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Ki-67 Breast Cancer Cut-off

The Correlation Between Ki

Ki-67 shows proven clinical utility as a predictive clincal biomarkers for breast cancer

As shown in Table , Pearsons test and Students t-test indicated that Ki-67 expression levels were significantly associated with histological grade in all patients and in each IHC-based different subtype .

Table 1 Correlation of Ki-67 and tumoral grade in breast cancer patients among IHC-based subtypes.

In addition, the analysis results showed that to some extent, Ki-67 can predict histological grade, with an area under the curve of 0.73 in all patients. Similar results were observed when restricted to certain subtypes .

Clinical Implications Of The Ki

When the Ki-67 cut-off of 14% was applied in the authors sample, the concordance rate between PAM50 and IHC was 70.6% 91 out of the 143 patients were classified correctly. Within this group, 72 out of the 95 tumours that were classified as luminal A using PAM50 were correctly classified as such in the IHC analysis, whereas 29 out of the 48 tumours classified as luminal B using PAM50 were correctly classified as such in the IHC analysis.

When the Ki-67 cut-off was set at 20%, the concordance rate between IHC and PAM50 was 76.2% . The percentage of patients who were correctly classified as having luminal A based on IHC and who were later confirmed with PAM50 was 75.2% . In the case of luminal B tumours, the percentage of tumours that were correctly classified with IHC was 80% .

In the authors sample, the cut-off values below 14% showed reduction in sensitivity, leading to inaccurate classification of luminal A tumours, despite the improvement in the concordance rate for luminal B tumours. Conversely, when the cut-off values were higher than 20%, the increase in sensitivity improved the concordance rate for luminal A tumours. However, the significant loss in specificity entailed the nearly total disappearance of the correct classification of luminal B tumours.

Clinical Characteristics In Breast Cancer

Patient characteristics are summarized in Table 1. One hundred and twenty-three FFPE tissue samples were used in this study. Cases were randomly collected according to Korean breast cancer prevalence according to age distribution, followed as 12 cases in 30 s, 38 cases in 40 s, 42 cases in 50 s, 19 cases in 60 s, and 12 cases over 70 s. ER IHC positive cases were 82 . PR IHC positive cases were 70 . HER2 IHC positive cases were 79 .

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Tumor Biomarker Application In The Clinic: Important Semantics

In 2009, Teutsch et al. , representing the Evaluation of Genomic Application in Practice and Prevention initiative, described 3 critical elements to determine if a germ-line genetic test should be used to manage care: 1) analytical validity, 2) clinical validity, and 3) clinical utility. Building on the EGAPP initiative, the United States Food and Drug Administration and the National Institutes of Health convened a group of stakeholders to jointly develop a glossary to better define and harmonize biomarker terminology: the Biomarkers, Endpoints, and Other Tools Resource . Broadly, the Biomarkers, Endpoints, and Other Tools Resource defines the acceptability of analytical validity in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics. The level of acceptability of analytical performance of Ki67 differs among applications and intended uses.

The efforts of the IKWG over the last decade aimed first to determine analytical validity for Ki67 IHC and to promote standardization. The IKWG has not yet formally addressed clinical utility. At the October 2019 meeting, the IKWG addressed several questions that were considered essential in order for Ki67 to be used to manage patient care.

Statistic Analysis And Software

Prognostic Value of Proliferation Markers: Immunohistochemical Ki

The prospective database was built by Microsoft® Access. The statistical analysis was carried out by IBM-SPSS®. In order to compare categorical and continuous variables, Chi-square test and Students t test were used. Disease-Related Survival and Disease-Free Survival were calculated from the surgical procedure, plotting the curves by the KaplanMeier method and the Log-rank test was used for statistical comparisons.

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Patient And Tumor Characteristics In Relation To Different Molecular Subtypes

Table 2 reveals statistically significant association among molecular subtypes of cases with both tumor grade and Ki-67 positivity . Luminal A cases showed the highest proportion of grades 1 and 2 cases . HER2 and triple-negative subtypes comprised a high proportion of grades 3 and 2 cases . Ki-67 < 15% was present in 100% of luminal A, 31% of luminal B, 66% of HER2, and 40% of triple-negative cases. Ki-67 > 15% was present in 0% of luminal A, 69% of luminal B, 34% of HER2, and 60% of triple-negative cases. No statistically significant association was observed among molecular subtypes of the studied cases and age, mitotic count, tumor size, nodal status, stage, histological subtype, or patient outcome .

Quantification Of Ki67 Change As A Valid Prognostic Indicator Of Luminal B Type Breast Cancer After Neoadjuvant Therapy

  • 1Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
  • 2Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
  • 3Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
  • 4Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
  • 5Breast Center, The Affiliated Hospital of Qingdao University, Qingdao, China

Introduction: Ki67 value and its variation before and after neoadjuvant chemotherapy are commonly tested in relation to breast cancer patient prognosis. This study aims to quantify the extent of changes in Ki67 proliferation pre- and post-neoadjuvant chemotherapy, confirm an optimal cut-off point, and evaluate its potential value for predicting survival outcomes in patients with different molecular subtypes of breast cancer.

Ki67% can aid in predicting patient prognostic outcome, provide a measurement of NAC efficacy, and assist in further clinical decisions, especially for patients with Luminal B breast cancer.

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Immunohistochemistry For Biomarker Detection

Histopathology is regarded as the gold standard for diagnosis. All breast tumor specimens were acquired from core needle biopsy or surgical resections, and every specimen was affixed into formalin-fixed, paraffin-embedded tissue sections for preservation. IHC staining was performed using Dako Autostainer Plus and EnVision Dual Link detection reagent with DAB . Biomarker status, including ER, PR and HER2, were defined by IHC in strict accordance with European Quality Assurance guidelines. ER and PR staining were assessed based on the American Society of Clinical Oncology/College of American Pathologists Guidelines . Antibodies used in IHC include as anti-ER , anti-PR , and Ki67 . Hematoxylin II was used to counterstain specimens automatically. All tests incorporated external positive and negative controls. ER and PR stains were considered positive if immunostaining was seen in more than 1% of immunoreactive cells. HER2 status was ascertained via IHC using the Hercep Test kit . HER2 expression was scored as 0, 1+, 2+, and 3 + according to ASCO guidelines. A score of 3+ was regarded as HER2+, with 0/1+ defined as HER2-. For cases scoring HER2 2+, a fluorescent in situ hybridization test could be conducted. The measurement of Ki67 index was based on the spot with the highest intensity in a high-power field and 5002000 cells were counted .

Region Of Interest Selection

Standardization with Clinical Digital Pathology – The Ki-67 Case

Image selection

Two radiologists , who were blinded to the patients pathologic information, retrospectively reviewed the MRI images electronically on the picture archiving and communication system . In the case of disagreements, the two radiologists would reach a final decision by discussion and consensus. The final MRI images selected were exported from the PACS workstation in BMP format for histogram analysis. During export, the window width and window level were adjusted thus, all images had consistent window width and window level, and they were saved on the hard disk.

Histogram analysis

Figure 2Figure 3

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Original Articledo You Know The Ki

Limiting the number of observers can improve reproducibility of Ki-67 assessments.

Comparison with published data-sets helps to define adequate Ki-67 cut-off levels.

Lobular breast cancers have a significantly lower Ki-67 than ductal breast cancers.

Ki-67 values and standard deviation increase parallel to increasing tumor grade.

Ki-67, properly assessed, remains important for decision making in breast cancer.

Availability Of Data And Materials

The datasets generated and/or analysed during the current study are not publicly available due to issues of sensitivity and limitations determined in the conditions for approval by the Regional Ethics Committee. However, they can be made available from the corresponding author on reasonable request.

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Assessment Of The Prognostic Efficacy Of Ki67 Expression Status Before And After Nac

The average Ki67 status before NAC was 39.66% ± 22.61%. In comparison, the average value after NAC was 25.00% ± 22.91%. The downward trend of Ki67 before and after NAC is displayed in Figure 3 for the whole cohort , Luminal subtype , HER2-enriched subtype , and TN subtype . As shown in the figure, Ki67 change before and after NAC presented a statistical difference in Luminal subtype. However, in HER2-enriched and TN breast cancer, the difference of Ki67 represented no statistical significance. To evaluate the degree of Ki67 decline, we compared post-NAC and pre-NAC proliferation indices [define post-NAC Ki67 as A, define pre-NAC Ki67 as B, the computational formula was

status in NAC-treated luminal-B subtype patients.

FIGURE 5. Forest plot of DFS and OS in Luminal B breast cancer The left side of the figure is exhibiting the forest plot of DFS in Luminal B subtype. The right side of the figure presents the forest plot of OS in Luminal B subtype. The two forest plots both present the multivariate-analyses results Abbreviations: BMI, body mass index NAC, neoadjuvant chemotherapy IBC-NST, invasive breast carcinoma of no special type DFS, disease-free survival OS, overall survival.

Among patients with TN breast cancer,

status in NAC-treated TNBC subtype patients.

Correlation Of Adc Histogram Parameters With Ki

Development of a Ki

The correlation between the ADC histogram parameters and Ki-67 expression are shown in Table 3. The mean value, and the 1st, 10th, 50th, 90th, and 99th percentiles were negatively correlated with the expression of Ki-67 , with a correlation coefficient of 0.624, 0.749, 0.717, 0.621, 0.500, and 0.410, respectively. However, neither variance, skewness, nor kurtosis showed a significant correlation with Ki-67 expression .

Table 3

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Luminal A Vs Luminal B

There are many types of breast cancer. Oncologists recommend treatment based on several different characteristics of the cancer cells. Often, doctors will look at the genes of the cancer cells to better identify and treat the disease. There are several different groupings of cancer types. According to the Mayo Clinic, these are called luminal groups.

Among breast cancers that are hormone-positive, there are two distinct subtypes that have different prognoses and may respond differently to treatment regimens.

Ki-67 has been used as part of the data to separate tumors into these two categories. There are many other tests being studied to help with this classification system. One type, MCM2 appears to be a promising alternative. The two categories are:

  • Luminal A tumors : are estrogen receptor-positive , progesterone receptor-positive , HER2-negative and have a Ki-67 index less than 14%.
  • Luminal B tumors: Luminal B tumors are estrogen receptor and/or progesterone receptor-positive, HER2-negative, and have a Ki-67 index greater than 14%. Or, they are estrogen receptor and/or progesterone receptor-positive, HER2-positive, and have any Ki-67 index.

Your healthcare team will consider your pathology report, the genetic traits of your cancer, and your overall health, to work with you to make a treatment plan for your breast cancer. Scientists are studying the genetic makeup of cancer hoping better understanding will lead to more effective treatments.

Adc Histogram Parameters Between Low

The results of the analysis of the ADC histogram parameters for the low Ki-67 group and the high Ki-67 group are shown in Table 4. The mean value, and the 1st, 10th, 50th, 90th, and 99th percentiles in the high-proliferation and low-proliferation groups, were significantly different however, no significant differences were found in variance, skewness, or kurtosis . Examples are shown in Figures 2 and 3. In Figure 4, box plots of the significant ADC histogram parameters between the two groups are presented.

Table 4Figure 4

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Test Of Equality Of Survival Distributions For Different Levels Of Ki

Figure 2 shows that patients with Ki-67 < 15% exhibited better OS than those with Ki-67 > 15% .Figure 3 illustrates that patients with Ki-67 > 15% were more likely to develop recurrence and distant metastasis than those with Ki-67 < 15% .

Disease free survival of breast cancer patients. Patients with Ki-67 > 15% are more likely to develop recurrence and distant metastasis than those with Ki-67 < 15% .

Basic Demographic Features And Baseline Characteristics

Surgery, chemotherapy and radiation increase chances of survival when treating breast cancer

Patients with primary breast cancer who were treated with NAC were selected based on strict standards. 942 patients were initially included in the cohort, but 114 patients were eliminated for various reasons. A total of 828 female patients with primary breast cancer who received NAC were ultimately included in this retrospective study .

FIGURE 1. Patient selection flow diagram for the study.

Basic demographic and pathologic features are shown in Table 1. The median age of entire cohort was 51 ± 9.65 years old , of which 10.0% of patients were under 40 years old at diagnosis. Body mass index was used to distinguish subjects: overweight patients with index greater than or equal to 24.9 accounted for 48.2%, underweight patients with index under 18.9 accounted for 8.2 and 43.6% of patients had a healthy BMI between 18.924.9. Breast cancer pathological subtype was confirmed as invasive carcinoma of NST for 84.4% of patients. All other histological types represented 15.6% of the full cohort. A median of 4 NAC cycles were received , with NAC classified into three groups: texane-based , anthracycline-based and texane + anthracycline . The average maximum tumor diameters before and after NAC were 3.41 ± 1.651 and 2.26 ± 1.648 cm, respectively. 81.9% patients presented with node-positive status at diagnosis. Finally, 138 subjects who received NAC achieved pCR, a commonly used measurement of NAC efficacy.

TABLE 1. Demographic and clinicopathological features of whole cohort .

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Establishment Of The Ki

The ROC curve for Ki-67, an independent surrogate marker, as determined by IHC is shown in Figure 1. The area under the curve of the ROC curve is 0.78 . The Ki-67 cut-off showing the most homogeneous values for sensitivity and specificity was 14% . A Ki-67 cut-off of 10% showed a significant increase in specificity at the expense of a pronounced decrease in sensitivity . The opposite trend was observed when the Ki-67 cut-off was increased to 20% there was a considerably marked increase in sensitivity with a sharp fall in specificity .

Figure 1: Receiver operating characteristic curve of Ki-67 as an independent diagnostic marker of luminal breast cancer.

The Ki-67 cut-off values of at least 25% demonstrated a 100% sensitivity. By contrast, the specificity was compromised. At a cut-off of 25%, the specificity was 23% and it progressively decreased with the increase in cut-off value. A 100% specificity was reached when the Ki-67 cut-off was 3%, although the shift in threshold from 12% to 10% involved an increase in specificity from 56% to 94% and it entailed a decrease in sensitivity from 76% to 43%.

Correlation Between Patient Features And Pathological Response To Nac Or Survival

We chose pCR as our evaluation criterion of pathological response to NAC. The median follow-up time was 62.00 ± 21.43 months. A associations between patient features and pathological response to NAC or survival were assessed via the Chi-square test , with results shown in Table 2. Age, body mass index, maximum tumor diameter before NAC, and HER2 status all had p values > 0.05, indicating no significant influence on prognosis. However, different carcinoma pathology subtypes, maximum diameter after NAC, and nodal status at diagnosis were all significantly associated with pCR, with all p values < 0.05. The IHC biomarkers ER, PR and Ki67 status before and after NAC, all associated with pathological response to NAC. The log-rank test was used for in analysis of different parameters with DFS and OS fully considering the follow-up time . For DFS and OS, BMI and Ki67 after NAC both presented p value < 0.05.

TABLE 2. The univariate relationship between above features with pCR

TABLE 3. The univariate relationship between above features with DFS and OS .

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Evaluation Of An Optimal Cut

  • Affiliation Surgery, Kumamoto City Hospital, Kumamoto, Japan

  • Affiliation Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan

  • Affiliation Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan

  • Affiliation Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan

  • Affiliation Pathology, Kumamoto City Hospital, Kumamoto, Japan

  • Affiliation Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan

  • Affiliation Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan

  • Affiliation Pathology, Kumamoto City Hospital, Kumamoto, Japan

Establishment Of The International Ki67 In Breast Cancer Working Group

Development of a Ki

In 2011, we established the International Ki67 in Breast Cancer Working Group to review methods of determination of Ki67 levels in breast cancer . Because of the multiplicity of assays and the apparent poor standardization of them for this marker, we set out to establish internationally acceptable methods for the determination of Ki67. Since 2011, as described in the remainder of this article, we and others have made substantial efforts to address both the technical and scoring aspects of Ki67 assessment. Nonetheless, current guidelines remain skeptical about the technical validity of Ki67 IHC assays. For example, the recent American Joint Committee on Cancer guideline on cancer staging states As a single factor, Ki-67 was not considered a reliable factor for implementation in clinical practice because of the known lack of reproducibility . Consistent or similar statements are present in many national and international guideline documents .

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