Utility of Serum HER2 Extracellular Domain Assessment in Clinical Decision Making

[Rich66]

J Clin Oncol. 2009 Apr 1;27(10):1685-93. Epub 2009 Mar 2. Links

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.
Winship Cancer Institute, Emory University, School of Medicine, 1701 Uppergate Dr, Atlanta, GA 30322, USA; LEYLAND@emory.edu.
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 - in process]

[Rich66]

Meanwhile..Siemens releases this..suggesting a tool to combine available info for evaluating status:

1: IDrugs. 2009 Apr;12(4):238-42.

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.
PMID: 19350468 [PubMed - in process

[Rich66]

In the current report, patients who did not have
a significant decline (20%) in serum HER-2/neu
levels had decreased benefit from trastuzumab-based
therapy. Monitoring changes in serum HER-2 levels
at a median of 1 month after trastuzumab treatment
to predict clinical response may be valuable for identifying
a patient population that might benefit from
additional treatment regimens with other HER-2/
neu-targeted therapies. Currently, although trastuzumabshould not be stopped based on the absence of
a decline in serum HER-2 levels, prospective clinical
trials evaluating the use of other HER-2-directed
therapies (ie, lapatinib, Hsp-90 inhibitor, sheddase
inhibitor) with and without continued trastuzumab
therapy are warranted for patients who do not
achieve a 20% decline in serum HER-2.

[Rich66]

HER-2/neu diagnostics in breast cancer