Human Epidermal Growth Factor Receptor-2 Status Research Articles

Outcome of Male Breast Cancer: A Matched Single-Institution Series

BackgroundBreast cancer occurs rarely in men, accounting for approximately 1% of all breast carcinomas. Data on prognosis principally derive from retrospective studies and from extrapolation of female breast cancer series. Patients and MethodsA total of 99 men with invasive breast cancer were matched with 198 women with breast cancer who had surgery at the same institution from 1999 to 2010. Matching variables were year of surgery, age, primary tumor size, nodal involvement, hormone receptor status, status of HER2 (human epidermal growth factor receptor 2 [ERBB2]), Ki-67, and grade. Median follow-up was 8.6 years. ResultsDisease-free survival (DFS) was significantly poorer in the men (10-year DFS, 51.7% vs. 66.5%; hazard ratio [HR], 1.79; 95% CI, 1.19-2.68; P = .004). Similar results were observed for overall survival (OS) (10-year OS, 70.7% vs. 84.2%; HR, 1.79; 95% CI, 1.01-3.15; P = .043). The cumulative incidence of death for causes not related to the primary breast cancer was significantly higher for men than for women (HR, 2.87; 95% CI, 1.58-5.22; P = .001), whereas the breast cancer–specific survival (BCSS) was similar between the 2 groups (10-year BCSS, 81.5% vs. 88%; HR, 1.27; 95% CI, 0.62-2.59; P = .517). ConclusionThis comparative series found that men with breast cancer had a poorer DFS and OS when compared with women. The men also had a higher risk of contralateral tumors and second primaries. Appropriate counseling, surveillance, and prevention are recommended to improve survival for these individuals.

HER2 in Breast Cancer

HER2 (human epidermal growth factor receptor 2) receptor is a membrane tyrosine kinase and when activated affects cell proliferation and survival. The HER2 oncogene is located on chromosome 17q12. HER2 amplification is the primary pathway of HER2 receptor overexpression and is a major driver of tumor development and progression in a subset of breast cancers. HER2 is amplified in about 15% to 20% of breast cancers. The overexpressed HER2 receptor is a valuable therapeutic target. The 2007 ASCO guidelines mandate that HER2 should be evaluated in every invasive breast cancer, either at the time of diagnosis or recurrence to guide therapy. Currently HER2 testing is carried out by several methods. It is crucial to standardize testing techniques to accurately assess HER2 status. The aim of this review on HER2 in breast cancer is to discuss the important aspects of HER2 biology, its significance in breast cancer, and the current standards for its detection.

Comparison of HER2 status in breast cancer patients using CISH and immunohistochemical protocols

The evaluation of human epidermal growth factor receptor-2 (HER2) status in invasive breast carcinoma has been proven to be of prognostic value for the patients. HER2 overexpression is found in about 20% of the breast cancer cases and is thought to be associated with a poor clinical outcome. The test can be performed by different molecular methods, including in situ hybridization or immunohistochemistry. We evaluated the accuracy of our immu-nohistochemical protocol for HER2 breast cancer testing in comparison to the chromogenic in situ hybridization method (CISH). A total of 19 cases were analyzed. Using the HercepTest from Dako, three cases were initially evaluated as 3+ strong positive (with concomitant hormone receptor positivity). Fifteen cases were evaluated as 2+ weak positive and one triple negative case as 1+ negative. The results from CISH confirmed HER2 gene amplification in all three 3+ positive cases, whereas 46.7% of the 2+ cases showed gene amplification. The triple negative 1+ case did not reveal HER2 gene amplification. These results indicate that our immunohistochemical protocol has satisfactory sensitivity for detecting HER2 3+ positive cases and can reliably be used to select the HER2 negative cases. Nevertheless, CISH protocol should be used to clarify all ambiguous cases.

Overexpression of HER-2/neu protein attenuates the oxidative systemic profile in women diagnosed with breast cancer

About 20% of breast cancer patients over-express the human epidermal growth factor receptor-2 (HER2), which is associated with enhanced tumor malignancy. The influence of HER2 overexpression on oxidant/antioxidant parameters in humans remains unknown; therefore, we investigated the oxidative profile in women according to their HER2 status. Fifty-two controls and 52 breast cancer (BC) patients were enrolled. The BC patients were subdivided into HER-, negative for HER2 overexpression, and HER+, positive for HER2 overexpression. Oxidative stress profilling was measured by malondialdehyde (MDA), free 8-isoprostane F2, protein carbonyl content, nitric oxide (NO), total radical antioxidant parameter (TRAP), superoxide dismutase (SOD), catalase activity, and glutathione (GSH) levels. Total thiol content and lipoperoxidation were evaluated in HCC1954 and MCF-7. Cells overexpressing HER2 presented enhanced oxidative stress. Increased erythrocyte lipoperoxidation was found in BC patients, while plasma lipoperoxidation was detected in both the BC and HER- groups. Decreased MDA levels were found in the HER+ group, suggesting that HER2 overexpression may protects against plasma lipoperoxidation. No alteration was found for 8-isoprostane F2, NO, and carbonyl content. TRAP was decreased in BC patients, while HER2 overexpression increased SOD and prevented decreased GSH levels. These data help to understand the HER2 overexpression in oxidative signaling and may enable the development of new strategies for anti-HER2 therapy.

Evaluation of Serum Levels of HER2, MMP-9, Nitric Oxide, and Total Antioxidant Capacity in Egyptian Breast Cancer Patients: Correlation with Clinico-Pathological Parameters

Breast cancer is by far the most common cancer in women worldwide and the main cause of cancer-related mortality. Breast cancer accounts for 38% of all malignancies among Egyptian women. The aim of our study was to evaluate the serum levels of human epidermal growth factor receptor-2 (HER2), matrix metalloproteinase-9 (MMP-9), nitric oxide (NO), and total antioxidant capacity (TAC) in breast cancer patients and to correlate these markers with clinico-pathological parameters. Serum HER2, MMP-9, and carcinoma antigen 15-3 (CA 15-3) were assessed in 80 breast cancer patients and ten healthy subjects as a control group by the enzyme-linked immunosorbent assay (ELISA) technique while NO and TAC were assessed by a colorimetric method. Serum HER2 was ≥15 ng/mL in nine patients (11.3%). High HER2 ECD levels were significantly associated with tissue HER2 (P<0.0001), metastasis (P= 0.0024), and negativity of both estrogen (P=0.0075) and progesterone (P=0.0239) receptors. Serum MMP-9 (P=0.0013), NO (P<0.0001), and CA 15-3 (P<0.0001) were significantly increased while serum TAC was significantly (P=0.01) decreased in breast cancer patients as compared to the control group. Serum MMP-9 was increased significantly (P=0.028) in metastatic patients as compared to non-metastatic patients. We found a positive correlation between serum HER2 and CA 15-3 (r=36, p=0.005). In conclusion, serum HER2 reflects the tissue HER2 status of breast cancer, so the determination of serum HER2 is helpful in assessing HER2 status, but in addition, a high level may reflect metastatic disease. Also, serum MMP-9 can be useful for denoting the development of metastasis in breast cancer patients. Follow-up is needed to evaluate the value of serum HER2 and MMP-9 as prognostic markers.

HER2 status in elderly women with breast cancer

HER2 (human epidermal growth factor receptor 2) is an important biomarker in breast cancer, but its prevalence in elderly women is not well established. Previous studies reported HER2 status based on either immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) interchangeably. However, the tests may give discordant results. We report the prevalence of HER2 amplification in elderly women using only FISH. We retrospectively identified women 65 years and older undergoing core biopsy, lumpectomy or mastectomy for primary breast malignancy at a single institution between 2009 and 2011. Data collected included age, histopathological type, hormone receptor status, and HER2 status. Descriptive statistics were performed using SAS Software, Version 9.2. One hundred fifty-eight women were included in the study. Most had invasive ductal carcinoma (74.7%), and were positive for either estrogen (ER) or progesterone (PgR) receptors (82.3% and 70.0%, respectively). Only 17% were negative for both ER and PgR; 11.4% were triple negative. Nineteen samples (12.0%) were positive for HER2. In univariate analyses, hormone receptor and HER2 status did not vary with age. When stratified by age, 60% of women with hormone receptor/HER2 positive tumors were younger than 70 years, compared with 22.2-33.3% of women in other subgroups. The difference was not statistically significant (p=0.20). This study adds to the knowledge of the biology of breast cancer in elderly women. Triple negative tumor incidence was similar to that previously reported for women under 70 years old, but HER2 positive tumors were less common. Additional prospective studies are needed to confirm our findings.

Association of estrogen receptor, progesterone receptor and HER2 following neoadjuvant systemic treatment in breast cancer patients undergoing surgery

The aim of this study was to analyze the association between the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) in breast cancer with neoadjuvant therapy by using tissue biopsy and surgical specimens. This study included 78 patients with breast cancer, who presented to our hospital between June 1999 and June 2011, and were treated with neoadjuvant therapy and subsequent mastectomy or partial mastectomy. All clinicopathological data regarding pre-neoadjuvant biopsy and definitive surgical specimens were reviewed for accuracy. The status of ER, PR, and HER2 was determined by immunohistochemistry. Paired samples from 78 women (mean age 51.4 ± 11.7 years) were successfully analyzed. A switch in the status of ER was identified in 16 patients (20 %); PR, in 18 (23 %); and HER2, in 27 (35 %). There were no significant differences in the status of ER, PR, and HER2 between the primary tumor and the resected tumor after neoadjuvant therapy. Neoadjuvant therapy does not significantly influence the status of the steroid hormone receptors and the HER2 level in our study. Initial biopsy may be reliable for determining the appropriate adjuvant therapy, but final pathology are still needed to evaluate the prognosis and provided the alternative treatment when tumor recurrence. Further prospective study is needed to optimize the care available for breast cancer patients.

Distribution and prognosis of molecular breast cancer subtypes defined by immunohistochemical biomarkers in a Spanish population-based study

BackgroundThe objective of this study is to analyze the distribution, clinicopathological features, relative survival rate and excess risk of death among females diagnosed with invasive breast cancer and classified by molecular subtype from ten Spanish cancer registries. MethodThree thousand four hundred and eighty incident cases of women – mostly diagnosed in 2005 – were classified into five molecular subtypes according to immunohistochemical status of hormonal receptors and HER2 (human epidermal growth factor receptor 2): estrogen receptor (ER) and/or progesterone receptor (PR)+ and HER2−, ER+ and/or PR+ and HER2+, HER2-overexpressed (ER−, PR− and HER2+), triple negative (ER, PR and HER2−) and unclassified (hormonal receptor or/and HER2 unknown). Relative survival rates at 1, 3 and 5years and relative excess risks (RER) of death adjusting for molecular subtype, age, stage and histological grade were estimated. ResultsMarked differences in clinicopathological characteristics and relative survival rate were observed between molecular subtypes. Compared with women with ER+ and/or PR+ and HER2−, ER+ and/or PR+ and HER2+ cases had an RER of 1.00 (95% CI: 0.66 to 1.52) after adjusting for age, stage and histological grade, whereas HER2-overexpressed, triple negative and women with unclassified subtypes presented an RER of 1.72 (95% CI: 1.15 to 2.57), 3.16 (95% CI: 2.26 to 4.41) and 2.55 (95% CI: 1.96 to 3.32), respectively. ConclusionThe prognostic value of molecular subtype persists when adjusting for age, stage and histological grade. Hormone receptor-positive tumors were associated with a better prognosis when compared with HER2-overexpressed and triple negative subtypes. Further research is required to improve triple negative prognosis.

Evaluation of serum HER2 extracellular domain in in metastatic gastric or gastroesophageal junction cancer: Correlation with HER2 status by immunohistochemistry and fluorescence in situ hybridization and clinicopathologic parameters.

4107 Background: To explore the association between serum human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD) and tissue HER2 status, their relationship with clinicopathological parameters and impact on overall survival (OS) in metastatic gastric or gastro-oesophageal junction (GEJ) adenocarcinoma. Methods: A total of 219 histologically confirmed inoperable locally advanced, recurrent, or metastatic gastric or GEJ adenocarcinoma were included. Serum HER2 ECD was measured by chemiluminescent assay. Tissue HER2 status was accessed by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) assay. Results: The median serum ECD level was 9.3 ng/ml (range 3.0 to &gt;350). Tissue HER2 status was positive (IHC3+ or 2+ with FISH amplification) in 37 patients (16.9%) and negative in 182 patients (83.1%). Statistically significant associations were found between serum HER2 ECD level and HER2 status assessed by IHC and FISH. The ROC-analysis suggested the cutoff of 16.35 ng/ml (24 of 219 patients had HER2 ECD &gt;16.35 ng/ml ) could produce a sensitivity of 51.4% and a specificity of 97.3% to predict tissue HER2 status. If the cutoff value was increaseed to 22 ng/ml, then all 12 patients with serum HER2 ECD &gt;22 ng/ml were HER 2 positive in primary tumor, corresponding to a specificity of 100% and a sensitivity of 32.4%. High serum HER2 ECD levels were strongly associated with liver metastasis (P &lt; 0.001), the intestinal histologic type (Lauren's classification) (P =0.003), large number of metastais (&gt;2) (P=0.012) and increased LDH level (P &lt; 0.001) . High serum HER2 ECD levels were more common in GEJ adenocarcinoma although the difference had no stastical significance. HER2 ECD levels did not show a significant impact on OS. Conclusions: A significant association was observed between serum HER2 ECD levels and tissue HER2 status in metastasis gastric or GEJ adenocarcinoma. The high specificity of serum HER2 ECD assay to predict tissue HER2 status suggests its potential use as a surrogate marker of the HER2 status in gastric cancer.

Joint detection of multiple immunohistochemical indices and clinical significance in breast cancer

Breast cancer is one of the most common malignancies in women. This study was conducted to analyze the association between the expressions of eight immunohistochemical (IHC) indices and clinicopathological characteristics in breast cancers (BCs) and investigate the clinical significance. IHC Envision ldpe-g-nvp was used to detect the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), p53, type II topoisomerase (TOPO II) and Ki-67 in postoperative paraffin blocks of 286 cases of invasive BC and statistically analyzed their correlations with clinicopathological characteristics. The positive rates of ER, PR, HER2, VEGF, p53, EGFR, TOPO II and Ki-67 expression were 62.24, 41.96, 57.34, 53.85, 81.82, 46.85, 54.55 and 69.93%, respectively. ER expression was negatively correlated with age, tumor size and histological grade (P<0.05) and PR expression was negatively correlated with age and histological grade (P<0.05). Among the ER, PR and c-erbB-2 statuses, a significant correlation was observed between ER expression and PR status (P=0.0000), whereas the expression of ER and PR exhibited a negative correlation with HER2 status (P<0.05). We also demonstrated a significant correlation between EGFR expression and lymph node metastasis (P=0.0240), p53 expression and tumor size (P=0.0300), p53 and Ki-67 expression and histological grade (P<0.05) and the expressions of VEGF, EGFR, p53, TOPO II, Ki-67 and HER2 status (P<0.05). In addition, the Luminal B and HER2/neu subtypes exhibited a close correlation with age (P<0.01), while the HER2/neu and triple-negative subtypes were positively correlated with poor histological grade (P<0.05). In conclusion, there is a definite correlation between IHC indices and clinicopathological characteristics in BCs. Combined detection of these indices may be significant in the evaluation of biological behavior and prognosis of BC and thus in the diagnosis and comprehensive treatment of this disease.

Phosphorylation of estrogen receptor α at serine 118 is correlated with breast cancer resistance to tamoxifen

The aim of the present study was to explore the correlation between estrogen receptor α (ERα) phosphorylation at serines 118 and 167 and the responsiveness of patients with primary breast cancer to tamoxifen. Tumors from 104 patients with primary breast cancer who received adjuvant tamoxifen therapy at The Affiliated Cancer Hospital of Shantou University Medical College between January 2001 to December 2007 were subjected to immunohistochemical analysis with specific antibodies against ERα phosphorylated at either serine 118 (pERα-S118) and/or serine 167 (pERα-S167). ERα phosphorylation at the two sites was correlated with either the disease-free survival or the overall survival rate of these patients using the Kaplan-Meier survival analysis. pERα-S118 and pERα-S167 were found to be expressed in the cell nucleus of 25.0% (26/104) and 26.9% (28/104) of breast cancers, respectively. The expression of pERα-S118 was positively correlated with the human epidermal growth factor receptor-2 (HER-2) status (χ2=6.85, P=0.01). The Kaplan-Meier analysis revealed a poorer disease-free (P=0.022) and overall survival (P=0.013) in breast cancer patients expressing pERα-S118, but not in those expressing pERα-S167. In conclusion, pERα-S118 was correlated with the HER-2 status and predicted breast cancer resistance to tamoxifen.

Quantitative detection of HER2 protein concentration in breast cancer tissue does not increase the number of patients eligible for adjuvant HER2-targeted therapy

Human epidermal growth factor receptor-2 (HER2) is overexpressed in 15-20% of breast cancer patients and is associated with an aggressive tumor and a poor prognosis. Currently, patients are selected for adjuvant HER2-targeted therapy based on HER2 status by immunohistochemistry (IHC) and fluorescence insitu hybridization (FISH). In this study, we assessed the clinical significance of tissue HER2 status determined by a quantitative immunoassay using ADVIA Centaur. We investigated the hypothesis that the clinical outcome is worse in a group of patients defined as tissue HER2-positive only by Centaur, but not treated with adjuvant HER2-targeted therapy, compared to patients defined as HER2-positive by IHC/FISH and therefore treated with adjuvant HER2-targeted therapy. Tumor tissue was obtained at primary surgery from 415breast cancer patients between 2004 and 2010. HER2 status was determined by quantitative immunoassay of fresh-frozen tissue and by IHC/FISH of corresponding paraffin-embedded tissue. We compared the clinical outcome in four groups of patients defined by tissue HER2 status and adjuvant HER2-targeted therapy. The final analysis included 379patients after a median follow-up of 3.9 years for invasive disease-free survival (IDFS) and 4.2 years for overall survival (OS). The quantitative Centaur assay defined a greater number of patients (100patients, 26.4%) as HER2-positive than IHC/FISH (63patients, 16.6%) (P<0.0001). No significant difference in IDFS (P=0.159) and OS (P=0.150) was observed among the four groups of patients. However, in the IHC/FISH-positive group without adjuvant HER2-targeted therapy (group2), a significantly greater number of events was found compared to the Centaur-positive group without adjuvant HER2-targeted therapy (group3) for both IDFS (P=0.025) and OS (P=0.020). Quantitative HER2 determination by Centaur did not define a new group of patients eligible for HER2-targeted therapy. Currently, tissue HER2 status defined by IHC/FISH analysis remains the gold standard.

Effects of polysomy 17 on HER-2 gene and protein expression and its clinicopathologic significance in breast cancer

To explore the effects of polysomy 17 on human epidermal growth factor receptor-2 (HER-2) testing and study its clinicopathologic significance. We retrospectively analyzed the HER-2 status by fluorescence in situ hybridization (FISH) and HER-2 protein expression by immunohistochemistry (IHC) in a cohort of 619 patients with invasive breast cancer. The relationship between polysomy 17 and various clinicopathologic parameters was assessed. Polysomy 17 was observed in 31.8% of cases, but more frequently in the IHC(3+) (41.9%) than in the IHC(2+)(27.7%) and IHC(1+/0) (11.1%) subgroup (P = 0.001). There was no significant correlation between the frequency of polysomy 17 and HER-2 status in each IHC subgroup (P > 0.05). Among the cases without gene amplification by FISH, 9 of 15 IHC(3+) cases showed polysomy 17. As compared with the amplified group, un-amplified polysomy 17 patients were associated with such good prognostic indicators as greater hormone receptor positivity (P < 0.001) and lower Ki-67 index (P = 0.003) with a trend towards those with neither amplification or polysomy. The frequency of polysomy 17 is partially correlated with HER-2 protein expression but not HER-2 amplification. And polysomy 17 is a major factor in strong HER-2 protein overexpression in 3+ non amplified cases. Tumors displaying un-amplified polysomy 17 resemble more HER-2-negative than HER-2-positive counterparts.

Central reporting of human epidermal growth factor receptor-2 (HER2) status and adherence to testing and adjuvant trastuzumab treatment guidelines in Ontario.

166 Background: Quality monitoring pertaining to trastuzumab treatment requires knowledge of 1) HER2 status, 2) testing methods and sequence, and 3) treatment received. We examined the patterns of HER2 test documentation for early-stage breast cancer (ESBC) patients in Ontario and the adherence of practice patterns to Canadian HER2 testing consensus guidelines and adjuvant trastuzumab treatment guidelines from Cancer Care Ontario (CCO). Methods: Using tumor pathology reported centrally to the Ontario Cancer Registry (OCR) a population-based retrospective cohort of ESBC patients diagnosed in 2006 or 2007 was identified. We evaluated the use of subsequent HER2 fluorescence in situ hybridisation (FISH) after initial immunohistochemical testing, and predictors of trastuzumab use. HER2 test type, sequence, result(s) and status, tumour grade, and hormone receptor status were determined. Trastuzumab treatment was determined from linked drug funding records. Sociodemographic characteristics, prior surgical, radiation and anthracycline treatment, and comorbidity were also determined from administrative data sources. Logistic models estimated adjusted odds ratios for factors associated with guideline (non-)adherence. Results: A HER2 test was documented for 66% of the 13,396 patient cohort. HER2 equivocal tumors were more likely to be retested vs. positive: OR 116 (95% confidence interval [CI] 79, 169). Patients diagnosed with stage III disease had higher odds of having a FISH test vs. stage I (OR 1.5 [CI 1.1, 2.1]). HER2 status was the largest predictor of trastuzumab use, with HER2 equivocal, negative or unknown patients less likely to receive treatment than positive. Patients with advanced age (≥70y) had lower odds of trastuzumab treatment compared to younger patients (OR 0.48 [0.32, 0.73]). Higher tumor grade was associated with higher odds of treatment. Reporting, testing, and treatment all varied significantly by region. Conclusions: Despite limitations in centrally-reported tumour pathology at the time, the use of FISH testing and trastuzumab treatment in Ontario was largely consistent with guidelines, though practices vary across regions.

Prognostic and predictive role of ESR1 status for postmenopausal patients with endocrine-responsive early breast cancer in the Danish cohort of the BIG 1-98 trial

Estrogen Receptor 1 (ESR1) aberrations may be associated with expression of estrogen receptor (ER) or progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2) or Ki-67 labeling index and prognosis. ESR1 was assessed in 1129 (81%) of 1396 postmenopausal Danish women with early breast cancer randomly assigned to receive 5 years of letrozole, tamoxifen or a sequence of these agents in the Breast International Group 1-98 trial and who had ER ≥ 1% after central review. By FISH, 13.6% of patients had an ESR1-to-Centromere-6 (CEN-6) ratio ≥ 2 (amplified), and 4.2% had ESR1-to-CEN-6 ratio <0.8 (deleted). Deletion of ESR1 was associated with significantly lower levels of ER (P < 0.0001) and PgR (P = 0.02) and more frequent HER2 amplification. ESR1 deletion or amplification was associated with higher-Ki-67 than ESR1-normal tumors. Overall, there was no evidence of heterogeneity of disease-free survival (DFS) or in treatment effect according to ESR1 status. However, significant differences in DFS were observed for subsets based on a combination of ESR1 and HER2 status (P = 0.02). ESR1 aberrations were associated with HER2 status, Ki-67 labeling index and ER and PgR levels. When combined with HER2, ESR1 may be prognostic but should not be used for endocrine treatment selection in postmenopausal women with endocrine-responsive early breast cancer.

Abstract 962: Multiplexed mutational profiling of breast tumor as an efficient clinical tool for personalized breast cancer treatment

Abstract Introduction: Breast cancer is increasingly being recognized as a heterogeneous disease and previous studies have reported various oncogenic mutations in breast cancer specimens. However, a validated methodology for clinical assessment of mutation profiles is lacking. Applying such technologies will be increasingly important to accelerate development of targeted therapies toward tumor-specific oncogene pathways. Utilizing a high-throughput genotyping platform we evaluated the commonly described somatic mutations in tumor tissue among women diagnosed with metastatic breast cancer. Methods: We developed a CLIA (Clinical Laboratory Improvement Amendments) validated, highly sensitive multiplexed PCR-based assay (SNaPshot) to simultaneously identify 130 previously described mutations in 13 cancer genes using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. Data regarding demographics, tumor phenotype based on estrogen and progesterone receptor (ER, PR) status, HER-2 (Human Epidermal growth factor Receptor-2) status, BRCA carrier status, and clinical outcomes, was abstracted from clinical charts. Results: A total of 138 tumors from women with metastatic breast cancer, median age 69 (range 29-82), were analyzed. In this study, 34.7% of tumors had a detectable mutation, with PIK3CA mutation (70.8%) being the most common mutation detected followed by TP53 (27.1%), and Akt (4%). Unanticipated mutations in KRAS and BRAF were observed at lower frequencies. Detectable mutations were seen in all tumor sub-types although the frequency varied by tumor phenotype: ER+/PR+ (34.5%), ER+/PR- (52.6%), HER-2+ (44.4%), and triple negative (23.2%) tumors. Similarly, while the type of mutation varied somewhat by tumor phenotype, the common driver mutations were seen in all tumor subtypes. For PIK3CA mutations: ER+/PR+ (27.7%), ER+/PR- (42.8%), HER-2+ (29.6%), triple negative (6.7%) tumors, and for TP53 mutations: ER+/PR+ (3.6%), ER+/PR- (14.2%), HER-2+ (18.5%) and triple negative (10%) tumors. Correlation with clinical outcomes is ongoing. BRCA1/2 carriers were less likely to have a detectable somatic mutation in their tumor (15.3%) than patients with negative BRCA1/2 status (25.8%). Only 4 patients (2.8%) had more than one detectable somatic mutation. Conclusion: Oncogenic driver mutations can be detected by SNaPshot from routinely-collected FFPE tissue specimens obtained from women seen in the oncology clinic for metastatic breast cancer. While the type and frequency of mutation varies somewhat by tumor phenotype, the common oncogenic mutations are seen in all breast cancer subtypes and are often found in isolation. These findings highlight the necessity for broad tumor mutational analysis, independent of traditional breast cancer subtype, to efficiently tailor personalized therapies in the clinic based on individual tumor genetic profiles. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 962. doi:1538-7445.AM2012-962

The Effect of Cold Ischemia Time and/or Formalin Fixation on Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor-2 Results in Breast Carcinoma.

Aims. To compare the results of estrogen and progesterone receptors (ER, PR), and human epidermal growth factor receptor-2 (HER2) expression status on biopsy and excision specimens and to evaluate the effect of cold ischemia time and/or formalin fixation on these biomarkers. Methods. Breast carcinomas that were diagnosed between 2007 and 2009 by core needle biopsy, and subsequently excised in our institution, were included in the study. Data regarding the tumor morphology, grade, and ER, PR, and HER2 status were retrospectively collected from the pathology reports. Results. Five out of 149 (3.4%) cases with ER-positive receptor status in the biopsy specimen became ER-negative in the subsequent excision specimen. Nine out of 126 (7.1%) cases with PR-positive receptor status in the biopsy specimen became PR-negative in the excision specimen. Receptor status change was predominantly seen in tumors with low ER and PR receptor expression. HER2 results were consistent between biopsy and excision specimens in all cases tested. Conclusions. Cold ischemia time and/or formalin fixation affect mainly ER and PR testing with low Allred scores and support the implementation of the ASCO/CAP guidelines. HER2 results, however, were not affected in our limited number of patients.

Accuracy of estrogen receptor, progesterone receptor, and HER2 status between core needle and open excision biopsy in breast cancer: a meta-analysis

Accurate determination of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER2) status was very important in selecting breast cancer treatment. Discordance of ER, PR, and HER2 status between core needle biopsy (CNB) and open excision biopsy (OEB) varied among reported studies. We performed a meta-analysis to compare the accuracy of CNB with that of OEB for ER, PgR, and HER2 status detection in breast cancer. Medical subject heading (MeSH) terms (Breast Neoplasm) and key words (biopsy OR mammotome) AND (incision OR excision OR surgery) AND (estrogen OR progesterone OR HER2 OR hormone). Patients with HER2 immunohistochemical 3+ or fluorescence in situ hybridization positive were classified into HER2[b] group. A total of 27 studies were eligible in this study. Aggregate positive ER and PgR rate was 80.0 and 69.5% for CNB; and 77.7 and 66.2% for OEB, respectively. The HER2 positive rate difference between CNB and OEB was only 0.2%. The pooled sensitivity of evaluating ER, PgR, and HER2 status in CNB compared with OEB was 0.970, 0.911, and 0.799 (0.813 for HER2[b]), respectively. All of AUC values for these status determination were larger than 0.9. Heterogeneity between studies was introduced by various factors in PgR and HER2[b] analysis. Subgroup analysis showed that the specificity and OR of CNB in studies with ER positive rate >78% was lower than studies with ER positive rate ≤78% (P < 0.05). This meta-analysis indicated that CNB had high diagnostic accuracy in evaluating ER, PgR, and HER2 status compared with OBE in breast cancer patients. In terms of 2-3% positive rate difference, ER and PgR status should be detected both on CNB and OEB samples, especially to retest their expression on CNB in patients with hormonal receptor negative tumors in OEB.

Over-expression of HER-2 is associated with the stage in carcinomas of the urinary bladder

BackgroundThe frequency of over-expression of human epidermal growth factor receptor-2 (HER-2) in bladder cancer is one of the highest among all human malignancies. This over-expression is thought to play a role in aberrant proliferation of cancer cells. Studies on HER-2 expression in bladder carcinoma have shown heterogeneous results.PurposeThe aim of the study was to evaluate the status of HER-2 protein expression in patients with invasive carcinomas of the urinary bladder as related to tumor grade and stage.Materials and methodsArchival samples from 39 patients (6 women, 33 males) with urinary bladder cancer were analyzed for HER-2 over-expression, using immunohistochemistry with the HercepTest.ResultsHER-2 over-expression was observed in 23/39 tumors (59%) and was more frequent in high-grade than in low-grade carcinomas, but the difference was not statistically significant. A significant correlation was established between HER-2 over-expression and tumor stage (p=0.011). HER-2 expression was more frequent in transitional cell carcinomas (TCC) and adenocarcinomas (AC) as compared with squamous cell carcinoma (SCC). Patients’ age and sex were not related to HER-2 over-expression.ConclusionOver-expression of HER-2 was frequent in carcinomas of the urinary bladder. Knowing the HER-2 status would be helpful in formulating a rational treatment strategy for patients with urinary bladder cancer.

The Prognostic Significance of Human Epidermal Growth Factor Receptor-2 (HER2) Positivity and Breast Cancer Subtype in Patients (PTS) with Microinvasive Breast Cancer (MIBC)

Pts with HER2-positive, T1a,b node-negative breast cancer (BC) have a higher risk of recurrence than pts with similarly-staged HER2-negative BC, supporting the consideration of anti-HER2 adjuvant therapy. It is unclear if HER2 positivity has similar prognostic significance in MIBC. Our goal was to determine the association between HER2, estrogen-receptor (ER) and progesterone-receptor (PR) status and recurrence after treatment for MIBC.