Monitoring serum HER2 levels in breast cancer patients

Abstract

Background: We have developed a new approach to reduce the serum interference for ELISA. The purpose of this study is to investigate if we can use the optimized ELISA (MBB-ELISA) to detect serum soluble HER2/neu (sHER2) in early stage primary breast cancer and monitor its change during treatments.

Findings: We collected sera preoperatively from 118 primary breast cancer patients. Serum samples were also collected sequentially from a subset of patients during and after adjuvant treatment. sHER2 in these samples was measured by the MBB-ELISA. Only 16.7 % of tissue HER2 (tHER2) positive patients had significantly elevated sHER2 levels in serum. Interestingly, sera of some patients with tHER2 negative tumors, including those that were 2+ by IHC but negative by FISH, demonstrated slightly elevated sHER2 levels. Multivariate analysis demonstrated that patients with elevated sHER2 (> = 7 ng/ml) had significantly worse disease free survival. During treatments, sHER2 levels consistently fell in response to adjuvant therapies. Nevertheless, in all 4 patients who developed metastases, a steady rise in sHER2 levels was noted before metastatic disease became clinically evident.

Conclusions: For early stage breast cancers, sHER2 is a poor biomarker to predict tHER2 status, but may have value to supplement tissue tests to identify patients with HER2 tumors. Our results also suggest that sHER2 is worth further study as a biomarker to monitor breast cancer patients during treatments.

Keywords: Biomarker; Breast cancer; HER2/neu; MBB buffer; SHER2.

Fig. 1

Correlation between MBB assay and the commercial Wilex assay for serum sHER. Forty serum samples were grouped into either tHER2 negative (blue diamond) or positive (red triangle) and tested by both assays. Both groups showed good correlation of sHER2 levels between these two assays

Fig. 2

Elevated sHER2 levels in tissue HER2 positive patients (tHER2+). sHER2 levels were determined by MBB ELISA. tHER2+ patients had significantly higher average sHER2 levels

Fig. 3

Disease free survival of breast cancer patients after surgery. Kaplan-Meier analyses showing the association of preoperative sHER2 with adverse patient outcome in two cohorts using recurrence-free survival as clinical endpoints

Fig. 4

Monitoring sHER2 levels in 4 patients who eventually developed recurred diseases. Serum samples of these patients were collected periodically and tested using MBB-HER2 ELISA. Treatments and recurrence / metastasis were indicated. a Patient#10004 failed to respond to adjuvant therapies and had a local recurrence. After bilateral mastectomy, sHER steadily went up, even in the presence of radiation and additional Herceptin treatments. Brain metastasis was identified during the sHER2 rising phase, and eventually the patient developed liver metastasis. b Patient#10048 showed a drop of sHER2 after chemo/Herceptin treatments and mastectomy. After about 2 months of staying at the bottom, sHER2 gradually went up after local recurrence was identified. The patient was treated with several kinds of chemotherapies with Herceptin, but sHER2 kept surging. Eventually the navelbine/Herceptin combination was able to change the course of rising sHER2 levels. c In patient #10041, sHER2 responded to the initial chemo/Herceptin treatment and dropped to < 2 ng/ml. The level rebounded to ~ 4 ng/ml during the Herceptin alone treatment. After radiation, the level was reduced again to a very low level (<1 ng/ml). However, sHER2 level rose again and brain metastasis was identified. d sHER2 levels in #10061 was restricted in a very narrow range over the course of treatment. After bilateral mastectomy and radiation, sHER2 gradually bottomed out at 2 ng/ml. In less than 2 months, sHER2 rose from 2 ng/ml to 4 ng/ml. Two months later, brain metastasis was detected. Serum samples right before metastasis was not available and it is not clear if the upward trend of sHER2 continued until brain metastasis. Treatments: A: Adriamycin; Cy: Cytoxan; T: Taxol; H: Herceptin; X: Xeloda; Ha: Halaven; L: Lapatinib; Na: Navelbine; Rad: radiation