carcinomas offer another avenue for future research in this field of comparative oncology.

Standardization of Ki-67 assessment for breast cancer patients with preoperative endocrine therapy.

e11007 Background: Change in Ki-67 levels is a predictive marker of breast cancer, and it has been widely investigated in patients treated with preoperative endocrine therapy. Several studies have compared Ki-67 expression in untreated specimens obtained by core needle biopsy (CNB) and surgery. We conducted a retrospective study to assess Ki-67 expression between these two specimen types. Methods: 307 patients underwent primary operations for early breast cancer at Tokyo-West Tokushukai Hospital from August 2008 to October 2011. Among them, 193 patients who underwent CNB prior to the operation were enrolled. Patients with ductal carcinoma in situ and those undergoing neoadjuvant chemotherapy were excluded. A cutoff value of 20% was used as the Ki-67 positive criterion. We also examined ER, PgR, and HER2 expression and compared it with Ki-67 expression. Statistical significance for concordance rates between the two types of specimens was evaluated by Wilcoxon t-test. To evaluate the consequences of formalin and genetic heterogeneity, parameters such as operative method and tumor size were analyzed using chi-square test. We reexamined Ki-67 expression in the central laboratory among the Ki-67 discordant group to evaluate the discordance between the pathologist’s judgments. Results: The Ki-67 expression concordance rate between the two types of specimens was 77.7%, which was significantly lower than that for ER, PgR, and HER2 expression at 94.8%, 88%, and 91%, respectively. No significant differences in the operative method (mastectomy vs. breast conserving surgery) or tumor size (≤2cm vs. &gt;2cm) were observed between the groups. We reexamined Ki-67 expression in the Ki-67 discordant group and found that the Ki-67 concordance rate had improved to 93.8%. Conclusions: The Ki-67 expression concordance rate between the two types of specimens was significantly lower than that of ER, PgR, and HER2 expression. However, a reexamination of Ki-67 expression in the central laboratory revealed no significant difference, suggesting the need for a standard pathological assessment of Ki-67 expression to clinically use Ki-67 as a predictive marker.

The Reliability of Assessment of Ki-67 Expression on Core Needle Biopsy and the Surgical Specimens of Invasive Breast Cancer: Comparison of Local Pathologists’ Assessment and Central Review

Purpose: The aim of this study was to assess the reliability of Ki-67 expression on core needle biopsy (CNB) and the surgical specimens of invasive breast cancer. We examined the concordance rate of Ki-67 expressions, hormone receptors, and human epidermal growth factor receptor 2 (HER2) status from a CNB with from a surgery in invasive breast cancer. Methods: A retrospective study was conducted on a clinical database of patients who underwent surgery for early breast cancer. Of these, 193 patients who underwent CNB before the surgery were enrolled. A cut-off value of 20% was used for Ki-67-positive criteria. Expression of estrogen receptor (ER), progesterone receptor (PgR), and HER2 were examined and compared with that of Ki-67. To evaluate discordance between the pathologists’ earlier assessments, we re-examined Ki-67 expression among the Ki-67 discordant group in a central laboratory. Results: The concordance rate for Ki-67 expression between the two specimen types was 77.7%, which was significantly lower than that for ER, PgR, and HER2 expression (95.9%, 88.1%, and 91.6%, respectively). The concordance rate for re-examined Ki-67 expression among the Ki-67 discordant group improved to 93.8% and was not significantly different from that for the other receptors. Conclusion: The concordance rate for Ki-67 expression between biopsy and surgical specimens was significantly lower than that for ER, PgR, and HER2 expressions, but re-examination of Ki-67 expression in a central laboratory revealed no significant difference among the receptors, suggesting the need for standard pathological assessment of Ki-67 expression for clinical use as a predictive marker of breast cancer.

P1-07-15: The Reliability of Ki-67 Expression Assessment Using Core Needle Biopsy and Surgical Specimens of Invasive Breast Cancer: Can Ki-67 Change Predict Benefits of Preoperative Endocrine Therapy?

Abstract Background: The use of Ki-67 change as a predictive marker in breast cancer has been widely investigated in patients treated with preoperative endocrine therapy. It has been assumed that Ki-67 expression determined using core needle biopsy and surgical specimens of invasive breast cancer is concordant. Many studies have suggested the concordance of the results obtained using core needle biopsy and surgical specimens for expression of the estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor type2 (HER2) status in early-stage breast cancer. However, there was few study to compare Ki-67 expression in the core needle biopsy and surgical specimens. We conducted a retrospective study of Ki-67 expression assessment between the two types of specimens to answer this question. Methods: A total of 269 patients underwent primary operations for early-stage breast cancer at Tokyo-West Tokushukai Hospital from August 2008 to May 2011. Among these patients, 169 patients who received core needle biopsy prior to operation were enrolled. Patients with ductal carcinoma in situ and those with neoadjuvant chemotherapy were excluded. A cutoff value of 20% was used for Ki-67-positive criteria. We also examined ER, PgR, and HER2 expression and compared it with Ki-67 expression. Statistical significance for concordance rates between the two types of specimens was evaluated by Wilcoxon t-test. To evaluate the consequence of formalin and genetic heterogeneity, parameters such as operative method and tumor size were analyzed by χ2 analysis. Results: The concordance rate between the two types of specimens for Ki-67 expression was 76%, and this was significantly lower than that for ER expression, which was 96%. The concordance rates for PgR and HER2 expression were 88% and 91%, respectively, and they were not significantly different from the rate for Ki-67 expression. 45 patients(34.6%) had received mastectomy in the Ki-67 concordant group, and 14 patients(34.1%) in the discordant group. 55 patients(42.0%) showed T2∼ tumor size in the concordant group, 13 patients(31.7%) in the discordant group. No significant differences of parameters such as operative method (mastectomy vs breast conserving surgery) and tumor size (T1 vs T2∼) were observed between the two patient groups. Conclusion: The reliability of Ki-67 concordance rate assessment using core needle biopsy specimens was significantly lower than that of ER expression. A standard pathological assessment of Ki-67 expression might be needed for the possible use of Ki-67 as a predictive marker for preoperative endocrine therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-15.