Human Epidermal Growth Factor 2 Positivity Research Articles

Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort study

BackgroundHuman epidermal growth factor receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in advanced stage and recurrent uterine serous carcinoma (USC). The significance of tumoral HER2 expression in early-stage disease has not been established. MethodsThis multi-center cohort study included women with stage I USC treated from 2000 to 2019. Demographic, treatment, recurrence, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0–3+. Equivocal IHC results (2+) were further tested with fluorescence in-situ hybridization (FISH). HER2 positivity was defined as 3+ IHC or FISH positive. ResultsOne hundred sixty-nine patients with stage I USC were tested for HER2; 26% were HER2-positive. There were no significant differences in age, race, stage, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. Presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p = .003).After a median follow-up of 50 months, there were 43 (25.4%) recurrences. There were significantly more recurrences in the HER2-positive cohort (50.0% vs 16.8%, p < .001). HER2 positive tumors were associated with worse progression-free (PFS) and overall survival (OS) (p < .001 and p = .024). On multivariate analysis, HER2 positive tumors were associated with inferior PFS (aHR 3.50, 95%CI 1.84–6.67; p < .001) and OS (aHR 2.00, 95%CI 1.04–3.88; p = .039) compared to HER2-negative tumors. ConclusionsGiven its significant association with worse recurrence and survival outcomes, HER2 positivity appears to be a prognostic biomarker in women with stage I uterine serous carcinoma. These data provide support for clinical trials with anti-HER2-directed therapy in early-stage disease.

Abstract P3-02-12: CAV1, MCT1, and MCT4 expression in ductal carcinoma in situ of the breast and its association with clinicopathologic features

Abstract Background: Multicompartment tumor metabolism and metabolic coupling are markers of aggressive tumor behavior, clinically manifested as disease recurrence and progression. Loss of caveolin-1(CAV1) in stromal cells and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, in both stromal and cancer cells have been identified as playing an important role in the metabolic coupling necessary for release and uptake of metabolites. However, this phenomenon has only scarcely been described in ductal carcinoma in situ (DCIS) of the breast. The purpose of this study was to investigate the role of CAV1, MCT1, and MCT4 in DCIS carcinogenesis and its association with clinicopathologic factors. Materials and methods: CAV1, MCT1, and MCT4 expression was examined in 9 pairs of DCIS tissues and matched normal adjacent tissues at mRNA and protein levels by qRT-PCR, RNAscope in situ hybridization (ISH) and immunohistochemistry. Immunohistochemical staining of CAV1, MCT1, and MCT4 was done in 79 DCIS samples with known hormone receptor (HR) and human epidermal growth factor 2 (HER2) expression using tissue microarray. Results: CAV1 mRNA expression by qRT-PCR analysis was significantly decreased in DCIS tissues compared to their corresponding normal tissues. On the other hand, MCT1 and MCT4 mRNA expression in DCIS tissues were increased compared with corresponding normal tissues and the difference was statistically significant in MCT1. Compared with their corresponding normal tissues, DCIS tissues showed decreased stromal CAV1 mRNA and protein expression and increased epithelial MCT1 and MCT4 mRNA and protein expression by ISH and immunohistochemistry. Low stromal CAV1, high epithelial MCT1, and high epithelial MCT4 expressions were observed in 29 (36.7%), 51 (64.6%) and 15 (18.9%) cases with DCIS, respectively. Low stromal CAV1 expression was significantly associated with high nuclear grade (P &amp;lt; 0.05). High epithelial MCT4 expression was associated with larger tumor size and HER2 positivity (P &amp;lt; 0.05 and P &amp;lt; 0.05, respectively). Although not statistically significant, low stromal CAV1 and high epithelial MCT4 expression tended to be associated with recurrence of DCIS. No associations were observed between stromal CAV1 expression and epithelial MCT 1 or MCT4 expression. Conclusions: These results suggested that changes in CAV1, MCT1, and MCT4 are associated with carcinogenesis of DCIS, and further studies are needed for their clinical usefulness. Keywords: Ductal carcinoma in situ; CAV1; MCT1; MCT4; Metabolism Citation Format: Ji Shin Lee, Nah Ihm Kim, Min Ho Park. CAV1, MCT1, and MCT4 expression in ductal carcinoma in situ of the breast and its association with clinicopathologic features [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 P3-02-12.

HER2 as a limited predictor of the therapeutic response to neoadjuvant therapy in locally advanced rectal cancer

Human epidermal growth factor 2 (HER2) is a candidate therapeutic and prognostic marker for rectal cancer treated with neoadjuvant chemoradiotherapy. The specific frequency and prognostic role of HER2 protein expression and HER2 gene amplification in those rectal cancers has not been fully investigated. Pretreatment biopsied and surgically resected formalin-fixed paraffin-embedded tissues from 74 patients were retrospectively evaluated for HER2 protein expression and HER2 gene copy number using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. The tumor response to chemoradiation was evaluated with TNM staging and tumor regression grading (TRG) systems. Good response to chemoradiation therapy (TRG3), poor response (22 TRG1 and 19 TRG2), and TNM downstaging achieved in 33 (44.6%), 41 (55.4%), and 42 (56.8%) patients, respectively. The frequency of HER2 positivity is 17.6%, all of which were low-level HER2 gene amplification with 2.2 of median gene copy number ratio, detected in IHC0 (3/39), IHC1+ (2/18), IHC2+ (5/14) and IHC3+ (2/3). There was no association of HER2 positivity with clinicopathological parameters or survival. However, older age (≥61 years) and HER2 positivity were the independent predictive factors for non-down staging, while poorly differentiation and the papillary pattern were predictors for poor response. In multivariate analysis, good response proved as an only independent favorable prognostic factor affecting survivals. In conclusion, HER2 positivity may be predictive for a high-risk therapeutic resistance in rectal cancers. The discrepancy between IHC and gene amplification may result from the low-level amplification, which may explain lack of prognostic impact of HER2 positivity.

High Fidelity of Breast Biomarker Metrics: A 10-Year Experience in a Single, Large Academic Institution.

Recommendations for standardization of breast biomarkers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) led to the creation of American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines to provide continuous guidance. Included in these recommendations is the "ongoing assay assessment procedures." We report these biomarker metrics as there is a dearth of published information on this topic. ER, PR, and HER2 positivity rates of all newly diagnosed, recurrent, and metastatic invasive breast cancers on core biopsies, and repeated testing on resection specimen by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) were collected from April 1, 2008 to December 31, 2017. The positivity rates of ER, PR, and HER2 over almost 10 years of monitoring showed high fidelity. Total ER-positive rate was 83.6% (81.4% to 86.8%), ER+/PR+ was 71.7% (68.6% to 75.5%), ER+/PR- was 17.6% (11.0% to 15.0%), ER-/PR- was 16.0% (13.5% to 18.2%), and ER-/PR+ was 0.6% (0.2% to 1.0%). The HER2-positive rate was 13.7% (10.2% to 17.4%) including 9.9% (7.3% to 11.9%) by IHC and 3.8% (1.9% to 5.9%) by FISH reflexed from IHC 2+ results. FISH amplification rate of HER2 IHC 2+ cases was 11.0% (5.8% to 19.2%). Annual quality-assurance check for HER2 IHC/FISH percent positive and percent negative agreement (as defined by Food and Drug Administration) was 96% to 100%. This longitudinal active assessment of 9564 breast biomarker cases shows the achievement of high fidelity of breast biomarker results when following the ASCO/CAP guidelines. Continuous monitoring of breast biomarkers may minimize assay analytical drift and assure quality clinically relevant results.

Intraocular Metastases Secondary to Breast Carcinoma Correlates With Upregulation of Estrogen and Progesterone Receptor Expression in the Primary Tumor

To compare estrogen (ER), progesterone (PR), and human epidermal growth factor-2 (HER2) receptor expression in the primary tumor of patients affected by choroidal metastases from breast carcinoma (BC) versus those with extraocular metastases. Eighteen consecutive patients affected by choroidal metastases from BC were included. We defined ER, PR, and HER2 positivity of the primary tumor following standard guidelines. Breast carcinoma molecular subtypes were also identified (luminal A, luminal B, HER2-enriched, and triple negative). Forty consecutive patients affected by metastatic BC without choroidal involvement were included as a control group. The study group and the control group were similar for age, sex, race, histopathologic classification of the primary tumor (ductal, lobular, others), and American Joint Committee on Cancer Tumor-Node-Metastasis stage at the time of primary tumor diagnosis (P > 0.05). Patients affected by choroidal metastases from BC showed a significantly higher expression of ER (P = 0.009) and PR (P = 0.018) receptors in the primary tumor compared with nonchoroidal metastatic BC. Across all patients, the luminal B molecular subtype was related to the presence of choroidal involvement (P = 0.003). Considering luminal tumors only, the luminal B subclassification was also related to the presence of choroidal involvement (P = 0.009). Choroidal metastases from BC are associated with ER and PR expression in the primary tumor and the luminal B molecular subtype.

HER-2 incidence in gastric cancer, its association with prognosis and clinicopathological parameters.

Human epidermal growth factor-2 (HER-2) overexpression has prognostic value in breast cancer. However, the significance of HER-2 positivity in gastric cancer is controversial. In this study, we investigated the frequency of overexpression of HER-2 and its relationship with clinicopathological findings and impact on survival in gastric cancer. Gastric cancer patients, operated in Marmara University Faculty of Medicine, Pendik Training and Research Hospital, General Surgery Department, between January 2012-December 2013 were enrolled in this study. Medical records were retrospectively evaluated. Tissue samples were stained by immunohistochemistry (IHC) method, and were followed by fluorescence in situ hybridization (FISH) in those with positive results. HER-2 expression rates and its association with other histopathological features and survival have been analyzed. 135 patients were enrolled in the study, with 88 (65%) male and 47 (35%) female patients. The median age was 61 (29-84) years. Only 11 patients (8%) were positive for HER-2. HER-2 positive patients were similar to negative patients in terms of age, gender, tumor size, tumor location, tumor T stage, lymph node metastasis, histological type, differentiation, lymphovascular invasion, perinodal, perineural invasion and stage. No significant difference was detected on 1 and 2-year overall and disease-free survival rates between receptor positive and negative groups. Consistent with the literature data, HER-2 positivity rate in this study was approximately 8%, but this positivity has not been found to be associated with either clinical and pathological parameters or overall and disease-free survival.

HER2 Expression in Gastric Adenocarcinoma-a Study in a Tertiary Care Centre in South India.

According to the literature available, HER2(human epidermal growth factor 2)status in gastric carcinoma has been studied worldwide, however there is a paucity of published data from India. Hence, this study was taken up to evaluate HER2 overexpression in gastric adenocarcinoma patients and to assess the relationship between its expression and clinicopathological tumor parameters. Prospective study was conducted in a teaching hospital over a period of 27months. Total or subtotal gastrectomy resection specimens and small biopsies were included in the study. Immunohistochemistry (IHC) was carried out on all the cases to evaluate the expression of HER2 in formalin-fixed paraffin-embedded tissue samples. Fluorescence Insitu Hybridization (FISH) was done for equivocal cases on IHC. The data was analyzed using Chi square test / Fisher's Exact Test. Odds ratio was computed between HER2 and other pathologic variables. HER2 overexpression was confirmed in 16 (27.6%) cases of which 15 (93.8%) cases were of intestinal type whereas only 1 (6.2%) case of diffuse type adenocarcinoma. Hence, HER2 positivity was significantly more common in the intestinal type of gastric cancer compared to the diffuse type (p = 0.045). Positivity of HER2 was more in small biopsies as compared to the resection specimens in this study but the p value was not significant. There was no difference in HER2 overexpression in relation to the age, gender, tumor site, tumor differentiation and stage. HER2 overexpression is more prevalent in the intestinal subtype. The relatively high percentage of HER2 positive tumors may provide a useful target for immunotherapy of these cancers.

Prognostic implications of receptor discordance between primary and recurrent breast cancer.

Discordance rates of hormone receptor (HR) and human epidermal growth factor-2 (HER2) status between primary and recurrent breast cancer were reported to be in the wide range of 10-40 %, although its prognostic relevance remains to be elucidated. Fifty-five breast cancer patients had biopsies or resections of recurrent lesions. Pathological assessments of the HR and HER2 status of primary and recurrent lesions were performed in a single laboratory at Keio University Hospital. Tumors were classified as luminal (HR+ and HER2-), luminal/HER2 (HR+ and HER2+), HER2 (HR- and HER2+), or triple negative (HR- and HER2-). Discordance rates in estrogen receptor (ER), progesterone receptor (PgR) and HER2 status between primary tumors and recurrent lesions were 16.4, 30.9 and 10.2 %, respectively. Overall, 14 patients (25.5 %) changed subtypes at recurrent lesions. Patients with a gain in ER and PgR status had a significantly longer disease-free interval compared with the corresponding concordant-negative patients (ER: 99.0 vs. 18.5 months, p = 0.037, PgR: 141.0 vs. 24.4 months, p = 0.011). Patients with a loss of HER2 status experienced a trend toward shorter time to progression, compared with patients who maintained HER2 positivity (4.0 vs. 18.4 months, p = 0.051). Discordance in receptor status between primary and recurrent breast cancers were seen in 10-30 %. A gain in HR status was significantly associated with better prognosis.

The significance of the HER-2 status in esophageal adenocarcinoma for survival: an immunohistochemical and an in situ hybridization study

BackgroundIn esophageal adenocarcinoma (EAC), concordance and prognostic significance of human epidermal growth factor 2 (HER-2) protein overexpression and gene amplification are equivocal, which led us to reevaluate this by immunohistochemistry (IHC) and in situ hybridization. MethodsOne hundred and fifty-four patients were included in a tissue micro array (TMA). HER-2 gene amplification was assessed by fluorescence and silver-enhanced in situ hybridization (FISH and SISH) and expression with the HercepTest™. ResultsHER-2 was amplified in 16% by SISH and 18% by FISH. HER-2 positivity (IHC 3+ or 2+ with ISH+) was seen in 12% and overexpression (IHC 2+/3+) in 14%. Concordance was 92% between SISH/IHC, 90% between FISH/IHC and 95% between SISH/FISH. All IHC 3+ cases were amplified by SISH and in 93% by FISH. Of the IHC 2+cases, this was 33% (SISH) and 50% (FISH). Of the IHC 1+ cases, still 6% (SISH) and 8% (FISH) showed amplification. HER-2 positivity, overexpression and amplification were all associated with poor cancer-specific survival, in univariate analysis. Furthermore, HER-2 positivity and amplification (SISH) were independently associated with poor survival (hazard ratio, HR 6.343; 95% CI 1.218–36.234; P = 0.029 and HR 3.231; 95% CI 1.092–9.563; P = 0.034). ConclusionHER-2 positivity and gene amplification are fairly frequent and independently associated with poor survival.

The incidence and prognostic value of HER2 overexpression and cyclin D1 expression in patients with gastric or gastroesophageal junction adenocarcinoma in Israel

Human epidermal growth factor 2 (HER2) positivity rates for gastric or gastroesophageal junction (GEJ) adenocarcinoma have been reported at 15–25%. Cyclin D1 (BCL1) is a non-specific proliferative marker. The prognostic significance of HER2 and cyclin D1 is inconclusive, with contradictory data. The aim of this study was to evaluate the incidence of HER2 overexpression in gastric or GEJ patients. The presence of a possible correlation between HER2 status and cyclin D1 staining was assessed; both were evaluated as prognostic markers for survival. The clinical data and histological specimens of 150 consecutive patients diagnosed with gastric or GEJ adenocarcinoma, and treated at our hospital from June 2005 to March 2009, were analyzed. Pathological specimens were immunohistochemically stained for HER2. Immunoreactivity was determined according to the scoring system for gastric carcinoma. Cyclin D1 immunoreactivity was also tested. The results demonstrated that HER2 was positive in 14/150 (9.3%) patients. HER2-positive (HER2+) and HER2-negative (HER2−) patients did not differ significantly with regard to other clinicopathological parameters. In a multivariate analysis, HER2 positivity was revealed to be a poor prognosis variable (P=0.046; 95% CI, 1.03–3.58). In patients with non-metastatic disease, median survival was 59 months for HER2− and 42 months for HER2+ patients, but this difference was not significant. In patients with metastatic disease, median survival was 9.5 months and 2.5 months for HER2− and HER2+ patients, respectively (P=0.041). Cyclin D1 was not idemonstrated to be a prognostic factor and was not associated with HER2 overexpression. The rate of positive HER2 status in the current group of unselected patients with gastric and GEJ adenocarcinoma was relatively low compared with that observed in the literature. Nevertheless, HER2 positivity was associated with a poor prognosis.

Oracle HER2 Bond immunohistochemistry system validation

The Leica Oracle human epidermal growth factor 2 (HER2) Bond immunohistochemistry (IHC) system is a fully automated testing kit available for the purpose of evaluating HER2 oncoprotein status of invasive breast tumors. This kit is compared to the existing technology of the DAKO antibody clone A0485 used within the Histology laboratory at Cabrini Hospital by way of a validation study on 80 archival breast tumor blocks and scored by a qualified pathologist not knowing the original HER2 status. The kit was firstly optimized for use at Cabrini’s histology facility with consideration paid to tissue fixation protocols and antigen retrieval regimes using in-house tissue controls and cell line controls included in the kit. The overall concordance was low when the Oracle HER2 results were compared to the original DAKO HER2 results. Some of the reasons are a combination of over-retrieval of the HER2 antigen leading to overcalling HER2 scores in invasive breast cancers, scoring HER2 positivity in DCIS and benign lesions and not having access to the corresponding H&E slides when scoring HER2 immunohistochemistry. Also, HER2 immunohistochemistry is subject to a certain amount of bias when scoring. From 2010 onwards and before this study was completed, all invasive breast tumors now undergo HER2 in-situ hybridization studies regardless of the HER2 IHC result at Cabrini Hospital.

An immunohistochemical study of chromogranin A and human epidermal growth factor‐2 expression using initial prostate biopsy specimens from patients with bone metastatic prostate cancer

To investigate, using prostate needle-biopsy specimens at diagnosis from patients with bone metastatic prostate cancer, whether the relationship between neuroendocrine (NE) cell differentiation and human epidermal growth factor-2 (HER-2) expression is a prognostic factor for outcome. The study included 50 patients diagnosed as having bone metastatic prostate cancer between January 1998 and December 2001. We tested for NE cell differentiation by using immunohistochemical (IHC) staining for chromogranin A (CgA), and for HER-2, using a commercial test for IHC staining. Eleven patients (22%) were positive for CgA; there was a significant difference in the time to recurrence (P = 0.025) but no significant differences in cause-specific survival rate or survival rate after recurrence. In all, 21 patients (42%) were positive for HER-2; the cause-specific survival rate, time to recurrence and survival rate after recurrence were all significantly more favourable in the HER-2-negative group (P = 0.008, 0.049 and 0.025, respectively). In the 49 patients for whom both factors could be determined, there was no significant correlation between CgA and HER-2 positivity. NE cell differentiation of the primary tumour in patients with bone metastatic prostate cancer does not reflect the prognosis, whereas HER-2 overexpression is a prognostic factor for an unfavourable outcome. These results suggest that NE cell differentiation is not induced by HER-2.

Topoisomerase IIα Gene Amplification and Response to Anthracycline-Containing Adjuvant Chemotherapy in Breast Cancer

In this issue of the Journal of Clinical Oncology, Tanner et al report the therapeutic benefit from tailored and dose-escalated adjuvant anthracycline-based chemotherapy in high-risk breast cancer patients with coamplification of the genes encoding human epidermal growth factor-2 (HER2) and topoisomerase II (TOP2A). Adjuvant chemotherapy can substantially reduce the risk of recurrence and death in high-risk patients with breast cancer, and a number of chemotherapy combinations have established efficacy and safety data. Adjuvant chemotherapies can be broadly classified into three groups: cyclophosphamide/ methotrexate/fluorouracil (CMF) combinations, anthracyclinebased combinations such as doxorubicin or epirubicin, and taxane-containing combinations such as paclitaxel or docetaxel. In patients with hormone receptor-positive disease, the value of endocrine therapies (ovarian ablation or suppression, antiestrogens, and, more recently, aromatase inhibitors) have been well established also. The availability of techniques to detect hormone receptors has made it possible to identify the patients who might benefit from endocrine therapies. Patients whose tumors lack hormone receptors do not achieve any benefit from endocrine therapies and are thus treated only with adjuvant chemotherapies. The value of chemotherapy is established from the data from individual randomized trials and from the Oxford overview’s 15year meta-analyses of randomized chemotherapy trials. It is now accepted that anthracycline-containing therapies are superior to CMF combinations. The Oxford overview data showed that anthracycline-based chemotherapies reduce the risk of recurrence by 11% 0.03% ( standard error) and reduce the risk of death by 16% 0.03% compared with CMF combinations. However, anthracycline-containing combinations carry a small risk of cardiac dysfunction. At the present time, there are no reliable, validated, predictive biologic markers (like hormone receptors for endocrine therapies) that can guide the selection of an appropriate type of adjuvant chemotherapy. The mechanisms of action of chemotherapy drugs are complex, and these drugs affect a number of cellular pathways. In the past two decades, efforts to identify a subset of patients who would benefit from a given type of systemic adjuvant therapy have met with limited success, but these efforts have resulted in a better understanding of the biology of this disease. For example, overexpression of HER2 and TOP2A, which regulate cellular processes, such as replication and transcription, has been shown in a number of retrospective studies to be associated with poor survival. Tumors overexpressing HER2 have been shown to respond more favorably to anthracycline-based chemotherapies, and HER2 has become a standard predictive marker for response to treatment with the humanized monoclonal antibody trastuzumab. The HER2 proto-oncogene, which is located on chromosome band 17Q21, is overexpressed or amplified in approximately 15% to 25% of invasive breast cancers. Tanner et al reported that HER2 was amplified in 32.7% of their patients; of those, 37% had coamplification of TOP2A. Data obtained over the past few years have established that TOP2A amplification occurs only in the presence of HER2 amplification in most patients. In one series, approximately 8% of HER2-negative patients had changes in TOP2A that would have been overlooked if they had not been specifically investigated. The number of patients with TOP2A amplification in the absence of HER2 positivity may be in the range of 1.7 to 10.9%. Although HER2 and TOP2A are located on chromosome 17, they are on separate amplicons, as supported by the fact that HER2 and TOP2A often have different copy numbers within the same tumor. In breast cancer, TOP2A functions as more than just a proliferation marker: topoisomerases in the cell nucleus allow access to the information stored in DNA by regulating cellular processes such as replication and transcription. Deletion of the TOP2A gene can lead to reduced protein expression and, consequently, possible chemoresistance to topoisomerase inhibitors. The subpopulation of patients in which TOP2A overexpression is induced by gene amplification may be the ones who would benefit from treatment with topoisomerase inhibitors. Tanner et al noted that patients who had coamplification of HER2 and TOP2A had better relapse-free survival after nine cycles of tailored doseescalated anthracycline adjuvant therapy compared with the patients who had only three cycles of anthracycline-based therapy followed by treatment with high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin. Similarly, in other retrospective studies, patients with topoisomerase II-amplified breast cancer treated with anthracycline-based JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 16 JUNE 1 2006