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Breast cancer with HER 2 overexpressed. From laboratory to clinical practice

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BIOLOGY OF HER2

HER2 (also known as erbB2) and its relatives HER1 (epidermal growth factor receptor; EGFR), HER3 and HER4 belong to the HER family of receptor tyrosine kinases. A large family of ligands (reviewed in(1) induces receptor dimerization, with each ligand favoring some dimeric combinations over others in a specific hie- rarchical order, with a marked preference for HER2 as a dimer partner (2,3). In normal cells, activation of this receptor tyrosine kinase family triggers a rich net- work of signaling pathways that control normal cell growth, differentiation, moti- lity and adhesion in several cell lineages (4-8). The formation of heterodimers and the ensuing activation are temporary and spatially controlled in normal cells and tissue, but dysregulation of this network due to increase expression levels of HER2 (9,10) provided a growth advantage. Indeed, overexpression of HER2, which occurs in about 25% of breast cancers (11), activates the “survival” pathway, and favors cell proliferation (10,12-14). The tumorigenic action of HER2 is not limited to a poten- tial proliferative effect. In fact, HER2 has been shown to be a metastasis-promoting factor. Changes in HER2 levels and in its activation by different EGF-like and here- gulins (HRGs) ligands have been associated with increased invasiveness in vitro and a more metastatic phenotype in vivo. Notwithstanding the abundance of studies on the biology of HER2 and its receptor family, many pathways interacting with HER2 are still not fully understood or exploited for therapeutic purposes.

HER2 OVEREXPRESSION IDENTIFIES A PARTICULAR SUBSET OF BREAST CARCINOMAS

The availability of new molecular biology techniques has allowed a new subset clas- sification of breast carcinomas based on the gene expression profile revealed by microarray analysis (15,16). HER2 overexpression, which is associated with overex-

overexpressed. From laboratory to clinical practice

S. Menard

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pression of other genes that are probably co-amplified in the same amplicon, toge- ther with a series of other co-expressed genes, has been reported to identify a parti- cular subset of tumors characterized by the lack of expression of genes associated with hormone receptor signaling pathway; high-level expression of a cluster of genes associated with proliferation; and expression of keratins related to undifferen- tiated stem cells (17-19). These findings suggest a pattern of gene expression pecu- liar to HER2-expressing tumors, and raise the possibility that all the clinical features thus far associated with HER2, e.g., prognosis, prediction of response to therapy, might actually be related to the biological behaviors of the subset and not directly to the presence of the oncoprotein. For example, sensitivity to anthracyclins might be related to the growth characteristics of the HER2-expressing subset rather than to the HER2 receptor pathway itself, as also suggested by in vitro studies (20).

RISK FACTORS AND HER2

The 3 well-defined risk factors for breast carcinomas development are not related with the onset of this subset of tumors. Indeed, tumors genetically-determined by Brca1 and Brca2 mutations display no alteration in HER2. Also hormone-related risk factors are not relevant for HER2-positive tumors. Indeed, in patients from ‘protected’ group, as for example those with more than 3 children and those with late menarche, the fre- quency of HER2 positivity increases since the total number of tumors in lower (pro- tected group) with no reduction of those with HER2 (21). Also irradiation, the third variable known to be associated with breast carcinoma appears to be not involved in HER2 overexpression. Indeed, in a small series of breast carcinomas from patients irradiated for Hodgkin lymphoma, no noteworthy increase in HER2 positivity was observed. It seems therefore that the cause of HER2 amplification is still to be identi- fied. Since HER2 overexpression is more frequent in young patients, these tumors are likely associated with an early event during the life (Figure 1).

Figure 1 - HER2-positivity according to age at diagnosis

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HER2 STATUS ASSESSMENT IN TUMORS

Since HER2 identifies a particular subset with peculiar progression, it is important to identify it correctly. The advent of standardized, FDA-approved tests for protein overexpression by immunohistochemistry (IHC) or gene amplification by FISH (Figure 2) has led to an overall improvement in HER2 status assessment (22-25) as indicated by several quality control studies performed around the world (26-28).

However, evaluation even with standardized IHC methodology has demonstrated still some difficulties in the HER2 status determination, mainly in the tumors with intermediate expression (2+) and the HER2 signature may help in these cases.

Stability of HER2 amplification has been recently questioned (29) but new more convincing data are required.

Figure 2 - Immunohistochemistry score 3+, 2+ and Neg. and FISH with amplification

HER2 STATUS IN PROGNOSIS

Various clinical studies have evaluated the relationship between HER2 and breast cancer outcome, and most have shown that women with HER2-positive tumors have a poorer prognosis than women with HER2-negative tumors (30-32).

However, while the prognostic value of HER2 amplification/overexpression in node-positive patients has been widely demonstrated, there is no consensus on its value in node-negative cases (33-36). Although a few studies on small series have shown some prognostic impact of HER2-positivity in node-negative patients,

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others, including our study of a large cohort of node-negative cases, argue against a prognostic role for HER2 in this patient subset (Figure 3) (37). Accordingly, in a recent microarray analysis to identify genes associated with poor prognosis (poor signature) and good prognosis (good signature) in node-negative patients, HER2 was not included in the 70 prognostic genes identified (38).

In any event, the prognostic impact of HER2-positivity is related only to the first 3-4 years after surgery, as indicated by the peak of early recurrences (37). The rea- sons for the early recurrences in HER2-positive tumors have been suggested to rest in events occurring at time of surgery. Indeed, growth factors released during wound-healing (39,40) have been shown to preferentially stimulate the growth of HER2-positive tumors (41). These growth factors are more likely to have a stimula- tory effect in patients with disseminated micrometastasis (node-positive patients) of an HER2-positive tumor, which might also explain the prognostic impact of HER2 according to nodal status.

Figure 3 - Hazard rate of relapse according to nodal status and HER2. A: N-, HER2-; B: N+, HER2- ; C : N+, HER2- ; D : N+, HER2+

HER2 AND SURGERY

The level of growth factors of the EGF family in post-surgical sera from breast car- cinoma patients has been shown to correlate with surgical invasiveness (42). To determine whether the growth of tumors overexpressing HER2 is affected by the extent of surgery, HER2 status of primary tumors from node-positive patients included in a randomized clinical trial addressing conservative versus invasive sur- gery was analyzed retrospectively using immunohistochemistry and the standar-

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dized Herceptest. Survival analysis according to surgery indicated no differences in HER2-negative cases but an earlier onset of relapse for HER2-positive patients who underwent mastectomy in comparison to those who had conservative surgery (Figure 4). This indicates that invasive surgery can be detrimental for patients with HER2-positive breast tumors. In keeping, also early local relapses after conservative surgery were found more frequently in HER2-positive tumors, suggesting again that they are anticipated by surgery.

Figure 4 - Survival according to type of surgery and HER2-positivity

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HER2 AND PREDICTION OF RESPONSE TO THERAPY

There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression has been implicated as a potential indicator of responsiveness to doxorubicin. Indeed, the study by the Cancer and Acute Leukemia Group B (CALGB) of node-positive patients randomly allocated to three dose levels of CAF (cyclophosphamide, doxorubicin and fluorouracil) (43), as well as the study by Paik et al. (44) from the National Surgical Adjuvant Breast and Bowel Project (NSABP) examining the effect of doxorubicin in node-positive patients, and others (45) indicated that administration of doxorubicin was of signi- ficant benefit in HER2-positive tumors but without any beneficial effect in HER2- negative tumors.

Contrary to expectations based on most previous studies, HER2-positive tumors were recently shown to benefit from cyclophosphamide, methotrexate, and fluorouracil (CMF) treatment (46,47); however addition of doxorubicin to the CMF regimen further improved survival only in patients with HER2-positive tumors (Figure 5) (48). Also addition of taxanes provides a preferential benefit to patients with HER2-positive tumors (49). HER2-positivity has been related to endocrine therapy unresponsiveness, even in hormone receptor-positive patients (50,51). The recent observation that the level of expression of estrogen receptor is inversely correlated with HER2 expression (52), together with clinical data indica- ting that only high estrogen receptor-expressing tumors are sensitive to the anti- estrogen reagent tamoxifen (53), likely explain the tamoxifen-resistance of HER2- positive tumors. Furthermore, a cross-talk between hormones and growth factors has been identified (54,55) and the increase HER2 expression on the tumor cell

Figure 5 - survival according to adjuvant treatment and HER2-positivity. CMF+DXR ; -- CMF

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membrane is observed after treatment with Tamoxifen might explain the detri- mental effect of Tamoxifen on survival of patients with HER2-positive tumor.

Surpringly, anti-aromatase treatment was found more active on HER2-positive tumors (56), indicating that the mechanism of action of this new hormone therapy as far from being fully understood.

HER2 AS A TARGET FOR THERAPY

Passive immunotherapy

Differential levels of HER2 expression in normal versus HER2-overexpressing tumor cells, together with the clear involvement of HER2 in tumor progression, make HER2 an ideal target for therapeutic approaches. The therapeutic activity of the antibody directed against HER2 (trastuzumab or Herceptin), has been evaluated as a single agent given before (57) or after (58) traditional chemotherapy, and in combination with a variety of chemotherapy agents (59), in women with HER2- overexpressing metastatic breast cancer. The results indicated a therapeutic benefit of addition of trastuzumab to the therapeutic protocol. A recent study has also shown that preoperative trastuzumab in combination with other chemotherapeutic agents was active against HER2-overexpressing early-stage breast cancer (60,61).

Thus, trastuzumab has become a standard of care for women with HER2-overex- pressing metastatic breast cancer and its clinical efficacy seems to be clear, even though cardiac toxicity when given in association with anthracyclins must be kept in mind (62,63). However the in vivo mechanism(s) of action of this reagent is not completely understood, and analyses of trastuzumab activity in experimental models have evidenced at least three different possible mechanisms: HER2 downre- gulation, antibody-dependent cell cytotoxicity (ADCC), and alteration of vessel development. In vitro treatment of HER2-overexpressing breast carcinoma cell lines with trastuzumab resulted in downmodulation of the receptor and inhibition of tumor growth (64,65). Indeed, trastuzumab induces obligate formation of HER2 homodimers, leading to an increase of ligand-mediated endocytosis of the receptor and, consequently, to significant removal of HER2 from the plasma membrane and decreased receptor-initiated constitutive signaling (65-67). In contrast, the activity of trastuzumab examined in animal models was found to depend on the engage- ment of Fc-receptor expressing lymphocytes (68), indicating ADCC as the major mechanism of antibody action. In FcRg+/+ nude mice injected subcutaneously with HER2-overexpressing human breast carcinoma cells, trastuzumab treatment resulted in near-complete (96%) inhibition of tumor growth. This protective effect was reduced more than 50% after disrupting the antibody’s ability to engage cellular Fcg receptor or in antibody-treated FcRg-/- mice. Clearly, the precise delineation of trastuzumab mechanism of action in patients is essential for the design of more suc- cessful antibody treatment protocols in breast carcinoma patients. In a pilot study on 11 patients treated with trastuzumab in neoadjuvant setting, a role of patients’lymphocytes in the clinical response was clearly underlined but larger series are required to definitively understand the mechanism of action of the antibody (69). Nevertheless, If the major mechanism is ADCC, the combination of trastu-

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zumab with immunosuppressive chemotherapeutic drugs requires optimal timing of trastuzumab delivery to enable rescue of ADCC effectors such as NK cells after chemotherapy. In that context, clinical studies have demonstrated a synergistic action between trastuzumab and the drug taxane (59), which induces suppression of adaptive immunity, but selectively increases NK activity (70). To improve thera- peutic activity, stimulation of NK activity might also be considered, utilizing cyto- kines or “danger signals” such as unmethylated CpG-oligodeoxynucleotides that enhance innate immunity (71).

Active immunotherapy

Although HER2 is generally indicative of a poor prognosis, its overexpression is associated with a better outcome when inflammatory infiltrates are present in the tumor, suggesting a role for HER2 in tumor immunosurveillance (72-74). In kee- ping, development of HER2-specific antibodies has been documented in patients with primary HER2-positive tumors (75-77), and T cells reactive to HER2 were found to occur in patients with HER2-positive tumors (78), confirming the immu- nogenicity of the molecule.

HER2-derived vaccines have been used in efforts to redirect immunity to induce rejection of HER2-positive tumors (79-81). Immunization regimens of active immunotherapy have been devised that generate specific T cell responses with or without accompanying antibody responses and are currently being tested in animal models or in clinical trials (79,80,82-84).

Immunotherapeutic strategies such as immunization with MHC class I- and class II-restricted HER2-specific peptides with or without adjuvants, HER2 DNA, HER2 recombinant protein, and dendritic cells loaded with HER2 peptides are now being tested in animal models and phase I clinical trials (79,80,85,86). The vaccine preparation consisted of HER2 peptides containing putative T-helper epitopes and

Figure 6 - Incidence of mammary carcinoma in HER2-transgenic mice. ÇHER2 DNA vacci- nated-mice; <control mice

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HLA-A2 binding motifs, with recombinant human GM-CSF administered as adju- vant. In the majority of immunized patients, long-lasting T cell-mediated immunity was revealed by in vitro and in vivo monitoring and, most importantly, immunity to the HER2 protein was significantly associated with epitope “spreading,” reflecting the initiation of an endogenous immune response (86).

Conclusions

Breast carcinoma with HER2 amplification and overexpression represents a parti- cular subset of tumors displaying a peculiar tumor progression and response to conventional and targeted therapy. The identification of HER2 is therefore manda- tory since the diagnosis of the disease in order to offer to the patient the best clinical management.

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