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Vol. 7, 2605–2607, September 2001 Clinical Cancer Research 2605 Editorial Is Circulating HER-2 More Than Just a Tumor Marker? Jose Baselga1 chemotherapy; and the selection patients for trastuzumab ther- Medical Oncology Service, Vall d’Hebron University Hospital, apy and the monitoring of response to trastuzumab (8, 9). Barcelona 08035, Spain. In this regard what does the study by Hayes et al. (10) add to our current knowledge? In this study, 242 patients who were enrolled in Cancer and Leukemia Group B (CALGB) prospec- HER2/neu (also known as neu and as c-erbB-2) is a proto- tive therapeutic trials for metastatic breast cancer were assayed oncogene of the EGF2 receptor family of receptor tyrosine for circulating ECD/HER-2 using a commercially available kinases (1). HER2/neu encodes a Mr185,000 transmembrane sandwich enzyme immunoassay (10). In their study, elevated glycoprotein receptor (HER2, or c-erbB-2) that has partial ho- ECD/HER-2 levels were observed in 37% of patients and were mology with the other members of the EGF receptor family, and associated with a shorter overall survival. However, in a multi- which also includes the EGF receptor (also called HER1), variate analysis, ECD/HER-2 did not independently correlate HER3, and HER4. These receptors are composed of an extra- with survival. Furthermore, ECD/HER-2 levels were not pre- cellular binding domain, a transmembrane lipophilic segment, dictive for time to progression and for response to megestrol and an intracellular protein tyrosine kinase domain with a reg- acetate or chemotherapy, including a subgroup of patients ulatory carboxyl terminal segment (2). HER2 is overexpressed treated with an anthracycline-containing regimen. The authors in 25–30% of breast cancers and its overexpression is associated concluded appropriately that, like most other circulating tumor with a high risk of relapse and death (3). ECD/HER-2 can be markers, circulating levels of ECD/HER-2 are most likely as- released by proteolytic cleavage from the full-length HER2 sociated with a high tumor burden, and that their utility may be receptor and detected in the serum of patients. restricted to monitoring the clinical course in patients undergo- A humanized antibody directed against the extracellular ing therapy. domain of HER2 has shown clinical activity against HER2- Is there more to ECD/HER-2 than just another marker of overexpressing breast tumors and has been recently approved tumor burden? The answer is probably yes. This notion stems for clinical use given alone or in combination with chemo- from the very nature of ECD/HER-2 generation and release therapy (4 – 6). Taking these data into consideration, tissue from the tumor cells into the serum. A large body of experi- HER2 determination in breast cancer by either immuno- ments with cultured cells indicate that transmembrane, full- histochemistry or fluorescence in situ hybridization has length HER2 undergoes a proteolytic event that results in the become increasingly important to provide optimal care to release of the soluble ECD/HER-2 fragment and, concomitantly, patients with breast cancer (7). The issues remain which of in the production of an amino-terminally truncated, cell-associ- the available methods to determine HER2 overexpression/ ated, HER2 fragment that contains the kinase domain (desig- amplification may be used and whether a plasma-based assay nated as HER2 p95 because of its molecular weight) with may have a role in the clinic. Levels of circulating ECD/ potentially enhanced signaling activity (11–14). It is tempting to HER-2 are easily detectable in the serum of breast cancer speculate that the adverse prognosis observed in patients with patients, and the Food and Drug Administration has recently high levels of ECD/HER-2 may be related, at least in part, to the approved an ELISA-based HER-2 serum test for use in the fact that it should reflect a concomitant increase of truncated, follow-up and monitoring of patients with metastatic breast signaling-competent, HER2 p95. Studies measuring serum cancer (Bayer Diagnostics, Tarrytown, NY). Over the last ECD/HER-2 and tumor HER2 p95 are needed to fully support years, the measurement of serum ECD/HER-2 levels in pa- this possibility. As examples of the signaling activity of trun- tients with breast cancer has been suggested as useful for cated receptors, it has been shown that the cleavage of HER4, a several clinical applications. These include: the monitoring receptor of the same family that HER2, or the TrkA neurotro- of women with metastatic breast cancer to aid in patient phin receptor, produces active tyrosine kinase fragments that management; detecting the early appearance of recurrent breast cancer; predicting response to hormonal therapy or resemble the activated full-length receptors (15, 16). These results suggest that the extracellular domains of these receptors prevent spontaneous activation of the intracellular kinase do- main. Conceivably, ligand-binding or ectodomain cleavage might counteract this inhibitory effect on the kinase domain. Received 6/6/01; accepted 6/15/01. This hypothesis is strengthened by studies showing that an The costs of publication of this article were defrayed in part by the engineered deletion of the ECD/HER-2 markedly increases the payment of page charges. This article must therefore be hereby marked tyrosine kinase activity and transforms efficiency of the result- advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ing NH2-terminally truncated HER2 protein (17). In support of 1 To whom requests for reprints should be addressed, at Medical On- the in vivo signaling activity of the truncated HER2 p95 frag- cology Service, Vall d’Hebron University Hospital, Paseo Vall ment, we have found that it is phosphorylated in human breast d’Hebron 119-129, Barcelona 08035, Spain. Phone: 34-93-274-6077; Fax: 34-93-2-74-6059; E-mail: email@example.com. cancer tumors (14). In addition, the level of HER2 p95 in 2 The abbreviations used are: EGF, epidermal growth factor; ECD/ primary breast tumors is associated with the presence of lymph HER-2, extracellular domain of HER2. node metastases, whereas the level of full-length HER2 did not 2606 Circulating HER-2 Extracellular Domain as Tumor Marker show such an association (12).3 Hence, these data support a role the constitutive activation of the membrane-bound truncated of HER2 cleavage in human breast cancer progression. In a receptor that occurs upon shedding of the extracellular domain. complementary fashion, the study by Hayes et al. (10) reports a In closing, what is the clinical utility of determining ECD/ positive correlation between high serum ECD/HER-2 with poor HER-2 in the serum of breast cancer patients? The study by prognosis and visceral metastasis. Because these findings sup- Hayes et al. (10) indicates that serum HER-2/ECD is not a port that ECD/HER-2 plays a role as a marker of an aggressive predictive factor for response to either hormonal agents or to breast cancer biology, it is warranted to address in future studies chemotherapy including anthracyclines, but it is a prognostic the question of whether we can improve the prognostic value of factor in breast carcinoma. If basally elevated, serum ECD/ tissue HER2 protein expression or HER2 gene copy number by HER-2 may be a very useful tool in monitoring early and overall adding the information of serum ECD/HER-2 levels. response to therapy, including trastuzumab (19, 20). Likewise, Current data indicate that patients with breast tumors over- rising ECD/HER-2 levels may be an early indication of disease expressing HER2 commonly have high levels of serum ECD/ recurrence or progression. In addition, because there is a corre- HER-2 (4, 5, 18 –20). On the basis of this association, additional lation between ECD/HER-2 levels and HER-2 expression in the studies are needed to assess, in the population of breast cancer tumor, one might consider selecting patients for trastuzumab patients with known tissue HER2 overexpression/amplification, therapy on the basis of high ECD/HER-2 levels, if tissue is not whether serum ECD/HER-2 levels might be better serum mark- available. Finally, elevated ECD/HER-2 levels may reflect a ers to monitor tumor relapse than others commonly used, such subgroup of tumors with a higher level of HER-2 cleavage and as CA15–3 or CEA, as suggested in a recent study (18). How- shedding. This subgroup of tumors may have a more aggressive ever, there are cases with high levels of ECD/HER-2 in the clinical course and, as mentioned, could be specially suited for absence of HER2 tissue overexpression and vice versa. These targeted therapies such as trastuzumab, matrix metalloprotease discrepancies again might be explained by the regulated process inhibitors, and receptor tyrosine kinase inhibitors. Therefore, of HER2 cleavage. In this respect, we have shown that the there is strong evidence to support that ECD/HER-2 is not just cleavage of HER2 is a highly regulated, metalloprotease- another tumor marker but, rather, a biological indicator of a dependent, event, and that breast cancer cells have the HER2 distinct subgroup of HER-2-overexpressing breast tumors. cleavage machinery ready to act on HER2 well beyond their basal activity (13, 14, 21). There are diverse mechanisms that can activate this machinery (i.e., phosphorylation/dephosphoryl- References ation, metalloprotease activation, and possibly expression of 1. Coussens, L., Yang-Feng, T. L., Liao, Y. C., Chen, E., Gray, A., McGrath, J., Seeburg, P. H., Libermann, T. A., Schlessinger, J., erbB ligands), and which may have a role in vivo. Therefore, it Francke, V., Levinson, A., and Ullrich, A. Tyrosine kinase receptor with seems likely that breast tumors may have different levels of extensive homology to EGF receptor shares chromosomal location with these activators of HER2 cleavage, which presumably may lead neu oncogene. Science (Wash. DC), 230: 1132–1139, 1985. to variations in serum ECD/HER-2 for a given level of tissue 2. Pinkas-Kramarski, R., Alroy, I., and Yarden, Y. ErbB receptors and EGF-like ligands: cell lineage determination through combinatorial sig- HER2 expression. Hence, serum ECD/HER-2 may reflect, in naling. J. Mammary Gland Biol. Neoplasia, 2: 97–108, 1997. part, the activation state of the shedding machinery that acts on 3. Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., HER2, instead of being solely a measure of HER2 expression and McGuire, W. L. Human breast cancer: correlation of relapse and and tumor burden. It will be necessary first to identify the key survival with amplification of the HER-2/neu oncogene. Science (Wash. metalloprotease(s) involved in HER2 cleavage to study this DC), 235: 177–182, 1987. hypothesis in clinical breast cancer samples. 4. Baselga, J., Tripathy, D., Mendelsohn, J., Baughman, S., Benz, C. C., Dantis, L., Sklarin, N. T., Seidman, A. D., Hudis, C. A., Moore, J., HER-2 cleavage may also provide an opportunity for ther- Rosen, P. P., Twaddell, T., Henderson, I. C., and Norton, L. Phase II apeutic intervention. Interestingly, the monoclonal antibody study of weekly intravenous recombinant humanized anti-p185HER2 trastuzumab appears to have a direct inhibitory effect on basal monoclonal antibody in patients with HER2/neu-overexpressing meta- and induced HER-2 cleavage, likely attributable to antibody static breast cancer. J. Clin. Oncol., 14: 737–744, 1996. binding to the receptor ectodomain in a way that may hide the 5. Cobleigh, M. A., Vogel, C. 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