Activation (Tyrosine Phosphorylation) of ErbB-2 (HER-2/neu): A Study of Incidence and Correlation With Outcome in Breast Cancer

PURPOSE: We hypothesize that phosphorylated ErbB-2 (P-ErbB-2, identified by a novel antibody PN2A) may provide either more significant or additional prognostic marker data for breast cancer patients. This study was designed to compare the incidence and prognostic value of ErbB-2 (HER-2/neu) and P-ErbB-2 immunoexpression in archival breast cancer samples. MATERIALS AND METHODS: Eight hundred sixteen invasive breast cancers with a median of 16.3 years of follow-up were immunostained for ErbB-2 (using antibody CB11) and P-ErbB-2 (using antibody PN2A). ErbB-2 and P-ErbB-2 data were compared with clinical, histologic, immunohistochemical, and outcome variables. RESULTS: Of 816 primary breast cancers, 307 (38%) were positive for ErbB-2 and 37 (12% of ErbB-2 positive and 5% of the study population) expressed P-ErbB-2. P-ErbB-2 was not detected in ErbB-2–negative cases (n = 509). ErbB-2 immunohistochemical data were bimodal; patients with ≥ 80% cellular expression had the shortest disease-free and disease-specific survival. P-ErbB-2 was associated with a higher percentage of ErbB-2–positive cells, a higher number of positive lymph nodes, and cellular proliferation. ErbB-2 and P-ErbB-2 were indicators of poor prognosis in node-positive patients in both univariate and multivariate analyses. We found that either P-ErbB-2 expression or high (≥ 80%) ErbB-2 expression provided the most significant prognostic value in node-positive cases by multivariate analyses. There were too few P-ErbB-2–positive cases and events in the node-negative patient group to allow statistical analysis of P-ErbB-2 in that subgroup. CONCLUSION: PN2A immunostaining identified a subset (approximately 12% of ErbB-2–positive breast cancers) with activation (phosphorylation) of the receptor ErbB-2. P-ErbB-2 expression was strongly associated with higher levels of ErbB-2 expression (≥ 80%), although it was not a surrogate. Identification of cases with a high percentage of invasive breast cancer cells expressing ErbB-2 or determination of receptor activation via P-ErbB-2 may provide additional prognostic value in node-positive breast cancers.

Download Full-text

The Pattern of Proline, Glutamic Acid, and Leucine-Rich Protein 1 Expression in Chinese Women with Primary Breast Cancer

The International Journal of Biological Markers ◽

10.5301/jbm.5000078 ◽

2014 ◽

Vol 29 (1) ◽

pp. e1-e7 ◽

Cited By ~ 1

Author(s):

Yanzhi Zhang ◽

Peng Wang ◽

Mumu Shi ◽

Hironobu Sasano ◽

Monica S.M. Chan ◽

...

Keyword(s):

Breast Cancer ◽

Glutamic Acid ◽

Primary Breast Cancer ◽

Chinese Women ◽

Cancer Prognosis ◽

Clinicopathological Parameters ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Ki 67 ◽

Her 2

Background Disparities of biomarkers’ expression in breast cancer across different races and ethnicities have been well documented. Proline, glutamic acid, and leucine-rich protein 1 (PELP1), a novel ER coregulator, has been considered as a promising biomarker of breast cancer prognosis; however, the pattern of PELP1 expression in Chinese women with breast cancer has never been investigated. This study aims to provide useful reference on possible racial or ethnic differences of PELP1 expression in breast cancer by exploring the pattern of PELP1 expression in Chinese women with primary breast cancer. Methods The expression of PELP1 in primary breast cancer samples from 130 Chinese female patients was detected by immunohistochemistry and correlated to other clinicopathological parameters; for comparison, the expression of PELP1 in 26 benign breast fibroadenomas was also examined. Results The overall value of the PELP1 H-score in breast cancer was significantly higher than that in breast fibroadenoma (p<0.001). In our breast cancer patients, the ER/HER-2-positive group had significantly higher PELP1 H-scores than their negative counterparts (p=0.003 for ER and p=0.022 for HER-2); the Ki-67-high group also showed significantly higher PELP1 H-scores than the Ki-67-low group (p=0.008). No significant association between PELP1 H-scores and other clinicopathological parameters was found. Finally, the PELP1 H-score in breast cancers of the luminal B subtype was significantly higher than that in the triple negative subtype (p=0.002). Conclusion Overexpression of PELP1 in Chinese women with primary breast cancer appears to be associated with biomarkers of poor outcome; these results are similar to other reports based on Western populations.

Download Full-text

p53 and bcl-2 expression correlates with clinical outcome in a series of node-positive breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.5.1604 ◽

1996 ◽

Vol 14 (5) ◽

pp. 1604-1610 ◽

Cited By ~ 89

Author(s):

R Silvestrini ◽

E Benini ◽

S Veneroni ◽

M G Daidone ◽

G Tomasic ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

Mitochondrial Protein ◽

Axillary Node ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Prognostic Information ◽

P53 Overexpression ◽

P53 Expression ◽

Node Positive

BACKGROUND AND PURPOSE The tumor-suppressor gene TP53 and the proto-oncogene bcl-2 encode, respectively, for a nuclear phosphoprotein and for a mitochondrial protein involved in multiple cellular functions. The proteins provide prognostic information in node-negative breast cancer and are supposed to influence treatment responsiveness. We analyzed the predictive role of p53 and bcl-2 expression, alone and in association with other variables, in postmenopausal women with node-positive, estrogen receptor-positive (ER+) breast cancers treated with radical or conservative surgery plus radiotherapy and adjuvant tamoxifen for at least 1 year. PATIENTS AND METHODS On 240 resectable cancers, we determined the expression of p53 and bcl-2, using immunohistochemistry, cell proliferation (3H-thymidine labeling index [3H-dT LI]), and ER and progesterone receptors (PgR). RESULTS p53 expression and 3H-dT LI were weakly related to one another and both were unrelated to bcl-2. Relapse-free and distant metastasis-free survival at 5 years were significantly lower for patients with tumors that highly expressed p53 (P = .0001) and for those that weakly expressed or did not express bcl-2 (P = .02). However, p53, but not bcl-2, provided prognostic information independent of tumor size, axillary node involvement, steroid receptors, and 3H-dT LI. Moreover, the simultaneous p53 overexpression and lack of PgR identified patients at maximum risk of relapse, whereas bcl-2 overexpression, associated with a low 3H-dT LI or the presence of PgR, improved the prognostic resolution for low-risk patients. CONCLUSION p53 expression appears to be indicative of clinical outcome in postmenopausal patients treated with tamoxifen. Whether p53 overexpression and weak bcl-2 expression are indicators of biologic aggressiveness, regardless of treatment, or of hormone resistance remains to be defined.

Download Full-text

Value and Limitations of Measuring HER-2 Extracellular Domain in the Serum of Breast Cancer Patients

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.3989 ◽

2009 ◽

Vol 27 (10) ◽

pp. 1694-1705 ◽

Cited By ~ 50

Author(s):

Alexandra F. Leary ◽

Wedad M. Hanna ◽

Marc J. van de Vijver ◽

Frederique Penault-Llorca ◽

Josef Rüschoff ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Tissue ◽

Extracellular Domain ◽

Prognostic Indicator ◽

Early Recurrence ◽

Response To Treatment ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Her 2 ◽

American Society

The human epidermal receptor-2 (HER-2) is overexpressed or amplified in 15% to 25% of breast cancers. Determination of HER-2 tumor status offers clinically useful information, as it selects patients who may benefit from treatment with trastuzumab, the monoclonal antibody against HER-2. Currently approved methods for HER-2 testing include immunohistochemistry or fluorescent in situ hybridization using tumor tissue. A fragment of HER-2 composed of its extracellular domain (ECD) can also be detected in the serum of some patients with breast cancer. As an easily accessible tumor marker, it could offer additional useful prognostic or predictive information. This review will briefly address the biology of the circulating HER-2 ECD and discuss the evidence to support the role, if any, for measuring HER-2 ECD levels in women with breast cancer. In particular, we focus on the value and limitations of serum ECD in both early and advanced breast cancer in the following clinical contexts: as a marker of HER-2 tumor tissue status; clinical implications of raised levels in women who have a tumor not overexpressing HER-2; as a prognostic indicator and as a predictor of response to treatment; and as a monitoring tool for early recurrence. On the basis of our review of the literature, we conclude that there is currently insufficient evidence to support the use of serum HER-2 ECD in the routine management of individual patients with breast cancer. This conclusion is in agreement with the 2007 American Society of Clinical Oncology guidelines on the use of biomarkers in breast cancer.

Download Full-text

Disease-free survival pattern in breast cancer patients in India treated in a single institution.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e12030 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e12030-e12030 ◽

Cited By ~ 1

Author(s):

Basavalinga S. Ajaikumar ◽

Kodaganur Srinivasachar Gopinath ◽

B S Srinath ◽

Ramesh Bilimagga S ◽

Nalini K Rao ◽

...

Keyword(s):

Breast Cancer ◽

Locally Advanced ◽

Disease Free Survival ◽

Advanced Breast ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Free Survival ◽

Distant Failure ◽

Her 2 ◽

Disease Free

e12030 Background: This study elucidates data from a 5 year retrospective study evaluating survival rates and prognostic factors in breast carcinoma patients in a private cancer set up in south India. Methods: 1046 patients who were treated between years 2003 to 2008 were analyzed. Clinical data including stage, histopathology type, age, node positivity, treatment plan, chemotherapy regimen, ER/ PR and Her2 Neu status, type of surgery etc were abstracted in a database. Five year disease free survival, local failure free survival and distant failure free survival was calculated using Kaplan Meier survival curves. Log rank mantel hazel tests were used to compare two survival curves. Results: Local recurrence was seen in 4% and distant metastases in 22% of the study sample. 62% of patients presented with early breast cancer (AJCC Stage I, II and IIIA). 85.6% of early and 73.1% of locally advanced breast cancers were disease free at 5 years (p<0.001).90.6% of early and 82.4% of locally advanced breast cancers had distant failure free survival at 5 years (p=0.001). Local failure free survival was 96.1% in both early and locally advanced breast disease at 5 years.94.9% of her 2 negative and 83.5% Her 2 positive were disease free at 5 years (p=0.001). 5 years progression free survival was 91.5% for breast conservation surgery vs 84.1% for mastectomy with axillary clearance (p=0.01). 75.4% with triple negative status and 80.8% non triple negative receptor status had 5 years DFS. Conclusion: This is a first report of survival patterns of breast cancer patients treated in a single centre in India. High early stage patient numbers and high median disease free survival times could be because of improvement in screening and treatment of breast cancer in a developing country like India.

Download Full-text

Effects of different chemotherapy regimens and tamoxifen for HER2 over-expressed breast cancer adjuvant therapy

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.11048 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 11048-11048

Author(s):

J. Zhang ◽

Y. Liu ◽

X. Hao ◽

Z. Fang ◽

L. Ning

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Subgroup Analysis ◽

Negative Group ◽

Breast Cancer Patients ◽

Node Negative ◽

Over Expression ◽

Node Positive ◽

Her 2

11048 Background: To evaluate effects of different adjuvant chemotherapy regimens and TAM in HER-2-overexpressed breast cancer patients. Methods: To study 1625 primary breast cancer cases after operation from 2002.7 to 2005.11 given adjuvant chemotherapy ,600 cases given CMF, 600 cases given CEF, and 425 cases given T-regimen (anthracyclines follow taxanes),1090 HR+ cases given tamoxifen. HER-2 expression were measured by immunohistochemistry (IHC). Median follow-up time is 42 months. Results: (1)3yr DFS of HER-2 over-expression is inferior to HER-2 negative ones in CMF group(p<0.05), no difference between HER-2- overexpressed and HER-2-negative group treated with either CEF or taxanes-based regimen (p>0.05). Subgroup analysis suggested: patients treated with CMF, 3yr DFS of HER-2 over-expression is inferior to HER-2-negative ones in node-positive subgroup, but no difference in node-negative ones; HER-2 expression has no influence on effects of CEF or T-regimen in node-positive or node-negative subgroup. (2) 425 HER-2 over-expressed patients(183 cases given CMF , 121 cases given CEF , and 121 cases given T-regimen): compared to CMF, anthracyclines and taxanes are more effective, but no difference between anthracyclines and T-regimen. (3) 235 patients with HER-2 over- expression and node-postive (72 cases given CMF , 68 cases given CEF, and 95 cases given T-regimen):, anthracyclines and taxanes are more effective than CMF, but no difference between anthracyclines and T-regimen. (4)3yr DFS is 91.23% in HER-2 over-expressed group and 93.42% in HER-2-negative group (p=0.04) with TAM. HER-2 over-expressed patients are resistant to TAM. (5) Subgroup analysis suggested that: 3yr DFS is 88.67% with HER-2 over-expression and 92.20% with HER-2-negative in postmenopausal node-positive subgroup(p=0.0069), postmenopausal patients with HER-2 over-expression and node-positve are resistant to TAM; no difference in either premenopausal or postmenopausal node-negative subgroup (p>0.05). Conclusions: No difference between Anthracyclines based and T-regimens for HER2 over-expressed patients with node-positive for 3yr DFS.Postmenopausal ER+/PR+ patients with HER2 over- expression are resistant to Tamoxifen endocrine therapy. No significant financial relationships to disclose.

Download Full-text

Serum HER-2 extracellular domain: Relationship with clinicobiological presentation and prognostic value before and after primary treatment in 701 breast cancer patients

The International Journal of Biological Markers ◽

10.5301/jbm.2008.1233 ◽

2004 ◽

Vol 19 (1) ◽

pp. 14-22 ◽

Cited By ~ 19

Author(s):

M. Saghatchian ◽

S. Guepratte ◽

K. Hacene ◽

R. Neumann ◽

J.-L. Floiras ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Prognostic Value ◽

Extracellular Domain ◽

Primary Treatment ◽

Breast Cancer Patients ◽

Before And After ◽

Her 2

Download Full-text

Chromosome enumeration probe 17 (CEP) ratio to predict chemosensitivity in HER-2 overexpressing breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e11600 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e11600-e11600

Author(s):

D. Miura ◽

Y. Saitoh ◽

T. Iwatani ◽

H. Kawabata ◽

N. Inoshita

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Operable Breast Cancer ◽

Chromosome 17 ◽

Primary Cancer ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Cancer Society ◽

Her 2

e11600 Background: Precise assessment of HER-2 is critical in breast cancers and predicts benefit of trastuzumab (T). Although subset analysis of CALGB 9840 suggests benefit in FISH-negative patients with chromosome 17 polysomy (C17), clinical significance of C17 in FISH-positive patients is still less known. To analyze the epidemiologic feature of C17 in Japanese patients, consecutive operable breast cancer patients during 05–07 treated in single institution were studied. Methods: HER-2 status of consecutive 307 patients excluding DCIS and whose specimens were poor quality for study, were analyzed with Pathvysion (FISH). We defined HER- 2 (+) and C17 as HER-2/chromosome 17 ratio ≥ 2.2 and CEP ratio ≥ 2.2, respectively. Pathological response following neoadjuvant chemotherapy (NACT) was assigned according to the Japanese Breast Cancer Society (G3; no invasive or in situ residual tumor in the breast, G2; up to two thirds of primary cancer cells having pathologically severe changes or disappearance, G1; up to one third to two thirds of primary cancer cells having pathologically severe changes or disappearance). Results: HER-2 (+) was found in 22% (67/307) and C17 in 25% (77/307). Twenty-four of 67(36%) in HER-2 (+) had C17 and 53 of 240 (22%) in HER-2 (-) did C17. Among HER-2 (+), 23 cases received T-contained regimens as NACT (FEC/EC followed by PAC+T in 18 and DOC+CPA+T in 5). Six of 9 (67%) with C17 had G3 and 2 of 14 (14%) with non-C17 did G3. CEP ratio significantly predicts to have G3 (p=0.02) but HER-2/chromosome 17 ratio by logistic regression analysis. Conclusions: C17 was found in 25% of Japanese operable breast cancer patients of which was similar to that of CALGB. CEP ratio is a good predictive marker for chemo- sensitivity in HER-2 (+) subset. No significant financial relationships to disclose.

Download Full-text

Impact of selected tumor and patient characteristics on outcome of lymph node-positive breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.28_suppl.66 ◽

2015 ◽

Vol 33 (28_suppl) ◽

pp. 66-66

Author(s):

Ahmed Aly Nagy ◽

Hager Ibrahim ◽

Lamiaa Eid ◽

Fatma Sayed ◽

Mohamed Reda Kelany ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Cancer Patients ◽

Tumor Size ◽

Patient Characteristics ◽

Breast Cancer Patients ◽

Node Positive ◽

Her 2 ◽

Lymph Node Positive ◽

Positive Breast Cancer

66 Background: Axillary lymph node (ALN) involvement remains the most significant factor affecting long term survival in breast cancer (BC) patients, and the risk of treatment failure is increased with the higher the number of ALN involvement, The aim of this study was to determine the impact of tumor characteristics; tumor size and number of positive lymph nodes and, ER and HER-2, as well as patient characteristics on DFS of patients with Lymph node positive Breast Cancer Patients who received Adjuvant Treatment. Methods: We retrospectively reviewed data of 704 patients with BC and ALN involvement who received adjuvant treatment in the period between 2010 and 2012. DFS outcomes were estimated with the Kaplan-Meier method and compared using the log rank test to determine. The effect of prognostic factors on BC outcomes. Results: Median age was 50 years (SD±12.024, Range 21-88). About 83.7% of the tumors were IDC,. About 30.4%of the tumors were grade III. Median tumor size was 5 cm (SD± 1.3745, Range 1-7).Median number of positive axillary LN was 4 (SD± 4.987, Range 1-37). Regarding receptor expression; 21.2% were HER-2 +ve, 58.7% were ER +ve and about 30.4 were triple negative. Median DFS was 20 months (SD± 14.511, Range 1-60). Cox regression showed that age, positive ER status and more than 3 ALN involvement had a statistically significant impact on DFS ( p<0.001 for all ), however, Tumor size, HER-2 overexpression, patient menstrual status had no significant effect. ER positive age >50 years was associated with prolonged DFS of 23 months (95%CI=20.641-25.359) versus 19 months (95% CI=17.598-20.402) for age≤50 years (p<0.001). ER positive status was associated with prolonged DFS of 22 months (95%CI=20.290-23.710) versus 17 months (95% CI=14.049-19.951) for ER negative (p<0.001).The group of patients with ≤3 positive dissected LN was associated with statistically significant prolonged DFS of 25 months (95%CI=22.286-27.714) versus 15 months (95%CI = 12.353-17.647) for patients with>3 positive dissected LN (p<0.001). Conclusions: These study indicate that the age, ER status and more than 3 ALN involvement have impact on DFS in Lymph node positive Breast Cancer Patients.

Download Full-text