Immunohistochemistry profiles of breast ductal carcinoma: factor analysis of digital image analysis data (original) (raw)
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BMC cancer, 2017
Unexpected differences in Ki-67 values among HER2 & ER/PgR defined subgroups were found. This study aims to detect possible subdivisions beyond the conventional breast cancer types. One thousand one hundred eighty consecutive patients with invasive ductal breast carcinoma were included and distributed in 16 subgroups (four HER2 phenotypes (0+, 1+, 2+ and 3+) times four ER/PgR phenotypes). Complex distributions of Ki-67 values were tested by expectation maximization (EM) clustering. Pooled Ki67 values of all patients showed the presence of three EM clusters (defined as LMA-low mitotic activity, IMA-intermediate mitotic activity and HMA-high mitotic activity) with expected mean Ki-67 values of 1.17%, 40.45% and 77.79%, respectively. Only ER-PgR- tumors significantly dispersed in three clusters (29.75% tumors in LMA, 46.95% in IMA and 23.30% in the HMA cluster), while almost no detected HMA tumors were of ER + PgR+ or ER + PgR- phenotypes. Among 799 ER + PgR+ patients distribution in c...
Research Square (Research Square), 2023
Background Immunohistochemistry (IHC) for ER, PR, HER2, and Ki67 is used in breast cancer (BC) pathology to assess tumor properties and predict patient outcomes and therapy responses. Visual scoring of the IHC biomarkers by pathologists, apart from reproducibility issues, does not su ciently account for the intratumoral heterogeneity (ITH), often a subvisual feature within the tumor tissue. It has been reported that the ITH indicators of IHC biomarker expression can provide independent prognostic value. In this study, we applied digital image analysis (DIA) and computational pathology methods to investigate the prognostic value of IHC ITH indicators in hormone receptor-positive (HR-positive) BC patients. Methods Whole slide images of surgically excised specimens stained for ER, PR, Ki67, and HER2 from 178 patients with a diagnosis of HR-positive invasive ductal carcinoma were used in the study. Digital tumor tissue segmentation and detection of biomarker-positive and negative cells were performed. The DIA-generated data were systematically subsampled by a hexagonal grid to compute Haralick's texture indicators for ER, PR, Ki67, and HER2. Univariate and multivariable Cox regression analyses were performed to assess the prognostic signi cance of the IHC and ITH indicators in the context of clinicopathologic variables, including conventional assessment of the IHC results provided by pathologists. Results In multivariable analysis, the ITH of Ki67-positive cells, measured by Haralick's texture entropy, emerged as an independent prognostic factor associated with worse overall survival (hazard ratio = 11.40, p-value = 0.021). Remarkably, the entropy representing the spatial disarrangement of tumor proliferation outperformed the proliferation rate per se established either by pathology reports or DIA. None of the clinicopathologic variables were selected as independent prognostic features in our dataset. Conclusions These results add to the evidence from previous studies that ITH of IHC biomarkers, in particular, ITH of Ki67 proliferation index, exceeds the informative value of Ki67% per se (both visual and digital) in HRpositive BC. The study further demonstrates the bene ts of high-capacity DIA-generated data for quantifying the essentially subvisual ITH properties.
IP innovative publication pvt ltd, 2020
Introduction: In India, for the year 2012, 144,937 women were newly detected with breast cancer and 70,218 women died of it. For every 2 women newly diagnosed with breast cancer, one lady is dying of it. The aim of this study is to evaluate clinical parameters and pathological findings including various Immunohistochemistry (IHC) markers like ER, PR, HER-2 NEU, CK5/6, EGFR, Ki-67 in cases of carcinoma breast and classify them into molecular classification based on IHC markers and try to correlate them clinically. Materials and Methods: This prospective, observational study was carried out in 56 patients with early carcinoma breast (stage-I and stage-II) and IHC evaluation for various markers was done. Data was analysed by using Molecular Classification, divide them into estrogen positive (luminal HER-2, luminal A and luminal B) and estrogen negative (Triple negative or basal cell type, HER-2Neu type and normal breast like phenotype) subtypes. We had correlated this data with parameters like age of the patient, clinical and pathological staging of the breast carcinoma, presence or absence of nodes and presence or absence of other IHC parameters. Results: We used ANOVA-F test to catagories variables and measure the test of significance. On IHC in Her-2 neu equivocal cases (patients who had two “++” positive points), we performed FISH test. Out of these 17 equivocal cases, only 3 were positive, 10 were negative and 4 patients did not underwent this test due to several reasons. Finally, Ki-67 value is significantly high in triple negative and Luminal-B patients. NPI is also having low ‘P’value, although not reaching the level of significance. Conclusion: Types of breast carcinoma, which look histologically similar behaves differently in their clinical presentation and in prognosis. In our study only Ki-67 was correlated with poor prognostic subtype of molecular classification but no any poor risk of clinical or histological parameter was correlated significantly with bad prognostic subtype of molecular classification as Luminal-B or triple negative type. We can say that this molecular classification is different in terms of prognosis in patients with similar looking clinical and histological parameters.
International Journal of Breast Cancer, 2011
There is a paucity of data regarding molecular subtypes of pure ductal carcinoma in situ (pDCIS). We evaluated the expression of ER, PR, HER2, Ki67, and p53 and DNA ploidy in 118 pDCIS and 100 invasive breast carcinomas (IBCAs) by routine IHC and classified them according to molecular subtypes. Quantification of biomarkers and DNA ploidy was performed by image analysis. Expression of ER, PR, and high ki67 was more frequent in pDCIS compared to IBCA. High-grade tumors had lower ER and PR expression, high Ki67, overexpression of HER2 and p53, and DNA aneuploidy. Luminal A and HER2 subtypes were more common in pDCIS, and triple negative was more prevalent in IBCA. In both groups, HER2 and triple negative subtypes were characterized by high ki67, overexpression of p53, and DNA aneuploidy compared to luminal subtypes. Molecular subtypes of IBCA are distinct from those of pDCIS. Invasion is characterized by change in phenotype in some tumors.
A predictive and prognostic biomarker profile of carcinoma breast
IP innovative publication pvt ltd , 2020
Context: The immunohistochemical (IHC 4) biomarker profile is part of the standard histopathology report of all newly diagnosed and recurrent cases of carcinoma Breast. This profile is the basis for all neoadjuvant and adjuvant treatment planning in these cases. Aims: 1. To study the IHC4 biomarker profile of Carcinoma Breast cases at our Institute. 2. To study the correlation of the five types of molecular subgroups with various clinical and histological parameters. Settings and Design: 271 cases of carcinoma breast diagnosed and treated at our Institute, during the period 1st July 2017 till 30th June 2018. This is a prospective, observational study. Materials and Methods: All the cases of biopsy proven carcinoma Breast were subjected to immunohistochemical staining for four markers- ER, PR, Her 2, and Ki 67. Fo rmalin Fixed Paraffin Embedded tumor tissue was stained for 4 biomarkers and scored with appropriate method. (Interpretive Guide: ASCO - CAP Test Guidelines Recommendations 2013) Manual method of staining was employed, using commercially available reagents. The cases were classified into five molecular subtypes. Results: Triple negative breast carcinoma was the most frequent subgroup, followed by the luminal B and A types and the Her2 enriched cases were lowest in number. A few cases showed triple positive staining pattern. Conclusions: The IHC 4 biomarker findings in every case of carcinoma has a direct impact on the treatment decision making and also on risk stratification of the patients.
International Surgery Journal, 2022
Background: Breast cancer is a systemic disease which has different biological subtypes with vast natural history, clinical presentation, various pathological types and molecular features which has impact on prognostic profile and outcome. Present study aims to evaluate correlation of receptor status (ER, PR and HER 2neu) with other tumor characteristics. Methods: The present study was a prospective observational study of 50 breast cancer patients and was conducted from January 2020 to June 2021 in surgical unit of the department of general surgery at MDM hospital attached with Dr. S. N. medical college, Jodhpur, Rajasthan. Results: Most common age group was 41-50 years in 38% cases. Majority of patients were females (49, 98%). The 88% cases had invasive duct carcinoma. ER, PR and HER 2neu positivity had statistically significant correlation with age (p<0.0001), histological grade (p<0.0001) and tumor size (p=0.04). HER 2neu had statistically significant negative correlation with ER and PR (p<0.05). Conclusions: Immunohistochemistry (IHC) markers (ER, PR, HER 2neu) are positively correlated with increasing age, tumor size, tumor grade and positive axillary lymph nodes, also there is statistically significant correlation between HER 2neu overexpression and hormone receptor (ER, PR) negativity in study population.
Intratumoral Heterogeneity of Immunohistochemical Marker Expression in Breast Carcinoma
Applied Immunohistochemistry & Molecular Morphology, 2010
Core needle biopsies of breast carcinomas provide diagnostic, prognostic, and predictive information before neoadjuvant therapy. Possible intratumoral heterogeneity of biomarker expression questions the validity of core needle biopsy interpretation in small biopsy specimens. Using tissue microarray (TMA) technology, we studied intratumoral heterogeneity of 7 immunomarkers. Five TMAs were constructed from 44 breast carcinomas and 5 normal breast tissues, each represented by 1-mm cores in triplicate from each of 3 foci. TMAs were immunostained for monoclonal estrogen receptor (ER), monoclonal progesterone receptor (PR), polyclonal human epidermal growth factor receptor 2 (HER2), monoclonal E-cadherin (E-cad), monoclonal epidermal growth factor receptor (EGFR), monoclonal p53, and monoclonal MIB-1. Expression was quantified visually by light microscopy and by image cytometry as intensity, percentage of cells positive, and score. Using intraclass correlation coefficient, heterogeneity in the expression of the immunomarkers within subjects was compared with the overall variance. Intratumoral heterogeneity was seen with 5 immunomarkers: ER, PR, HER2, p53, and MIB-1. E-cad and EGFR failed to show intratumoral heterogeneity. Intratumoral heterogeneity in ER, PR, HER2, p53, and MIB-1 indicates their problematic interpretation in small biopsy specimens as indicative of the status of the entire tumor. A negative result does not exclude the expression of these markers in the remainder of the tumor. E-cad (positive in ductal carcinomas) and EGFR lacked heterogeneity. *High (>0.75) is equivalent to no heterogeneity; low (r0.75) is equivalent to heterogeneity. EGFR indicates epidermal growth factor receptor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.
Omission of Chemotherapy in HR+/HER2− Early Invasive Breast Cancer Based on Combined 6-IHC Score?
Clinical Breast Cancer, 2021
1. This study involves the clinical determination of whether HR + /HER2 − early BC needs chemotherapy and seeks for a more accurate and cheaper method. 2. Select genes related to BC invasion and metastasis, and establish a scoring model for their immunohistochemical results by Cox regression. 3. The scoring model can well judge the prognosis of HR + /HER2 − BC patients. Purpose: Current methods of judging whether HR + /HER2 − breast cancer (BC) require adjuvant therapy, such as Ki67 and multigene prognostic tests, cannot balance accuracy with the price most patients can afford. Methods: A retrospective analysis of 330 HR + /HER2 − BC patients was conducted. Six BC-related genes (Cathepsin L2, MMP11, CyclinB1, Aurora A, Survivin, and Ki67) were screened using univariate and multivariate COX regression, and correlate clinical follow-up with immunohistochemical expression (designated as 6-IHC). All the included patients were divided randomly at a 7:3 ratio into training and testing cohorts. The cutoff prognosis index (PI) of 6-IHC was determined by multivar iate Cox r isk regression analysis after calculating the PI of each patient in training cohort and confirmed in testing cohort. Kaplan-Meier (KM) method was used to analyze Disease-free survival (DFS) and overall survival (OS). Six-IHC score and other factors associated with survival benefit of adjuvant chemotherapy were compared with Ki67 index. Results: The receiver operating characteristic curve analysis showed that the patients can be divided into 6-IHC score "High" and "Low" risk groups. The 8-year DFS and OS of the KM curves showed that chemotherapy did not significantly improve the DFS in the 6-IHC score "Low" risk group (P = 0.830), but significantly improved the DFS in the 6-IHC score "High" risk group (P = 0.012). Conclusions: Combined 6-IHC score could be a reliable tool in predicting cancer-specific recurrences and survival in HR + /HER2-breast cancer patients, with additional advantages over using immunohistochemical expression of Ki67.
Breast Cancer Research and Treatment, 2015
The aim of the present study was to evaluate to what extent the combination of standard histopathological parameters determines the biology of breast cancer and the effect on therapy and prognosis. The Clinical Cancer Registry Regensburg (Bavaria, Germany) included n = 4,480 female patients with primary, non-metastatic (M0) invasive breast cancer diagnosed between 2000 and 2012. Immuno-histochemical analyses, i.e., estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 (4-IHC), defined the tumor biological subtypes Luminal A, Luminal B, HER2-like, and Basal-like. Subtype-related differences in therapies and overall survival (OS) were analyzed using multivariable statistical methods. 4344 patients (97.0 %) could be classified into the four common tumor biological subtypes. The two most frequent entities were Luminal A (48.4 %), Luminal B (24.8 %), HER2-like (17.8 %), and Basal-like subtype (9.0 %). A multivariable Cox regression model showed that the best 7-year OS was seen in Luminal A patients and that OS of Luminal B and HER2-like patients was comparable (HR = 1.59, P \ 0.001 versus HR = 1.51, P = 0.03). Lowest OS was seen in patients with Basal-like tumors (HR = 2.18, P \ 0.001). In conclusion, the classification of tumor biological subtypes by the ER, PR, HER2, and Ki-67 biomarkers is practical in routine clinical work. Providing that quality assurance of these markers is ensured, this classification is useful for making therapy decisions in the routine clinical management of breast cancer patients. Keywords 4-IHC Á Tumor biological subtypes Á Breast cancer Á Cancer registry Á Overall survival
Annals of Oncology
Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/ predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2− BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC). Methods: In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2− patients (n = 459). Results: Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2− patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors. In unselected and HR+/HER2− patients, CG3 and luminal-Alike subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-Alike subtype; within HR+/HER2− (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor. In multivariate interaction analysis (including central and genomic grade), luminal-Blike subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2− patients. Conclusion: In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are † These authors contributed equally.