Is Circulating HER-2 More Than Just a Tumor Marker by po9383


									Vol. 7, 2605–2607, September 2001                                                                                 Clinical Cancer Research 2605


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
  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:
                                                                        cancer tumors (14). In addition, the level of HER2 p95 in
  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. L., Tripathy, D., Robert, N. J., Scholl, S.,
                                                                                 Fehrenbacher, L., Wolter, J., Paton, V., Shack, S., Lieberman, G., and
     cleavage site from the protease responsible for HER-2 shedding              Slamon, D. J. Multinational study of the efficacy and safety of human-
     (14). It is attractive to hypothesize that this inhibition of HER2          ized anti-HER2 monoclonal antibody in women who have HER2-
     cleavage by trastuzumab may have therapeutic value by pre-                  overexpressing metastatic breast cancer that has progressed after chem-
     venting the formation of the potentially deleterious truncated              otherapy for metastatic disease. J. Clin. Oncol., 17: 2639 –2648, 2000.
     HER-2 p95 fragments. Other approaches may include the use of                6. Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V.,
     matrix metalloprotease inhibitors, which could prevent receptor             Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M.,
                                                                                 Baselga, J., and Norton, L. Use of chemotherapy plus a monoclonal
     cleavage, or HER tyrosine kinase inhibitors, which could revert             antibody against HER2 for metastatic breast cancer that overexpresses
                                                                                 HER2. N. Engl. J. Med., 344: 783–792, 2001.
                                                                                 7. Pauletti, G., Dandekar, S., Rong, H., Ramos, L., Peng, H., Seshadri,
                                                                                 R., and Slamon, D. J. Assessment of methods for tissue-based detection
                                                                                 of the HER-2/neu alteration in human breast cancer: a direct comparison
      M. A. Molina, R. Saez, E. E. Ramsey, M. J. Garcia-Barchino, A.             of fluorescence in situ hybridization and immunohistochemistry. J. Clin.
     Evans, J. Albanell, E. J. Keenan, A. Lluch, J. Garcıa-Conde, J. Baselga,
                                                        ´                        Oncol., 18: 3651–3664, 2000.
     and G. M. Clinton. NH2-terminally truncated HER-2/neu protein, but          8. Schwartz, M. K., Smith, C., Schwartz, D. C., Dnistrian, A., and
     not full-length receptor, correlates with lymph node metastasis in breast   Neiman, I. Monitoring therapy by serum HER-2/neu. Int. J. Biol. Mark-
     cancer, submitted for publication.                                          ers, 15: 324 –329, 2000.
                                                                                                                             Clinical Cancer Research 2607

9. Yamauchi, H., Stearns, V., and Hayes, D. F. When is a tumor marker        16. Vecchi, M., Rudolph-Owen, L. A., Brown, C. L., Dempsey, P. J.,
ready for prime time? A case study of c-erbB-2 as a predictive factor in     and Carpenter, G. Tyrosine phosphorylation and proteolysis. Pervana-
breast cancer. J. Clin. Oncol., 9: 2334 –2356, 2001.                         date-induced, metalloprotease-dependent cleavage of the ErbB-4 recep-
10. Hayes, D. F., Yamauchi, H., Broadwater, G., Cirrincione, C. T.,          tor and amphiregulin. J. Biol. Chem., 273: 20589 –20595, 1998.
Rodrigue, S. P., Berry, D. A., Younger, J., Panasci, L. L., Millard, F.,     17. Segatto, O., King, C. R., Pierce, J. H., Di Fiore, P. P., and Aaronson,
Duggan, D. B., Norton, L., and Henderson, I. C. Circulating HER-2            S. A. Different structural alterations upregulate in vitro tyrosine kinase
extra cellular domain (ECD/HER-2) as a prognostic factor in patients         activity and transforming potency of the erbB-2 gene. Mol. Cell. Biol.,
with metastatic breast cancer: Cancer & Leukemia Group B study 8862.         8: 5570 –5574, 1988.
Clin. Cancer Res., 7: 2703–2711, 2001.
                                                                             18. Sugano, K., Ushiama, M., Fukutomi, T., Tsuda, H., Kitoh, T., and
11. Lin, Y. L., and Clinton, G. M. A soluble protein related to the
                                                                             Ohkura, H. Combined measurement of the c-erbB-2 protein in breast
HER-2 proto-oncogene product is released from human breast carci-
                                                                             carcinoma tissues and sera is useful as a sensitive tumor marker for
noma cells. Oncogene, 6: 639 – 643, 1991.
                                                                             monitoring tumor relapse. Int. J. Cancer, 89: 329 –336, 2000.
12. Christianson, T. A., Doherty, J. K., Lin, Y. J., Ramsey, E. E.,
Holmes, R., Keenan, E. J., and Clinton, G. M. NH2-terminally truncated       19. Gianni, L., Albanell, J., Eiermann, W., Bianchi, G., Bourquez, D.,
HER-2/neu protein: relationship with shedding of the extracellular do-              `
                                                                             Vigano, L., Molina, R., Raab, G., Locatelli, A., Vanhauwere, B., and
main and with prognostic factors in breast cancer. Cancer Res., 15:          Baselga, J. Feasibility, pharmacology, and antitumor activity of Hercep-
5123–5129, 1998.                                                             tin (H) with doxorubicin and Taxol followed by weekly Taxol (AT&T)
13. Codony-Servat, J., Albanell, J., Lopez-Talavera, J. C., Arribas, J.,     in women with HER2-positive advanced breast cancer (ABC). Proc.
and Baselga, J. Cleavage of the HER2 ectodomain is a pervanadate-            Am. Soc. Clin. Oncol., 20: 44a, 2001.
activable process that is inhibited by the tissue inhibitor of metallopro-   20. Pegram, M. D., Lipton, A., Hayes, D. F., Weber, B. L., Baselga,
teases-1 in breast cancer cells. Cancer Res., 59: 1196 –1201, 1999.          J. M., Tripathy, D., Baly, D., Baughman, S. A., Twaddell, T., Glaspy,
14. Molina, M. A., Codony-Servat, J., Albanell, J., Rojo, F., Arribas, J.,   J. A., and Slamon, D. J. Phase II study of receptor-enhanced chemo-
and Baselga, J. Trastuzumab (herceptin), a humanized anti-HER2 re-           sensitivity using recombinant humanized anti-p185HER2/neu mono-
ceptor monoclonal antibody, inhibits basal and activated HER2 ectodo-        clonal antibody plus cisplatin in patients with HER2/neu-overexpressing
main cleavage in breast cancer cells. Cancer Res., 61: 4744 – 4749,          metastatic breast cancer refractory to chemotherapy treatment. J. Clin.
2001.                                                                        Oncol., 16: 2659 –2671, 1998.
15. Cabrera, N., Diaz-Rodriguez, E., Becker, E., Martin-Zanca, D., and       21. Codony-Servat, J., Albanell, J., Arribas, J., and Baselga, J. Regu-
Pandiella, A. TrkA receptor ectodomain cleavage generates a tyrosine-        lation of HER2 cleavage in breast cancer cells: activation by receptor
phosphorylated cell-associated fragment. J. Cell Biol., 132: 427– 436,       ligands and inhibition by Herceptin. Proc. Am. Assoc. Cancer Res., 41:
1996.                                                                        68, 2000.

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