Importance Of Ki-67 Research Articles

Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms.

In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.

Chromosome clustering in mitosis by the nuclear protein Ki-67.

Ki-67 is highly expressed in proliferating cells, a characteristic that made the protein a very important proliferation marker widely used in the clinic. However, the molecular functions and properties of Ki-67 remained quite obscure for a long time. Only recently important discoveries have shed some light on its function and shown that Ki-67 has a major role in the formation of mitotic chromosome periphery compartment, it is associated with protein phosphatase one (PP1) and regulates chromatin function in interphase and mitosis. In this review, we discuss the role of Ki-67 during cell division. Specifically, we focus on the importance of Ki-67 in chromosome individualisation at mitotic entry (prometaphase) and its contribution to chromosome clustering and nuclear remodelling during mitotic exit.

Role of expression of p53 and Ki67 in the progression of Wilms tumor; correlation with survival

Background: Wilms tumor (WT) is the most frequent renal tumor of childhood and is a highly responsive tumor to chemotherapy. P53 and ki67 are two of the most important markers that have been evaluated in many cancers. The role of p53 in the pathogenesis and progression of WT is only partly understood. Over the past decade, the importance of Ki-67 in the prognosis of breast cancer has been widely studied. On the other hand, fewer studies are available for this in WT. Aim: To study the possible role of p53 and ki67 in the progression and outcome of Wilms tumor cases. Methods: Immunohistochemical (IHC) staining for p53 and ki67 were done and correlated with clinicopathological data of Wilms tumor cases. Results: There was a positive correlation between p53 and ki67 expression and unfavorable histology, higher tumor stage, shorter disease-free survival (DFS) and overall survival (OS). Conclusion: Ki67 and p53 expression was positively correlated with aggressive behavior of Wilms tumor

Abstract P2-16-20: Treatment outcomes in triple negative breast cancer patients undergoing neoadjuvant chemotherapy. The importance of Ki-67

Abstract Aim of study: The aim of this retrospective project is to evaluate the treatment outcomes including pathological complete response (pCR), time to progression and overall survival in patients (pts) treated with taxane, and/or anthracycline/alkylating agents based neoadjuvant chemotherapy (NAC). Background: Ki-67 immunohistochemical determination is a widely used biomarker of cell proliferation in pts undergoing endocrine treatment for breast cancer. The role of Ki-67 in triple negative breast cancer (TNBC) pts undergoing NAC for early disease remains controversial. Pathological Complete Response following NAC has been proposed as a prognostic indicator of long-term outcome. Methods: We analyzed retrospectively data on 86 pts with TNBC. Pathological complete response (pCR) was defined as the complete disappearance of the invasive cancer in the breast and absence of tumor in the axillary lymph nodes examined by axillary clearance. The purpose of this analysis was to investigate factors associated with combined pCR. Results: There were 35 pCR’s (40.7%). At 2 years 82% of pts who attained a pCR were disease free compared to 67% of pts who did not attain a pCR (log rank test p < 0.0117). On univariate analysis factors associated with higher combined pCR included primary tumor size (T1=84% vs T2 and T3 =50% of pts, chi2= 6.81, p<0.03317), Ki67 (>30=68% vs. eq or < 30%= 18% of pts, p<0.00020), age (< than 50 =71% vs. equal or >50 =44% of pts), tumor grade (1=88% vs. 2=60% vs. 3=44% of pts, chi2 = 6.2560 p<0.04381) and stage (I= 89% vs. IIA=60% vs. IIB=46% vs. III=40% of pts, p<0.01350). Factors not associated with a higher pCR included menopausal status, extranodal spread and lympho-vascular invasion. In a logistic regression model Ki-67 as a continuous variable (p<0.012577) and age < than 50 (p<0.03318) retained its significance; while tumor size, stage of disease, tumor grade loss significance. Conclusion: Ki67 and age are independent prognostic factors of pCR in pts with early TNBC undergoing NAC. Citation Format: Bernardo Leon Rapoport, Jacqui Barnard-Tidy, Ronwyn van Eeden, Teresa Smit, Simon Nayler, Carol Benn. Treatment outcomes in triple negative breast cancer patients undergoing neoadjuvant chemotherapy. The importance of Ki-67 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-20.

Abstract P1-15-25: Prognostic factors associated with pathological complete response in early breast cancer patients undergoing neoadjuvant chemotherapy. The importance of Ki-67 and molecular subtype

Abstract Background: Ki-67 immunohistochemical determination is a widely used biomarker of cell proliferation in patients (pts) undergoing endocrine treatment for breast BC. The role of Ki-67 in pts undergoing neoadjuvant chemotherapy (NAC) for early BC remains controversial. Methods: We analyzed retrospectively data on 137 patients undergoing taxane and/or anthracycline, transtuzumab based NAC. Luminal A was documented in 6 pts, Luminal B in 29 pts, Her-2 positive in 30 pts and triple negative breast cancers (TNBC) in 72 pts. Pathological complete response (pCR) was defined as the complete disappearance of the invasive cancer in the breast and absence of tumor in the axillary lymph nodes examined by axillary clearance. Results: The pCR rate of the entire cohort was 41.6%. At 2 years 92% of pts who attained a pCR were disease free compared to 80% of pts who did not attain a pCR (log rank test p < 0.0147). On univariate analysis factors associated with higher pCR included primary tumor size (T1 68% vs. T2 41% vs. T3 or T4 0%, Chi2=20.05, p<0.00017), nodal disease (N0 49% vs. N1 39% vs. N2 8%, p<0.02948), ER receptor status (negative 59% vs. positive 14%, p<0.00000), PR receptor status (negative 53% vs. positive 17%, p<0.00002), molecular subtype (TNBC 53.4%, Her2=50% and Luminal A + B was 8.5%, p<0.00002), Ki67 (>40=55% vs. 15-39=34% vs. <15=0%, p<0.00060) and Stage (I= 85% vs. IIA=49% vs. IIB=36% vs. III=5%, p<0.00006). Factors not associated with a higher pCR included age, menopausal status, extranodal spread and lympho-vascular invasion. In a logistic regression model Ki-67 as a continuous variable (p<0.01203) and molecular subtype (p<0.02228) retained its significance; while tumor size, stage of disease, nodal status, ER and PR loss significance. Conclusion: Ki67 and molecular subtype (Her-2 positive disease and TNBC) are independent prognostic factors of pCR in pts with early BC undergoing NAC. Citation Format: Rapoport BL, Barnard-Tide J, Smit T, Nayler S, Benn C-A. Prognostic factors associated with pathological complete response in early breast cancer patients undergoing neoadjuvant chemotherapy. The importance of Ki-67 and molecular subtype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-25.

235P - Prognostic factors associated with pathological complete response in early breast cancer patients undergoing neoadjuvant chemotherapy: The importance of Ki-67 and molecular subtype

235P - Prognostic factors associated with pathological complete response in early breast cancer patients undergoing neoadjuvant chemotherapy: The importance of Ki-67 and molecular subtype

Expression of Ki-67 in Low-Grade and High-Grade Astrocytomas

Objective. This review aims to carry out a survey on the importance of Ki67 in the astrocytomas study. Methods. A search in the electronic database of Medline via PubMed and using MESH terms was carried out. Articles were published between January 2005 and December 2015. All studies were analyzed by two experienced researchers, using inclusion and exclusion criteria for the selection of studies. Results. Five studies showed an association between cell proliferation and survival time. Four articles mentioned as cut-off point for survival a Ki67 of 10% and a fifth article a Ki67 of 14.3. A study showed an association between therapeutic failure and Ki67. Four studies have made the association between Ki67 and World Health Organization classification. Conclusion. High levels of Ki67 are associated to high grade astrocytomas and lower survival time.

Abstract P1-07-05: AIB1 is a new putative prognostic biomarker in the luminal A and B-like (HER2-negative) classification of invasive lobular carcinoma

Abstract Background: Estrogen receptor (ER) positive HER2-negative breast cancer comprises 75–80% of all breast cancer. This fraction is even higher (>90%) in invasive lobular carcinoma (ILC). According to the St Gallen surrogate definitions of the intrinsic subtypes, Ki67 and progesterone receptor (PgR) are used to classify these tumors as luminal A- and luminal B-like (HER2-negative). These guidelines are based on information derived from patient materials with mixed histological types, where the vast majority of the patients have invasive ductal carcinoma. The `luminal-like classification´ together with histological grade, tumor size and lymph node status is widely used in the clinic for prognostication. The aim of the present study was to investigate if the same markers are applicable for ILC, and furthermore, if additional biomarkers involved in the endocrine signaling system, e.g. Amplified in breast cancer 1 (AIB1) and the putative G protein-coupled estrogen receptor (GPER), might provide complementary prognostic information. Patients: Two hundred and thirty-three (N = 233) well-characterized patients with primary ILC, diagnosed between 1980 and 1991 were included. Forty-two percent of the patients received adjuvant endocrine treatment and 2 % received adjuvant chemotherapy. All biomarkers were analyzed immunohistochemically on tissue microarray, whereas histological grade was evaluated on whole sections according to Elston and Ellis (NHG). The primary endpoint was breast cancer mortality (BCM). Results: In univariable analyses with 10-year follow-up, Ki67 (high vs. low), NHG (3 vs. 1+2) and AIB1 (high vs. low) were significantly associated to BCM (Hazard Ratio: 4.7, 95% CI: 2.1–10.4, p <0.001; HR: 3.1, 95% CI: 1.5–6.4, p = 0.003; HR: 3.2, 95% CI: 1.4–7.2, p = 0.005 respectively), whereas PgR (<1% vs ≥1%) and GPER (linear 0-4) were not (p = 0.25; p = 0.31 respectively). Essentially the same effect was seen after multivariable adjustment for lymph node status (+ vs. -), tumor size (>20 mm vs. <20 mm), adjuvant treatment and age (continuous). Subgrouping the tumors into luminal A- and B-like (HER2-negative) according to St Gallen surrogate definitions did not show significant prognostic differences between the two groups (p = 0.12). Patients with <20 mm, lymph node negative breast cancer and favorable tumor characteristics (low Ki67, NHG 1+2, and low AIB1) had a 10-year BCM of 4.2% (95% CI: 1.4–12%). This group constituted 34% of the patients included in the present study. Conclusions: In contrast to other previous studies, where breast cancers of mixed histological types were included, PgR was not significantly associated to prognosis in the ER-positive HER2-negative subgroup in the present study, consisting only of ILC. The prognostic role of PgR and the clinical usefulness of the luminal A and B-like (HER2-negative) classification (using only Ki67 and PgR) in ILC is still to be further investigated. The prognostic importance of Ki67 and NHG in this subgroup was, however, confirmed also in ILC, and AIB1 might be a new putative prognostic factor. By combining Ki67, NHG, and AIB1, together with lymph node status and tumor size, a group of patients with an excellent prognosis could be identified. Citation Format: Narbe U, Forsare C, Bendahl P-O, Lövgren K, Alkner S, Sjöström M, Rydén L, Leeb-Lundberg F, Ingvar C, Fernö M. AIB1 is a new putative prognostic biomarker in the luminal A and B-like (HER2-negative) classification of invasive lobular carcinoma [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-05.

Is Overexpression of Ki-67 a Prognostic Biomarker of Upper Tract Urinary Carcinoma? A Retrospective Cohort Study and Meta-Analysis

Background: Upper tract urinary carcinoma (UTUC) is a relatively uncommon but aggressive disease. The Ki-67 antigen is a classic marker of cellular proliferation, but there is still controversy regarding the significance and importance of Ki-67 in tumor progression. Methods: In this study, we first detected Ki-67 expression in UTUC patients by immunohistochemistry (IHC). Subsequently, we quantitatively combined the results with those from the published literature in a meta-analysis after searching several databases. Results: IHC results demonstrated that patients with muscle-invasive tumors (T2-T4) had higher Ki-67 expression than those with non-muscle-invasive tumors (Tis-T1), suggesting that high Ki-67 expression may be associated with the aggressive form of UTUC. Kaplan-Meier curves showed that patients with high Ki-67 expression had significantly poorer cancer-specific survival (CSS) and disease-free survival (DFS). Furthermore, multivariate analysis suggested that Ki-67 expression was an independent prognostic factor for CSS (hazard ratio, HR=3.196) and DFS (HR=3.517) in UTUC patients. Then, a meta-analysis of the published literature investigating Ki-67 expression and its effects on UTUC prognosis was conducted. After searching the PubMed, Medline, Embase, Cochrane Library and Scopus databases, 12 articles met the eligibility criteria for this analysis. The eligible studies included a total of 1740 patients with a mean number of 82 patients per study (range, 38-475). The combined results showed that increased Ki-67 levels were associated with poor survival and disease progression, with a pooled HR estimate of 2.081 and 2.791, respectively. In subgroup analysis, the pooled HR was statistically significant for cancer-specific survival (HR=2.276), metastasis-free survival (HR=3.008) and disease-free survival (HR=6.336). Conclusions: In conclusion, high Ki-67 expression was associated with poor survival in patients with UTUC, as well as a high risk of disease progression, although these findings need to be interpreted with caution. Large-scale, adequately designed, prospective trials are needed to further confirm the value of Ki-67 in prognosis of UTUC patients.

Abstract P6-08-43: Histological grade provides significant prognostic information in the discrimination between luminal A-like and luminal B-like HER-2 normal subtypes of breast cancer according to St Gallen 2013

Abstract Objective: According to St Gallen recommendations from 2013, estrogen receptor (ER), progesterone receptor (PR), HER-2, and Ki-67 defines two subtypes of ER-positive and HER-2 normal breast cancer (BC): Luminal A-like and Luminal B-like. Patients with Luminal B-like BC are often recommended chemotherapy in addition to endocrine therapy, whereas endocrine therapy may be sufficient for patients with Luminal A-like BC. Histological grade (G) 1, 2 and 3 are not included in the St Gallen recommendations. Our unpublished data from a series of 161 premenopausal N0 BC patients with long-term follow-up show that the classification of Luminal A-like vs Luminal B-like HER-2 normal BC is strongly associated to G. Luminal A-like BC is often G1 or G2 and Luminal B-like BC is usually G2 or G3. We also found that the few G3 (n=6) Luminal A-like cases had a prognosis more similar to Luminal B-like and that the few G1 (n=2) Luminal B-like HER-2 normal cases had a prognosis more similar to Luminal A-like. The aim of this study is to evaluate in other cohorts if these findings can be confirmed. Methods: G and St Gallen subtypes were evaluated in three BC cohorts from altogether 547 pre- and postmenopausal chemotherapy naïve T1-2N0-N1M0 patients. The endpoint was distant disease-free survival with 10 years of follow-up. We compared the Luminal A-like and the Luminal B-like HER-2 normal subtype definition according to the original St Gallen recommendation from 2013 based on ER, PR, HER-2 and Ki-67 (St Gallen 2013) with our proposal, where ER-positive, HER-2 normal, G1 BC is defined as Luminal A-like, independent of Ki-67 and PR, and ER-positive, G3 BC is defined as Luminal B-like, independent of Ki-67 and PR (St Gallen 2013+G). The importance of Ki-67 and PR for subtyping was thus restricted to G2 BC. Results: The hazard ratio (HR) between Luminal B-like HER-2 normal (n=185) and Luminal A-like (n=362) defined according to St Gallen 2013+G, was 2.3 (95% confidence interval (CI) 1.6-3.4; p<0.0001) compared to 1.6 (95% CI: 1.1-2.4; p=0.025) according to St Gallen 2013. Twenty-five patients, classified as Luminal B-like HER-2 normal with St Gallen 2013 were G1 and consequently reclassified as Luminal A-like with St Gallen 2013+G. None of these twenty-five patients developed metastases during the follow-up period. Thirty-eight patients showed the opposite pattern (G3 Luminal A-like with St Gallen but Luminal B-like according to St Gallen 2013+G). Seventeen of these patients developed distant metastases already during the first five years. Conclusion: Our findings strongly suggest that ER-positive, HER-2 normal, and G1 BC is a good prognosis group, independent of Ki-67 and PR, and should be treated as Luminal A-like BC, whereas ER-positive, HER-2 normal, and G3 BC should be considered as a worse prognosis group, independent of Ki-67 and PR, and should be treated as Luminal B-like BC. Based on our findings the importance of Ki-67 and PR is restricted to G2 BC for the discrimination between Luminal A-like and Luminal B-like HER-2 normal subtypes of BC. Citation Format: Anna Ehinger, Per Malmström, Pär-Ola Bendahl, Christopher W Elston, Anna-Karin Falck, Carina Forsare, Dorthe Grabau, Lisa Rydén, Olle Stål, Mårten Fernö. Histological grade provides significant prognostic information in the discrimination between luminal A-like and luminal B-like HER-2 normal subtypes of breast cancer according to St Gallen 2013 [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 P6-08-43.

The importance of Ki-67, PCNA and Progesterone receptor expression in meningiomas

Purpose: Meningiomas with their potential biological and clinical behavior represents a broad brand group of tumors. Meningiomas are the most seen benign tumors of the central nervous system and types of atypical and malignant meningioma recurrence rate is high. In recent years, proliferation markers such as Ki-67 and PCNA are commonly used in meningiomas in order to predict recurrence. Materials and methods: In this study, 55 meningioma cases diagnosed in pathology departmant were reclassified according to the WHO 2000 and their histological subtypes and grades were determined. sections from selected paraffin blocks were immunostained with PCNA, Ki-67, EMA, vimentine, and progesterone receptor (PR); and their values in meningioms were investigated. Results: PCNA and Ki-67 values of benign meningiomas are lower than the atypical and malignant meningioms as statistically significant (p<0.05). In addition, the high values of progesterone receptor positivity on benign meningiomas and the lower levels of it on malignant and atypical meningiomas are considered to be statistically significant as well ( p<0.05). Conclusion: PCNA and Ki-67 proliferation rates of atypical and malignant meningiomas are observed to be higher than the benign meningioms. Benign meningiomas with high values of Ki-67 and PCNA should be observed with regard to recurrence although they are completely resected. Progesterone receptor positivity was associated with the differentiation of the tumor and prognosis alone is not enough, however in the differential diagnosis of the tumor was thought to be a good alternative to EMA and vimentine.

Comparative Validation of the SP6 and MIB1 Antibodies to Ki67 and Their Use in Tissue Microarray (TMA) and Image Analysis for Breast Cancer.

Abstract Aim: To compare SP6 and MIB1 antibodies against Ki67 for use with visual scoring, image analysis and TMA (tissue microarray) analysis.Background: Immunohistochemical detection of Ki67 has been widely used in assessing the proliferation fraction in breast cancer. Neoadjuvant studies revealed that changes in Ki67 predict benefit from endocrine treatment, and that on-treatment Ki67 measurements are better predictors of long-term outcome than pretreatment levels (Dowsett at al, JNCI 2007; 99:167-170). As a result Ki67 is the primary end-point for some pre-surgical trials. MIB-1 has been the preferred Ki67 antibody for over 10 years. A rabbit monoclonal antibody, SP6, has become available with apparently improved performance, e.g. reduced background non-nuclear staining. The importance of Ki67 led us to conduct a systematic series of studies to validate SP6 in comparison to MIB1.Methods: We used TMAs constructed from (i) 177 archival FFPE blocks of primary or locally recurrent breast tumours from women treated with an aromatase inhibitor (AI) for advanced disease (AI TMAs) and (ii) one set of replicate blocks (200 tumours) from the TransATAC program. The TMAs were of 600µm cores. Three replicate TMAs (A, B, C) were used. Staining was performed using DAKO Autostainer and DAKO REAL Kit Detection System. MIB-1 antibody (DAKO) was used at a dilution of 1:40, whereas 1:100 dilution was used for SP6 antibody (Abcam). Stained sections were examined either visually or using the Ariol image analysis system (Genetix Ltd.).Results: There was a strong correlation between the antibodies in AI TMAs scored manually (n=161, r=0.93, p&amp;lt;0.0001). Coefficient of variation was calculated in all cases with ≥2 available cores. MIB1 showed higher median CV [%] compared with SP6 (43.7 vs. 36.7, respectively) in AI TMAs, but a lower CV in TransATAC TMAs (42.0 vs. 51.4, respectively). In a univariate analysis of manual scores from AI TMAs there was a similar association of Ki67 with time to treatment failure (TTF) with the two antibodies (HR: 1.15; 95% CI: 1.00-1.33; p=0.052 and HR: 1.19; 95% CI: 1.00-1.43; p=0.045 for MIB1 and SP6 respectively). Correlation between manual and image analysis scores was markedly better with the SP6 antibody (r=0.71 and r=0.88 for MIB1 and SP6, respectively).Conclusions: SP6 and MIB1 provide highly comparable measures of Ki67 that predict progression of advanced disease similarly. SP6 is substantially better suited than MIB1 to image analysis, and is now our preferred antibody for future studies.Funded by Breakthrough Breast Cancer and The Mary-Jean Mitchell Green Foundation. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3048.