Correlation of tumor burden, liver and bone metastasis with serum extracellular domain HER2 expression in front-line metastatic breast cancer

Abstract #3146 Background: Although serum extracellular domain (sECD) HER2 levels can be easily measured by enzyme immunoassays, the potential clinical utility of HER2 extracellular domain protein shed in the serum is not established. High serum protein levels may be indicative of metastatic disease to the liver or perhaps greater tumor burden. EGF30008 is a double-blind, placebo-controlled phase III trial evaluating the effect of letrozole with/without lapatinib in previously untreated postmenopausal women with hormone receptor-positive metastatic breast cancer. Levels of sECD HER2 were collected on all 1,286 women at baseline and every 4 weeks on study including at disease progression. Methods: Baseline serum levels and tumor characteristics were collated in blinded fashion for all 1,286 patients in the trial (data cut off 12May08). Patients with baseline serum protein levels ≥ 15 ng/mL were defined as sECD HER2+. Correlations were assessed between baseline serum protein levels and baseline liver disease and bone-only disease and total tumor burden (as defined by number of metastatic sites). Chi-square test was applied to assess the correlation between serum protein levels and liver disease or bone-only disease. Wilcoxon rank-sum test using normal approximation was used to compare total tumor burden and baseline protein levels. Results: Among sECD HER2+ patients, 42% had at least one liver metastasis, whereas 20% of sECD HER2-negative patients had at least one liver metastasis (P < 0.0001). No correlation exists between baseline serum protein level and bone-only disease (P = 0.64). Patients who were sECD HER2+ had a greater total tumor burden (mean metastatic sites = 5.4; standard deviation = 3.2; median = 5) compared with patients who were sECD HER2-negative (mean metastatic sites = 4.4; standard deviation = 3.1; and median = 4; P < 0.0001). Conclusion: High baseline sECD HER2 strongly correlates with tumor burden. There was also a significant correlation between sECD and liver metastases, but no correlation at all with bone-only disease. These analyses will be repeated after the database is finalized and unblinded. Our analysis is limited to detection of the number of metastatic sites and is not sensitive to the individual sizes of metastases. In addition, another potential explanation for the low sensitivity of HER2 detection by sECD is that small metastatic deposits that are HER2+ in situ do not shed enough sECD into the serum to be detected by the assay. Conversely, some very large HER2-negative tumors do in fact shed measurable sECD if the tumor bulk is very high, even though in situ they may be nonamplified. A future analysis will take the sum of the longest diameters of all known lesions and compare it to sECD HER2 levels. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3146.