Combined Use of cyclinD1 and Ki67 for Prognosis of Luminal-Like Breast Cancer Patients

BackgroundKi67 is a biomarker of proliferation to be used in immunohistochemistry (IHC)-based surrogate assay to determine the necessity of cytotoxic therapy for Luminal-like breast cancer patients. cyclinD1 is another frequently used biomarker of proliferation. A retrospective study was performed here to investigate if these two biomarkers may be combined to improve the prognosis of Luminal-like patients.MethodsBoth Ki67 and cyclinD1 protein levels were measured absolutely and quantitatively using Quantitative Dot Blot method in 143 Luminal-like specimens. Optimized cutoffs for these two biomarkers were developed to evaluate their prognostic roles using Kaplan–Meier overall survival (OS) analysis.ResultscyclinD1 was found as an independent prognostic factor from Ki67 in univariate and multivariate OS analyses. At optimized cutoffs (cyclinD1 at 0.44 μmol/g and Ki67 at 2.31 nmol/g), the subgroup with both biomarkers below the cutoffs (n = 65) had 10-year survival probability at 90% in comparison to those with both biomarkers above the cutoffs (n = 18) with 8-year survival probability at 26% (log-rank test, p <0.0001). This finding was used to modify the surrogate assay using IHC-based cyclinD1 scores, with p-value decreased from 0.031 to 0.00061 or from 0.1 to 0.02, when the Ki67 score of 14 or 20% was used as cutoff, respectively, in the surrogate assay.ConclusionThe current study supports the prospective investigation of cyclinD1 relevance in the clinic.

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Combined use of absolutely quantitated cyclin D1 and Ki67 protein levels to improve prognosis of Luminal-like breast cancer

10.1101/2020.04.15.20066993 ◽

2020 ◽

Author(s):

Junmei Hao ◽

Wenfeng Zhang ◽

Yan Lv ◽

Jiarui Zou ◽

Yunyun Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Cyclin D1 ◽

Cancer Patients ◽

D1 Protein ◽

Rank Test ◽

Breast Cancer Patients ◽

Dot Blot ◽

Luminal A ◽

Surrogate Assay

AbstractPurposeBoth Ki67 and cyclin D1 are routinely used protein biomarkers of cell proliferation for breast cancer patients. Ki67 is used to differentiate Luminal A-like from Luminal-B like subtype in surrogate assay. These two proliferative factors are investigated in this retrospective study to evaluate their prognostic role on the overall survival (OS) of Luminal-like breast cancer patients.MethodThe cyclin D1 protein level was measured absolutely and quantitatively using Quantitative Dot Blot (QDB) method in 143 Luminal-like FFPE breast cancer specimens. An optimized cutoff at 0.71 μmole/g was identified and used to separate these specimens into cyclin D1 high and low groups alone, or in combination with Ki67, for overall survival (OS) analyses of these patients.ResultsCyclin D1 was found to be an independent prognostic factor from Ki67 in univariate and multivariate analysis. When both biomarkers were used to separate these Luminal-like specimens, the group with low expression of both biomarkers (n=52) had significantly improved 10 year survival probability at 94%, while the one with high expression of both markers (n=34) were at 41% based on Kaplan-Meier survival analysis of OS (Log rank test p<0.0001).ConclusionWe demonstrated cyclin D1 as an independent prognostic protein biomarker from Ki67 for Luminal-like breast cancers. The combined usage of cyclin D1 and Ki67 significantly improved the prognosis over current prevailing surrogate assay. We propose to incorporate cyclin D1 in surrogate assay to improve prognosis for Luminal-like breast cancer patients in future clinical practice.

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Improving prognosis of surrogate assay for breast cancer patients by absolute quantitation of Ki67 protein levels using Quantitative Dot Blot (QDB) method

10.1101/2020.03.11.20034439 ◽

2020 ◽

Author(s):

Junmei Hao ◽

Yan Lv ◽

Jiarui Zou ◽

Yunyun Zhang ◽

Shuishan Xie ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Survival Prediction ◽

Breast Cancer Patients ◽

Dot Blot ◽

Luminal A ◽

Luminal B ◽

Protein Levels ◽

Multivariate Survival ◽

Surrogate Assay

AbstractPurposeThe separation of Luminal A-like from Luminal B-like breast cancer subtypes in surrogate assay relies on Ki67 scores assessed by immunohistochemistry (IHC), a method known to be associated with subjectivity and inconsistency. We attempted to measure Ki67 levels absolutely, quantitatively and objectively in Formalin Fixed Paraffin Embedded (FFPE) specimens, and evaluate its influence on the performance of surrogate assay for breast cancer patients.MethodsThe Ki67 protein levels were assessed using both IHC and Quantitative Dot Blot (QDB) methods respectively in 253 specimens. These patients were assigned into Luminal A-like and Luminal B-like subtypes using either Ki67 score of 14% as cutoff in surrogate assay, or 2.31 nmole/g from QDB method as cutoff in adjusted surrogate assay. These two subtyping methods were compared with the Kaplan-Meier, univariate and multivariate survival analyses of the overall survival (OS) of Luminal-like patients.ResultsKi67 levels measured using QDB method was highly correlated with those by IHC analysis (r=0.7, p<0.0001). The survival prediction for Luminal A-like patients was improved significantly in adjusted surrogate assay than surrogate assay (p=0.03 vs p<0.00052). The prediction of Hazard Ratio (HR) was also improve from 2.14 (95%CI: 0.89-5.11, p=0.087) to 6.89 (95%CI: 2.66-17.84, p<0.00001) in multivariate survival analysis.ConclusionOur study demonstrated that the inherent subjectivity and inconsistency associated with IHC analysis has adverse effect on the performance of surrogate assay.This issue can be improved by objective and quantitative measurement of Ki67 levels with QDB method in daily clinical practice.

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Improving Prognosis of Surrogate Assay for Breast Cancer Patients by Absolute Quantitation of Ki67 Protein Levels Using Quantitative Dot Blot (QDB) Method

Frontiers in Oncology ◽

10.3389/fonc.2021.737781 ◽

2021 ◽

Vol 11 ◽

Author(s):

Junmei Hao ◽

Yan Lyu ◽

Jiarui Zou ◽

Yunyun Zhang ◽

Shuishan Xie ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Practice ◽

Cancer Patients ◽

Breast Cancer Patients ◽

Dot Blot ◽

Luminal A ◽

Luminal B ◽

Protein Levels ◽

Multivariate Survival ◽

Surrogate Assay

BackgroundImmunohistochemistry (IHC)-based surrogate assay is the prevailing method in daily clinical practice to determine the necessity of chemotherapy for Luminal-like breast cancer patients worldwide. It relies on Ki67 scores to separate Luminal A-like from Luminal B-like breast cancer subtypes. Yet, IHC-based Ki67 assessment is known to be plagued with subjectivity and inconsistency to undermine the performance of the surrogate assay. A novel method needs to be explored to improve the clinical utility of Ki67 in daily clinical practice.Materials and MethodsThe Ki67 protein levels in a cohort of 253 specimens were assessed with IHC and quantitative dot blot (QDB) methods, respectively, and used to assign these specimens into Luminal A-like and Luminal B-like subtypes accordingly. Their performances were compared with the Kaplan–Meier, univariate, and multivariate survival analyses of the overall survival (OS) of Luminal-like patients.ResultsThe surrogate assay based on absolutely quantitated Ki67 levels (cutoff at 2.31 nmol/g) subtyped the Luminal-like patients more effectively than that based on Ki67 scores (cutoff at 14%) (Log rank test, p = 0.00052 vs. p = 0.031). It is also correlated better with OS in multivariate survival analysis [hazard ratio (HR) at 6.89 (95% CI: 2.66–17.84, p = 0.0001) vs. 2.14 (95% CI: 0.89–5.11, p = 0.087)].ConclusionsOur study showed that the performance of the surrogate assay may be improved significantly by measuring Ki67 levels absolutely, quantitatively, and objectively using the QDB method.

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Correlation of AGR2 expression with the incidence of metastasis in luminal breast cancer

Breast Disease ◽

10.3233/bd-219015 ◽

2021 ◽

pp. 1-5

Author(s):

David Samuel Kereh ◽

John Pieter ◽

William Hamdani ◽

Haryasena Haryasena ◽

Daniel Sampepajung ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Mean Value ◽

Rank Test ◽

Luminal Breast Cancer ◽

P Value ◽

Strong Positive Correlation ◽

Breast Cancer Patients ◽

The Mean ◽

Spearman Test

BACKGROUND: AGR2 expression is associated with luminal breast cancer. Overexpression of AGR2 is a predictor of poor prognosis. Several studies have found correlations between AGR2 in disseminated tumor cells (DTCs) in breast cancer patients. OBJECTIVE: This study aims to determine the correlation between anterior Gradient2 (AGR2) expression with the incidence of distant metastases in luminal breast cancer. METHODS: This study was an observational study using a cross-sectional method and was conducted at Wahidin Sudirohusodo Hospital and the network. ELISA methods examine AGR2 expression from blood serum of breast cancer patients. To compare the AGR2 expression in metastatic patients and the non-metastatic patient was tested with Mann Whitney test. The correlation of AGR2 expression and metastasis was tested with the Rank Spearman test. RESULTS: The mean value of AGR2 antibody expression on ELISA in this study was 2.90 ± 1.82 ng/dl, and its cut-off point was 2.1 ng/dl. Based on this cut-off point value, 14 subjects (66.7%) had overexpression of AGR2 serum ELISA, and 7 subjects (33.3%) had not. The mean value AGR2 was significantly higher in metastatic than not metastatic, 3.77 versus 1.76 (p < 0.01). The Spearman rank test obtained a p-value for the 2 tail test of 0.003 (p < 0.05), which showed a significant correlation of both, while the correlation coefficient of 0.612 showed a strong positive correlation of AGR2 overexpression and metastasis. CONCLUSIONS: AGR2 expression is correlated with metastasis in Luminal breast cancer.

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Surgery for primary tumor benefits survival for breast cancer patients with bone metastases: a large cohort retrospective study

BMC Cancer ◽

10.1186/s12885-021-07964-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhangheng Huang ◽

Xin Zhou ◽

Yuexin Tong ◽

Lujian Zhu ◽

Ruhan Zhao ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

Bone Metastases ◽

Cancer Patients ◽

Primary Tumor ◽

Predictive Accuracy ◽

Rank Test ◽

Breast Cancer Patients ◽

Risk Of Death ◽

The Impact

Abstract Background The role of surgery for the primary tumor in breast cancer patients with bone metastases (BM) remains unclear. The purpose of this study was to determine the impact of surgery for the primary tumor in breast cancer patients with BM and to develop prognostic nomograms to predict the overall survival (OS) of breast cancer patients with BM. Methods A total of 3956 breast cancer patients with BM from the Surveillance, Epidemiology, and End Results database between 2010 and 2016 were included. Propensity score matching (PSM) was used to eliminate the bias between the surgery and non-surgery groups. The Kaplan-Meier analysis and the log-rank test were performed to compare the OS between two groups. Cox proportional risk regression models were used to identify independent prognostic factors. Two nomograms were constructed for predicting the OS of patients in the surgery and non-surgery groups, respectively. In addition, calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to evaluate the performance of nomograms. Result The survival analysis showed that the surgery of the primary tumor significantly improved the OS for breast cancer patients with BM. Based on independent prognostic factors, separate nomograms were constructed for the surgery and non-surgery groups. The calibration and ROC curves of these nomograms indicated that both two models have high predictive accuracy, with the area under the curve values ≥0.700 on both the training and validation cohorts. Moreover, DCA showed that nomograms have strong clinical utility. Based on the results of the X-tile analysis, all patients were classified in the low-risk-of-death subgroup had a better prognosis. Conclusion The surgery of the primary tumor may provide survival benefits for breast cancer patients with BM. Furthermore, these prognostic nomograms we constructed may be used as a tool to accurately assess the long-term prognosis of patients and help clinicians to develop individualized treatment strategies.

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FOLLOW-UP OF PATIENTS AND PROGNOSTIC IMPACT OF TUMOUR MARKER CA 15-3 ON PATIENTS OF BREAST CANCER: A RETROSPECTIVE COHORT STUDY

International Journal of Advanced Research ◽

10.21474/ijar01/12052 ◽

2020 ◽

Vol 8 (11) ◽

pp. 656-660

Author(s):

Anjali Vinocha ◽

Keyword(s):

Breast Cancer ◽

Cohort Study ◽

Cancer Patients ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Relative Survival ◽

Rank Test ◽

Prognostic Impact ◽

Breast Cancer Patients

Introduction:Breast cancer is the most common cancer in women, with 5- and 10-year relative survival rates are 91% and 84%, respectively for women with invasive breast cancer. This study aimed to detect the role of serum breast cancer marker CA 15-3 for early detection of metastasis, relapse or recurrence for management of breast cancer patients. Methods: It was a retrospective cohort study with a total of 132 breast cancer patients from the year 2010 to march 2020 were taken and followed up. For these patients demographic, biochemical parameters, radiological and clico-pathological data were collected and analysed. Result: The mean age at the time of presentation and mean duration of follow-up was 47 years and 31 months respectively. There was elevation in the serum level of CA 15-3 at the time of diagnosis of metastasis, recurrence or residual disease in 41 patients. This shows that sensitivity of elevated CA 15-3 (> 30 IU/ml) level in Ca Breast patients was 84%, 75 % and 75 % with respect to metastasis, recurrence and relapse. Log Rank test Chi- square value was 7.39 which was statistically significant (p=0.007). Cox proportional hazard model was created for effect of age at presentation, CA 15-3 at the time of diagnosis and MRM on distant metastasis and was statistically significant (p=0.037). Conclusion: We recommend that for the management of breast cancer patients, Cancer antigen (CA 15-3) levels can be used as prognostic marker for early diagnosis of metastasis, recurrence or relapse.

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Gasdermin D as a potential prognosis and treatment response prediction biomarker for invasive breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12548 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12548-e12548

Author(s):

Xianghou Xia ◽

Wenjuan Yin ◽

Jiefei Mao ◽

Jiejie Hu ◽

Dehong Zou ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Invasive Breast Cancer ◽

Response Prediction ◽

Chemotherapy Response ◽

Breast Cancer Patients ◽

Free Survival ◽

Kaplan Meier ◽

Kaplan Meier Plotter ◽

Treatment Response Prediction

e12548 Background: Pyroptosis is a type of inflammatory cell death mediated by gasdermins. Pyroptosis is critical for macrophage against pathogen infection. Recently growing evidences show that pyroptosis may affect development and progression of many cancers. We aim to explore the expression and related function of pyroptosis executioner Gasdermin D (GSDMD) in breast cancer. Methods: We investigated the expression level of GSDMD using TNM plotter and Breast Cancer landscape proteome with TCGA, GTEx and TARGET databases, and the prognostic value of GSDMD in invasive breast cancer using Kaplan-Meier plotter with TCGA, GEO and EGA databases. The treatment response prediction values of GSDMD in invasive breast were calculated using ROC-plotter with GEO database. Further validation of the prognostic value and chemotherapy response prediction value of GSDMD were carried out with immunohistochemical staining on tissues from 165 cases of breast cancer patients receiving neoadjuvant chemotherapy in our cancer center. Results: TNM plotter and breast cancer landscape proteome portal analysis shows that overall expression level of GSDMD in invasive breast cancer tissue is 1.67 folds higher than it is in breast normal tissues ( p=1.05*e-06). Expression of GSDMD in LuminalB subtype (p=0.019) and Her2 subtype(p=0.04) is significantly higher than it is in TNBC subtype. Calculations with Kaplan-Meier plotter show expression of GSDMD is negatively correlated with overall survival(OS), HR=0.61(0.4−0.95) p=0.027 and relapse free survival (RFS), HR =0.65(0.58−0.63), p=8.7*e-14 and distant metastasis free survival (DMFS) HR =0.75(0.61−0.91), p=0.0038 in breast cancer patients. ROC-plotter calculations show high GSDMD expression is a powerful endocrine therapy (AUC=0.731 p=6*e-09 ) and chemotherapy response (AUC=0.64 p=8*e-05 ) predictor based on 5-year RFS in overall breast cancer patients. Our IHC staining analysis shows consistent prognostic and chemotherapy prediction value of GSDMD expression in TNBC patients. Conclusions: In conclusion, our findings suggest that high expression of GSDMD is positively correlated with prognosis and therapeutic response in breast cancer. GSDMD is a promising prognostic marker and therapeutic response predictor in invasive breast cancer.

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Adjuvant Chemotherapy Guidance for pT1-3N0-1 Breast Cancer Patients with HR+, HER2- subtype: a study based on SEER database

10.21203/rs.3.rs-154913/v1 ◽

2021 ◽

Author(s):

juanjuan Qiu ◽

Li Xu ◽

Yu Wang ◽

Jia Zhang ◽

Jiqiao Yang ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

High Risk ◽

Cancer Patients ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

Rank Test ◽

Breast Cancer Patients ◽

Group Score

Abstract Background Although the results of gene testing can guide early breast cancer patients with HR+, HER2- to decide whether they need chemotherapy, there are still many patients worldwide whose problems cannot be solved well by genetic testing. Methods 144 735 patients with HR+, HER2-, pT1-3N0-1 breast cancer from the Surveillance, Epidemiology, and End Results database were included from 2010 to 2015. They were divided into chemotherapy (n = 38 392) and no chemotherapy (n = 106 343) group, and after propensity score matching, 23 297 pairs of patients were left. Overall survival (OS) and breast cancer-specific survival (BCSS) were tested by Kaplan–Meier plot and log-rank test and Cox proportional hazards regression model was used to identify independent prognostic factors. A nomogram was constructed and validated by C-index and calibrate curves. Patients were divided into high- or low-risk group according to their nomogram score using X-tile. Results Patients receiving chemotherapy had better OS before and after matching (p < 0.05) but BCSS was not significantly different between patients with and without chemotherapy after matching: hazard ratio (HR) 1.005 (95%CI 0.897, 1.126). Independent prognostic factors were included to construct the nomogram to predict BCSS of patients without chemotherapy. Patients in the high-risk group (score > 238) can get better OS HR 0.583 (0.507, 0.671) and BCSS HR 0.791 (0.663, 0.944) from chemotherapy but the low-risk group (score ≤ 238) cannot. Conclusion The well-validated nomogram and a risk stratification model was built. Patients in the high-risk group should receive chemotherapy while patients in low-risk group may be exempt from chemotherapy.

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Breast-Conserving Therapy is Associated with Better Survival than Mastectomy in Early-Stage Breast Cancer: A Propensity Score Analysis

10.21203/rs.3.rs-378418/v1 ◽

2021 ◽

Author(s):

Jiali Ji ◽

Shushu Yuan ◽

Jiawei He ◽

Hong Liu ◽

Lei Yang ◽

...

Keyword(s):

Breast Cancer ◽

Propensity Score ◽

Cancer Patients ◽

Propensity Score Analysis ◽

Early Stage ◽

Breast Conserving Therapy ◽

Early Stage Breast Cancer ◽

Breast Cancer Patients ◽

Kaplan Meier ◽

Score Analysis

Abstract Background: Recent retrospective studies have reported that breast-conserving therapy (BCT) led to improved overall survival (OS) than mastectomy in some populations. We aimed to compare the efficacy of BCT and mastectomy using the SEER database. Methods: Between 2010 and 2015, 99,790 eligible patients were identified. We included early-stage breast cancer patients with 5cm or smaller tumors and three or fewer positive lymph nodes in our study. We compared the OS results among patients with BCT and mastectomy. Kaplan-Meier plots, Cox proportional hazard regressions were used to evaluate the outcomes. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics. Results: In our study, 77,452 (77.6%) patients underwent BCT and 22,338 (22.4%) underwent mastectomy. The 5-year OS rate was 94.7% in the BCT group and 87.6% in the mastectomy group (P <0.001). After matching, multivariate analysis in the matched cohort showed that women underwent mastectomy was associated with worse OS results compared with those with BCT (Hazard ratio (HR) = 1.628; 95% confidence intervals (CIs) = 1.445- 1.834, P<0.001). Patients with different subtypes and age group (>50 years old; ≤50 years old) received BCT all showed significantly better OS than those received mastectomy. The effect of surgery choice on survival was the same in matched and all cohorts. Conclusions: Our study showed that BCT was associated with improved survival compared with mastectomy in early-stage breast cancer patients. It seems advisable to encourage patients to receive BCT rather than mastectomy in early-stage patients when feasible and appropriate.

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The Clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer

BMC Cancer ◽

10.1186/s12885-019-6311-z ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 17

Author(s):

Ru Wang ◽

Yayun Zhu ◽

Xiaoxu Liu ◽

Xiaoqin Liao ◽

Jianjun He ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Cancer Patients ◽

Stage Iv ◽

Clinicopathological Features ◽

Breast Cancer Patients ◽

Kaplan Meier ◽

Stage Iv Breast Cancer ◽

Multivariable Analyses ◽

Metastatic Sites

Abstract Background The features and survival of stage IV breast cancer patients with different metastatic sites are poorly understood. This study aims to examine the clinicopathological features and survival of stage IV breast cancer patients according to different metastatic sites. Methods Using the Surveillance, Epidemiology, and End Results database, we restricted our study population to stage IV breast cancer patients diagnosed between 2010 to 2015. The clinicopathological features were examined by chi-square tests. Breast cancer-specific survival (BCSS) and overall survival (OS) were compared among patients with different metastatic sites by the Kaplan-Meier method with log-rank test. Univariable and multivariable analyses were also performed using the Cox proportional hazard model to identify statistically significant prognostic factors. Results A total of 18,322 patients were identified for survival analysis. Bone-only metastasis accounted for 39.80% of patients, followed by multiple metastasis (33.07%), lung metastasis (10.94%), liver metastasis (7.34%), other metastasis (7.34%), and brain metastasis (1.51%). The Kaplan-Meier plots showed that patients with bone metastasis had the best survival, while patients with brain metastasis had the worst survival in both BCSS and OS (p < 0.001, for both). Multivariable analyses showed that age, race, marital status, grade, tumor subtype, tumor size, surgery of primary cancer, and a history of radiotherapy or chemotherapy were independent prognostic factors. Conclusion Stage IV breast cancer patients have different clinicopathological characteristics and survival outcomes according to different metastatic sites. Patients with bone metastasis have the best prognosis, and brain metastasis is the most aggressive subgroup.

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