Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer.

PURPOSE: Studies evaluating the relationship of HER-2/neu breast tumor status and response to adjuvant endocrine therapy have reached conflicting conclusions about resistance of HER-2/neu-positive tumors to this treatment. We studied 282 patients participating in a randomized controlled trial of adjuvant oophorectomy and tamoxifen or observation who had estrogen receptor-positive tumors and whose tumors were evaluated for HER-2/neu overexpression by immunohistochemistry. PATIENTS AND METHODS: Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier disease-free and overall survival estimate methods were used. RESULTS: HER-2/neu overexpression was a negative prognostic factor for overall survival. In univariate analyses, in HER-2/neu-positive patients, the hazard ratio (HR) for disease-free survival (DFS) with adjuvant endocrine therapy was 0.37 (95% confidence interval [CI], 0.26 to 0.89); for HER-2/neu-negative patients, the corresponding HR for DFS was 0.48 (95% CI, 0.31 to 0.71). The overall survival (OS) data were HR=0.26 (95% CI, 0.07 to 0.92) and HR=0.68 (95% CI, 0.32 to 1.42) for HER-2/neu-positive and HER-2/neu-negative patients, respectively. In multivariate models, the P values for tests of interaction of HER-2/neu status and response to adjuvant endocrine therapy were 0.18 and 0.07 for DFS and OS, respectively. Kaplan-Meier DFS and OS curves and 3-year DFS estimates were consistent in showing greater benefit to the HER-2/neu-positive subgroup given adjuvant treatment. CONCLUSION: HER-2/neu overexpression does not adversely and may favorably influence response to adjuvant oophorectomy and tamoxifen treatment in patients with estrogen receptor-positive tumors.     

Her2/neu-positive disease does not increase risk of locoregional recurrence for patients treated with neoadjuvant doxorubicin-based chemotherapy, mastectomy, and radiotherapy

PURPOSE: Preclinical data suggest that overexpression of Her2/neu confers cellular radioresistance. We retrospectively studied whether Her2/neu-positive disease was associated with locoregional recurrence (LRR) after postmastectomy radiotherapy (RT) for breast cancer. METHODS AND MATERIALS: Data from 337 patients treated in four institutional prospective clinical trials neoadjuvant doxorubicin-based chemotherapy, mastectomy, and RT were reviewed. The trials were conducted between 1989 and 2000. Of the 337 patients, 108 (32%) had tumors that were tested for Her2/neu, with positivity defined by 3+ immunohistochemistry staining or gene amplification detected by fluorescence in situ hybridization. RT was delivered to the chest wall and draining lymphatics (median dose, 50 Gy) followed by a chest wall boost (median dose, 10 Gy). RESULTS: Thirty-two patients had Her2/neu-positive disease and 76 patients had Her2/neu-negative disease. The Her2/neu-positive tumors were associated with a greater rate of estrogen receptor-negative disease (p = 0.03), the presence of supraclavicular disease at diagnosis (p = 0.027), and a greater number of positive lymph nodes after chemotherapy (p = 0.026). Despite these adverse features, the actuarial overall LRR rate was roughly equivalent for the patients with Her2/neu-positive tumors vs. those with Her2/neu-negative tumors (5-year rate 17.5% vs. 13.9%, respectively; 10-year rate 17.5% vs. 18.9%, respectively; p = 0.757). On Cox regression analysis of LRR adjusted for N stage and estrogen receptor status, the hazard ratio for Her2/neu positivity was 0.89 (95% confidence interval, 0.31-2.59; p = 0.83). CONCLUSION: Her2/neu overexpression does not appear to predispose to LRR after neoadjuvant doxorubicin-based chemotherapy, mastectomy, and RT.     

HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma.

PURPOSE: Amplification and/or overexpression of the HER-2/neu oncogene have been shown to correlate with poor clinical outcome in patients with axillary node-positive breast cancer. In contrast, the prognostic significance of HER-2/neu in node-negative disease is controversial. This study was undertaken to evaluate further the relationship between HER-2/neu and clinical outcome in node-negative disease. PATIENTS AND METHODS: Overexpression of HER-2/neu was evaluated by permanent-section immunohistochemistry in tumors from 613 patients with long-term clinical follow-up enrolled in the Intergroup Study 0011. Patients were stratified into low-risk (n = 307) and high-risk (n = 306) groups on the basis of tumor size and estrogen-receptor (ER) status. Low-risk patients were defined as having small (less than 3 cm), ER-positive tumors and were observed without additional treatment after initial surgery. High-risk patients had either ER-negative or large (greater than or equal to 3 cm), ER-positive tumors and were randomized to be observed (n = 146) or to receive adjuvant chemotherapy (n = 160) after surgery. RESULTS: The rate of HER-2/neu overexpression was 14.3% in all tumors combined and was higher in invasive carcinomas with (21.5%) than without (11.2%) a significant noninvasive or in situ histologic component (P less than .0001). There was no relationship between overexpression and clinical outcome in the natural history setting of combined low-risk and high-risk patients not receiving adjuvant therapy (n = 453). Based on the reasoning that the influence of HER-2/neu may have been obscured by high-risk features and/or the presence of noninvasive carcinoma, we also analyzed the subset of patients with low-risk lesions not containing a significant in situ component (n = 179). Patients of this group with HER-2/neu-positive tumors showed only 40% disease-free survival (DFS) at 5 years, compared with over 80% in patients with HER-2/neu-negative tumors (P less than .0001). A similar inverse correlation was observed between overexpression and overall survival in the same group of patients (P = .0001). In a separate analysis involving patients receiving adjuvant chemotherapy, those with HER-2/neu-negative tumors showed significantly improved DFS in response to therapy compared with patients with HER-2/neu-positive tumors. CONCLUSION: Overexpression of HER-2/neu is associated with poor clinical outcome in a subset of node-negative patients with small, ER-positive, predominantly invasive tumors and may play a role in resistance to adjuvant chemotherapy.     

Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors.

PURPOSE: The prognostic significance of Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder is largely unknown. Accurate determination of Her-2/neu overexpression may have therapeutic importance. EXPERIMENTAL DESIGN: Eighty consecutive cases of muscle-invasive urothelial carcinoma of the bladder treated by radical cystectomy with available follow-up were analyzed. In each case, one representative section was stained with anti-Her-2/neu. Staining was graded as 1 = faint/equivocal, 2 = moderate, and 3 = strong and was considered positive if > or =2. In those cases with a metastasis, the stain was also performed in the metastatic tumor. Results were correlated with survival. RESULTS: Twenty-two (28%) cases were considered Her-2/neu-positive in the primary tumor, and 17 of 32 (53%) were considered Her-2/neu-positive in the lymph node metastasis. Median survival for Her-2/neu-positive primary tumors was 33 months, compared with 50 months for Her-2/neu-negative cases (P = 0.46). Similarly, Her-2/neu overexpression in the lymph node metastasis did not predict survival. Sixty metastatic urothelial carcinomas were further studied by comparing Her-2/neu expression in the primary tumor with that of the lymph node and/or distant metastasis. Forty-five percent of Her-2/neu-negative primary tumors had a Her-2/neu-positive lymph node metastasis, whereas only one case (8%) of Her-2/neu-positive primary tumors was Her-2/neu-negative in the lymph node metastasis (P = 0.009). Similarly, 67% of Her-2/neu-negative primary tumors had a Her-2/neu-positive distant metastasis, whereas no Her-2/neu-positive primary tumor was negative in the metastasis (P = 0.429). CONCLUSIONS: Her-2/neu overexpression in primary or metastatic tumor did not predict survival in this cohort of muscle-invasive tumors. Overexpression in the primary tumors consistently predicts overexpression in a distant or regional metastasis. However, some Her-2/neu-negative primary tumors may show overexpression in their corresponding metastasis. Her-2/neu analysis in a metastasis may be necessary to accurately determine Her-2/neu status in metastatic bladder urothelial carcinoma.     

Differences in breast cancer risk factors to neu (c-erbB-2) protein overexpression of the breast tumor.

To investigate whether overexpression of the neu protein in breast tumors differentiates risk factor patterns for breast cancer, neu protein overexpression was determined in 296 breast carcinomas of patients participating in an ongoing population-based case-control study. Risk factor information on these patients and 737 controls was obtained during home interviews. Most breast cancer risk factors showed similar associations with neu-positive and neu-negative tumors, but remarkable differences were found for breast-feeding and age at first full-term pregnancy. In contrast to the slightly protective effect of breast-feeding in the neu-negative group, the risk of neu-positive breast cancer was 4.2-fold increased in women who ever breast-fed. Increasing age at first full-term pregnancy was positively associated with both neu-positive and neu-negative breast cancer, but the association was about 2 times stronger for neu-positive tumors. We conclude that neu oncogene overexpression of the breast tumor seems to be associated with a distinct risk factor pattern.     

Effect of HER2/neu expression on survival in non-small-cell lung cancer

Major prognostic factors for early-stage non-small-cell lung cancer (NSCLC) are tumor size and nodal status. It has been suggested that HER2/neu overexpression may be related to poor prognosis in NSCLC. We evaluated the significance of HER2/neu overexpression on survival in patients with NSCLC. Data were collected on 239 patients treated surgically for stage I/II NSCLC between 1987 and 1996. None of the patients received adjuvant chemotherapy or radiation. Formalin-fixed, paraffin-embedded tumor tissue samples were stained with p185/HER2 receptor antibody. Results were reported as positive (2+, 3+) or negative (0, 1+) (Group A). A separate analysis considered only 3+ as positive (Group B). HER2/neu overexpression was seen in 18% in Group A (43 of 239) and 6% in Group B (15 of 239). HER2/neu overexpression was highest in bronchoalveolar cell carcinoma and adenocarcinoma. More stage I tumors were positive than stage II in both groups, but this was significant only in Group A (21% vs. 7%, P = 0.02). No difference was seen with age, gender, or grade for either group. In Group A, the relapse rate was 55% for HER2/neu-overexpressing tumors and 31% for HER2/neu-negative tumors (P = 0.003). Median time to relapse in patients with HER2/neu-positive tumors was 2.9 years; it was not reached in patients with HER2/neu-negative tumors. Median survival of patients with HER2/neu-positive tumors was 3.6 years compared to 5 years in patients with HER2/neu-negative tumors (P = 0.66). In Group B, the relapse rate was 60% for HER2/neu-overexpressing tumors and 33% for negative tumors (P = 0.036). Median time to relapse was 3.4 years in HER2/neu positive and had not been reached in negative tumors. There was no difference in 5-year survival rates for both groups (47% for HER2/neu positive and 50% for negative, P = 0.66).     

Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer.

PURPOSE: To determine the effect of elevation of serum HER-2/neu on response to hormone therapy. PATIENTS AND METHODS: Seven hundred nineteen metastatic patients with estrogen receptor-positive (ER(+)), progesterone receptor-positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels. RESULTS: Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with non-elevated and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median duration of treatment response (using the time to progression [TTP] variable for patients who responded) was shorter in the group with elevated serum HER-2/neu levels (11.7 months) compared with the patient group with non-elevated levels (17.4 months). TTP, time to treatment failure, and median survival (17.2 months v 29.6 months) were also significantly shorter in the patients with elevated serum HER-2/neu levels (P <.0001). CONCLUSION: Patients with ER(+) and serum HER-2/neu-positive metastatic breast cancer are less likely to respond to hormone treatment and have a shorter duration of response than ER(+) and serum HER-2/neu-negative patients. Their survival duration is also shorter.     

Evaluation of ER,PgR, HER-2, Ki-67, cyclin D1, and nm23-H1 as predictors of pathological complete response to neoadjuvant chemotherapy for locally advanced breast cancer

The purpose of this study was to evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant docetaxel plus epirubicin combination chemotherapy in patients with locally advanced breast cancer (LABC). Two hundred and twenty consecutive patients with LABC who had received neoadjuvant chemotherapy (NCT) with docetaxel and epirubicin from March 2006 to March 2009 were included in this retrospective study. The pre- and post-neoadjuvant chemotherapy (NCT) treatment expression levels and changes of Ki-67 proliferation index, estrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor 2 (HER-2), cyclin D1, and nm23-H1 were detected by immunohistochemistry (IHC). The pCR rate was 9.1% (95% CI, 5.3–12.9%). In univariate analysis, poor tumor differentiation, OR after 2 cycles of NCT, both negative of ER/PgR, negative HER-2, positive cyclin D1, and positive nm23-H1 were found to be significantly predictive of a pCR. Histological grade and ER/PgR status were significant for pCR on multivariate analysis (P = 0.023 and 0.003, respectively). The expression levels of cyclin D1 (median, 8% vs. 9%; P = 0.016) after NCT treatment increased significantly, while the median Ki-67 proliferation index was dramatically decreased after NCT treatment from 35 to 15% (P = 0.036). However, after a Bonferroni adjustment, only the difference of Ki-67 proliferation index was still significant (P = 0.026). Histological grade and ER/PgR status are independent predictive factors of pCR to neoadjuvant docetaxel plus epirubicin combination chemotherapy in locally advanced breast cancer. Expression of HER-2, Ki-67, cyclin D1, and nm23-H1 were not predictive for pCR.

     

Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer.

Amplification of the HER-2/neu oncogene and amplification of the topoisomerase IIalpha gene are important determinators of the response to chemotherapy in advanced breast cancer. Assays of these genes are usually carried out using primary tumor samples, because biopsies from metastatic lesions are not usually taken. We studied the concordance of Her-2/neu and topoisomerase IIalpha amplification in primary breast tumors and their metastases by immunostaining and DNA in situ hybridization. HER-2/neu amplification, present in 28% of the primary tumors (n = 46), was always associated with amplification in its metastasis. Conversely, no metastases with HER-2/neu amplification were seen without amplification in the primary tumor. Topoisomerase IIalpha gene copy status (amplification/deletion/unaltered) remained generally unchanged in HER-2/neu-positive tumors, but in three cases, the predominant cell population in metastatic tissue was present only as a subpopulation in the primary tumor. We conclude that amplification of HER-2/neu measured in primary tumor reflects the status of metastases. Minor discrepancies between primary and metastatic tumors in topoisomerase IIalpha gene copy status may reflect evolvement of the amplicon structure in successive cell divisions.     

Her-2/neu expression in locally advanced breast carcinomas: pre- and post-neoadjuvant chemotherapy

Clinical studies have shown a correlation of HER-2/neu amplification/over-expression and favorable response to neoadjuvant chemotherapy and anti-HER-2/neu antibody treatment. However, contradictory findings also have been reported. Some tumors may develop resistance to neoadjuvant chemotherapy after an initial period of sensitivity. Our study attempts to evaluate the effects of neoadjuvant chemotherapy on HER-2/neu status in locally advanced breast cancer. Thirty-nine patients with locally advanced breast cancers established by core needle biopsy received neoadjuvant chemotherapy and were compared with 60 patients with breast cancers who did not receive neoadjuvant chemotherapy. IHC for HER-2/neu was performed on paraffin sections of the core biopsy before treatment and the excised specimen following chemotherapy and scored as Negative (0-1+), 2+ and 3+. The results of the study and the controls were compared and analyzed using Fisher's exact test. HER-2/neu IHC scores decreased in 28.5% (15/39) of patients receiving neo-adjuvant chemotherapy compared to 11.7% (7/60) of patients in the control (p < 0.013). HER-2/neu IHC status changed from strongly positive to negative (3+ to 0) in five of 39 (12.5%) in the study group and in 2 of 60 (3.3%) in control group (p = 0.104). For patients receiving neoadjuvant chemotherapy in whom the tumor becomes refractory to chemotherapy or recurs, repeat testing for HER-2/neu status may be necessary. Elimination of HER-2/neu positive tumor cells may account for the changes in the IHC scores and the development of resistance to neoadjuvant chemotherapy.     

Specificity of HercepTest in determining HER-2/neu status of breast cancers using the United States Food and Drug Administration-approved scoring system.

PURPOSE: To evaluate the specificity of the HercepTest for Immunoenzymatic Staining (Dako Corp, Carpinteria, CA) for determining HER-2/neu protein expression in breast cancer. MATERIALS AND METHODS: Forty-eight invasive breast cancers previously found to be HER-2/neu-negative by two different immunohistochemical (IHC) assays and not amplified for the HER-2/neu gene by fluorescence in situ hybridization were studied using the HercepTest kit. HercepTest was performed according to the manufacturer's guidelines, and the results were scored on a 0 to 3+ scale using the United States Food and Drug Administration (FDA)-approved grading system. In this system, cases scored as 2+ or 3+ are considered HER-2/neu-positive. RESULTS: Among these 48 cases, the IHC score using the FDA-approved scoring system was 0 in four cases (8.3%), 1+ in 16 (33.3%), 2+ in 21 (43.8%), and 3+ in seven (14.6%). Therefore, 58.4% of these cases were categorized as HER-2/neu-positive, and the specificity of the HercepTest kit for HER-2/neu expression was 41.6%. However, with the use of a modified scoring system that took into account the level of staining of nonneoplastic epithelium, the specificity increased to 93.2%. CONCLUSION: Our results indicate that the HercepTest kit, when used in accordance with the manufacturer's guidelines and the FDA-approved scoring system, results in a large proportion of breast cancers being categorized as positive for HER-2/neu protein expression and that many of these seem to be false-positives. Consideration of the level of staining of nonneoplastic epithelium resulted in improved specificity. The current FDA-approved scoring system for HercepTest results should be reevaluated before its widespread use in clinical practice.     

Expression of HER-2/neu in testicular tumors

BACKGROUND: Although the overexpression of the Epidermal Growth Factor Receptor 2 (EGFR-2, HER-2/neu, c-erbB-2) in malignancies might predict chemoresistance and poor prognosis, its clinical relevance has not been widely studied and determined in testicular tumors. PATIENTS AND METHODS: Since teratomas are relatively chemoresistant tumors, we evaluated the HER-2/neu receptor status of 28 primary testicular tumors (7 pure teratomas, 21 mixed germ cell tumors containing teratomatous components) using a standardized immunohistochemical method (HercepTest Kit). RESULTS: Seven (25%) out of 28 non-seminomatous germ cell tumors showed HER-2/neu positivity. The teratomatous components of mixed GCTs showed HER-2/neu overexpression in 5 cases. Three of the 5 choriocarcinoma components of mixed tumors overexpressed HER-2/neu. In one case (teratoma + choriocarcinoma) both components showed HER-2/neu overexpression. No HER-2/neu overexpression was detected in other, less differentiated histological subtypes. Among the HER-2/neu-positive cases, 3 patients are in complete remission, 3 patients are in partial remission and one patient died after primary chemotherapy. CONCLUSION: Twenty-five percent of the non-seminomatous germ cell tumors which contain teratomatous components overexpress HER-2/neu protein. The overexpression is restricted to the more differentiated histotypes. Further molecular investigations and clinicopathological studies are necessary to determine the correlation between HER-2/neu overexpression and clinical resistance of testicular tumors.     

Clinical significance of Akt and HER2/neu overexpression in African-American and Latina women with breast cancer

Introduction

Breast cancer patients with HER2/neu overexpression have poor outcomes with a decrease in disease-free survival (DFS) and overall survival. The biology of HER2/neu overexpression in breast tumors in African-American and Latina women is poorly understood. The purpose of this study is to understand the clinical significance of activated Akt (phospho-Akt or pAkt) expression in breast tumors from African-American and Latina patients with corresponding tissue HER2/neu overexpression. Cellular and molecular studies have shown that activation of the cell signaling phosphatidylinositol-3-kinase/Akt cascade via the HER2/neu and other receptor tyrosine kinases induces cell proliferation.

Methods

A total of 234 African-American and Latina patients were selected retrospectively. From this group, 141 tumor tissue samples were analyzed for tissue pAkt by immunohistochemistry (IHC). This cohort consisted of 46 HER2/neu-positive (3+ by IHC) and 95 HER2/neu-negative tumors. The prognostic value of activated tissue Akt in relation to HER2/neu overexpression for DFS was determined.

Results

Patients with low pAkt and HER2-negative tumors had the best DFS. As expected, HER2/neu-overexpressing tumors with low pAkt had a decrease in DFS. Similarly, those with high pAkt and HER2-negative tumors also had poor DFS. However, those with an increase in both HER2 and pAkt had the worst DFS. An increase in pAkt was significantly associated with HER2/neu-positive and lymph node-positive breast tumors. Tumors with high HER2 and high pAkt were metastatic. Multivariate analysis demonstrated that, in addition to the common risk factors such as larger tumor size, lymph node involvement, estrogen receptor/progesterone receptor-negative tumors, and HER2/neu-positive tumors, overexpression of pAkt significantly was associated with a decrease in 5-year DFS. A decrease in DFS with an increase in pAkt was observed in both HER2/neu-positive and -negative groups. However, the DFS was similar between HER2/neu-positive/pAkt-negative and HER2/neu-negative/pAkt-positive groups.

Conclusion

Our data suggest that there may be differences in tumor phenotypes within the HER2/neu-overexpressing breast cancer patients. The overexpression of pAkt may be a powerful prognostic marker for predicting DFS and overall survival of breast cancer patients.     

Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer

BACKGROUND: HER-2/neu, which encodes a receptor tyrosine kinase, is amplified and overexpressed in 20%-25% of human breast cancers. Such tumors are often resistant to hormone therapy. Despite a general inverse association between HER-2/neu amplification/overexpression and estrogen receptor (ER) and/or progesterone receptor (PR) expression, a fraction of patients are both HER-2/neu- and hormone receptor (HR)-positive. The efficacy of hormone therapy in this group is currently a matter of debate. To better understand the relationship between HER-2/neu positivity and HR expression, we analyzed HER-2/neu, ER, and PR as continuous variables in breast cancer cell lines and two cohorts of primary breast cancer patients. METHODS: HER-2/neu and ER/PR expression was analyzed by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), respectively, in 14 human breast cancer cell lines, some of which had been transfected with the HER-2/neu gene. For the clinical study population, HER-2/neu protein levels were assessed by ELISA (cohort A, n = 665), and HER-2/neu gene copy number was determined using fluorescence in situ hybridization (cohort B, n = 894). ER/PR expression was analyzed by EIA (cohort A) or radioligand binding (cohort B). Associations between HER-2/neu and ER/PR expression were analyzed using Spearman's rho correlation and the chi-square test, and absolute levels were compared using the Mann-Whitney U test. All statistical tests were two-sided. RESULTS: HR-positive human breast cancer cell lines transfected with the HER-2/neu gene expressed statistically significantly lower levels of ER and PR than parental lines. In the clinical cohorts, levels of HER-2/neu overexpression and gene amplification were inversely correlated with ER/PR levels (Cohort A [n = 112]: for ER, r = -0.34, P<.001; for PR, r = -0.24, P =.010. Cohort B [n = 188]: for ER, r = -0.39, P<.001; for PR, r = -0.26, P<.001). Among patients with HR-positive tumors, HER-2/neu-positive tumors had statistically significantly lower ER/PR levels than HER-2/neu-negative ones (Cohort A: for ER, median = 25 fmol/mg [interquartile range [IQR] = 13-78] versus median = 38.5 fmol/mg [IQR = 17-99] and P =.031; for PR, median = 35 fmol/mg [IQR = 12-119] versus median = 88.5 fmol/mg [IQR = 22-236] and P<.001. Cohort B: for ER, median = 44 fmol/mg [IQR = 13-156] versus median = 92 fmol/mg [IQR = 35-235] and P<.001; for PR, median = 36 fmol/mg [IQR = 13-108] versus median = 84 fmol/mg [IQR = 24-250] and P<.001). Patients with higher levels of HER-2/neu overexpression or amplification had statistically significantly lower levels of ER/PR than patients with lower levels of HER-2/neu overexpression or amplification. CONCLUSION: Because absolute HR levels are strongly related to response to hormone therapy in primary and advanced breast cancer, reduced ER/PR expression may be one mechanism to explain the relative resistance of HER-2/neu-positive:HR-positive tumors to hormone therapy.     

Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer

The HER-2/neu gene is amplified and overexpressed in 20% to 30% of invasive breast carcinomas and is associated with increased metastatic potential and less tamoxifen sensitivity. We generated the DNA methylation profiles of 143 human breast tumors and found significant differences in HER-2/neu expression and DNA methylation of five genes. For three of these five genes [PGR (coding for the progesterone receptor), HSD17B4 (coding for type 4 17-beta-hydroxysteroid dehydrogenase, an enzyme that mainly degrades active 17-beta-estradiol into inactive metabolites), and CDH13 (coding for H-cadherin)] a higher prevalence of DNA methylation in HER-2/neu-positive cancers was confirmed in an independent set of microdissected primary breast cancers. DNA methylation was not only present in cancer cells but also in the tumor stroma fraction. Of the isolated fractions in HER-2/neu-positive versus -negative cancers, 27.1% versus 10.5%, respectively, showed DNA methylation of the five genes (P = 0.011, Fisher's exact test). In Her-2++/+++ breast cancers, HSD17B4 mRNA expression was inversely associated with HSD17B4 methylation (P = 0.04). These data support the view that in addition to HER-2/neu-associated signaling, epigenetic changes in cancer as well as in tumor stroma cells might attribute to the specific biological features of HER-2/neu-positive cancers.     

Race modifies the association between breast carcinoma pathologic prognostic indicators and the positive status for HER-2/neu

BACKGROUND: Inferences about the variations in the biology of breast carcinoma between African-Americans and Caucasians have been reported. The difference in the prevalence of positive HER-2/neu breast carcinoma was evaluated and the race-specific risk was assessed for positive HER-2/neu among a cohort of women diagnosed with their first primary breast carcinoma, given the accepted prognostic pathologic indicators for positive HER-2/neu status. METHODS: Demographic, clinical, and pathologic data were collected from existing databases. The status of HER-2/neu was considered positive if the immunohistochemistry score was 3+ or if the fluorescent in situ hybridization indicated a ratio greater than 2. Multivariable logistic regression was used to determine the race-specific risk for HER-2/neu positive breast carcinoma. RESULTS: The difference in the prevalence of HER-2/neu-positive status between African-American and Caucasian women was not statistically significant (P = 0.46). For Caucasian women the likelihood for positive HER-2/neu was statistically significant and increased almost linearly within each stage with nuclear grade dedifferentiation relative to the reference group, women with Stage 1, Grade 1 carcinomas. For African-American women, this risk was not significantly associated with stage, nuclear grade, their interaction term, or other pathologic prognostic indicators. CONCLUSIONS: The findings suggest that race modifies the association between the pathologic prognostic indicators of breast carcinoma and the likelihood of HER-2/neu-positive carcinoma. So far, clinical correlative studies of HER-2/neu have not included race as an independent variable. Concerns about the limited generalizability and the need for validation of the findings across racial lines have been expressed previously.     

Serum HER-2/neu conversion to positive at the time of disease progression in patients with breast carcinoma on hormone therapy

BACKGROUND: Prolonged exposure of breast carcinoma cells in vitro to tamoxifen results in tamoxifen resistance. Tamoxifen-resistant cells express increased HER-2/neu mRNA and protein. The objective of this study was to determine whether patients with metastatic or locally advanced breast carcinoma who have negative serum HER-2/neu status at the initiation of first-line hormone therapy with letrozole or tamoxifen convert to positive serum HER-2/neu status at the time of disease progression and to determine whether serum HER-2/neu conversion to positive status is associated with response to therapy and overall survival. METHODS: Serum samples were obtained at baseline and at the time of disease progression from 240 patients who initially had negative serum HER-2/neu status (< 15 ng/mL). A manual microtiter, enzyme-linked immunosorbent assay that was specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to quantitate serum levels. RESULTS: Among 240 patients, 61 patients (26%) converted from serum HER-2/neu negative to positive (> 15 ng/mL) at the time of disease progression. Thirty-two of 129 patients (25%) who were treated with tamoxifen and 29 of 111 patients (26%) who were treated with letrozole became converted to positive serum HER-2/neu status at the time of disease progression. The response rate and the time to disease progression on first-line hormone therapy were not affected by serum HER-2/neu conversion. The survival of patients who converted to positive serum HER-2/neu status was significantly shorter compared with the survival of patients who remained negative for serum HER-2/neu. A multivariate analysis revealed that conversion to positive serum HER-2/neu status was an independent prognostic variable for survival. CONCLUSIONS: Conversion to positive serum HER-2/neu status occurred in approximately 25% of patients who received first-line hormone therapy. Conversion to serum HER-2/neu-positive status occurred with equal frequency in antiestrogen and aromatase-inhibitor therapy. The current results showed that serum conversion to HER-2/neu-positive status was an independent risk factor for decreased survival in patients with breast carcinoma.     

HER-2/neu overexpression in patients with radically resected nonsmall cell lung carcinoma. Impact on long-term survival

BACKGROUND: Using immunohistochemistry, the authors prospectively investigated the expression of HER-2/neu protein in radically resected specimens of nonsmall cell lung carcinoma (NSCLC) and evaluated its impact on long-term prognosis. METHODS: Between January 1991 and February 1992, surgical specimens from 130 consecutive patients who underwent radical resection for NSCLC (60 squamous cell carcinoma, 48 adenocarcinoma cases, and 22 large cell carcinomas) and that were staged (according to the TNM staging system) pathologically as Stage I (41 cases [32%]), Stage II (37 cases [28%]), and Stage IIIA (52 cases [40%]) were investigated for the expression of HER-2/neu using an avidin-biotin complex immunohistochemical technique. A semiquantitative four-stage grading system was used (0%, 1-5%, 6-20%, and > 20% positive cells) and an average number of 1500 cells/section was considered. Data were correlated with clinical and pathologic variables. RESULTS: Normal bronchial tissue was found to be completely negative for HER-2/neu expression whereas 21 of the 130 tumor specimens (16%) were positive (range 1-> 20%). HER-2/neu positivity did not appear to differ significantly among pathologic stages and histotypes. Using a predetermined cutoff value of 5% positive cells, 15 tumor specimens (12%) were found to be above this value. The median survival time (85 weeks vs. 179 weeks) and overall survival rate were significantly lower in patients with > 5% HER-2/neu-positive tumors (hazard ratio for the group with > 5% positive cells: 2.94, 95% confidence interval, 1.62-5.34; P < 0.0004). On multivariate analysis, HER-2/neu and extent of tumor emerged as independent factors for disease-related mortality. CONCLUSIONS: In NSCLC, the negative impact of HER-2/neu overexpression on survival was maintained in the long-term follow-up of radically resected patients. HER-2/neu overexpression may be a valuable prognostic factor as well as a potential target for biologic therapies.     

HER-2/neu expression as a predictive factor for response to anthracycline-based chemotherapy in a Mexican Population of locally advanced breast cancer patients

Breast cancer is the second most frequent tumor in Mexico—30–50% are diagnosed in locally advanced stages requiring neoadjuvant chemotherapy. The overexpression of HER-2/neu has been identified as a chemotherapy response predictor. The objective of our study was to identify response predictive factors to anthracycline-based neoadjuvant chemotherapy in locally advanced breast cancer. Data were collected from clinical records of patients with neoadjuvant anthracycline-based chemotherapy, for clinical stage III breast cancer from 1992 to 1997. Paraffin blocks were reviewed to determine histologic grade, HER-2/neu expression, and ploidy. Patients were divided in two groups: A, 56 cases responding to chemotherapy and, B, 20 nonresponders. Mean age was 50.1 and 45.4 for groups A and B, respectively (OR 7.02, p=0.004), and those premenopausal were 43% and 70%, respectively (OR 3.1, p=0.04). Mean tumor size was 5 cm in responders and 8 cm for nonresponders (OR 4, p=0.02). Clinical stage III-B 16% and 70% for groups A and B (OR 12.2, p=0.000); tumors were aneuploid in 39% of responders and 18.7% for nonresponders. HER-2/neu was overexpressed in 64.2% and 50% for groups A and B (OR 3.6, p=0.06). On multivariate analysis significance was conserved only for age, clinical stage, and size. HER-2/neu lost significance. Age and size were importantly related to tumor response, a higher percentage of HER-2/neu overexpression was observed in responders, without significance due to small sample size. It would be important to study a larger number of patients to obtain more conclusive results.     

Identification and relationship of HER-2/neu overexpression to short-term mortality in primary malignant brain tumors

INTRODUCTION: HER-2/neu overexpression has been associated with poor prognosis in solid tumors. The extent to which HER-2/neu is overexpressed in human central nervous system malignancies is unclear. We retrospectively analyzed a large cohort of patients with primary brain tumors to evaluate the prognostic role of HER-2/neu overexpression and clinical characteristics at presentation in patients with shortened survival (< 6 months). MATERIALS AND METHODS: Between 1986 and 2001, 136 patients (81 males, 55 females) with a mean age of 69 years (age range: 49-78 years), with a biopsy-proven diagnosis of a primary malignant brain tumor and survival of < six months from the time of diagnosis, were identified. Archival tissue samples were analyzed for HER-2/neu overexpression using the Hercep immunohistochemical assay. A score of 2+ or greater on the assay was considered positive for HER-2/neu overexpression. Short-term mortality (less than 6 months) and its predictors were evaluated using multiple logistic regression. RESULTS: Mean overall survival was 2.8 months. HER-2/neu overexpression was detected in 23 out of 136 specimens (17%). However, HER-2/neu overexpression did not predict increased 6-month mortality (p = 0.43). Interestingly, the presence of HER-2/neu overexpression was associated with a significantly increased risk of an associated second primary malignancy in addition to the primary brain tumor. Other factors examined did not predict increased 6-month mortality either, including site of tumor (p = 0.54), tumor histology (p = 0.77) and presenting symptoms (p = 0.32). CONCLUSION: Her-2/neu overexpression was detected in 17% of patients with primary brain tumors, but, did not predict increased short-term mortality in patients with brain tumors surviving less than six months. We were not able to identify any clinical variables that could predict survival in our patient population. At present, there are few reliable prognostic indicators for brain tumors. Further studies are needed to specify whether certain tumor subtypes are more likely to overexpress HER-2/neu and to evaluate the role of HER-2/neu as a target for therapy in malignant brain tumors.