Hormone Receptor Expression Status Research Articles

Unveiling the mysteries of HER2-low expression in breast cancer: pathological response, prognosis, and expression level alterations

BackgroundThe novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood.MethodsThe patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression.ResultsIn this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P < 0.014), have more premenopausal patients (P < 0.001), a higher proportion of hormone receptor (HR) positive patients (P < 0.001), and less proportion of stage III V patients (P < 0.034). When NAT was finished, the pCR rate became 23.6% in the HER2-0 group while 22.1% in the HER2-low group, and there was also a higher pCR rate in HR- patients in comparison with that in HR + patients (P < 0.01). Considering HER2 expression inconsistency, the overall HER2 inconsistency rate was 30.4% (Kappa = 0.431, P < 0.01). Among patients initially diagnosed as HER2-0, 34% (N = 61) were re-diagnosed as HER2-low after NAT. After stratification by HR expression status, HR+/HER2-0 patients transformed to HER2-low after NAT in 37%, and 32% of HR- patients changed from HER2-0 to HER2-low. In this survival analysis, there were both better DFS rates (P = 0.009) and OS rates (P = 0.026) in the HR-/HER2-low patients in comparison with the HR-/HER2-0 patients, while the HER2-0 and HER2-low patients in the HR + group had no significant survival difference. Additionally, for non-pCR patients, there was better DFS (P = 0.029) and OS (P = 0.038) in the HER2-low group in comparison with that of the HER2-0 group, while no significant survival difference exists between pCR patients.ConclusionAfter HR stratification, there are unique clinical characteristics and prognostic outcomes in HER2-low expression breast cancer, which indicates the potential to become a specific molecular subtype of breast cancer. The significant instability of HER2-low expression status between primary tumor and residual invasive disease suggests that multiple detections of HER2 status should be emphasized in NAT strategies.

Abstract B082: Early risk stratification of ER+/HER2– breast cancer patients using digital pathology and multi-task, weakly-supervised deep learning

Abstract Breast cancer prognostication guides treatment decisions, with transcriptomic assays like Prosigna and Oncotype DX providing valuable risk of recurrence (ROR) scores in ER+/HER2– patients. However, these tests are costly and require sufficient biopsy tissue for accuracy. Pathology images are routinely available and could expedite rapid risk stratification at lower cost. We propose a multi-modal, multi-task deep neural network that learns transcriptomic ROR using digital pathology images and hormone receptor expression status. Because the incorporation of both pathology images and clinical data has proven beneficial in other deep learning models, we hypothesized that incorporation of this complementary information would improve ROR predictions compared to using pathology images alone. We modified the “clustering-constrained-attention multiple-instance learning” (CLAM) deep learning method to perform multi-task regression and infer continuous risk scores (instead of discrete risk categories). We evaluated (1) PAM50 ROR-P, calculated using a multivariate model based on intrinsic subtype centroids and a proliferation score, and (2) a 21-gene assay recurrence score (RS) (research version of Oncotype DX), calculated from component scores relating to proliferation, ER, HER2, and invasion. Using data from 899 patients in the Carolina Breast Cancer Study, a population-based study of diverse patients including 50% Black women and 50% women under age 50, we constructed training (n=714), validation (n=93), and test (n=92) sets. Genomic data were assayed by Nanostring, and digital pathology was based on H&amp;E-stained whole slide images (WSIs). Models were assessed using Pearson correlation between measured and predicted ROR-P or RS. The model with the highest correlations on the test set used H&amp;E WSIs and ER/PR/HER2 expression status as inputs and generated 10 independent outputs: ROR-P, four PAM50 centroid correlations (i.e., Basal, HER2-enriched, Luminal A, and Luminal B), RS, and four RS component scores. Prediction was strong when considering all participants in the test set (ROR-P, 0.78; RS, 0.83, N, 92) but was reduced among more clinically homogeneous ER+/HER2– patients (ROR-P, 0.55; RS, 0.49; N, 49). For RS, correlations were higher in models that included ER/PR/HER2 (Overall, 0.83; ER+/HER2–, 0.50) than in those that relied on pathology alone (Overall, 0.60, ER+/HER2–, 0.34). Future models will consider strategies to enhance performance in ER+/HER2– patients, such as oversampling of ER+/HER2– patients and use of loss functions designed to focus learning on mis-predicted examples. In summary, multi-task, tissue-based regression deep learning models recapitulate transcription-based risk assays with high correlations and, with optimization (especially integration of additional clinicopathologic data), hold promise for personalized treatment decisions from early, routinely-collected biopsy images. Citation Format: Jakub R Kaczmarzyk, Luke A Torre-Healy, Richard A Moffitt, Rajarsi Gupta, Alina M Hamilton, Tahsin M Kurc, Katherine A Hoadley, Melissa A Troester, Joel H Saltz. Early risk stratification of ER+/HER2– breast cancer patients using digital pathology and multi-task, weakly-supervised deep learning [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B082.

Magnetic resonance differential analysis for different hormone receptor expression status in HER-2-positive breast cancer.

Currently, it is difficult to assess the expression status of hormone receptor (HR) in breast malignant tumors with human epidermal growth factor receptor 2 (HER-2)-positive in the early preoperative stage, and it is difficult to predict whether it is non-invasively. This study aims to explore the value of MRI on the different HR expression status (HR+/HR-) in HER-2 positive breast cancer. Thirty patients with HR+ HER-2-positive breast cancer (HR+ group) and 23 patients with HR-HER-2-positive breast cancer (HR- group) from the First Hospital of Hunan University of Traditional Chinese Medicine between January 7, 2015 and November 26, 2021 were selected as subjects, and all the patients were examined by MRI and all were confirmed by surgery or pathological biopsy puncture. The immunohistochemical staining results were used as the gold standard to analyze the basic clinical conditions, peri-lesion conditions and MRI sign characteristics in the 2 groups. There were all significant differences in terms of mass margins, internal reinforcement features, and apparent diffusion coefficient (ADC) values between the HR+ group and the HR- group (all P<0.05). The logistic multivariate regression model showed that: when the lesion presented as a mass-type breast cancer on MRI, the internal enhancement features of the lesion were an independent predictor for differentiation in the 2 types of breast cancer [odds ratio (OR)=5.95, 95% CI: 1.223 to 28.951, P<0.05], and the mass margin (OR=0.386, 95% CI: 0.137 to 1.082, P>0.05) and ADC value (OR=0.234, 95% CI: 0.001 to 105.293, P>0.05) were not the independent predictors in distinguishing the 2 types of breast cancer. Multiparametric MRI has good diagnostic value for HR expression status in HER-2-positive breast cancer. Combined logistic regression analysis to construct a predictive model may be helpful to the identical diagnosis.

Survival analysis in patients with invasive lobular cancer and invasive ductal cancer according to hormone receptor expression status in the Korean population.

BackgroundWe compared the clinicopathological characteristics and survival outcomes of invasive lobular carcinoma (ILC) cases with those of invasive ductal carcinoma (IDC) cases in various hormone receptor expression subgroups.MethodsWe compared clinicopathological characteristics, overall survival (OS), and breast cancer-specific survival (BCSS) between patients with IDC (n = 95,486) and ILC (n = 3,023). In addition, we analyzed the effects of different hormone receptor expression subgroups on survival.ResultsThe ILC group had more instances of advanced stage and hormonal receptor positivity than did the IDC group (p < 0.001), but the IDC group had higher histological grade and nuclear grade, as well as higher frequency of human epidermal growth factor receptor 2 and Ki67 expression than did the ILC group (p < 0.001). The OS and BCSS were not significantly different between the IDC and ILC groups. The 5-year OS of the IDC group was 88.8%, while that of the ILC group was 90.6% (p = 0.113). The 5-year BCSS of the IDC group was 94.8%, while that of the ILC group was 95.0% (p = 0.552). When analyzing each hormone receptor expression subgroup, there were no significant differences in survival between the IDC and ILC groups. However, the estrogen receptor (ER) negative/progesterone receptor (PR) negative subgroup showed differences in survival between the IDC and ILC groups. Moreover, the hazard ratio of ILC in the ER negative/PR negative subgroup was 1.345 (95% confidence interval: 1.012–1.788; p = 0.041).ConclusionsHormone receptor expression should be considered when determining prognosis and treatment regimen for IDC and ILC. Researchers should further study the ER negative/PR negative population to identify treatment and prognostic models that will facilitate the development of individualized therapy for these patients, which is needed for good outcomes.

Abstract PS18-34: Physician adoption and molecular landscape of next-generation sequencing in breast cancer patients from community-based clinics

Abstract Background: Molecular biomarkers such as the expression status of hormone receptors (HR) and HER2 influence disease diagnosis, prognosis, and treatment decisions in breast cancer patients. Recent advances in genetic sequencing technologies and targeted therapies have revealed additional actionable biomarkers including PIK3CA, ESR1, and BRCA1/2; however, it remains unclear whether physicians in community-based clinics are universally adopting molecular profiling practices. Here, we describe the utility of next generation sequencing (NGS) in the care of breast cancer patients in community-based clinics with a focus on physician behaviors and molecular landscapes. Methods: Sarah Cannon provides clinical research services to medical oncology practices who order NGS panels as part of standard of care. Genospace, Sarah Cannon’s web-based precision medicine platform, links NGS test results with electronic medical records to identify and analyze clinico-genomic data of molecularly-profiled cancer patients. Here, a total of 2,673 NGS reports from 2,313 unique patients dated between January 2014 and December 2019 were analyzed. Hormone statuses were abstracted from physician notes using natural language processing capabilities and manual abstraction. Linear regression modeling was used for statistical analysis. Results: Physician ordering of NGS tests for breast cancer patients increased 6.3-fold from 2014 to 2019. Ordering of plasma-based NGS tests increased from 0.6% (versus 99.4% tissue) in 2014 to 47.0% (versus 53.0% tissue) in 2019. The time from initial diagnosis to NGS results increased from a median of 1008 days in 2015 to 1296 days in 2019 (p &amp;lt; 0.05), while the time from specimen collection to NGS test results (tissue only) decreased from 53 days in 2015 to 28 days in 2019 (p &amp;lt; 0.01). The majority of NGS-tested breast cancer patients were HR+/HER2- (62.6%), followed by HR-/HER2- (21.5%), HR+/HER2+ (8.4%), HR-/HER2+ (4.4%), and HER2 equivocal (3.0%). Plasma-based NGS testing was utilized more commonly in HR+ cancers (43.4% of HR+; 25.3% of HR-). In agreement with published studies, BRCA1 alterations were enriched in HR- cancers (1.7% of HR+; 6.6% of HR-) and BRCA2 alterations were enriched in HR+ cancers (6.4% of HR+; 3.2% of HR-). Amplifications in CCND1 (21.7% of HR+; 2.2% of HR-) and FGFR1 (18.1% of HR+; 6.2% of HR-) were also enriched in HR+ cancers, as were mutations in ESR1 (18.9% of HR+; 1.0% of HR-). PIK3CA mutations occurred most frequently in HR+ cancers (45.0%), but were also present in HR- cancers (20.9%). TP53 mutations were comparatively high in HR- cancers (42.9% of HR+; 94.8% of HR-). Conclusions: The usage of NGS for the care of breast cancer patients is increasing in community settings. Plasma-based NGS tests are ordered more frequently in HR+ cancers, likely as a result of difficult-to-biopsy and poor yield bone-only disease. Despite increased testing frequencies, NGS tests are ordered later-in-care which may be a reflection of earlier diagnosis or the development of more efficacious standard of care therapies in front line settings. The tissue specimens sent for sequencing are collected closer to the test date, indicating improved tissue processing systems and prioritization of fresh specimen collection for NGS testing. Overall, physicians are adopting NGS-testing as part of standard of care for breast cancer patients in the community setting and are discovering actionable mutations. Frequency of detection of molecular biomarkers in NGS-tested breast cancer patientsTissueTissueTissueTissuePlasmaPlasmaPlasmaPlasmaGeneAlterationHR+/HER2-HR-/HER2-HR+/HER2+HR-/HER2+HR+/HER2-HR-/HER2-HR+/HER2+HR-/HER2+ERBB2Amp1.1%0.5%45.4%67.9%0.0%0.8%10.4%45.5%CCND1Amp21.3%1.7%21.8%5.1%7.5%1.7%5.2%0.0%MYCAmp9.3%15.5%18.5%17.9%1.3%5.8%1.3%9.1%FGFR1Amp17.4%6.8%18.5%3.8%6.5%3.3%2.6%0.0%PIK3CAMutation43.8%19.1%49.6%32.1%49.5%25.0%50.6%30.3%ESR1Mutation19.4%1.2%13.4%0.0%41.7%4.2%31.2%0.0%BRCA1Mutation1.9%7.2%0.8%3.8%5.1%5.0%2.6%9.1%BRCA2Mutation6.7%3.6%5.9%1.3%8.8%5.8%14.3%3.0%ERBB2Mutation3.4%1.4%11.8%6.4%9.5%1.7%15.6%12.1%TP53Mutation42.2%94.7%51.3%93.6%65.8%96.7%68.8%93.9%PTENMutation8.8%10.6%2.5%3.8%12.6%10.8%7.8%6.1%PALB2Mutation1.6%1.2%0.8%0.0%0.2%0.0%0.0%0.0%MTORMutation0.7%0.2%0.8%0.0%2.7%0.0%0.0%0.0%ARID1AMutation9.0%4.8%12.6%2.6%11.0%11.7%7.8%3.0%KRASMutation3.2%3.1%0.8%2.6%6.5%8.3%5.2%6.1%AKT1Mutation6.5%3.4%2.5%1.3%7.5%6.7%1.3%0.0%n=856n=414n=119n=78n=602n=120n=77n=33 Citation Format: Emma Sturgill, Amanda Misch, Rebecca Lachs, Carissa Jones, Dan Schlauch, Suzanne Jones, Mythili Shastry, Denise Yardley, Howard Burris, David Spigel, Erika Hamilton, Andrew McKenzie. Physician adoption and molecular landscape of next-generation sequencing in breast cancer patients from community-based clinics [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-34.

Constraining Multi‐Drug Resistance in Breast Cancer Cells by Energy Restriction

The resistance of breast cancer to chemotherapy constitutes a major roadblock for a successful treatment. The development of multidrug resistance (MDR) is one of the common mechanisms for resistance to various chemotherapeutic agents including doxorubicin (DOX). In this context, we tested the hypothesis that energy restriction mimetic agents (ERMAs) such as OSU‐GC5 could synergize the antitumor effects of DOX through restraining the availability of energy that is essential for the activity of MDR efflux carriers. Subclones of MCF‐7 and MDA‐MB231 breast cancer cell lines resistant to DOX have been established by subjecting the cells to increasing concentrations of DOX over 6 months. The MDR phenotype was verified via the upregulated expression of ATP binding cassette (ABC) protein ABCC1, ABCB1 and ABCG2 together with a reduced cellular accumulation of DOX. Fluorescence‐activated cell sorting analysis indicated that the percentage of CD44+/CD24− stem cell‐like population was enriched in the resistant subclones. Combination analysis demonstrated a synergistic antitumor interaction between OSU‐CG5 and DOX accompanied by augmented activation of mitochondrial apoptosis and AMPK signaling as verified by Western blot analysis. Co‐treatment with OSU‐CG5 and DOX significantly reduced cellular ATP content and NADP+/NADPH ratio, while it significantly enhanced ROS production. Concomitant exposure to ROS scavenger, N‐acetylcysteine, eliminated the synergy between OSU‐CG5 and DOX. This study recommended OSU‐CG5 as a promising adjuvant to overcome MDR resistance. This combinatorial strategy can be extrapolated to breast cancer treatment regardless of the hormone receptor expression status, which encourages future research in syngeneic murine tumor xenograft models.Support or Funding InformationThis work was supported by a research grant from Al Jalila Foundation, United Arab Emirates (Grant number AJF201610)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impact of Obesity on Clinicopathologic Characteristics and Disease Prognosis in Pre- and Postmenopausal Breast Cancer Patients: A Retrospective Institutional Study.

Purpose To investigate the association between obesity and breast cancer clinicopathologic characteristics at presentation along with prognostic impact among Jordanian breast cancer patients. Such data are lacking in Arabian countries. Methods In this retrospective study, 348 breast cancer patients were included. Analyses were conducted for associations between body mass index (BMI) and age at diagnosis, tumor clinicopathologic characteristics, and molecular subtypes. Eight prognostic factors were considered, and total prognostic scores were calculated. The analysis was stratified by menopausal status. Multivariate logistic stepwise regression analysis was conducted to identify predictors for breast cancer recurrence and death. Results Mean age at diagnosis was 50.98 ± 10.96 years. Mean BMI at diagnosis was 29.52 ± 5.32 kg/m2. Mean age at diagnosis was significantly higher for overweight and obese patients compared to underweight/normal patients (P < 0.001). A significant positive correlation was observed between patient age and BMI at diagnosis (r = 0.251, P < 0.001). Grade of carcinoma was significantly correlated with BMI in the whole population examined (P=0.003). Obese breast cancer patients had significantly higher prognostic scores compared to nonobese cases, indicating worse prognostic features at presentation (P=0.034). Stratification of data analysis based on menopausal status revealed significant associations between obesity and each of tumor stage and grade among postmenopausal but not premenopausal patients (P=0.019 and P=0.031, respectively). Similarly, postmenopausal obese patients had significantly higher prognostic scores compared to nonobese counterparts (P=0.007), indicating worse prognosis, a finding which was also absent among premenopausal breast cancer patients. No significant association between BMI with expression status of hormone receptors, HER2, lymphovascular invasion, and molecular subtypes was found among patients. BMI was a significant predictor for disease recurrence in which obese breast cancer patients had greater odds (2-fold) to develop locoregional and distant recurrence compared to nonobese cases (P=0.011). Conclusions Obesity was associated with advanced stage and grade of breast carcinoma at diagnosis. The impact of BMI on clinicopathologic characteristics and prognosis was confined to postmenopausal cases. Jordanian obese breast cancer patients are at greater risk of breast cancer recurrence and reduced survival compared to their nonobese counterparts.

Analysis of Hormone Receptor Status in Primary and Recurrent Breast Cancer Via Data Mining Pathology Reports.

BackgroundHormone receptors of breast cancer, such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her-2), are important prognostic factors for breast cancer.ObjectiveThe current study aimed to develop a method to retrieve the statistics of hormone receptor expression status, documented in pathology reports, given their importance in research for primary and recurrent breast cancer, and quality management of pathology laboratories.MethodA two-stage text mining approach via regular expression-based word/phrase matching, was developed to retrieve the data.ResultsThe method achieved a sensitivity of 98.8%, 98.7% and 98.4% for extraction of ER, PR, and Her-2 results. The hormone expression status from 3679 primary and 44 recurrent breast cancer cases was successfully retrieved with the method. Statistical analysis of these data showed that the recurrent disease had a significantly lower positivity rate for ER (54.5% vs 76.5%, p=0.001278) than primary breast cancer and a higher positivity rate for Her-2 (48.8% vs 16.2%, p=9.79e-8). These results corroborated the previous literature.ConclusionText mining on pathology reports using the developed method may benefit research of primary and recurrent breast cancer.

Differential Association of the Lifestyle-Related Risk Factors Smoking and Obesity with Triple Negative Breast Cancer in a Brazilian Population

Background:A longer lifespan and changing lifestyle-related and reproductive risk factors have led to an increased incidence of breast cancer in Brazil. There have been few studies about associations of specific risk factors with molecular subtypes of the disease. The aim of the present study was to identify factors that modulate the risk of triple negative breast cancer.Materials and Methods:A case-case analysis was performed. Data for 236 breast cancer patients from two reference centres in North-eastern Brazil were applied to assess the association of risk factors with triple negative breast cancer relative to the luminal A subtype. Molecular subtypes were defined by expression status of hormone receptors and amplification of HER2. Nominal logistic regression was used to estimate odds ratios and to generate a model of independent variables.Results:Smoking and body mass index were differentially associated with likelihood of triple negative breast cancer compared to the Luminal A subtype (p= 0.013; p= 0.004): Women who ever smoked some time in their lives were 4.016 (OR= 0.249; CI 95%: 0.09- 0.71) times less likely to have triple negative breast cancer. Obese and overweight patients, respectively, were 4.489 (CI 95%: 1.32- 15.28) and 1.340 (CI 95%: 0.38- 4.69) times more likely to have triple negative breast cancer.Conclusions:Case-case analysis with the Luminal A subtype as the reference group indicated that smoking and body mass index are differentially associated with risk of triple negative breast cancer.

Association between GSTP1 genotypes and hormone receptor phenotype in invasive ductal carcinomas of breast.

Eighty six cases of invasive ductal breast carcinomas were utilized to investigate GSTP1 polymorphisms in certain immunohistochemistry (IHC) subtypes of breast cancer with respect to ER, PR and HER2 expression. The frequency of wild allele homozygote, heterozygote and variant allele homozygote genotypes were 46.5%, 52.3% and 1.16% respectively; Whereas 54.3% of the control subjects were GSTP1 wild type allele homozygous, 40.0% were heterozygous and 5.71% mutant allele homozygous. There was dramatic inverted relation between positive IHC ER staining and increasing grade of tumors in general (100%, 88.6%, 40.4%) and especially among tumors with heterozygote genotype of GSTP1 (70%, 35.4%, 22.7). There was increase in positive IHC HER2 staining consistent with higher grades in general (20%, 29.6%, 50.0%), especially among tumors with GSTP1 wild allele homozygote genotype (5.0%, 9.1%, 31.8%). A remarkable reverse relation was also observed between the fraction of IHC hormone receptor phenotype ER+/PR+/ HER2- and increased grade of tumors (60.0%, 45.5%, and 27.3%) especially among tumors with GSTP1 heterozygote genotype, and a similar link was noted regarding ER+/PR-/ HER2- and tumor grade. There was increase in frequency of ER-/PR-/ HER2- (0.0%, 6.8%, and 18.2%) and ER-/PR-/ HER2+ (0.0%, 4.54%, and 40.9%) consistent with the higher grades of tumors in general and especially GSTP1 heterozygote genotype tumors. As a conclusion, there is no correlation between GSTP1 polymorphism and increased risk of breast cancer i.e. the mutant allele is randomly distributed in cancer and control cases. However, there is a link between GSTP1 genotypes and hormone receptor expression status and certain phenotypes of breast cancer, which may have clinical importance.

Receptor Expression Discrepancy between Primary and Metastatic Breast Cancer Lesions

SummaryBackground: Recent studies have shown that the expression status of hormone receptors and human epidermal growth factor receptor 2 (HER2) in breast cancer may change during disease progression. The aim of this study was to determine and compare the estrogen receptor (ER), progesterone receptor (PR), and HER2 expression status in primary breast cancer and metastatic lesions. Methods: 58 patients with registered biopsy reports or available samples of the primary tumor and distant metastases were included in the final analysis. Biopsy samples were re-stained using immunohistochemical methods to determine receptor status (if not already recorded in previous reports) and re-examined by 2 independent pathologists. Results: Discordance rates for receptor expression status of the primary tumor and distant metastases for ER, PR, and HER2 were 17.4, 45.4, and 13.3%, respectively. No statistically significant difference in overall survival due to receptor expression discordance between the primary tumor and metastatic sites (p > 0.05) was found, although a tendency toward worse survival time was observed in patients with HER2 expression discrepancies. Conclusion: This study showed receptor discordance rates between primary and metastatic breast cancer sites for ER, PR, and HER2 of 17.8, 45.4, and 13.3%, respectively. Re-biopsy and IHC evaluation of metastatic sites for receptor status may change treatment decisions in patients with relapsed/progressed BC.

Higher Ki67 Expression is Associates With Unfavorable Prognostic Factors and Shorter Survival in Breast Cancer

The prognostic value of the Ki67 expression level is yet unclear in breast cancer. The aim of this study was to investigate the association between Ki67 expression levels and prognostic factors such as grade, Her2 and hormone receptor expression status in breast cancers. Clinical and pathological features of the patients with breast cancer were retreived from the hospital records. In this study, 163 patients with breast cancer were analyzed, with a mean age of 53.4±12.2 years. Median Ki67 positivity was 20% and Ki67-high tumors were significantly associated with high grade (p<0.001), lymphovascular invasion (p=0.001), estrogen receptor (ER) negativity (p=0.035), Her2 positivity (p=0.001), advanced stage (p<0.001) and lymph node positivity (p<0.003) . Lower Ki67 levels were significantly associated with longer median relapse-free and overall survival compared to those of higher Ki67 levels. High Ki67 expression is associated with ER negativity, Her2 positivity, higher grade and axillary lymph node involvement in breast cancers. The level of Ki67 expression is a prognostic factor predicting relapse-free and overall survival in breast cancer patients.

Abstract 3466: Reduced expression of CYLD is an independent prognostic factor in breast cancer and confers treatment resistance and migratory activity in vitro.

Abstract Background: CYLD was originally identified as a tumor suppressor that is mutated in familial cylindromatosis. CYLD has deubiquitinase activity and can negatively regulate NF-κB pathways. Recent study has revealed that CYLD plays important roles in tumor progression as well as immune response and osteoclastogenesis. CYLD loss of function has been associated with several tumors. Despite the broad relevance of CYLD to various tumors, its clinical and biological significances in breast cancer are still largely unknown. Materials and Methods: We assessed CYLD expression in 171 primary breast cancer tissues by immunohistochemistry and examined the correlations with CYLD expression and clinicopathological factors as well as patients’ prognosis. In addition, we investigated effects of CYLD knockdown by using siRNA on malignant state in breast cancer cell lines. Results: Our immunohistochemical analysis revealed a significant correlation between loss of CYLD expression and poor patients’ disease free survival (log-rank, p = 0.004), particularly in luminal and triple negative breast cancer patients. Multivariate analysis revealed that loss of CYLD expression was an independent poor prognosis factor (Hazard ratio 2.95, 95% CI 1.20 - 7.98, p = 0.02) in addition to hormone receptor expression status. Loss of CYLD expression correlated with high nuclear grade but not hormone and HER2 status. Consistent with our clinical data, repression of CYLD increased CD44 high/ CD24 low cancer stem-like cell population with acquisition of resistance to apoptosis induced by conventional therapy in MDA-MB-231 cells. Moreover, CYLD knockdown promoted migration through downregulation of Maspin which is a potent suppressor of breast cancer metastasis. Conclusions: CYLD expression was an independent prognostic factor in primary breast cancer. Reduced CYLD function may promote breast cancer progression and treatment resistance. Citation Format: Mitsuhiro Hayashi, Satoru Shinriki, Hirofumi Jono, Takuya Nakamura, Jianying Guo, Yutaka Yamamoto, Hirotaka Iwase, Yukio Ando. Reduced expression of CYLD is an independent prognostic factor in breast cancer and confers treatment resistance and migratory activity in vitro. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3466. doi:10.1158/1538-7445.AM2013-3466

JS4-1 - Histological Significance of Intrinsic Subtype Classification

ABSTRACT For a long time, biological properties of breast cancer have been classified histologically in view of histological type and grades. Although these histological classifications were effective for the description of pathology report and for the prediction of patients' prognosis, they were not very specific for the prediction of response of the cancer cells to systemic drug therapies. In 2000, Perou et al. proposed the molecular classification of breast cancer based on molecular profiles identified by using DNA microarray technique. They classified invasive ductal/lobular carcinomas and ductal carcinoma in situ into five subtypes: luminal A, luminal B, HER2 (c-erbB-2)-enriched, basal-like, and normal breast-like. These subtypes were not only correlated with patient prognosis but also useful for choosing effective drug therapies to patients. Because the assay system of molecular classification was expensive and was not established for diagnostic use, a surrogate ‘intrinsic subtype’ classification has come to be used widely. In the ‘intrinsic subtype’ classification, invasive breast cancers were categorized into four groups according not only to the expression status of hormone receptors (HR) and HER2 but also to Ki67 labeling index. If Ki67 labeling index is unreliable, substitution by histological/nuclear grade is allowed. Therefore, today's pragmatic ‘intrinsic subtype’ classification is based on the markers for indication of hormonal therapy and anti-HER2 therapy and a marker for tumor cell proliferation. Luminal A is defined as HR(+)/HER2(-)/Ki67-low, luminal B as either HR(+)/HER2(-)/Ki67-high or HR(+)/HER2(+), HER2-enriched as HR(-)/HER2(+), and triple-negative breast cancer (TNBC) as HR(-)/HER2(-). Problems remain in the classification in the cut-off value of the HR status; the method and cut-off value on Ki67 measurement; retesting with in situ hybridization of immunohistochemically HER2-equivocal cases; and subclassification of TNBC according to biological properties and sensitivity to therapies. Detailed histopathological and/or immunohistochemical examinations based on further research data might aid for much more useful classification toward individualized therapies.

Dose-dense chemotherapy versus conventional chemotherapy for early breast cancer: A systematic review with meta-analysis

BackgroundDespite the widespread acceptance of dose-dense (DD) regimens as adjuvant chemotherapy for early breast cancer (EBC), studies of efficacy offer contradictory findings. This systematic review evaluates the real impact of DD chemotherapy. MethodsRandomized controlled trials comparing conventional adjuvant chemotherapy versus a DD regimen for EBC patients were searched in electronic databases. Dose-dense regimens included the same drugs and total amount as conventional chemotherapy, but applied in shorter intervals. Meta-analyses were performed using a fixed-effects model. Hazard ratios (HRs) or odds ratios (ORs) were expressed with 95% confidence intervals (95% CI). The outcomes were overall survival (OS), disease-free survival (DFS), and toxicities. Analyses were conducted according to tumor hormone receptor expression, plus tests for interaction. ResultsFour studies (3418 patients) were included. The meta-analysis demonstrated that DD therapy can improve DFS (3356 patients; HR = 0.83; 95% CI 0.73–0.95; p = 0.005), independent of hormone receptor expression status. There was no OS benefit with DD therapy (3356 patients; HR = 0.86; 95% CI 0.73–1.01; p = 0.06) irrespective of tumor hormone receptor status (OS in hormone-positive stratum HR = 0.94; 95% CI 0.74–1.21; OS in hormone-negative stratum HR = 0.78; 95% CI 0.62–0.99; interaction test p = 0.28). DD regimens caused a small increase in anemia and mucositis, but had no impact on cardiac events, leukemia or myelodysplasia. ConclusionsDD adjuvant chemotherapy can improve DFS of EBC patients with little impact on safety. However there is no clear benefit in OS. Further research may indicate if there is any impact on OS not presently seen due to small sample size, and which patients may derive greater benefit.

Abstract 2124: Comprehensive analysis of hormone receptor status during prostate cancer progression: A novel prognostic role for pAR and ERbeta

Abstract Aims: Patients with advanced prostate cancer (PrCa) are usually treated with androgen withdrawal. Although this therapy is effective at the beginning, nearly all prostate cancers become refractory to it. Hormone receptors play a crucial role during this progression. Aim of this study was to analyze the genomic and expression status of hormone receptors in prostate cancer and the evolution of these markers in the development of castration-resistance. Methods: We selected 915 transurethral resection (TURP) specimens from 107 untreated PrCa and from 101 castration-resistant (CR) PrCa. These samples were used for the construction of a tissue microarray (TMA). In addition, we included 56 distant metastases. We analyzed the androgen receptor (AR) gene copy number by fluorescence in-situ hybridization and the expression profiles of AR, phosphorylated AR (pAR), ERβ, ERα and the proliferation marker Ki67 by immunohistochemistry. Results: AR gene amplification was almost restricted to PrCa and was significantly associated with increased AR protein expression (p&amp;lt;0.0001) and higher tumor cell proliferation (p=0.001). Interestingly, although pAR was predominantly found in the CR PrCa (p=0.003), pAR expression in untreated PrCa patients identified a subgroup of patients with poor survival (p&amp;lt;0.05). In contrast to ERα expression, which was restricted to CR PrCA cells (10%), ERβ was found in 40% of the PrCa, independent of treatment status. Similar to pAR, the presence of ERβ in untreated patients was significantly associated with adverse prognosis (p&amp;lt;0.005). Conclusions: This is the first comprehensive study comparing the hormonal receptor status in a large cohort of hormone-naïve and CR PrCa. Our results strongly suggest a major role for pAR and ERβ in untreated PrCa. Expression of these markers might be a mechanism of CR tumor growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2124. doi:10.1158/1538-7445.AM2011-2124

How to Treat Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Amplified Breast Cancer

How to Treat Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Amplified Breast Cancer

An expression study of hormone receptors in spontaneously developed, carcinogen-induced and hormone-induced mammary tumors in female Noble rats

The Noble (Nb) rat model has been used in the study of hormonal carcinogenesis of mammary and prostate glands, as this rat strain is susceptible to tumor induction in these glands by hormonal treatments. Recently, we demonstrated that this rat strain can develop spontaneously mammary tumors at high incidence in aged animals and also show high sensitivity to chemical carcinogens (DMBA and MNU) and combined treatments with sex hormones in mammary tumor induction. In the present study, we examined and compared the expression of hormone receptors [including estrogen receptors (ERalpha and ERbeta), androgen receptor (AR), progesterone receptor (PR), prolactin receptor (PRLR)] and prolactin (PRL) by immunohistochemistry, Western blotting and RT-PCR in spontaneous mammary tumors, and mammary tumors induced by sex hormones (T+E2 and T+DES for 8-10 months) and DMBA in Nb rat model. Immunohistochemistry and Western blotting showed that both the spontaneously developed and hormone-induced carcinomas exhibited strong immunoreactivity of ERalpha, ERbeta, AR, PR and PRLR, while the spontaneous fibroadenomas showed weak to moderate immunoreactivity of ERalpha and PRLR, whereas the DMBA-induced carcinomas exhibited weak to moderate immunoreactivity of ERalpha, AR, PR and PRLR, and sporadic weak ERbeta immunoreactivity. RT-PCR analyses showed that mRNA expression pattern of these markers resembled that of proteins. In addition, weak mRNA expression of PRL was detected in spontaneous carcinomas and carcinomas induced by DMBA and hormones, suggesting that PRL could be produced locally within the tumors. The results showed that the expression status of hormone receptors and PRL was different in spontaneous mammary tumors and tumors induced by carcinogen or hormones, suggesting that the extent of involvement of steroid hormones and their receptors in the spontaneous, carcinogen- or hormone-induced mammary carcinogenesis might be different.