Trastuzumab plus Paclitaxel or Docetaxel in HER-2–Negative/HER-2 ECD–Positive Anthracycline- and Taxane-Refractory Advanced Breast Cancer

Abstract

Trastuzumab is considered effective against human epidermal growth factor receptor (HER)-2-positive breast cancer as assessed by immunohistochemistry (IHC) and fluorescence or chromogenic in situ hybridization (FISH/ CISH) on biopsy material. Trastuzumab is now approved in both the adjuvant and metastatic settings for this patient population. Because HER-2 extracellular domain (ECD) levels have been correlated with disease progression in the metastatic setting, we considered trastuzumab salvage therapy plus a taxane in heavily pretreated trastuzumab-naive relapsed breast cancer patients with high serum levels of HER-2 ECD (>15 ng/ml). All patients had previously failed at least two lines of anthracycline-and taxane-based regimens and were HER-2 negative by IHC and FISH/CISH prior to a centralized reanalysis, and were serum positive for HER-2 ECD (>15 ng/ml) at baseline. Regular serum accounts of HER-2 ECD were recorded and compared with response and survival outcomes. Twenty-two patients were finally eligible for salvage therapy. Minor responses were observed in five (23%) and stable disease (SD) was observed in 11 patients, leading to a clinical benefit rate of 73% (16 of 22 patients). The median time to progression and overall survival time were 5 (6.5 months in minor responders and SD) and 12 months, respectively; 11 and eight patients remained progression free for >6 and >12 months, respectively. Eleven and seven patients were alive at 12 and 15 months, respectively, after treatment start. Furthermore, in total, 13 (59.1%) patients obtained a biochemical response. In our study, patients with conventionally HER-2-negative disease but with expression of HER-2 ECD above the normal limit (>15 ng/ml) displayed a rapid response, both biochemically and clinically, to the trastuzumab-taxane combination. This is the first study assessing anti-HER-2-based treatment in HER-2-negative advanced breast cancer according to HER-2 ECD positivity; if our results are confirmed, additional patients with "hidden" HER-2-positive breast cancer might benefit from anti-HER-2 treatment. The Oncologist

Serum HER2 Extracellular Domain as a Potential Alternative for Tissue HER2 Status in Metastatic Gastric Cancer Patients

“…In our experiment, some cases with negative tissue HER2 also showed high serum HER2 ECD concentrations. Ardavanis et al found that the HER2 tissue negative but serum positive patients can be benefited from trastuzumab therapy [23]. Thus, a potential utility of serum HER2 ECD is to identify patients who missed the opportunity of being treated with HER2-targeted therapies due to a lack of overexpression of HER2 in tumor tissues.…”

Comparison of the 2007 and 2013 ASCO/CAP evaluation systems for HER2 amplification in breast cancer

“…Trastuzumab, a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2), is routinely used to treat patients with breast carcinoma who overexpress HER2 [2,3]; when combined with chemotherapy in the metastatic setting, trastuzumab improves progression-free survival and overall survival by years [4]. Other HER2-targeting drugs (e.g., the kinase inhibitor lapatinib [5], the antibody pertuzumab [6], the antibody-drug conjugate adotrastuzumab emtansine [T-DM1] [7]) have been approved for use in the treatment of HER2-positive metastatic breast cancer. At the same time, it has been shown that lapatinib (when added to paclitaxel) [8] and pertuzumab (as a single agent) [9] offer no clinical benefit to patients with HER2-negative metastatic disease.…”

Pharmacogenomic biomarkers as inclusion criteria in clinical trials of oncology-targeted drugs: a mapping of ClinicalTrials.gov

“…15 Indeed, 16 of 22 HER-2-negative patients with an HER-2 extracellular domain level >15ng/mL showed a clinical benefit, which led to the concept of "hidden" HER-2-positive breast cancer. 16 Furthermore, contrary to expectations, the level of HER-2 did not predict clinical response and showed a U-shaped relationship, which suggested that trastuzumab could be effective in HER-2-negative tumors. 17 Another example is cetuximab, the anti-epidermal growth factor receptor (EGFR) drug, originally studied only in patients with EGFR-expressing tumors until it was found to be beneficial for some patients with EGFR negative tumors as well.…”