Human Epidermal Growth Factor Receptor-2 Positivity Research Articles

Clinical utility of molecular imaging in newly diagnosed metastatic breast cancer.

1019 Background: Optimizing patient outcome prediction in metastatic breast cancer (MBC) can potentially reduce patients’ and healthcare burden. Molecular imaging to visualize early metabolic change, baseline whole-body human epidermal growth factor receptor-2 (HER2) and estrogen receptor (ER) expression might achieve this. In the prospective multicenter IMPACT study, we evaluated the clinical utility of molecular imaging to improve standard diagnostics in patients with newly diagnosed MBC of all subtypes. Methods: Patients underwent extensive workup, including baseline metastasis biopsy, [18F]FDG-PET, [89Zr]trastuzumab-PET (HER2-PET), [18F]FES-PET, and early [18F]FDG-PET after 2 weeks. Treatment was based on HER2 or ER subtype determined in biopsy (immunohistochemistry, IHC; standard-of-care) or PET findings (HER2- and [18F]FES-PET; investigational) in case of negative biopsy but positive HER2 and/or [18F]FES-PET scan. Clinical utility of molecular imaging was defined as the capacity to identify poor patient outcome, measured as progressive disease (PD) on CT at 8 weeks, progression-free survival (PFS), and overall survival (OS). Results: Two hundred patients were included. Progression on early [18F]FDG-PET was related to poor outcome in all subtypes (median PFS 4.1 versus 19.4 months, OS 19.4 versus 45.0 months). Early [18F]FDG-PET correctly predicted non-PD on 8 week CT (specificity 90.5%, negative predictive value 94.1%), but sensitivity and positive predictive value for PD was low (50 and 37.5%, respectively). However, early [18F]FDG-PET related better to long-term outcome than CT: patients with non-PD on 8 week CT, but with progression on early [18F]FDG-PET, had a median PFS and OS of 9.5 and 22.3 months respectively, compared to 19.4 and 50.1 months without [18F]FDG-PET progression (PFS HR 1.76 (95%CI 1.0 – 2.9), OS HR 1.93 (1.0 – 3.5)). HER2 or ER subtype was discrepant between biopsy and PET in 52 out of 200 (26%) patients, yielding investigational PET-based treatment options in 41 (21%) patients. In patients with HER2-positive biopsy IHC disease who received standard HER2-targeting treatment, median PFS with positive- versus negative HER2-PET was 23.2 and 4.5 months, respectively. In patients with biopsy IHC HER2-negative disease but positive HER2-PET, median PFS was with investigational HER2-targeted treatment 11.4 months, without 7.4 months. The pattern was similar in ER-positive disease, although less pronounced for biopsy- and PET-based subtypes. Conclusions: This study supports the clinical utility of molecular imaging with [18F]FDG-PET, HER2-PET, and [18F]FES-PET, to improve standard diagnostics for outcome and subtype assessment in patients with newly diagnosed MBC. Clinical trial information: NCT01957332 .

Abstract PO4-02-14: Parity and age first full term pregnancy affects the odds of different breast cancer subtypes defined by estrogen receptor and human epidermal growth factor receptor-2

Abstract Background: A rising trend in the incidence of estrogen receptor (ER)-positive subtype over time is observed in several high-income countries, while the incidence of ER-negative subtype is decreasing in some areas. It has been found that decreased parity and late age at 1st full-term pregnancy (FTP1) can increase the risk of breast cancer (BC). This study aims at investigating the association between two reproductive factors, parity and FTP1, and the odds of BC subtypes in premenopausal and postmenopausal patients. Patients and method: This study included patients diagnosed with early-stage BC after the age of 34, who were treated in UZ Leuven between January 2000 and November 2020. The patients were classified into four subtypes defined by ER and human epidermal growth factor receptor-2 (HER2). ER positivity was defined as >1% of cells staining positive while HER2 positivity was based on fluorescence in situ hybridization (FISH) testing of samples with immunohistochemistry score of 2+ or 3+. Baseline-category logit models with subtype as the response (ER+/HER2- as the baseline) and adjusted for age at diagnosis and BMI, were performed for premenopausal and postmenopausal patients separately. First, we exclude nulliparous patients. Parity (1-2 or ≥3) and FTP1 (continuous) were included in the models as the covariates of interest in the first model. To evaluate the effects of reproductive patterns compared to nulliparity, a new variable reproductive pattern was created by taking intersection of parity groups and FTP1 groups (< 27, ≥27). Reproductive pattern was set as the covariate of interest in the second model. Result: After imputing the missing values, we included 9606 patients in the study. 8125 of them were parous. In parous patients, high FTP1 was associated with low odds of ER-/HER2- BC relative to ER+/HER2- BC for both premenopausal and postmenopausal patients (table 1). In postmenopausal patients, low parity was associated with low odds of ER-/HER2- BC and high odds of ER+/HER2+ BC relative to ER+/HER2- BC. There was no evidence that parity affects the odds of subtypes in premenopausal patients. When investigating the effect of different reproductive patterns compared to nulliparity on the odds of subtypes, there was no evidence that reproductive patterns will affect the odds of subtypes in premenopausal patients. Postmenopausal patients who had FTP1 before 27 years old and had at least three children tended to have higher odds of ER-/HER2- BC relative to ER+/HER2- BC compared to nulliparous patients. Conclusion: In parous patients, increased FTP1 was associated with reduced odds of ER-/HER2- relative to ER+/HER2- BC. In postmenopausal patients, patients with at least three children tended to have low odds of ER-/HER2- BC and high odds of ER+/HER2+ BC relative to ER+/HER2- BC. When compared to nulliparity, the combination of having at least three children and having the first child before 27 years old increased the odds of ER-/HER2- BC relative to ER+/HER2- BC in postmenopausal patients. Table 1 Effect of FTP1, parity on subtype odds Menopause Subtype Effect Odds ratio (95%CI) p-value pre ER-/HER2- FTP1 (continuous) 0.960 (0.935, 0.985) 0.0021 post 0.969 (0.948, 0.990) 0.0047 pre ER-/HER2+ 0.992 (0.952, 1.034) 0.7166 post 1.005 (0.977, 1.034) 0.7081 pre ER+/HER2+ 0.976 (0.949, 1.004) 0.0962 post 1.015 (0.992, 1.039) 0.1969 pre ER-/HER2- Parity 1-2 vs ≥3 1.194 (0.899, 1.585) 0.2200 post 0.784 (0.648, 0.949) 0.0124 pre ER-/HER2+ 1.152 (0.723, 1.834) 0.5521 post 0.896 (0.684, 1.173) 0.4228 pre ER+/HER2+ 1.080 (0.795, 1.469) 0.6220 post 1.300 (1.022, 1.654) 0.0329 The baseline category is ER+/HER2- subtype Effect of age at first full-term pregnancy and parity on subtype odds Citation Format: Zhao Liu, Jiumeng Zhang, Karen Van Baelen, Maja Vangoitsenhoven, Hans Wildiers, Adelheid Soubry, Patrick Neven. Parity and age first full term pregnancy affects the odds of different breast cancer subtypes defined by estrogen receptor and human epidermal growth factor receptor-2 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-14.

Molecular Targeting of the Human Epidermal Growth Factor Receptor-2 (HER2) Genes across Various Cancers.

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well-characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancer types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer; however, there have been strong advancements made in the incorporation of anti-HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core, incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since its groundbreaking discovery there have been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, and advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of.

Efficacy of post‑mastectomy radiotherapy in patients with T1‑2N1 breast cancer aged ≤35years or with a positive HER‑2 status.

Post-mastectomy radiotherapy (PMRT) is highly recommended for patients with breast cancer with one to three positive nodes; however, there remains some controversy regarding its use. The present retrospective study aimed to explore which patients may be able to avoid PMRT and its associated side effects. A total of 728 patients with T1-2N1 breast cancer who were treated with or without PMRT were included in the present study. The results suggested that PMRT significantly decreased the locoregional recurrence rate (LRR) [hazard ratio (HR)=5.602, 95% confidence interval (CI)=3.139-9.998, P<0.01; 3-year LRR: 4 vs. 17%] and improved overall survival (OS) (HR=0.651, 95% CI=0.437-0.971, P=0.03; 3-year OS: 91 vs. 87%) for patients with T1-2N1 breast cancer. By contrast, PMRT had no significant effect on the distant metastasis (DM) rate (HR=0.691, 95% CI=0.468-1.019, P=0.06; 3-year DM: 10 vs. 15%). Further stratified analysis revealed that PMRT did not reduce the LRR and DM, or improve OS in patients aged ≤35 years or in those with a positive human epidermal growth factor receptor-2 (HER-2) status. The analysis of 438 patients treated with PMRT revealed that patients aged ≤35 years or those with a positive HER-2 status were more likely to experience local recurrence even following PMRT. Thus, the benefits of using PMRT in patients with T1-2N1 breast cancer who are aged ≤35 years or in those with a positive HER-2 status need to be carefully considered. Further studies are required to confirm whether this patient group may be exempted from PMRT.

The Role of Serum CD26 in the Diagnosis of Gastric Cancer.

PurposeThe value of serum cluster of differentiation 26 (CD26) in gastric cancer remains unknown. We investigated serum CD26 as a non-invasive serological marker for the diagnosis of gastric cancer and its relationship with serum human epidermal growth factor receptor-2 (HER2) levels.Patients and MethodsWe enrolled 393 gastric cancer patients treated with endoscopic resection or surgery, and 90 healthy controls. HER2 positivity in tissue was evaluated by immunohistochemistry staining, and the serum CD26 and HER2 levels were measured using an enzyme-linked immunosorbent assay.ResultsSerum CD26 levels were significantly lower in gastric cancer patients than in healthy controls (582.2 ± 254.3 vs 862.7 ± 410.6 ng/mL, P<0.001). Serum CD26 levels were significantly lower in advanced gastric cancer compared to early gastric cancer (642.2 ± 333.9 vs 503.4 ± 332.7 ng/mL, P<0.001), and tended to decrease with gastric cancer progression. To diagnose gastric cancer, the optimal cut-off value of serum CD26 was 762.7 ng/mL with 75.6% sensitivity and 64.4% specificity. Serum CD26 levels were weakly correlated with serum HER2 levels (rs=0.363, P<0.001). However, no difference in serum CD26 levels was observed between tissue HER2-negative and HER2-positive gastric cancer groups (586.2 ± 362.1 vs 579.6 ± 264.8 ng/mL, P=0.898).ConclusionCD26 is a useful non-invasive serological marker for gastric cancer diagnosis; however, its levels do not correlate with HER2 status.

Risk Factors and Timing of Additional Surgery after Noncurative ESD for Early Gastric Cancer.

Background Patients with early gastric cancer undergoing noncurative endoscopic submucosal dissection (ESD) have a risk of tumor recurrence and metastasis, and some patients need additional surgery. The purpose of this study was to explore the risk factors of cancer residue and lymph node (LN) metastasis after noncurative ESD for early gastric cancer and to compare the short outcome of early and delayed additional surgery. Methods The clinicopathological characteristics of 30 early gastric cancer patients who received noncurative ESD and additional surgery were studied retrospectively. Multivariable regression was utilized to examine the independent risk factors for residual cancer and LN metastasis. Receiver operating characteristic curve was used to analyze the multivariable model's predictive performance. Furthermore, the perioperative safety and radical tumor performance of early surgery (≤30 days, n = 11), delayed surgery (>30 days, n = 11) after ESD, and upfront surgery (n = 59) were compared. Results Multivariable regression showed that diffuse type of Lauren classification, submucosal invasion, and positive human epidermal growth factor receptor-2 (HER-2) were risk factors for residual cancer. Undifferentiated carcinoma, vascular invasion, and positive vertical margin were risk factors for LN metastasis. The area under the curve (AUC) of the multifactor model predicting cancer residue and LN metastasis was 0.761 and 0.792, respectively. The early surgery group experienced higher intraoperative blood loss and a longer operation time than the delayed surgery and upfront surgery groups. There was no significant difference in the number of LN dissections, LN metastasis rate, and postoperative complications among the three groups. Conclusion Diffuse type of Lauren classification, submucosal invasion, and positive HER-2 are risk factors for residual cancer, while undifferentiated carcinoma, vascular invasion, and positive vertical margin are risk factors for LN metastasis. Delayed additional surgery after ESD (>30 days) has higher intraoperative safety, without affecting the radical resection in early gastric cancer patients.

Identification of New Prognostic Markers and Therapeutic Targets for Non-Muscle Invasive Bladder Cancer: HER2 as a Potential Target Antigen

Bacillus Calmette–Guérin (BCG) is the gold standard adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). However, given the current global shortage of BCG, new treatments are needed. We evaluated tumor microenvironment markers as potential BCG alternatives for NMIBC treatment. Programmed death-ligand 1, human epidermal growth factor receptor-2 (HER2), programmed cell death-1 (PD1), CD8, and Ki67 levels were measured in treatment-naïve NMIBC and MIBC patients (pTa, pT1, and pT2 stages). Univariate and multivariate Cox proportional hazard models were used to determine the impact of these markers and other clinicopathological factors on survival, recurrence, and progression. EP263, IM142, PD1, and Ki67 levels were the highest in the T2 stage, followed by the T1 and Ta stages. HER2 and IM263 expressions were higher in the T1 and T2 stages than in the Ta stage. In NMIBC, the significant prognostic factors for recurrence-free survival were adjuvant therapy, tumor grade, and HER2 positivity, whereas those for progression-free survival included age, T-stage, and IM263. Age, T-stage, EP263, PD1, CD8, and Ki67 levels were significant factors associated with overall survival. IM263 and HER2 are potential biomarkers for progression and recurrence, respectively. Therefore, we propose HER2 as a potential target antigen for intravesical therapeutics as a BCG alternative.

Clinicopathologic significance of human epidermal growth factor receptor 2 expression and gene amplification in gastric carcinoma.

This study is aimed at determining the human epidermal growth factor receptor-2 (HER-2) gene status in gastric cancers using immunohistochemistry (IHC) and silver DNA in situ hybridization (SISH) technique and investigating the relationship between HER-2 status and clinicopathological variables. We examined 104 gastric carcinoma cases with gastrectomy specimens. The age, sex, histopathological tumor type, tumor differentiation, tumor localization, tumor size, invasion depth, lymph node metastasis status, HER-2 IHC evaluation results, and SISH evaluation results of the cases were recorded. In the present study, the SISH-confirmed HER-2 positivity rate (SISH amplification) is 14.4%. A statistically significant relationship was found between HER-2 status and tumor invasion depth (P = 0.03). It was observed that as the depth of invasion increased, HER-2 positivity decreased. No statistically significant relationship was found between HER-2 status and sex, age, tumor size, differentiation, histopathological classification, lymph node metastasis, and tumor localization (P > 0.05). The rate of HER-2 2+ cases was found to be high. HER-2 status is negatively correlated with the depth of invasion in gastric cancers, and HER-2 positivity increases as the depth of invasion decreases. HER-2 may be early molecular evidence in oncogenesis. Immunohistochemically, HER-2 2+ cases should be confirmed by the in situ hybridization (ISH) technique.

Retrospective analysis of HER2-low in young breast cancer patients.

e12515 Background: Traditionally, breast cancer (BC) is considered human epidermal growth factor receptor-2 (HER2) positive based on HER2 overexpression or amplification (HER2 3+ or ISH positive HER2 2+). However, an emerging subgroup of HER2 negative (HER2 1+ or 2+ and ISH negative) known as HER2-Low is associated with poor prognosis than HER2-normal (HER2 0). Currently, there is an increased interest in developing new drugs targeting HER2-Low BC to improve survival. The fact that BC in young constitutes a significant minority outside the western world but is underrepresented in clinical trials, it is worth conducting a dedicated study of HER2-low in this population to determine whether it affects their outcome. Methods: Confirmed HER2 negative BC patients aged ≤40 diagnosed in 2012-2017 were retrospectively reviewed in two centers in Alexandria, Egypt. Patients were classified as HER2-low (1+, 2+) and HER2-normal. The clinicopathological characteristics and survival outcome were determined and compared. Results: There were five hundred HER2 negative BC patients; 82% were hormone receptor-positive (HR+) vs.18% triple-negative (TNBC). Among the HER2 negative, only 31% were HER2-Low (n = 155), of which 20% was HER2-Low 1+ while 11% was HER2-Low 2+. In comparison, HER2-Low was significantly more HR+ than HER2-normal (89% vs. 79% respectively, p = 0.009). Other tumor characteristics (T-size, nodal status, Ki-67, lymphovascular invasion - LVI, extracapsular extension - ECE) were similar in HER2-Low and HER2-normal. So were the disease-free survival (DFS) and overall survival (OS). Nevertheless, sub-grouping HER2-Low into 1+ and 2+ showed significant differences in tumor characteristics between HER2-normal, HER2-Low 1+, and HER2-Low 2+, in nodal status, tumor stage, ECE, and HR status. Moreover, DFS was significantly lower in HER2-Low 2+ (63.5%) compared to HER2-normal (70%) and HER2-Low 1+ (75%); p = 0.039. Also, the OS was also significantly lower in HER2-Low 2+ compared to HER2-normal, 90% vs 96% respectively, p = 0.023. Conclusions: Our results suggest no significant difference in DFS and OS between HER2-Low and HER2-normal in young BC patients. However, subdividing HER-low into HER2-low 1+ and HER2-Low 2+ better discriminates this group; HER2-Low 2+ had significantly poor DFS and OS and this should be considered in the clinical trials.

Histogram analysis of quantitative parameters from synthetic MRI: Correlations with prognostic factors and molecular subtypes in invasive ductal breast cancer

PurposeTo evaluate intra-tumoral heterogeneity through a histogram analysis of quantitative parameters obtained from synthetic MRI (magnetic resonance imaging), and determine correlations of these histogram characteristics with prognostic factors and molecular subtypes of invasive ductal carcinoma (IDC). MethodsA total of 122 IDC from 122 women who underwent preoperative synthetic MRI and DCE (dynamic contrast enhancement)-MRI were investigated. The synthetic MRI parameters (T1, T2, and PD (proton density)) were obtained. For each parameter, the minimum, 10th percentile, mean, median, 90th percentile, maximum, skewness, and kurtosis values of tumor were calculated, and correlations with prognostic factors and subtypes were assessed. The Mann-Whitney U test or the Student's t test were utilized to analyze the association between the histogram features of synthetic MRI parameters and prognostic factors. The Kruskal-Wallis test followed by the post-hoc test was used to analyze differences of synthetic MRI parameters among molecular subtypes. ResultsIDC with high histopathologic grade showed statistically higher PDmaxium, T1mean and T1median values than those with low grade (p = 0.003, p = 0.007, p = 0.003). The T110th were significantly higher in cancers with PR (progesterone receptor) negativity than those with PR positivity (p = 0.005). ER-negative cancers had significant higher values of T210th, T2mean, and T2median than ER-positive cancers (p = 0.006, 0.002, and 0.006, respectively). The values of PDmedian were significantly higher in IDC with HER2 (human epidermal growth factor receptor 2) positivity than those with HER2 negativity (p = 0.001). When discriminating molecular subtypes of IDC, the T2mean achieved the highest performance. The T2mean values of TN (triple-negative), luminal B and luminal A types are arranged in descending order (p < 0.0001). ConclusionsHistogram features derived from synthetic MRI quantifies the distributions of tissue relaxation time and proton density, and may serve as a potential biomarker for discriminating histopathological grade, hormone receptor status, HER2 expression status and breast cancer subtypes.

Variability in Breast Cancer Biomarker Assessment and the Effect on Oncological Treatment Decisions: A Nationwide 5-Year Population-Based Study.

Simple SummaryBiomarkers that define breast cancer treatment recommendations include estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth-factor receptor 2 (HER2); histological grade; and in many countries, the Ki67 proliferation index. However, the subjective nature and degree of variability in breast cancer biomarker assessment might result in under- or overtreatment. We demonstrated that limited variability exists in ER, PR, and HER2 positivity rates among 29 departments in Sweden, including 43,261 patients. However, even a few outlier labs affect endocrine and anti-HER2 treatment rates in a clinically relevant proportion, indicating a need for improvement. Despite international guidelines, standardized protocols, and external quality control procedures, very high variability was found in Ki67 scoring and histological grading, indicating a need for new methods. Monitoring rates of biomarker expression and treatments among departments should be mandatory in order to detect variability issues affecting the clinical management of breast cancer.We compared estrogen receptor (ER), progesterone receptor (PR), human epidermal growth-factor receptor 2 (HER2), Ki67, and grade scores among the pathology departments in Sweden. We investigated how ER and HER2 positivity rates affect the distribution of endocrine and HER2-targeted treatments among oncology departments. All breast cancer patients diagnosed between 2013 and 2018 in Sweden were identified in the National Quality Register for Breast Cancer. Cases with data on ER, PR, HER2, Ki67, grade, and treatment were selected (43,261 cases from 29 departments following the guidelines for biomarker testing). The ER positivity rates ranged from 84.2% to 97.6% with 6/29 labs out of the overall confidence intervals (CIs), while PR rates varied between 64.8% and 86.6% with 7/29 labs out of the CIs. HER2 positivity rates ranged from 9.4% to 16.3%, with 3/29 labs out of the overall CIs. Median Ki67 varied between 15% and 30%, where 19/29 labs showed significant intra-laboratory variability. The proportion of grade-II cases varied between 42.9% and 57.1%, and 13/29 labs were outside of the CI. Adjusting for patient characteristics, the proportion of endocrine and anti-HER2 treatments followed the rate of ER and HER2 positivity, illustrating the clinical effect of inter- and intra-laboratory variability. There was limited variability among departments in ER, PR, and HER2 testing. However, even a few outlier pathology labs affected endocrine and HER2-targeted treatment rates in a clinically relevant proportion, suggesting the need for improvement. High variability was found in grading and Ki67 assessment, illustrating the need for the adoption of new technologies in practice.

HER-2 positivity is a high risk of recurrence of stage I gastric cancer

Background/AimsThe treatment of gastric cancer remains unsatisfactory. We aimed to investigate the prognostic value of immunohistochemical staining in gastric cancer.MethodsWe analyzed 505 (279 early staged, 226 advanced-staged) gastric cancer tissues from patients who underwent radical gastric resection between January 2014 and December 2016. Available surgical specimens immunohistochemically stained for p53, epidermal growth factor receptor (EGFR), human EGFR 2 (HER-2), E-cadherin, and Ki-67 were reviewed. We evaluated the association between positivity to various biomarkers and disease recurrence, disease-free survival, lymph node metastasis, and microscopic lymphovascular invasion.ResultsThe median follow-up duration was 32.5 months (range, 7 to 70). Advanced gastric cancer cases showed high Ki-67 expression; other cases showed unremarkable expression. Concerning disease recurrence, lymphatic invasion, and disease-free interval, all biomarkers had no prognostic effects. HER-2-positive stage I gastric cancer tended to occur in old patients and in the upper one-third of the stomach (p = 0.01). HER-2 positivity was significantly correlated with disease recurrence (p = 0.01), lymphatic invasion (p = 0.03), and vascular invasion (p = 0.03) in stage I cases.ConclusionsOnly HER-2 was associated with the recurrence of stage I gastric cancer. HER-2-positive stage I gastric cancer requires additional therapy despite curative resection.

HER2 positivity is not associated with adverse prognosis in high-risk estrogen receptor-positive early breast cancer patients treated with chemotherapy and trastuzumab

Co-expression of human epidermal growth factor receptor-2 (HER2) and hormone receptor (HR) predicted worse prognosis in early breast cancer before trastuzumab was developed. We aimed to investigate whether HER2 positivity was still associated with worse outcome in high-risk estrogen receptor (ER) positive patients treated with trastuzumab and chemotherapy. In the present study, 227 ER+/HER2+ patients treated with trastuzumab and chemotherapy (HER2-pos-T group) and 1097 ER+/HER2-patients treated with chemotherapy alone (HER2-neg group) during 2009 and 2015 were retrospectively enrolled for the comparison of disease-free survival (DFS) and overall survival (OS). At a median follow-up of 59 months, 174 DFS events and 69 deaths were observed. The estimated 5-year DFS rate was 94.2% in the HER2-pos-T group and 87.4% in the HER2-neg group (Log-rank P = 0.014). HER2-pos-T group was associated with significantly better DFS in multivariate analysis (HR 0.38, 95% CI: 0.22–0.67, Log-rank P = 0.001). The estimated 5-year OS rates for the two groups were 97.2% and 95.7%, respectively (Log-rank P = 0.183). In multivariable analysis, patients in the HER2-pos-T group had significantly better OS compared with those in the HER2-neg group (HR 0.40, 95% CI: 0.17–0.95, Log-rank P = 0.037). We concluded that high-risk ER+/HER2+ breast cancer patients treated with chemotherapy and trastuzumab had superior prognosis compared with ER+/HER2-patients. Therefore, HER2 positivity itself may not be considered as an unfavorable factor for ER + patients in the era of trastuzumab.

Differential prognostic value of positiveHER2 status determined by immunohistochemistry or fluorescence in situ hybridization in breast cancer.

Human epidermal growth factor-receptor-2 (HER2) is a membrane-tyrosine-kinase that is amplified/overexpressed up to 20% in breast cancer. HER2 positive status is associated with faster disease progression, higher metastatic potential, and shorter disease-free/overall survival and also has emerged as an important therapeutic target in breast cancer. HER2 status can be determined by in-situ-hybridization (ISH) or immunohistochemistry (IHC). Although the concordance rate between ISH and IHC is well-known, the prognostic power of both technologies if tested in parallel on the same tumor has not been studied extensively. In this study we retrospectively analyzed a large HER2 positive breast cancer cohort tested both with fluorescence labeled ISH (FISH) and IHC in parallel on each case. We stratified HER2 positive results by FISH and IHC with long-term overall survival, 5-year survival and metastases/recurrence rates. Positive HER2 status both FISH and IHC was available in 364 patients. The number of HER2 FISH-positive and FISH-negative patients was 342 and 22, respectively. The number of HER2 IHC 0/1 + , IHC 2 + , and IHC 3 + patients was 12, 42, and 310, respectively. Among the patients with IHC 3 + status, 288 were FISH-positive and 22 FISH-negative. HER2 status determined by FISH correlated with clinical outcomes (overall survival and with metastases/recurrence, p = 0.036, p = 0.039), whereas HER2 status determined by IHC did not. Our results indicate that prognostic information in HER2 positive breast cancer also depends on the methodology of how positivity was determined. In our cohort, FISH was superior to IHC based positive HER2 status.

Pharmacokinetics, Tissue Distribution, and Druggability Prediction of the Natural Anticancer Active Compound Cytisine N-Isoflavones Combined with Computer Simulation.

Cytisine N-methylene-(5,7-dihydroxy-4'-methoxy)-isoflavone (CNF2) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides. Preliminary pharmacodynamic studies demonstrated its activity in inhibiting breast cancer cell metastasis. This study examined the pharmacokinetics, absolute bioavailability, and tissue distribution of CNF2 in rats, and combined computer-aided technology to predict the druggability of CNF2. The binding site of CNF2 and the breast cancer target human epidermal growth factor receptor-2 (HER2) were examined with molecular docking technology. Next, ACD/Percepta software was used to predict the druggability of CNF2 based on the quantitative structure-activity relationship (QSAR). Finally, a simple and effective HPLC method was used to determine plasma pharmacokinetics and tissue distribution of CNF2 in rats. Prediction and experimental results show that compared with the positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity with HER2, suggesting that its efficacy is stronger; and the structure of CNF2 complies with the Lipinski's Rule of Five and has good drug-likeness. The residence time of CNF2 in rats is less than 4 h, and the metabolic rate is relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%, mainly distributed in the stomach, intestine, and lung tissues, where the CNF2 contents were 401.20, 144.01, and 245.82 µg/g, respectively. This study constructed rapid screening and preliminary evaluation of active compounds, which provided important references for the development and further research of such compounds.

Abstract P5-02-09: The prevalence of invasive lobular carcinomas with unconventional immunohistochemical phenotypes

Abstract Background The prognosis of invasive lobular carcinoma (ILC) is controversial. Some studies report equivalent or better outcomes than invasive ductal carcinoma, likely due to ILC’s favorable prognostic phenotype. Classic ILC (CL) is typically of low histologic grade, estrogen receptor (ER) positive and human epidermal growth factor receptor-2 (HER2) negative. However, worse long term outcomes have been observed because ILC tends to be multicentric, bilateral, and to show higher rates of late metastases in uncommon sites. Additionally, subtypes of ILC, including solid (SOL) and pleomorphic (PL), have been reported to display more aggressive behavior. Yet current treatment paradigms are distinguished by hormone receptor profile and stage, not by tumor morphology. This study aimed to evaluate the clinicopathologic and immunohistochemical (IHC) characteristics of ILC, particularly those with unusual patterns. Methods From 2009-2018, consecutive in-house biopsy and resection specimens with the diagnosis of ILC were identified by a retrospective review of our institutional database. Demographic, morphologic, and IHC data were obtained from pathology reports. Cases with equivocal HER2 IHC results are sent for fluorescence in situ hybridization analysis at our Center. CL ILC was defined by small cells with low nuclear grade and discohesive growth arranged in single file or cords. PL ILC is composed of larger, more atypical cells, which still exhibit discohesion typical of lobular phenotype. SOL ILC consists of tumors growing in large sheets with minimal intervening stroma. Results Over the nine year study period, a total of 3,028 ILCs from 2,322 patients were identified. Most (74%, 2229/3028) cases were classified as CL while 22% (665/3028) were PL and 4% (134/3028) SOL (Table 1). The median patient age was 60 years (range 32-95). The median tumor size was larger for PL (2.3 cm) and SOL (2.4 cm) subtypes than CL (1.1 cm). IHC results were available for 896 specimens. The majority of all ILCs showed an expected phenotype: ER positive and HER2 negative (99% CL, 84% PL, 97% SOL). A smaller subset of ER positive ILC were also HER2 positive (1% CL, 8% PL, 3% SOL). No CL or SOL ILC were ER negative; in contrast 8% (21/270) of PL ILC were ER negative. Twelve (5%) PL ER negative cases were also HER2 negative. Overall, 15% of ILC were HER2 positive, with the PL variant showing the highest incidence (11%, 30/270). Lymph node (LN) metastases were seen in 22% (66/291) of CL cases, 55% (53/96) PL and 29% (17/58) SOL. Metastases in 10 or more LN (N3) was seen only in PL and SOL cases (13% and 5%, respectively). Conclusions In this study, up to 8% of ILC cases were found to be ER negative, a finding unique to the PL variant. No CL or SOL ILC was ER negative. HER2 positivity, not typically expected in ILC, was seen in 15% of cases, most commonly in the PL type. ILC that was both negative for ER and HER2 was observed in 5% of cases, and only within the PL subgroup. PL ILC showed higher median tumor size at presentation than CL and nodal metastases were also more common in PL than in CL or SOL ILC (55% vs 22% and 29%, respectively). Our findings are in keeping with prior observations that compared to CL ILC. PL ILC exhibits features associated with unfavorable clinicopathologic features, such as higher tumor and nodal stage at presentation. Additionally, this is the first study to systematically examine the prevalence of unconventional IHC phenotypes of ILC (ER negativity and/or HER2 positivity) in a large series from one institution. Table 1. Summary of Clinicopathologic FeaturesClassicPleomorphicSolidILC types (n=3028)2229665134Median age, (range)60 yrs (32-94)61 yrs (31-95)66 yrs (44-93)Median size, cm 1.12.32.4Immunophenotype (n=896)ER+/HER2-99% (551/559)84% (228/270)97% (65/67)ER+/HER2+1% (8/559)8% (21/270)3% (2/67)ER-/HER2+0% (0/559)3% (9/270)0% (0/67)ER-/HER2-0% (0/559)5% (12/270)0% (0/67)Lymph node status (n=445)N077% (225/291)45% (43/96)71% (41/58)N120% (59/291)31% (30/96)19% (11/58)N22% (7/291)11% (11/96)5% (3/58)N30% (0/291)13% (12/96)5% (3/58) Citation Format: Matthew G Hanna, Anne Grabenstetter, Dara S Ross, Lee K Tan. The prevalence of invasive lobular carcinomas with unconventional immunohistochemical phenotypes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-09.

Abstract P2-10-09: Aggressive tumour biology contributes to poor breast cancer outcomes for indigenous Australians

Abstract Breast cancer (BrCa) incidence is lower in Aboriginal Australian women but carries more than double the risk of death. However, rates of Aboriginal BrCa diagnosis are increasing, hypothesized to be due to lifestyle changes. Thus, with rising incidence and higher mortality, deaths due to BrCa are rising in absolute terms in Aboriginal women. Studies of this higher death rate thus far have been epidemiological, exploring factors such as higher stage at diagnosis, younger age, increased co-morbidities, remoteness, socioeconomic disadvantage, and access to culturally sensitive health services. Collectively, these factors do not fully explain this higher rate of death. However, no study has explored any aspect of tumour or host biology in Aboriginal BrCa. We have studied a cohort of 262 Aboriginal women identified from the WA Cancer Registry comprising all cases diagnosed with BrCa in Western Australia for the period 2001-2016. Remoteness, in the form of an Accessibility/Remoteness Index of Australia (ARIA) score, was calculated from address at the time of diagnosis for each patient. All participants were then matched 2:3 by remoteness of residence and age with non-Aboriginal patients. Mortality data including cause was collected through state Death Registry linkage. Basic tumour parameters as well as receptor expressions were extracted from routine pathology assessment data with extra sections scored for missing values when tissue was available. A BrCa sub-type was assigned to each participant based on a modified IHC4 method using tumour grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status. A significant detriment was found for Indigenous BrCa mortality, univariate hazard ratio (HR)=4.19 (95% confidence interval (CI) 2.42 - 7.25, p&amp;lt;0.001) after matching for remoteness and age, multivariate HR=2.55 (95% CI 1.39 - 4.67, p=0.003) after further adjustment for lymph involvement and size.Supporting the hypothesis that Indigenous BrCa is more likely to be aggressive, substantially more tumours in Aboriginal women were greater than 2cm (51 v 23%, p&amp;lt;0.0001), grade 3 (45 v 26%, p&amp;lt;0.0001) and lymph node positive (56 v 33%, p=0.011). Considering individual receptors, HER2 positivity was substantially more common (21 v 12%, p=0.009) although ER and PR did not differ. Combining grade and receptor status revealed substantially higher proportions of the higher risk sub-types luminal B (29 v 16%) and HER2-enriched (11 v 5%), but no difference in triple negative cancers (15 v 15%), overall p=0.001 for sub-type differences. These biological differences explained part but not all of the survival detriment observed for Aboriginal women with attenuated survival detriment seen within each biological sub-type. Further studies on more detailed aspects of tumour biology are ongoing. Citation Format: Andrew David Redfern, Lisa J Spalding, Edward YC Lee, Connor F Redfern, Leanne Pilkington, Max Bulsara, Richard Trevithick, Katie Meehan. Aggressive tumour biology contributes to poor breast cancer outcomes for indigenous Australians [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-09.

Correlation of Muscle Invasion in Bladder Cancer with Cell Adhesion Properties and Oncoprotein Overexpression Using E-Cadherin and HER2/neu Immunohistochemical Markers.

BACKGROUND: Most of bladder cancers are proven to be of urothelial origin (transitional cell carcinomas). Above 75% of them are of non-muscle invasive bladder cancer (NMIBC) type at presentation and the remainder are MIBC. Recent studies suggest that both are most probably two different categories based on both the histopathological and molecular features. The comprehensive understanding of the biomarkers expression in both categories will help in understanding the molecular event underlying each of them and may provide possible chances for targeted therapeutic options.&#x0D; AIM: This study aims to study the differential expression of both E-cadherin and human epidermal growth factor receptor-2 (HER2) in the two categories of bladder cancer NMIBCs and MIBCs.&#x0D; MATERIALS AND METHODS: A total of 40 blocks were collected retrospectively from cases of cancer bladder, segregated as 20 cases NMIBCs and 20 cases MIBCs, subjected for E-cadherin and HER2 immunostaining.&#x0D; RESULTS: E-cadherin showed positive expression in 65% of cases of NMI group and in 10% of the MI group, with high statistical significance (p &lt; 0.001). Regarding HER2, positive expression was seen in 25% of NMI cases and in 90% of MI cases, with statistical significance (p &lt; 0.001). Comparison of the results of both markers and their correlation per case showed that 90% of tumors with muscle invasion were E-cadherin negative and HER2 positive.&#x0D; CONCLUSION: The significant association of loss of E-cadherin immunohistochemistry expression and positive HER2 overexpression in MIBC versus NMIBC figured out more differences between the two categories and added to the understanding of their biology. The possibility of validation of HER2-targeted therapy in MIBC cases is now strongly suggested.

Can Ultrasonographic Vascular and Elastographic Features of Invasive Ductal Breast Carcinoma Predict Histologic Aggressiveness?

To investigate if preoperative ultrasonographic vascular and shear-wave elastographic examinations can predict histologic aggressiveness. Preoperative ultrasonographic vascular features and shear-wave elasticities were retrospectively evaluated for 147 invasive ductal carcinomas. Vascular feature was assessed using four-tier vascularity score. Mean and maximum elasticities (Emean and Emax), and the lesion-to-fat ratio (Eratio) were documented. Histologic parameters were reviewed for tumor size, multiplicity, axillary lymph node status, lymphovascular invasion, histologic grade, estrogen receptor, progesterone receptor, human epidermal growth factor receptor2 (HER2), Ki-67, p53, and histologic subtype. Vascularity score and elasticities were correlated with histologic parameters and histologic parameters were compared between the group with low vascularity score and elasticities and the group with high vascularity score and elasticities using ANOVA, chi-squared test, and regression analysis. Vascularity score was independently associated with tumor size (p = 0.010) and HER2 (p = 0.007). Emean and Emax were associated with tumor size, histologic grade, and lymphovascular invasion, and Eratio was associated with tumor size, histologic grade, estrogen receptor, progesterone receptor, Ki-67, and histologic subtype (p < 0.05). Emean and Emax were independently associated with tumor size (p < 0.001). The group with high vascularity score and Eratio showed large tumor size (p < 0.001) and HER2 positivity (p = 0.039) in comparison to the group with low vascularity score and Eratio. Ultrasonographic vascular features were associated with tumor size and HER2. SWE elasticities were associated with tumor size, histologic grade, hormonal receptor, and histologic subtype. Therefore, preoperative vascular and elastographic examinations could predict histologic aggressiveness of invasive ductal breast carcinoma.

276P - Overexpression of HER3 and the survival of ovarian cancer

Background: Human epidermal growth factor receptor-2 (HER2) and 3 (HER3) belongs to epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases which is responsible for cell survival and proliferation, but their role in ovarian cancer is not yet established. In this study, their status in specimens of epithelial ovarian cancer was determined with immunohistochemistry (IHC) and in situ hybridization (ISH) and was analyzed to find out the correlation with clinical features of ovarian cancer. Methods: Tissue microarrays (TMAs) were prepared from paraffin blocks of 105 ovarian tumor samples. The immunohistochemical expression of HER2, HER3, PI3K, Akt, p-Akt, mTOR, p-mTOR, S6 and p-S6 were investigated. HER2 and HER3 gene amplifications were evaluated by ISH. The correlation between status of materials and disease outcome of the patients were analyzed. Results: HER2 positivity was 3.8% on IHC and 5.7% on ISH, otherwise HER3 showed 12.4% and 8.6% expression respectively. The concordances of IHC and ISH were 98.1% (103/105) in HER2, and 82.9% (87/105) in HER3. HER2 status was not related with disease outcome of ovarian cancer. However, the HER3 status on FISH was associated with rapid disease progression, and this was a significant risk factor even after adjusting other possible risk factors in multivariate analysis. Conclusions: HER3 could be an independent marker for poor prognosis in ovarian cancer, because HER3 signaling pathway might be distinguished from that of HER2. The possibility of target therapy in patients with HER3 gene alteration should be evaluated in the field of ovarian cancer. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.