Lee CK, et al (2016) J Clin Oncol, Serum human epidermal growth factor 2 extracellular domain as a predictive biomarker for lapatinib treatment efficacy in patients with advanced breast cancer, 34(9):936-944.

Trastuzumab plus paclitaxel or docetaxel in HER-2-negative/HER-2-positive anthracycline- and taxane-refractory advanced breast cancer. Ardavanis A, Kountourakis P, Kyriakou F, Malliou S, Mantzaris I, Garoufali A, Yiotis, I.Scorilas A, Baziotis N, Rigatos G (2008) The Oncologist. 13: 361-369. A study of twenty-two women who had severe progressive disease not responding to conventional cytotoxic chemotherapy. All had a negative tissue test in the past, so they had not received trastuzumab. But all had high sHER2/neu values. Each was treated with trastuzumab plus one of the drugs that had earlier failed. 73% of these patients experienced clinical benefit.

Serum HER-2 predicts response and resistance to trastazumab treatment in breast cancer. Peterson ERB, Sorensen, PD, Jacobsen, EH, Madsen, JS and Brandslund, I, Clin Chem Lab Med (2013) 47:1117-1123These authors describe decreasing sHER2/neu values greater than 20% during successful Herceptin treatment and rising values in progressive disease.When comparing women judged to be free of disease to women alive with recurrence, there was a dramatic shift in median sHER2/neu values.

Monitoring serum HER2 levels during neoadjuvant trastuzumab treatment within the GeparQuattro trial. Witzel I, Loibl S, von Minckwitz G, Mundhenke C, Huober J, Hanusch C, Henschen S, Hauschild M, Lantzsch T, Tesch H, Latos K, Just M, Hilfrich J, Barinoff J, zu Eulenburg C, Roller M, Untch M, Muller V, Breast Cancer Res Treat (2010) 123:437-445. This paper, summarizes data from a large German trial involving 175 patients. The authors looked at sHER2/neu during neo-adjuvant treatment, when chemotherapy is given before surgery to reduce tumor size and spare breast tissue at surgical removal. Monitoring sHER2/neu was helpful in predicting clinical response. This paper discusses an as yet unresolved issue—some sHER2/neu values in the range of “normal”, maybe as many as half, may still indicate the presence of a HER2 tumor and merit monitoring during treatment. 

Prognostic and predictive value of HER2 extracellular domain in metastatic breast cancer treated with lapatinib and paclitaxel in a randomized phase III study. Finn RS, Gagnon R, Di Leo A, Press MF, Arbushites M, Koehler M, J Clin Oncol (2009) October online. This study of 579 HER2 tissue-negative women with advanced breast cancer found 25% to have an elevated baseline sHER2/neu. The progression of the cancer in these women was more rapid than the women with normal serum HER2 levels but was reduced with effective medication. Therefore, serum HER2 was of prognostic value. The authors treated two small groups with paclitaxel and either lapitinib or a placebo. Both groups responded, so the authors concluded that an elevated serum HER2 was of no predictive value.

Human epidermal growth factor 2 (HER2) extracelluar domain levels are associated with progression-free survival in patients with HER2-positive metastatic breast cancer receiving laptinib monotherapy. Lipton A, Leitzel K, Ali SM, Carney W, Platek G, Steplewski K, West P, Lund R, Gagnon R, Martin A, Maltzman J, (2011) Cancer. The most reliable way to evaluate the utility of a sHER2/neu test during treatment is to study women treated with only one HER2-targeted drug. This article evaluated patients receiving only the HER2-targeted drug lapatinib. They observed a greater than 20% fall in sHER2/neu, often as early as four weeks, in patients responding clinically. These doctors, as have others, published very similar results with single drug trastuzumab treatment in a 2008 report. As the number of HER2-targeted drugs increases and the cost of treatment increases, a tool to detect early evidence of drug failure takes on new meaning.

Here are a few references and comments:

Over100 articles supporting serum HER2 (sHER2/neu) monitoring have been published during the past ten years. These articles have been written by teams of clinical researchers either reviewing medical records or conducting prospective studies structured to follow women during and after treatment. Most articles support sHER2/neu testing of women with metastatic breast cancer, repeating the test during treatment and periodically thereafter to detect any failure in treatment or progression. Not all doctors are aware or concur with these recommendations. Nevertheless, the evidence for monitoring continues to accumulate.