(Her2 studies with Herceptin support test in terms of monitoring response to Herceptin and baseline/selection for Herceptin in neoadjuvant, study w/Lapatinib supports level correlation with progression but claims no connection to Lapatinib treatment, Low EGFR w/increasing Her2=worse prog, serum Her2 relation to insulin BMI and weight)
EBCC: HER2 Levels May Predict Breast Cancer Response
http://www.medpagetoday.com/MeetingCoverage/EBCC/19229
EBCC: HER2 Levels May Predict Breast Cancer Response
By Charles Bankhead, Staff Writer, MedPage Today
Published: March 25, 2010
Reviewed by
Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
BARCELONA -- Monitoring HER2 levels during neoadjuvant breast cancer therapy may improve early identification of patients likely to benefit from trastuzumab (Herceptin), a prospective clinical trial suggests.
Elevated baseline levels of HER2 and a decline of at least 20% during treatment significantly increased the likelihood of pathologic complete response. In multivariate analysis, the 20% decline in HER2 levels remain statistically significant.
"Results of this study demonstrate that prechemotherapy serum HER2 levels as well as a decrease in serum levels to be a significant predictor of response to neoadjuvant chemotherapy for breast cancer," Isabell Witzel, MD, of the Medical University of Hamburg-Eppendorf in Hamburg, Germany, reported here at the European Breast Cancer Conference.
"Monitoring serum HER2 levels in the presence of trastuzumab treatment might be a promising adjunct to clinical evaluation during neoadjuvant chemotherapy in HER2-positive patients."
The neoadjuvant setting offers an opportunity to optimize treatment strategies for patients with nonmetastatic breast cancer. In patients with HER2-positive breast cancer, the extracellular domain of HER2 is shed into the serum, creating potential for a biological role of HER2 during treatment with trastuzumab, Witzel said.
To examine the association between serum HER2 levels and pathologic response, investigators used a commercially available assay to measure HER2 levels before and after neoadjuvant therapy in 90 patients with HER2-positive beast tumors and 85 patients with HER2-negative tumors. All patients with HER2-positive tumors received trastuzumab in addition to chemotherapy.
Pathologic complete response was defined as no microscopic evidence of invasive residual tumor cells in all resected specimens of the breast and lymph nodes. Neoadjuvant therapy led to pathologic complete response in 44 (49%) of HER2-positive patients compared with 12 (14%) HER2-negative patients (P<0.001).
Pretreatment median serum HER2 values were 7.7 ng/mL in the HER2-negative patients and 14.9 ng/mL in the HER2-positive group.
Receiver operating characteristic curve analysis identified 10 ng/mL as the optimal cutpoint for discriminating between HER2-positive and negative tumors, resulting in a sensitivity of 72%, specificity of 85%, positive predictive value of 85%, and negative predictive value of 73%.
Comparing baseline HER2 values and pathologic complete response, the investigators found that a baseline value >15 ng/mL was significantly associated with pathologic complete response (P=0.045). An even stronger association emerged from an analysis of the decline in serum HER2 levels in response to treatment (P=0.02).
In multivariate analysis, a decrease of >20% tripled the likelihood of pathologic complete response (OR 3.2, 95% CI 1.13 to 9.55, P=0.029).
Entire Paper
Citation: European Journal of Cancer Supplements Volume 8, No.3, March 2010, page 115
H. Makino1, K. Kuninaka1, C. Yoshida1, H. Hashidate2, M. Siotani3
1Niigata City General Hospital, Breast Oncology, Niigata, Japan
2Niigata City General Hospital, Pathology, Niigata, Japan
3Niigata City General Hospital, Radiology, Niigata, Japan
Background: Tumor markers can be an easier modality to detect cancer metastasis compared with diagnostic imaging, and its decrease or increase is often correlated with effectiveness of treatment.
Patients and Methods: Serum human epidermal growth factor receptor 2 extracellular domain (HER2-ECD) levels were reviewed in 56 breast cancer patients with metastasis and 21 patients who underwent preoperative systemic therapy (19: chemotherapy, 2: endocrine therapy). Patients were stratified into 2 groups, those with HER2-positive (group I) and negative (group II) breast cancer.
Results: In patients with metastatic disease, median serum HER2-ECD level was 14.6 ng/ml (group I) vs 12.9 ng/ml (group II, p = 0.14). furthermore, HER2-ECD levels were assessed in 17 patients at the detection of metastasis. In those, HER2-ECD was significantly higher in patients of group I (median: 17.2 ng/ml) than group II (12.2 ng/ml, p = 0.03), and proportion of patients with raised HER2-ECD (>15.3 ng/ml) was 75% (group I) vs 23% (group II, P = 0.099). In patients who undergoing preoperative treatment, median HER2-ECD level was 12.8 ng/ml (group I) vs 9.5 ng/ml (group II, p = 0.28). Proportion of patients with raised HER2-ECD was significantly higher in group I (60%) than in group II (0%, p = 0.008). In those patients, HER2-ECD levels decreased following chemotherapy, and were observed to be less than 15.3 ng/ml in patients who achieved pathological complete response. In 11 patients (85.7%) out of 14 who were evaluated both HER2-ECD levels and imaging diagnosis following systemic therapy, HER2-ECD was successfully associated with tumor response.
Conclusion: Serum HER2-ECD levels were observed to be raised in 75% of HER2-positive breast cancer patients at the time of detection of metastases, and well associated with tumor response in 85.7% of patients.
JCO Early Release, published online ahead of print Oct 26 2009
Journal of Clinical Oncology, 10.1200/JCO.2008.21.1763
Received November 27, 2008
Accepted April 17, 2009
Prognostic and Predictive Value of HER2 Extracellular Domain in Metastatic Breast Cancer Treated With Lapatinib and Paclitaxel in a Randomized Phase III Study
Richard S. Finn,* Robert Gagnon, Angelo Di Leo, Michael F. Press, Michael Arbushites, and Maria Koehler From the Geffen School of Medicine at UCLA; Norris Cancer Center, University of Southern California, Los Angeles, CA; Medicine Development Centre Oncology, GlaxoSmithKline, Collegeville, PA; and the Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
* To whom correspondence should be addressed. E-mail:
Rfinn@mednet.ucla.edu
Purpose: The HER2 extracellular domain (ECD) is enzymatically
cleaved from the cell membrane. Shed ECD in serum has been studied
as both prognostic and predictive markers. Lapatinib is a dual
inhibitor of HER2 and epidermal growth factor receptor kinases.
We examined the prognostic and predictive role of HER2 ECD in
a randomized trial of paclitaxel with placebo or lapatinib in
women with HER2-negative or -unknown breast cancer.
Patients and Methods: Patients (n = 579) with newly diagnosed metastatic
breast cancer (MBC) were randomly assigned to paclitaxel with
placebo or lapatinib. HER2 status was determined centrally.
ECD was centrally measured by enzyme linked immunoassay in available
samples at baseline (b; n = 472), week 9, and every 12 weeks
thereafter. Results were correlated to overall response rate
(ORR) and progression-free survival (PFS).
Results: Elevated
baseline ECD (bECD) levels (
16 ng/mL) did not predict HER2
tumor status (sensitivity, 62%; specificity, 75%). In HER2-negative
tumors, elevated bECD was not correlated with improved efficacy
for lapatinib plus paclitaxel versus placebo plus paclitaxel
(ORR: odds ratio, 1.6; 95% CI, 0.1 to 3.8;
P = .365; PFS: hazard
ratio, 0.94; 95% CI, 0.60 to 1.47;
P = .797).
ECD levels tended to decrease over time when bECD was elevated. ECD conversion from low to high was associated with worse PFS. Converting from high to low was associated with a better PFS. A consistently low ECD level had better PFS than a consistently elevated ECD. All associations were found to be independent of lapatinib.
Conclusion:
HER2 bECD does not predict lapatinib benefit in patients with
HER2-negative MBC. Changes in ECD status correlates with patient
outcome regardless of treatment given. Measuring HER2 ECD is
not currently recommended for predicting benefit to lapatinib.
J Clin Oncol. 2009 Apr 1;27(10):1685-93. Epub 2009 Mar 2.
Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer.
Lennon S,
Barton C,
Banken L,
Gianni L,
Marty M,
Baselga J,
Leyland-Jones B.
Roche Products Ltd, Welwyn Garden City, UK.
Comment in:
PURPOSE: Trastuzumab is a humanized monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2). Trastuzumab alone or in combination with chemotherapy has been shown to be effective in patients with HER2-positive early and metastatic breast cancer. The extracellular domain (ECD) of the HER2 protein may be shed into the serum and is detectable using an enzyme-linked immunosorbent assay. Correlations have been reported between raised baseline ECD levels and response to trastuzumab, suggesting that serum ECD levels may be useful in making treatment decisions in patients with HER2-positive breast cancer. We investigated this relationship, and also the effect of trastuzumab and chemotherapy on ECD levels, in patients with advanced breast cancer. METHODS: This study analyzed sequential ECD determinations on 322 patients treated with six different treatment regimens in four clinical trials. RESULTS: Baseline values were available in 296 patients, and of these, 205 (69%) had raised levels (> 15 ng/mL).
No clear relationship was found between baseline ECD levels and tumor response. After initiating combination therapy, ECD levels declined irrespective of treatment received and tumor response. For trastuzumab monotherapy, some trend between changes in ECD levels in early cycles and best response was discernable, but the overlap was too broad to be clinically useful. Disease progression was not reliably predicted by rising ECD levels in the majority of patients. CONCLUSION:
Based on our data, we cannot recommend using serum HER2 ECD levels to make trastuzumab or other treatment decisions for individual patients with advanced/metastatic breast cancer.
PMID: 19255335 [PubMed - indexed for MEDLINE]
1: IDrugs. 2009 Apr;12(4):238-42.Links
Hidden HER-2/neu-positive breast cancer: How to maximize detection.
Carney WP.
Oncogene Science, Siemens Healthcare Diagnostics Inc, 80 Rogers Street, Cambridge, MA 02142, USA. walter.carney@siemens.com.
The HER-2/neu oncoprotein is an important cellular target for the development of a variety of targeted therapies for HER-2/neu-positive breast cancer. Methods for tumor analysis such as immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) are routinely used to determine the HER-2/neu status of patients with breast cancer and their eligibility for HER-2/neu-targeted therapies, such as trastuzumab (Herceptin) and lapatnib (Tykerb). In a January 2008 article in the Wall Street Journal, it was reported that breast cancer patients may be receiving the wrong treatments or no treatment because of errors in the laboratory tests (IHC/FISH) that are widely used to determine the HER-2/neu status of breast cancers. Numerous reports have demonstrated that 20 to 30% of patients with primary breast cancer have HER-2/neu positive tumors. However, several studies have also shown that up to 40% of patients who are designated HER-2/neu negative with primary tumor analysis by IHC/FISH are actually HER-2/neu positive when the corresponding metastatic tumor is also evaluated by IHC/FISH. Studies have also demonstrated that up to 40% of patients with breast cancer who have a HER-2/neu-negative primary tumor as determined by IHC/FISH can develop elevated levels (> 15 ng/ml) of the circulating HER-2/neu oncoprotein during metastasis. Therefore, elevated serum HER-2/neu levels can be used to alert physicians of the possible presence of HER-2/neu-positive breast cancer in patients who have been previously classified as HER-2/neu negative. Collectively, these studies identify a population of women designated HER-2/neu negative that could have HER-2/neu-positive breast cancer, but have not been eligible for targeted therapies such as trastuzumab and lapatinib. Women who are incorrectly classified as HER-2/neu negative, but are also ineligible for approved HER-2/neu-targeted therapies, may also not be considered for clinical trials of additional HER-2/neu therapies in development. Several studies have also demonstrated that serum HER-2/neu can be elevated in patients with early breast cancer, and up to 90% of patients with HER-2/neu-positive metastatic breast cancer can have elevated serum HER-2/neu levels. These studies have also revealed that the frequency of patients who have HER-2/neu-positive breast cancer is greater than indicated previously by IHC/FISH. Thus, the number of patients classified incorrectly as HER-2/neu negative could be substantially greater than recognized previously. This feature review presents a HER-2/neu testing algorithm that combines the serum HER-2/neu test result with IHC/FISH test results to maximize the identification of patients who are HER-2/neu positive and could be potential candidates for HER-2/neu-targeted therapies. The HER-2/neu situation also exemplifies that multiple diagnostic tools are required to correctly and accurately identify patients for targeted therapies - an important lesson as many new biomarkers are identified for the multitude of new targeted therapies in development for various forms of cancers.
Cancer. 2008 Sep 15;113(6):1294-301.
Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer.
Ali SM,
Carney WP,
Esteva FJ,
Fornier M,
Harris L,
Köstler WJ,
Lotz JP,
Luftner D,
Pichon MF,
Lipton A;
Serum HER-2/neu Study Group.
Collaborators (8)Brault D,
Burstein H,
Gligorov J,
Leitzel K,
Neumann R,
Price CP,
Thiel RP,
Wheler J.
Department of Hematology-Oncology, Penn State Hershey Cancer Center, Penn State University/Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
BACKGROUND: Previous reports based on small patient numbers suggested that changes in serum HER-2/neu levels may predict response or lack of response to trastuzumab-based therapies in metastatic breast cancer (MBC). The objectives of this study were to pool data from 307 patients with MBC from 7 medical institutions to validate that the serum HER-2/neu profile predicts patient resistance to trastuzumab and to establish a clinically relevant cutoff. METHODS: This was an international, multicenter, retrospective analysis of individual pooled data from 307 patients with MBC who were treated with first-line trastuzumab-based therapy. Serum was collected at baseline and 30 to 120 days after the initiation of trastuzumab therapy. A serum HER-2/neu decrease >or=20% (receiver operating curve analysis) was defined as a significant HER-2/neu change. RESULTS:
Of the 307 patients with MBC, 191 patients (62%) had a significant decline (>20%) in serum HER-2/neu and 116 patients (38%) did not. The objective response rate was 57% for patients who achieved this decline in serum HER-2/neu (>20%) compared with 28% for patients who did not. Patients who achieved this decline in serum HER-2/neu also had a significantly longer time to disease progression (320 days vs 180 days; P < .0001), longer duration of response (369 days vs 230 days; P = .008), and longer overall survival (898 days vs 593 days; P < .018). CONCLUSIONS: In this pooled analysis of 307 patients with MBC, individuals who did not achieve a significant decline (>or=20%) in serum HER-2/neu levels had decreased benefit from trastuzumab-based therapy, and these patients should be considered for clinical trials evaluating additional HER-2/neu-targeted interventions. (c) 2008 American Cancer Society.
PMID: 18661530 [PubMed - indexed for MEDLINE]
EGFR and HER2-neu predict response to metronomic chemotherapy
2005;7(4):R436-43. Epub 2005 Apr 8.
Clinical utility of serum HER2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies.
Esteva FJ,
Cheli CD,
Fritsche H,
Fornier M,
Slamon D,
Thiel RP,
Luftner D,
Ghani F.
The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
festeva@mdanderson.org
INTRODUCTION: The purpose of this retrospective study was to determine the clinical utility of serum HER2/neu in monitoring metastatic breast cancer patients undergoing trastuzumab-based therapy and to compare these results with those obtained using cancer antigen (CA) 15-3. We also sought to determine whether early changes in serum HER2/neu concentrations could be a predictor of progression-free survival. METHODS: Sera were obtained retrospectively from 103 women at four medical institutions. Patients eligible for participation were women with metastatic breast cancer who had HER2/neu tissue overexpression and were scheduled to be treated with trastuzumab with or without additional therapies as per the established practices of the treating physicians. A baseline serum sample for each patient was taken before trastuzumab-based therapy was started. Patients were subsequently monitored over 12 to 20 months and serum samples were taken at the time of clinical assessment and tested with Bayer's HER2/neu and CA15-3 assays. RESULTS: Concordance between clinical status in patients undergoing trastuzumab-based treatment and HER2/neu and CA15-3 used as single tests was 0.793 and 0.627, respectively, and increased to 0.829 when the tests were used in combination.
Progression-free survival times did not differ significantly in patients with elevated baseline HER2/neu concentrations (> or = 15 ng/mL) and those with normal concentrations (<15 ng/mL). However, progression-free survival differed significantly (P = 0.043) according to whether the patient's HER2/neu concentration at 2 to 4 weeks after the start of therapy was >77% or < or = 77% of her baseline concentration. The median progression-free survival times for these two groups were 217 and 587 days, respectively. A similar trend was observed for a subcohort of patients treated specifically with a combination of trastuzumab and taxane. CONCLUSION:
These findings indicate that serum HER2/neu testing is clinically valuable in monitoring metastatic breast cancer patients undergoing trastuzumab-based treatment and provides additional value over the commonly used CA15-3 test. The percentage of
baseline HER2/neu concentrations in the early weeks after the start of therapy may be an early predictor of progression-free-survival.
PMID: 15987448 [PubMed - indexed for MEDLINE]
Nutr Metab (Lond). 2010 Feb 25;7:14.
Serum HER-2 concentration is associated with insulin resistance and decreases after weight loss.
Fernández-Real JM,
Menendez JA,
Frühbeck G,
Moreno-Navarrete JM,
Vazquez-MartÃ*n A,
Ricart W.
Department of Diabetes, Endocrinology and Nutrition, CIBERobn FisiopatologÃ*a de la Obesidad y Nutrición CB06/03/010, Instituto de Salud Carlos III, 28029 Madrid, Spain.
jmfernandezreal.girona.ics@gencat.cat.
ABSTRACT: BACKGROUND: HER2/neu is a member of the epidermal growth factor receptor family easily detectable in the serum of cancer patients. We aimed to evaluate circulating HER-2 concentrations in association with insulin resistance in healthy and obese subjects. METHODS: Insulin sensitivity (minimal model) and serum HER-2 concentrations were evaluated in a cross sectional study in men (cohort 1, n = 167) and longitudinally after weight loss in obese subjects (cohort 2, n = 30). RESULTS:
Serum HER-2 concentrations were positively associated with BMI and waist circumference (both r = 0.18, p = 0.02), post-load glucose (r = 0.28, p = 0.001) and fasting triglycerides (r = 0.26, p = 0.001); and negatively associated with insulin sensitivity (r = -0.29, p = 0.002, n = 109). Subjects with type 2 diabetes showed significantly increased soluble serum HER-2 concentrations. In different multivariate regression models,
fasting triglycerides emerged as the factor that independently contributed to 10-11% of serum HER-2 variance.Serum HER-2 concentrations correlated significantly with fasting triglycerides and insulin sensitivity index in subjects from cohort 2.
Weight loss led to a significant decrease of serum HER-2 concentrations. The change in serum HER-2 concentrations were significantly associated with the change in percent body fat and fasting triglycerides in young (below the median age of the cohort) subjects. CONCLUSIONS: Serum HER-2 concentrations might be implicated in the pathophysiology of insulin resistance and associated comorbidities.
PMID: 20184722 [PubMed - in process]
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