Association Of HER2 Expression Research Articles

Association of HER2 expression in advanced urothelial carcinoma (aUC) and treatment outcomes with immune checkpoint inhibitors and enfortumab vedotin.

599 Background: HER2 immunohistochemistry (IHC) is not routinely assessed in patients (pts) with aUC, but it is an emerging predictive biomarker with the advent of HER2-targeting agents. aUC outcomes with respect to HER2 status following treatment with immune checkpoint inhibitors (ICIs) and enfortumab vedotin (EV) are unknown. Methods: We retrospectively identified pts with aUC and available biopsies tested for HER2 IHC and fluorescence in situ hybridization (FISH). HER2 status was assessed using modified GI criteria as HER2 high (IHC 3+ or IHC 2+/FISH+), HER2 low (IHC 2+/FISH- or IHC 1+) or HER2 negative (IHC 0). Pt characteristics and outcomes were abstracted from chart review. We compared outcomes following ICI monotherapy and EV-based regimens in pts with HER2-high or HER2-low tumors relative to HER2-negative, and HER2-positive (≥IHC 1+) tumors relative to HER2-negative. Observed response rate (ORR) evaluated by local investigator was compared in pts with scans after ≥1 treatment cycles using logistic regression, while progression-free survival (PFS) and overall survival (OS) from treatment start were assessed using the Kaplan-Meier method and Cox proportional hazards model. Results: Biopsies from 181 pts with aUC obtained from 3/2016 – 3/2023 were tested for HER2 (34 high, 88 low, 58 negative, 1 indeterminate). In this group, 43 pts received ICI [38 (88%) pembrolizumab; 5 (12%) atezolizumab] and 37 EV [31 (82%) monotherapy; 6 (18%) combination regimen]. Pt characteristics and outcomes are shown in the Table. Among pts treated with EV, HER2-negative pts had decreased PFS (HR: 0.18, 95% CI 0.03 – 0.94, p=0.04) relative to HER2-high. No other differences were noted for any cross-group comparison. For pts treated with ICI, no differences in outcomes were observed for any comparisons based on HER2 status. Conclusions: In this single institution retrospective analysis, pts with aUC and HER2-high IHC expression had longer PFS relative to pts with HER2-negative expression when treated with EV-based regimens. No differences were observed in ICI outcomes based on HER2 expression. These hypothesis-generating results should be validated in larger cohorts. [Table: see text]

ASSOCIATION OF HER2/NEU EXPRESSION WITH PATIENT PROGNOSIS IN PRIMARY GASTRIC ADENOCARCINOMA

Introduction: Gastric carcinoma is the second leading cause of cancer related deaths in the world. Aim of the present study was to determine the association of HER2 overexpression with prognostic factors in gastric adenocarcinoma affected Pakistani patients.
 Methods: For this purpose, immunohistochemical staining of gastric cancer patients (n=200) was performed. HER2 was found to be overexpressed in 70% of cases included in the study. Association of HER2 expression with age greater than 40 years at the time of diagnosis, histological types and moderately differentiated grades of primary gastric adenocarcinoma was observed.
 Results: HER2 was found to be overexpressed in 20% of cases. No association of HER2 was identified with the gender of the patients. Interestingly, HER2, overexpression was present in 75% of intestinal and 37% of diffuse type gastric adenocarcinoma. Based on tumor differentiation, well-differentiated (grade I) and moderately differentiated type (grade II) adenocarcinoma showed overexpression of HER2 in 90 and 80% patients respectively. Moreover, 60% patients having poorly differentiated adenocarcinoma (grade III) also exhibited HER2 overexpression.
 Conclusion: Due to presence of HER2 overexpression in diffuse type gastric carcinoma as well, it is suggested that every case of gastric adenocarcinoma should be tested for HER2 overexpression so that they can be offered targeted molecular therapy for better survival.

Association of HER2 expression with pathologic features and prognosis in stage II and III colon cancer.

3524 Background: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression in stage II and III colon cancer after curative resection. Methods: Paraffin-embedded tumors from consecutive primary stage II and III colon cancer patients were analyzed for HER2 protein expression by immunohistochemistry between April, 2013 and May, 2020. HER2 determination of immunohistochemistry scores (0/1+/2+/3+) was according to HERACLES diagnostic criteria. Results: A total of 2088 stage II and III colon cancer patients were included (53.8% stage II, 46.3% stage III). HER2 scored positive (3+) was detected in 48(2.3%) tumors, and was correlated with younger age (P < 0.001), well/moderate differentiation (P = 0.026), proficient mismatch repair (pMMR) (P = 0.045) and KRAS wild-type (P < 0.001). HER2 scored positive (3+) was not significantly associated with disease-free survival (DFS) compared with HER2 scored negative (0/1+), neither in stage III patients (multivariable HR, 0.86; 95CI, 0.38 to 1.94; P = 0.717), nor in stage II patients (multivariable HR, 1.68; 95CI, 0.74 to 3.84; P = 0.218). In a separate analysis involving stage II patients without any high-risk factor (n = 741), those with HER2 scored positive (3+) tumors (n = 16) showed significantly reduced DFS (multivariable HR, 2.91; 95CI, 1.04 to 8.81; P = 0.041) compared with patients with HER2 scored negative (0/1+) tumors, independent of sex, age and MMR status. Conclusions: HER2 scored positive (3+) was independently associated with poor DFS in stage II colon cancer patients without high-risk factors. HER2 expression determination may help to judge the prognosis of those patients and guide adjuvant chemotherapy.

Association of HER-2 Expression with Age, Tumour Size, Grade, Differentiation and Lymph Node Deposit in Patients with Breast Cancer

Breast Cancer incidence is increasing, but its mortality has started to decrease. The existence of strong reliable prognostic and predictive factors is of utmost importance to the practicing clinician. Some factors are only prognostic such as age, tumor size, and lymph node status, while others are both prognostic and predictive such as hormone receptors and human epidermal receptor 2 (HER’s-2) status. This study was done to see the association of HER-2 positivity with age, tumour size, grade, differentiation and lymph node deposit in breast cancer patient. A cross-sectional type of descriptive study was conducted among 50 patients. Patient age range is from 22 to 64 years (mean 42.64 ± 10.26 years). Tumour size ranged from 1 to 8 cm (mean 4.39 ± 1.564cm). Well differentiated tumour was 20, moderately differentiated tumour was 18 cases and poorly differentiated was 12 cases. HER-2/neu negative included 35(70%) cases and positive included 15(30%) cases. In this study it was found that the association between age groups and tumour differentiation with HER-2/neu status was statistically significant (p= <0.05).
 TAJ 2019; 32(2): 14-21

A Study of Hormone Receptor Status in Breast Carcinoma and use of HER2-Targeted Therapy in a Tertiary Care Center of India

Abstract Aims: The aim is to study the hormone receptor status, association of HER2 expression with prognostic factors and use of HER2-targeted therapy in North Indian breast cancer patients. Subjects and Methods: Immunohistochemistry reports of 288 breast cancer patients registered in the department of Radiotherapy, SMS Medical College, Jaipur in 2015–2016 were analyzed for estrogen receptor (ER), progesterone receptor (PR), and c-erb B-2 protein (HER2/neu) expression. Equivocal HER2 (2+) was further confirmed by fluorescent in situ hybridization (FISH). Number of patients receiving HER2/neu-targeted therapy was also studied. Results: For ER, positive status was more common (56%), whereas for PR and HER2/neu, negative status was more common (59% and 60% resp.). HER2 status was unknown for 25% patients. The percentage of equivocal HER2 (immunohistochemistry 2+) cases showing amplification on FISH was also high (56.7%). The percentage of eligible cases for targeted therapy actually receiving it was low (28%). The percentage of triple negative phenotype (ER-/PR-/HER2-) was high (29.8%). Triple-negative breast cancer phenotype was more common in young-aged premenopausal women but was not statistically significant. All HER2/neu + cases were infiltrating ductal carcinoma. HER2/neu expression was significantly higher with large tumor size (P = 0.001), high tumor grade (P < 0.001), advanced stage (P = 0.001), greater number of positive lymph nodes (P = 0.02), and ER/PR negativity (P < 0.001). Conclusions: Most of the breast cancer patients are ER and/or PR positive and HER2/neu negative. The percentage of triple-negative phenotype is higher. More than half of HER2/neu 2+ cases show amplification on FISH assay. The percentage of eligible patients actually receiving targeted therapy is low. HER2/neu protein expression is significantly higher with adverse features such as large tumor size, high grade, advanced stage, greater number of positive lymph nodes, and ER/PR negativity.

Association of Her-2 Expression and Clinicopathological Parameters in Colorectal Carcinoma in Indian Population.

BACKGROUND:Human epidermal growth factor receptor 2 (HER-2) is an oncogenic gene and a well-established therapeutic target in several cancers including breast and ovary.AIM:The present study aimed to compare HER-2 expression status with histological grades as well as Clinicopathological parameters including age, bleeding per rectum, pain/burning sensation in defecation and exercise.METHODS:Her-2 status was assessed by immunohistochemistry (IHC).RESULTS:Results of the study shows that 40.96% patients were Her-2 positive for expression and a statistically significant difference (p-value = 0.004) was observed in histological grades where most of the cases were of grade II. We also observed a significant difference in histological grades with gender (p-value = 0.04), as well as in both the age groups ≤ 55 years and > 55 years (p-value = < 0.0001). Patients with the bleeding rectum and pain/burning sensation in defecation had grade II/III tumours (93.4%, 88.7%) respectively. A significant association was observed between bleeding per rectum and pain/burning sensation in defecation. About 95% of patients with pain/burning sensation in defecation had bleeding per rectum.CONCLUSION:To conclude, Her-2 can be a potential prognostic marker in CRC. The role of age, tumour grade and bleeding per rectum/burning sensation in defecation are of significant worth. Thus, CRC cases of high grades can be screened for HER-2/neu positivity so that they can be subjected to mAb-based individualised therapy.

Prognostic role of human epidermal growth factor receptor 2 in resectable gastric cancer: a meta-analysis

To investigate the prognostic association of human epidermal growth factor receptor 2 (HER-2) with resectable gastric cancer. The literature databases, such as PubMed, EMBASE, Cochrane Library, Web of Science, CBM,CNKI, and Wanfang database, were extensively searched to retrieve the clinical studies of HER-2 expression in resectable gastric cancer published before July, 2013. The association of HER-2 expression with overall survival(OS) was examined. The state 12.0 version software was used for meta-analysis. The quality of these studies were assessed using the Newcasthe-Ottawa scale. There were nine studies meeting the inclusion criteria for meta-analysis including 4787 cases and the scores of all studies are more than 6 points. Meta-analysis showed no significant heterogeneity (I(2)=10.6%, P=0.347) among these studies. There was no significant difference in overall survival between positive HER-2 and negative HER-2 patients (HR=1.16, 95% CI:0.97-1.38, P=0.114). HER-2 overexpression in the tumor is not identified as a significant prognostic factor in patients with resectable gastric cancer.

Lack of HER-2 gene amplification and association with pathological and clinical characteristics of differentiated thyroid cancer.

Human epidermal growth factor receptor 2 (HER-2) is a well recognized prognostic and predictive factor in breast cancer. However, the role of HER-2 in thyroid cancer remains controversial. The aim of this study was to evaluate HER-2 expression in differentiated thyroid cancer (DTC) and determine whether there is an association with other clinical and pathological characteristics. A total of 69 patients with DTC were investigated, 58 of whom had papillary and 11 follicular carcinomas. HER-2 was detected by immunohistochemical examination on sections from formalin-fixed, paraffin-embedded tumor tissues. Tumors with HER-2 expression classed as +1 and +2 were retested with chromogenic in situ hybridization. Clinicopathological data were retrieved from the hospital records of the patients. HER-2 overexpression was found in 4 (6.9%) of the 58 patients with papillary carcinoma, whereas there was no HER-2 overexpression in any of the 11 cases of follicular carcinoma. There was no association of HER-2 expression with tumor size, pathological grade and cervical lymph node metastasis. In conclusion, there were no HER-2 positive cases of follicular carcinoma and the incidence of HER-2 overexpression in papillary carcinoma was very low. Thus, HER-2 cannot be used routinely as a prognostic or predictive factor in DTC. The expression of other epidermal growth factor receptors in DTC merits further investigation.

(18)F-FDG PET/CT of advanced gastric carcinoma and association of HER2 expression with standardized uptake value.

Expression of HER2 in gastric carcinoma has direct prognostic and therapeutic implications in patient management. The aim of this study is to determine whether a relationship exists between standardized uptake value (SUV) and expression of HER2 in advanced gastric carcinoma. We analyzed the (18)F-FDG PET/CT results of 109 patients that underwent gastrectomy for advanced gastric carcinoma. The (18)F-FDG PET/CT imaging was requested at the initial staging before surgery. The examinations were evaluated semi-quantitatively, with calculation of maximum standardized uptake values (SUVmax). The clinicopathologic factors, including HER2 overexpression, were determined from tissue obtained from the primary tumor. Metabolic and clincopathologic parameters were correlated using a t-test, one way ANOVA and chi-square test. Immunohistochemically, 26 patients (23.8%) showed HER2 overexpression. This overexpression was significantly associated with high SUV level (P=0.02). The SUV level was significantly correlated with tumor size (P=0.02) and differentiation (P<0.001), and Lauren histologic type (P=0.04). Multivariate analysis showed HER2 overexpression, large tumor size, and differentiation (P=0.022, P=0.002, P<0.001) were significantly correlated with the high level of SUV in advanced gastric carcinoma. No association was found between SUV and T stage and lymph node metastasis. A receiver-operating characteristic curve demonstrated a SUVmax of 3.5 to be the optimal cutoff for predicting HER2 overexpression (sensitivity; 76.9%, specificity; 60.2%). An association exists between high SUV and HER2 overexpression and (18)F-FDG PET/CT could be a useful tool to predict the biological characteristics of gastric carcinoma.

The relationship between quantitative HER2 gene expression by the 21-gene RT-PCR assay and adjuvant trastuzumab (H) benefit in NCCTG (Alliance) N9831.

520 Background: There is considerable interest in developing HER2 testing criteria for adjuvant H. We used the 21-gene assay to examine the relationship of HER2 mRNA to benefit from H. Methods: N9831 compared adjuvant chemotherapy AC-T to concurrent chemotherapy-trastuzumab AC-TH in stage I-III HER2+ breast cancer. Recurrence Score (RS) and HER2 mRNA expression were determined by Oncotype DX (neg&lt;10.7, equiv 10.7 to &lt;11.5, and pos ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with H benefit for distant recurrence. Results: Median follow-up: 7.4 yrs. Of 1,940 total pts, 901 had consent and sufficient tissue. HER2 by RT-PCR was neg in 130 (14%), equiv in 85 (9%), and pos in 686 (76%) pts. Concordance between HER2 assessments was 95% for RT-PCR vs central IHC (&gt;10% + cells = +), 91% for RT-PCR vs central FISH (≥2.0 = pos) and 94% for central IHC vs central FISH. In the primary analysis, the association of HER2 expression with H benefit was marginally non-significant (P=0.057). In hormone receptor pos pts (local IHC) the association was significant (P=0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 mRNA expression levels. The observed treatment benefit in low HER2 pts was not due to imbalance between arms in RS and individual gene expression values. Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR was high. Association of HER2 mRNA expression with H benefit was marginally non-significant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in the pts with either IHC+ or FISH+ tumors. Benefit was observed in pts with high HER2 by RT-PCR but also observed for the small groups of pts with negative results by quantitative RT-PCR or FISH (Table). Plausible mechanisms for this observation will be discussed. [Table: see text]

HER2 status of patients with invasive breast cancer in a population at a single UK centre: Correlation with tumor characteristics

11094 Background: The human epidermal growth factor receptor 2 (HER2) overexpression, has been correlated with higher histological grade, increased tumour size, positive lymph node status, and negative or lower oestrogen receptor (ER) expression. Our aim was to look at the association between HER2 status, patient age and tumour histopathologic characteristics. Methods: We analysed retrospectively 735 cases of invasive breast cancer treated between the years 2000 and 2004. HER2 was measured by immunohistochemistry (IHC) and all IHC 2+ tumours were also tested by fluorescent in situ hybridisation (FISH). All information was collected from pathology reports in patient case records. Results: A total of 143 (19.5%) tumours were HER2 positive (120 IHC 3+ and 23 IHC 2+/FISH+). Of the 66 tumours that were IHC 2+, 23 (34.8%) were FISH-positive. The age of most patients (75.8%) was over 50 years but there was a higher incidence (28%) of HER2 overexpresion in the 40–49 age group compared to all other age groups, the incidence of HER2 overexpression was still at least 17–18% in all age groups, including patients aged =70 years. Although, a high proportion of patients (62.2%) had tumours less than 2 cm in size, comparison of tumours less than 2 cm with those greater than 2 cm showed no predictive effect of size on HER2 expression. Over half of the patients had lymph node-negative disease (55.2%) and despite some association of HER2 expression with lymph node involvement (odds ratio of 1.23 for comparison of lymph node-positive versus negative), 19% of lymph node-negative tumours overexpressed HER2. Most tumours were high grade (32.8% grade 3, 44.1% grade 2 ) and although the proportion of HER2 overexpression increased with increasing tumour grade, some grade 1 tumours still overexpressed HER2. A higher proportion (28%) of ER-negative tumours was HER2 positive compared to ER-positive tumours (18%); however, co-expression of HER2 and ER occurred in 14% (105/735) of all primary cancers. Conclusions: In conclusion, it is not possible to predict which patients will be HER2 positive. Therefore, it is essential that HER2 status should be determined in all patients with invasive breast cancer to allow a decision on the use of trastuzumab and guide the choice of chemotherapy. No significant financial relationships to disclose.

Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma?

Muscle-invasive urothelial carcinoma of the bladder is a highly lethal malignancy, particularly in the setting of locally advanced or metastatic disease. Prior reports of HER2/neu (c-erbB-2 or HER2) expression in bladder carcinoma have been mixed; therefore, its value in predicting metastasis or response to therapy has not been established in this tumor type. Thus, the authors evaluated a possible correlation between HER2 expression in patients with high-grade, muscle-invasive urothelial carcinoma of the bladder and outcome in patients who received paclitaxel-based chemotherapy. Archival tumor tissues from patients with advanced urothelial carcinoma who were enrolled on two clinical trials of paclitaxel-based chemotherapy regimens were analyzed for HER2/neu expression by immunohistochemistry (IHC). The authors correlated HER2 expression by IHC with clinical outcomes, such as response rate, progression free survival, and overall survival, using univariate analysis. Thirty-nine tumor specimens were assessed for HER2 expression, most of which (70%) were collected from patients with metastatic disease. All were high-grade urothelial carcinomas (transitional cell carcinomas, Grade 3). Strong HER2 expression (2+/3+) was seen in 28 patients (71%). Patients with responding disease had an HER2 expression rate of 78%, similar to the rate seen in patients with stable disease (75%). In contrast, patients with progressive disease had an HER2 expression rate of 50%, although this difference did not reach statistical significance. However, univariate analysis showed that increased HER2 expression predicted an improvement in progression free and overall survival. When HER2 status was used as a dichotomous variable, tumors with positive HER2 expression did not have any association with response or with progression free survival; however, positive HER2 status was associated significantly with a decreased risk of death (P = 0.03). This study of HER2 expression in bladder carcinoma focused on patients who were treated prospectively in a standardized fashion, unlike prior studies that have evaluated banked, archival specimens. The authors confirmed the findings of others that high-grade, muscle-invasive urothelial carcinoma of the bladder has a significant rate of HER2 expression (71%). However, contrary to other reports, the current study found that HER2 expression in the context of paclitaxel-based chemotherapy decreased the risk of death significantly. Further research is warranted on the possible association of HER2 expression with chemosensitivitiy in urothelial carcinoma as well as the efficacy of HER2-targeted therapies (such as trastuzumab) for patients with high-grade, muscle-invasive urothelial carcinoma of the bladder.